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Article(id=1195814097779471186, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1195814096831561845, articleNumber=1001-2494(2024)23-2241-08, orderNo=null, doi=10.11669/cpj.2024.23.005, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1716480000000, receivedDateStr=2024-05-24, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1763033898062, onlineDateStr=2025-11-13, pubDate=1733587200000, pubDateStr=2024-12-08, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763033898062, onlineIssueDateStr=2025-11-13, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763033898062, creator=13701087609, updateTime=1763033898062, updator=13701087609, issue=Issue{id=1195814096831561845, tenantId=1146029695717560320, journalId=1190317699101192196, year='2024', volume='59', issue='23', pageStart='2199', pageEnd='2298', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1763033897836, creator=13701087609, updateTime=1763034755097, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1195817692507718044, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1195814096831561845, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1195817692507718045, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1195814096831561845, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=2241, endPage=2248, ext={EN=ArticleExt(id=1195814098060489556, articleId=1195814097779471186, tenantId=1146029695717560320, journalId=1190317699101192196, language=EN, title=Effect and Mechanism of Danggui Buxue Decoction on Oxidative Stress in Rheumatoid Arthritis Rats with PI3K/Akt/Nrf2 Signaling Pathway as the Target, columnId=null, journalTitle=Chinese Pharmaceutical Journal, columnName=null, runingTitle=null, highlight=null, articleAbstract=

OBJECTIVE To investigate the mechanism by which Danggui Buxue Decoction (DBD) regulates oxidative stress in rats with rheumatoid arthritis based on phosphatidylinositol 3-kinase (PI3K)/protein kinase B(Akt)/nuclear factor E2-related factor 2(Nrf2) signaling pathway. METHODS Forty-eight Wistar rats were randomly divided into 6 groups [normal group, model group, tripterygium glycosides tablets group(9.45 mg·kg-1), DBD low dose (3.75 g·kg-1), medium dose(7.5 g·kg-1) and high dose group(15 g·kg-1)]. In addition to the normal group, the other groups were constructed collagen-induced arthritis (CIA) rat model, and given the corresponding drug treatment for 28 days. During the period, the body weight of the rats, the degree of ankle swelling, and the arthritis score were recorded regularly. The levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) and malondialdehyde (MDA) in serum of rats were determined by ELISA. The spleen index and thymus index were calculated. HE staining and safranin O-fast green staining were used to observe the pathological morphology of synovial membrane of knee joint in rats. The expression of PI3K, AKT, Nrf2 and HO-1 mRNA in synovial tissue was determined by qPCR. The expression of p-PI3K/PI3K, p-Akt/Akt, Nrf2 and HO-1 protein in synovial tissue was determined by Western blot. RESULTS Compared with the normal group, the body weight of the rats in the model group was lower (P<0.05), and the bilateral hind limbs were obviously red and swollen or even deformed. Compared with the model group, the body weight of rats in each administration group increased gently (P<0.05), the swelling degree of bilateral hind limbs was significantly reduced (P<0.05), and the arthritis score was significantly decreased (P<0.05). The level of MDA in joint tissue decreased (P<0.05), and the levels of GSH-Px, CAT and SOD increased (P<0.05). The expression of PI3K, Akt, Nrf2 and HO-1 mRNA in PI3K/Akt/Nrf2 pathway was increased (P<0.05). The ratio of p-PI3K/PI3K, p-Akt/Akt and the expression of Nrf2 and HO-1 protein were significantly increased (P<0.05). CONCLUSION DBD may inhibit the level of oxidative stress, attenuate the oxidative damage of synovial tissues and improve the pathological changes of synovium by regulating the PI3K/Akt/Nrf2 pathway in CIA rats, thus exerting an anti-RA effect.

, correspAuthors=Yinghang WANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=null, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Meixiu LUO, Zhi PAN, Lianyun DU, Lu TANG, Yinghang WANG), CN=ArticleExt(id=1195814188502265947, articleId=1195814097779471186, tenantId=1146029695717560320, journalId=1190317699101192196, language=CN, title=当归补血汤通过PI3K/Akt/Nrf2通路抑制类风湿关节炎大鼠氧化应激的作用与机制研究, columnId=1190352405612040510, journalTitle=中国药学杂志, columnName=论著, runingTitle=null, highlight=null, articleAbstract=

目的 研究当归补血汤(Danggui Buxue Decoction, DBD)基于磷脂酰肌醇3-激酶(phosphatidylinositol 3-kinase, PI3K)/蛋白激酶B(protein kinase B, Akt)/核因子E2相关因子2(nuclear factor erythroid 2-related factor 2, Nrf2)信号通路调控类风湿关节炎(rheumatoid arthrtis,RA)大鼠氧化应激的作用机制。方法 将48只Wistar大鼠随机分为6组[正常组、模型组、雷公藤多苷组(tripterygium glycoside tablets,TGT,9.45 mg·kg-1)、DBD低剂量组(3.75 g·kg-1)、中剂量组(7.5 g·kg-1)、高剂量组(15 g·kg-1)]。除正常组外,其余组均构建胶原诱导性关节炎(collagen-induced arthritis,CIA)大鼠模型,并给予相应药物治疗28 d。期间定期记录大鼠体质量、踝关节肿胀程度,进行关节炎评分;酶联免疫法(ELISA)法测定大鼠血清中超氧化物歧化酶(superoxide dismutase,SOD)、谷胱甘肽过氧化物酶(glutathione peroxidase,GSH-Px)、过氧化氢酶(catalase,CAT)水平及丙二醛(malondialdehyde,MDA)水平;计算脾脏指数、胸腺指数;苏木精-伊红(HE)染色法和番红O-固绿染色法观察大鼠膝关节滑膜组织病理学形态;qPCR法测定滑膜组织中PI3K、AKT、Nrf2、血红素加氧酶1(HO-1)mRNA表达量;Western blot法测定滑膜组织中磷酸化磷脂酰肌醇3-激酶(p-PI3K)/PI3K、磷酸化蛋白激酶B(p-Akt)/Akt、Nrf2、HO-1蛋白表达情况。结果 与正常组相比,模型组大鼠体质量偏低(P<0.05),双侧后肢明显红肿甚至变形。与模型组比较,各给药组大鼠体重平缓增加(P<0.05),双侧后肢肿胀程度明显减轻(P<0.05),关节炎评分显著下降(P<0.05);关节组织中MDA水平降低(P<0.05),GSH-Px、CAT含量和SOD水平增加(P<0.05);PI3K/Akt/Nrf2通路中PI3K、Akt、Nrf2、HO-1mRNA表达升高(P<0.05);p-PI3K/PI3K、p-Akt/Akt比值和Nrf2、HO-1蛋白表达明显升高(P<0.05)。。结论 DBD可能通过调控PI3K/Akt/Nrf2通路抑制CIA大鼠氧化应激水平,减轻滑膜组织氧化损伤,改善滑膜病理变化,从而起到抗RA作用。

, correspAuthors=王颖航, authorNote=null, correspAuthorsNote=
* 王颖航,女,博士,教授 研究方向:风湿免疫疾病研究 Tel:(0431)86763807
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骆美秀,女,硕士研究生 研究方向:中西医结合临床内科疾病研究

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骆美秀,女,硕士研究生 研究方向:中西医结合临床内科疾病研究

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骆美秀,女,硕士研究生 研究方向:中西医结合临床内科疾病研究

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J Ethnopharmacol, 2020, 260: 113039., articleTitle=Anti-angiogenic effect of Shikonin in rheumatoid arthritis by downregulating PI3K/AKT and MAPKs signaling pathways, refAbstract=null), Reference(id=1196079282171720281, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, doi=null, pmid=null, pmcid=null, year=2017, volume=70, issue=null, pageStart=66, pageEnd=75, url=null, language=null, rfNumber=[32], rfOrder=31, authorNames=PAN W, MIAO L, LIN Y, journalName=Fish Shellfish Immunol, refType=null, unstructuredReference=PAN W, MIAO L, LIN Y, et al. Regulation mechanism of oxidative stress induced by high glucose through PI3K/Akt/Nrf2 pathway in juvenile blunt snout bream (Megalobrama amblycephala)[J]. Fish Shellfish Immunol, 2017, 70: 66-75., articleTitle=Regulation mechanism of oxidative stress induced by high glucose through PI3K/Akt/Nrf2 pathway in juvenile blunt snout bream (Megalobrama amblycephala), refAbstract=null), Reference(id=1196079282226246234, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, doi=null, pmid=null, pmcid=null, year=2019, volume=35, issue=1, pageStart=112, pageEnd=121, url=null, language=null, rfNumber=[33], rfOrder=32, authorNames=HE S, GUO Y, ZHAO J, journalName=Int J Hyperth, refType=null, unstructuredReference=HE S, GUO Y, ZHAO J, et al. Ferulic acid protects against heat stress-induced intestinal epithelial barrier dysfunction in IEC-6 cells via the PI3K/Akt-mediated Nrf2/HO-1 signaling pathway[J]. Int J Hyperth, 2019, 35(1): 112-121., articleTitle=Ferulic acid protects against heat stress-induced intestinal epithelial barrier dysfunction in IEC-6 cells via the PI3K/Akt-mediated Nrf2/HO-1 signaling pathway, refAbstract=null), Reference(id=1196079282289160795, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, doi=null, pmid=null, pmcid=null, year=2018, volume=23, issue=11, pageStart=2781, pageEnd=null, url=null, language=null, rfNumber=[34], rfOrder=33, authorNames=HU S, WU Y, ZHAO B, journalName=Molecules, refType=null, unstructuredReference=HU S, WU Y, ZHAO B, et al. Panax notoginseng saponins protect cerebral microvascular endothelial cells against oxygen-glucose deprivation/reperfusion-induced barrier dysfunction via activation of PI3K/Akt/Nrf2 antioxidant signaling pathway[J]. Molecules, 2018, 23(11): 2781., articleTitle=Panax notoginseng saponins protect cerebral microvascular endothelial cells against oxygen-glucose deprivation/reperfusion-induced barrier dysfunction via activation of PI3K/Akt/Nrf2 antioxidant signaling pathway, refAbstract=null)], funds=null, companyList=[AuthorCompany(id=1196079274441617917, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, xref=1, ext=[AuthorCompanyExt(id=1196079274445812222, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, companyId=1196079274441617917, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1 College of Integrative Medicine, Changchun University of Traditional Chinese Medicine, Changchun 130117, China), AuthorCompanyExt(id=1196079274454200831, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, companyId=1196079274441617917, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1 长春中医药大学中西医结合学院, 长春 130117)]), AuthorCompany(id=1196079274517115392, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, xref=2, ext=[AuthorCompanyExt(id=1196079274542281217, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, companyId=1196079274517115392, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2 Jilin Institute of Ginseng Science, Changchun University of Chinese Medicine, Changchun 130117, China), AuthorCompanyExt(id=1196079274550669826, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, companyId=1196079274517115392, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2 长春中医药大学吉林省人参科学研究院, 长春 130117)]), AuthorCompany(id=1196079274668110340, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, xref=3, ext=[AuthorCompanyExt(id=1196079274676498949, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, companyId=1196079274668110340, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=3 Department of Rheumatology and Immunology, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun 130021, China), AuthorCompanyExt(id=1196079274684887558, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, companyId=1196079274668110340, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=3 长春中医药大学附属医院风湿免疫科, 长春 130021)])], figs=[ArticleFig(id=1196079277524431402, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, language=EN, label=Fig.1, caption=The changes of body weight, joint swelling rate, arthritis score and representative paw appearance of rats in each group.n=6,$\bar{x}±s$

A-body mass trend chart; B-joint swelling rate trend chart; C-arthritis score trend chart; D-appearance of rat paw; 1)P<0.05, vs control group; 2)P<0.05, vs model group; 3)P<0.05, vs TGT (9.45 mg·kg-1) group; 4)P<0.05, vs DBD (3.75 g·kg-1) low dose group.

, figureFileSmall=6dIeaP2kjqRH+crtwfdE9A==, figureFileBig=mrMw6VrB0ZdeZ3aGFub7tQ==, tableContent=null), ArticleFig(id=1196079277591540267, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, language=CN, label=图1, caption=各组大鼠体质量、关节肿胀率、关节炎评分变化情况及代表性足爪外观图。n=6,$\bar{x}±s$

A-体质量趋势图;B-关节肿胀率趋势图;C-关节炎评分趋势图;D-大鼠足爪外观图。与正常组比较,1)P<0.05;与模型组比较,2)P<0.05;与雷公藤多苷(TGT)(9.45 mg·kg-1)组比较,3)P<0.05;与当归补血汤(DBD)低剂量组(3.75 g·kg-1)比较,4)P<0.05。

, figureFileSmall=6dIeaP2kjqRH+crtwfdE9A==, figureFileBig=mrMw6VrB0ZdeZ3aGFub7tQ==, tableContent=null), ArticleFig(id=1196079277688009260, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, language=EN, label=Fig.2, caption=The pathological changes of knee joint in each group were observed by hematoxylin-eosin staining and safranin O-fast green staining(×200)

A-HE staining; black arrow-articular cavity; red arrow-inflammatory cell infiltration; green arrow-fibroblasts; blue arrow-pannus; B-safranine O-fastgreen staining.

, figureFileSmall=iC5zlWcXufNTLZoQ/mytIQ==, figureFileBig=t2mQU+ejaGX3vovNGxPFPw==, tableContent=null), ArticleFig(id=1196079277746729517, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, language=CN, label=图2, caption=苏木精-伊红(HE)染色、番红O-固绿染色观察各组大鼠膝关节病理改变(×200)

A-HE染色;黑色箭头-关节腔;红色箭头-炎细胞浸润;绿色箭头-成纤维细胞;蓝色箭头-血管翳;B-番红O-固绿染色。

, figureFileSmall=iC5zlWcXufNTLZoQ/mytIQ==, figureFileBig=t2mQU+ejaGX3vovNGxPFPw==, tableContent=null), ArticleFig(id=1196079277809644078, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, language=EN, label=Fig.3, caption=Effect of DBD on protein expression of p-PI3K, PI3K, p-Akt, Akt, Nrf2 and HO-1 signaling pathway in synovial tissue of rats with RA.n=3,$\bar{x}±s$

1)P<0.05, vs control group; 2)P<0.05, vs model group; 3)P<0.05, vs TGT (9.45 mg·kg-1) group; 4)P<0.05, vs DBD low dose(3.75 g·kg-1) group; 5)P<0.05, vs DBD medium dose(7.5 g·kg-1) group.

, figureFileSmall=lZFBVnzd8L/9+aqJQuiCLQ==, figureFileBig=WqMmFI7B0Ar6LFtkRMDrHQ==, tableContent=null), ArticleFig(id=1196079277876752943, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, language=CN, label=图3, caption=DBD对RA大鼠滑膜组织中磷酸化磷脂酰肌醇3-激酶(p-PI3K)、PI3K、磷酸化蛋白激酶B(p-Akt)、Akt、Nrf2、HO-1信号通路蛋白表达的影响。n=3,$\bar{x}±s$

与正常组比较,1)P<0.05;与模型组比较,2)P<0.05;与TGT组(9.45 mg·kg-1)比较,3)P<0.05;与DBD低剂量组(3.75g·kg-1)比较,4)P<0.05;与DBD中剂量组(7.5 g·kg-1)比较,5)P<0.05。

, figureFileSmall=lZFBVnzd8L/9+aqJQuiCLQ==, figureFileBig=WqMmFI7B0Ar6LFtkRMDrHQ==, tableContent=null), ArticleFig(id=1196079277943861808, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, language=EN, label=Tab.1, caption=

Scoring criteria of arthritis index in rats

, figureFileSmall=null, figureFileBig=null, tableContent=
Degree of limb joint lesions Joint score
No skin swelling joint symptoms 0 point
Redness of ankles or feet Slight swelling 1 point
Red ankle and foot slightly swollen 2 point
Redness of ankle and foot, moderate swelling of ankle and metatarsal joints 3 point
The entire ankle, foot and plantar redness and swelling is serious 4 point
), ArticleFig(id=1196079278052913713, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, language=CN, label=表1, caption=

大鼠关节炎指数的评分标准

, figureFileSmall=null, figureFileBig=null, tableContent=
Degree of limb joint lesions Joint score
No skin swelling joint symptoms 0 point
Redness of ankles or feet Slight swelling 1 point
Red ankle and foot slightly swollen 2 point
Redness of ankle and foot, moderate swelling of ankle and metatarsal joints 3 point
The entire ankle, foot and plantar redness and swelling is serious 4 point
), ArticleFig(id=1196079278149382706, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, language=EN, label=Tab.2, caption=

PCR primer sequences

, figureFileSmall=null, figureFileBig=null, tableContent=
Gene name Primer sequences Primer sequences(5'-3')
PI3K Forward primer GGCGAAACGCCCATCAAAAA
Reverse primer GACTCCCGTGCAGTCATCC
Akt Forward primer TGTGGATTTACCTTATCCCCTCA
Reverse primer GTTTGGCTTTGGTCGTTCTGT
Nrf2 Forward primer TCAGCGACGGAAAGAGTATGA
Reverse primer CCACTGGTTTCTGACTGGATGT
HO-1 Forward primer ACTTCCCAGAAGAGCTGCAC
Reverse primer TCTTGCACTTTGTTGCTGGC
β-actin Forward primer GTCGTACCACTGGCATTGTG
Reverse primer GTCGTACCACTGGCATTGTG
), ArticleFig(id=1196079278220685875, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, language=CN, label=表2, caption=

聚合酶链式反应(PCR)引物序列

, figureFileSmall=null, figureFileBig=null, tableContent=
Gene name Primer sequences Primer sequences(5'-3')
PI3K Forward primer GGCGAAACGCCCATCAAAAA
Reverse primer GACTCCCGTGCAGTCATCC
Akt Forward primer TGTGGATTTACCTTATCCCCTCA
Reverse primer GTTTGGCTTTGGTCGTTCTGT
Nrf2 Forward primer TCAGCGACGGAAAGAGTATGA
Reverse primer CCACTGGTTTCTGACTGGATGT
HO-1 Forward primer ACTTCCCAGAAGAGCTGCAC
Reverse primer TCTTGCACTTTGTTGCTGGC
β-actin Forward primer GTCGTACCACTGGCATTGTG
Reverse primer GTCGTACCACTGGCATTGTG
), ArticleFig(id=1196079278296183348, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, language=EN, label=Tab.3, caption=

Effects of DBD on thymus index and spleen index in rats with RA.n=6,$\bar{x}±s$

, figureFileSmall=null, figureFileBig=null, tableContent=
Group Thymus index Spleen index
Normal 0.11±0.02 0.13±0.01
Model 0.14±0.021) 0.21±0.031)
TGT (9.45 mg·kg-1) 0.09±0.022) 0.15±0.022)
DBD (3.75 g·kg-1) 0.12±0.012) 0.19±0.012)3)
DBD (7.5 g·kg-1) 0.11±0.012) 0.17±0.022)4)
DBD (15 g·kg-1) 0.10±0.012) 0.14±0.022)4)
), ArticleFig(id=1196079278380069429, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, language=CN, label=表3, caption=

当归补血汤(DBD)对类风湿关节炎(RA)大鼠胸腺指数和脾脏指数的影响。n=6,$\bar{x}±s$

, figureFileSmall=null, figureFileBig=null, tableContent=
Group Thymus index Spleen index
Normal 0.11±0.02 0.13±0.01
Model 0.14±0.021) 0.21±0.031)
TGT (9.45 mg·kg-1) 0.09±0.022) 0.15±0.022)
DBD (3.75 g·kg-1) 0.12±0.012) 0.19±0.012)3)
DBD (7.5 g·kg-1) 0.11±0.012) 0.17±0.022)4)
DBD (15 g·kg-1) 0.10±0.012) 0.14±0.022)4)
), ArticleFig(id=1196079278459761206, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, language=EN, label=Tab.4, caption=

The levels of catalase CAT, SOD, MDA and GSH-Px in serum of rats in each group were observed by ELISA.n=6,$\bar{x}±s$

, figureFileSmall=null, figureFileBig=null, tableContent=
Group CAT/U·mL-1 SOD/ng·mL-1 MDA/nmol·mL-1 GSH-Px/ng·mL-1
Normal 8.83±0.45 58.21±4.13 6.36±0.23 46.35±3.89
Model 5.96±0.341) 36.61±0.561) 9.20±0.561) 31.84±0.501)
TGT (9.45 mg·kg-1) 7.38±0.152) 48.89±2.762) 6.88±0.062) 39.06±0.412)
DBD (3.75 g·kg-1) 6.46±0.072)3) 40.94±0.902)3) 7.90±0.362)3) 35.10±0.672)
DBD (7.5 g·kg-1) 6.75±0.092)3) 44.52±1.092)3) 7.72±0.132)3) 37.72±0.632)
DBD (15 g·kg-1) 7.05±0.072)4) 44.56±1.102) 7.37±0.122) 40.57±0.552)4)
), ArticleFig(id=1196079278556230199, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, language=CN, label=表4, caption=

酶联免疫法(ELISA)观察各组大鼠血清中过氧化氢酶(CAT)、超氧化物歧化酶(SOD)、丙二醛(MDA)及谷胱甘肽过氧化物酶(GSH-Px)的水平。n=6,$\bar{x}±s$

, figureFileSmall=null, figureFileBig=null, tableContent=
Group CAT/U·mL-1 SOD/ng·mL-1 MDA/nmol·mL-1 GSH-Px/ng·mL-1
Normal 8.83±0.45 58.21±4.13 6.36±0.23 46.35±3.89
Model 5.96±0.341) 36.61±0.561) 9.20±0.561) 31.84±0.501)
TGT (9.45 mg·kg-1) 7.38±0.152) 48.89±2.762) 6.88±0.062) 39.06±0.412)
DBD (3.75 g·kg-1) 6.46±0.072)3) 40.94±0.902)3) 7.90±0.362)3) 35.10±0.672)
DBD (7.5 g·kg-1) 6.75±0.092)3) 44.52±1.092)3) 7.72±0.132)3) 37.72±0.632)
DBD (15 g·kg-1) 7.05±0.072)4) 44.56±1.102) 7.37±0.122) 40.57±0.552)4)
), ArticleFig(id=1196079278673670712, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, language=EN, label=Tab.5, caption=

Effects of DBD on mRNA expression of PI3K, Akt, Nrf2 and HO-1 in synovial tissue of rats with RA. n=3,$\bar{x}±s$

, figureFileSmall=null, figureFileBig=null, tableContent=
Group PI3K AKT Nrf2 HO-1
Normal 1.98±0.03 1.40±0.15 1.43±0.11 2.28±0.08
Model 1.43±0.071) 0.50±0.101) 0.96±0.061) 1.29±0.091)
TGT (9.45 mg·kg-1) 1.65±0.052) 1.12±0.102) 1.38±0.092) 2.01±0.182)
DBD (3.75 g·kg-1) 1.25±0.052)3)4) 0.88±0.092) 1.24±0.052) 1.63±0.042)3)
DBD (7.5 g·kg-1) 1.59±0.042)4) 1.00±0.092) 1.28±0.062) 1.92±0.042)
DBD (15 g·kg-1) 1.72±0.032)3) 1.20±0.112) 1.35±0.082) 2.00±0.112)4)
), ArticleFig(id=1196079278765945401, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195814097779471186, language=CN, label=表5, caption=

DBD对RA大鼠滑膜组织中磷脂酰肌醇3-激酶(PI3K)、蛋白激酶B(Akt)、核因子E2相关因子2(Nrf2)、血红素加氧酶1(HO-1) mRNA表达的影响。n=3,$\bar{x}±s$

, figureFileSmall=null, figureFileBig=null, tableContent=
Group PI3K AKT Nrf2 HO-1
Normal 1.98±0.03 1.40±0.15 1.43±0.11 2.28±0.08
Model 1.43±0.071) 0.50±0.101) 0.96±0.061) 1.29±0.091)
TGT (9.45 mg·kg-1) 1.65±0.052) 1.12±0.102) 1.38±0.092) 2.01±0.182)
DBD (3.75 g·kg-1) 1.25±0.052)3)4) 0.88±0.092) 1.24±0.052) 1.63±0.042)3)
DBD (7.5 g·kg-1) 1.59±0.042)4) 1.00±0.092) 1.28±0.062) 1.92±0.042)
DBD (15 g·kg-1) 1.72±0.032)3) 1.20±0.112) 1.35±0.082) 2.00±0.112)4)
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当归补血汤通过PI3K/Akt/Nrf2通路抑制类风湿关节炎大鼠氧化应激的作用与机制研究
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骆美秀 1 , 潘志 2 , 杜连云 2 , 唐录 2 , 王颖航 3, *
中国药学杂志 | 论著 2024,59(23): 2241-2248
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中国药学杂志 | 论著 2024, 59(23): 2241-2248
当归补血汤通过PI3K/Akt/Nrf2通路抑制类风湿关节炎大鼠氧化应激的作用与机制研究
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骆美秀1, 潘志2, 杜连云2, 唐录2, 王颖航3, *
作者信息
  • 1 长春中医药大学中西医结合学院, 长春 130117
  • 2 长春中医药大学吉林省人参科学研究院, 长春 130117
  • 3 长春中医药大学附属医院风湿免疫科, 长春 130021

    • 骆美秀,女,硕士研究生 研究方向:中西医结合临床内科疾病研究

通讯作者:

* 王颖航,女,博士,教授 研究方向:风湿免疫疾病研究 Tel:(0431)86763807
Effect and Mechanism of Danggui Buxue Decoction on Oxidative Stress in Rheumatoid Arthritis Rats with PI3K/Akt/Nrf2 Signaling Pathway as the Target
Meixiu LUO1, Zhi PAN2, Lianyun DU2, Lu TANG2, Yinghang WANG3, *
Affiliations
  • 1 College of Integrative Medicine, Changchun University of Traditional Chinese Medicine, Changchun 130117, China
  • 2 Jilin Institute of Ginseng Science, Changchun University of Chinese Medicine, Changchun 130117, China
  • 3 Department of Rheumatology and Immunology, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun 130021, China
出版时间: 2024-12-08 doi: 10.11669/cpj.2024.23.005
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目的 研究当归补血汤(Danggui Buxue Decoction, DBD)基于磷脂酰肌醇3-激酶(phosphatidylinositol 3-kinase, PI3K)/蛋白激酶B(protein kinase B, Akt)/核因子E2相关因子2(nuclear factor erythroid 2-related factor 2, Nrf2)信号通路调控类风湿关节炎(rheumatoid arthrtis,RA)大鼠氧化应激的作用机制。方法 将48只Wistar大鼠随机分为6组[正常组、模型组、雷公藤多苷组(tripterygium glycoside tablets,TGT,9.45 mg·kg-1)、DBD低剂量组(3.75 g·kg-1)、中剂量组(7.5 g·kg-1)、高剂量组(15 g·kg-1)]。除正常组外,其余组均构建胶原诱导性关节炎(collagen-induced arthritis,CIA)大鼠模型,并给予相应药物治疗28 d。期间定期记录大鼠体质量、踝关节肿胀程度,进行关节炎评分;酶联免疫法(ELISA)法测定大鼠血清中超氧化物歧化酶(superoxide dismutase,SOD)、谷胱甘肽过氧化物酶(glutathione peroxidase,GSH-Px)、过氧化氢酶(catalase,CAT)水平及丙二醛(malondialdehyde,MDA)水平;计算脾脏指数、胸腺指数;苏木精-伊红(HE)染色法和番红O-固绿染色法观察大鼠膝关节滑膜组织病理学形态;qPCR法测定滑膜组织中PI3K、AKT、Nrf2、血红素加氧酶1(HO-1)mRNA表达量;Western blot法测定滑膜组织中磷酸化磷脂酰肌醇3-激酶(p-PI3K)/PI3K、磷酸化蛋白激酶B(p-Akt)/Akt、Nrf2、HO-1蛋白表达情况。结果 与正常组相比,模型组大鼠体质量偏低(P<0.05),双侧后肢明显红肿甚至变形。与模型组比较,各给药组大鼠体重平缓增加(P<0.05),双侧后肢肿胀程度明显减轻(P<0.05),关节炎评分显著下降(P<0.05);关节组织中MDA水平降低(P<0.05),GSH-Px、CAT含量和SOD水平增加(P<0.05);PI3K/Akt/Nrf2通路中PI3K、Akt、Nrf2、HO-1mRNA表达升高(P<0.05);p-PI3K/PI3K、p-Akt/Akt比值和Nrf2、HO-1蛋白表达明显升高(P<0.05)。。结论 DBD可能通过调控PI3K/Akt/Nrf2通路抑制CIA大鼠氧化应激水平,减轻滑膜组织氧化损伤,改善滑膜病理变化,从而起到抗RA作用。

当归补血汤  /  类风湿关节炎  /  氧化应激  /  PI3K/Akt/Nrf2信号通路

OBJECTIVE To investigate the mechanism by which Danggui Buxue Decoction (DBD) regulates oxidative stress in rats with rheumatoid arthritis based on phosphatidylinositol 3-kinase (PI3K)/protein kinase B(Akt)/nuclear factor E2-related factor 2(Nrf2) signaling pathway. METHODS Forty-eight Wistar rats were randomly divided into 6 groups [normal group, model group, tripterygium glycosides tablets group(9.45 mg·kg-1), DBD low dose (3.75 g·kg-1), medium dose(7.5 g·kg-1) and high dose group(15 g·kg-1)]. In addition to the normal group, the other groups were constructed collagen-induced arthritis (CIA) rat model, and given the corresponding drug treatment for 28 days. During the period, the body weight of the rats, the degree of ankle swelling, and the arthritis score were recorded regularly. The levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) and malondialdehyde (MDA) in serum of rats were determined by ELISA. The spleen index and thymus index were calculated. HE staining and safranin O-fast green staining were used to observe the pathological morphology of synovial membrane of knee joint in rats. The expression of PI3K, AKT, Nrf2 and HO-1 mRNA in synovial tissue was determined by qPCR. The expression of p-PI3K/PI3K, p-Akt/Akt, Nrf2 and HO-1 protein in synovial tissue was determined by Western blot. RESULTS Compared with the normal group, the body weight of the rats in the model group was lower (P<0.05), and the bilateral hind limbs were obviously red and swollen or even deformed. Compared with the model group, the body weight of rats in each administration group increased gently (P<0.05), the swelling degree of bilateral hind limbs was significantly reduced (P<0.05), and the arthritis score was significantly decreased (P<0.05). The level of MDA in joint tissue decreased (P<0.05), and the levels of GSH-Px, CAT and SOD increased (P<0.05). The expression of PI3K, Akt, Nrf2 and HO-1 mRNA in PI3K/Akt/Nrf2 pathway was increased (P<0.05). The ratio of p-PI3K/PI3K, p-Akt/Akt and the expression of Nrf2 and HO-1 protein were significantly increased (P<0.05). CONCLUSION DBD may inhibit the level of oxidative stress, attenuate the oxidative damage of synovial tissues and improve the pathological changes of synovium by regulating the PI3K/Akt/Nrf2 pathway in CIA rats, thus exerting an anti-RA effect.

Danggui Buxue Decoction  /  rheumatoid arthritis  /  oxidative stress  /  PI3K/Akt/Nrf2 signaling pathway
骆美秀, 潘志, 杜连云, 唐录, 王颖航. 当归补血汤通过PI3K/Akt/Nrf2通路抑制类风湿关节炎大鼠氧化应激的作用与机制研究. 中国药学杂志, 2024 , 59 (23) : 2241 -2248 . DOI: 10.11669/cpj.2024.23.005
Meixiu LUO, Zhi PAN, Lianyun DU, Lu TANG, Yinghang WANG. Effect and Mechanism of Danggui Buxue Decoction on Oxidative Stress in Rheumatoid Arthritis Rats with PI3K/Akt/Nrf2 Signaling Pathway as the Target[J]. Chinese Pharmaceutical Journal, 2024 , 59 (23) : 2241 -2248 . DOI: 10.11669/cpj.2024.23.005
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类风湿关节炎(rheumatoid arthritis,RA)是一种慢性、自身免疫性疾病,滑膜增生、炎细胞浸润及血管翳生成是其主要病理特征。RA甚至造成关节破坏畸形、部分关节功能丧失等后果,严重影响患者的生活质量[1]。近年来RA发病率逐渐上升,全球发病率约0.5%~1%,中国大陆地区发病率约为0.46%[2]。迄今为止,RA的发病机制尚未完全明确,尽管非甾体抗炎药、改善病情的抗风湿药和生物制剂在应对RA引发的疼痛和炎症方面已经具有了较为显著的疗效,但由于副作用明显以及成本高等问题,这些药物在临床上的应用仍有诸多限制[3]。因此,研发更安全、更有效且成本较低的抗RA药物具有广阔前景。
现代研究表明氧化应激与RA的发生及发展密切相关[4]。氧化应激是指由于机体中活性氧(reactive oxygen species,ROS)的过量产生并伴随抗氧化系统能力下降,从而导致机体的氧化和抗氧化之间的失衡状态[5]。在RA病程中,氧化应激涉及多种信号通路,其中磷脂酰肌醇-3-激酶(phosphoinositide-3-kinase,PI3K)/蛋白激酶B(protein kinase B,Akt)信号通路是RA病程中对缺氧损伤起保护作用的信号通路,该通路的激活产生抗氧化应激、抑制免疫炎症的生物学效用,并对在RA发病过程中涉及的下游核因子E2相关因子2(nuclear factor erythroid 2-related factor 2,Nrf2)的转录发挥重要调控作用[6]。
RA缓解期多属中医学“痹证”范畴的气血虚痹型,由反复发作、迁延不治导致脏腑虚损、气血不足[7]。当归补血汤(Danggui Buxue Decoction,DBD),首载于《内外伤辨惑论》,是益气补血的经典方剂。黄芪益卫固表、补气健脾,当归补血活血、养血和营,两药合用具有扶正固本、气血双补的功效[8]。目前,DBD对RA的临床疗效已被证实[9-11]。研究表明DBD具有调节免疫功能、提高机体抗氧化能力的作用[12]。但对于DBD治疗RA 的具体作用机制研究较少。本研究建立胶原诱导性关节炎(collagen-induced arthritis, CIA)大鼠模型,以PI3K/Akt/Nrf2信号通路为基本方向,探讨DBD通过抑制氧化应激从而防治RA的潜在作用机制,旨在为DBD治疗RA的作用机制研究提供一定理论依据及数据支撑。
1 材 料
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1.1 实验动物
SPF级雄性Wistar大鼠48只,体质量(180±10)g,购自吉林省长春市亿斯实验动物技术有限责任公司,动物生产许可证号SCXK(吉)2020-0002,饲养于长春中医药大学动物实验中心,自由饮水和进食,温度(23±2)℃,相对湿度(50±5)%。实验经长春中医药大学实验动物伦理委员会批准,批准文号:2024271。
1.2 实验药材
雷公藤多苷片(上海复旦复华药业有限公司,国药准字Z31020415,批号:230505);黄芪饮片(河北仁心药业有限公司,批号:28122068)。经河北仁心药业有限公司研究员赵丽霞鉴定为正品。当归饮片(河北康益强药业有限公司,批号:23011601)。经河北康益强药业有限公司研究员赵丽丽鉴定为正品。
1.3 实验试剂
牛Ⅱ型胶原(美国Chondrex公司,批号:220563),弗氏完全佐剂(美国Sigma公司,批号:SLCL9648),苏木精-伊红(HE)染色液(长春赛默瑞特科技有限公司,批号:20230302、20230324),番红O-固绿染色液(北京索莱宝科技有限公司,批号:240001001),超氧化物歧化酶(SOD)、丙二醛(MDA)、过氧化氢酶(CAT)、谷胱甘肽过氧化物酶(GSH-Px)检测试剂盒(上海酶联生物科技有限公司,批号:34817B、30239B、30417B、35362B);p-PI3K抗体、PI3K抗体、p-AKT抗体、AKT1抗体、Nrf2抗体、HO-1抗体(ABclonal公司,批号:5500037646、3523022321、5500020007、3522111410、3522080814、3522111422),Goat anti-Rabbit IgG(H&L)-HRP(北京博奥森生物技术有限公司,批号:BA01235136),BCA蛋白浓度测定试剂盒(上海碧云天生物技术公司,批号:111622230705);ECL发光液(北京兰杰柯科技有限公司,批号:23328870),总RNA提取试剂盒(北京天根生化科技有限公司,批号:A0325A)
1.4 实验仪器
165-8000电泳仪、170-3930转膜仪(美国Bio-Rad公司);WB显影仪Tanon-5200(上海天能生命科学有限公司);3H16RI高速冷冻离心机(湖南赫西仪器装备有限公司);ETC811基因扩增仪(Eastwin公司);石蜡切片机、组织脱水机、石蜡包埋机(德国徕卡仪器有限公司,型号:RM2255、TP1020、EG1150H)。
2 方法
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2.1 DBD水煎液的制备
按照原方黄芪-当归(5∶1)的比例称取适量黄芪和当归,加入10倍量蒸馏水浸泡1 h,加热至沸腾后再煎煮45 min,过滤。再次加入5倍量蒸馏水煎煮滤渣45 min,再过滤。合并两次滤液,浓缩至生药量0.75 g·mL-1,即DBD中剂量组水煎液。同法制备0.375 g·mL-1的DBD低剂量组水煎液和1.5 g·mL-1的DBD高剂量组水煎液。
2.2 模型建立及给药
参考文献[13]方法,取40只大鼠适应性喂养后制备CIA模型。初次免疫在大鼠右后足趾皮内注射0.15 mL胶原乳剂,第7天按相同方法注射0.1 mL胶原乳剂进行二次免疫。二次免疫后7 d,大鼠的脚趾肿胀、关节炎症指标均明显升高,提示CIA模型建立成功。再将其随机分为模型组、雷公藤多苷组、DBD低、中、高剂量组。初次免疫后第14天开始给药,参照《中国药典》2020年版黄芪、当归成人服用剂量标准,2倍量设为临床用量,根据人与大鼠体表面积换算大鼠的等效剂量为DBD中剂量为7.5 g·kg-1,设DBD低剂量为3.75 g·kg-1,DBD高剂量15 g·kg-1。根据本课题组前期研究[14],同法换算确定雷公藤多苷的剂量为9.45 mg·kg-1。各组大鼠按10 mL·kg-1灌胃给予不同浓度的DBD水煎液和雷公藤多苷,每天灌胃1次,连续28 d。正常组和模型组给予等量蒸馏水。
2.3 观察指标
2.3.1 评估大鼠一般情况及踝关节肿胀率
实验全程观察大鼠的状态和一般行为学表现、关节的肿胀程度等。每周记录1次大鼠体质量。于首次免疫之前使用游标卡尺测量大鼠右后踝关节周径,之后每周用相同方法测量一次各组大鼠右后踝关节周径,计算踝关节肿胀率(公式1)。
足趾肿胀率(%)=(致炎后周径-致炎前足趾周径)/致炎前足趾周径×100%
2.3.2 评定大鼠关节炎指数
大鼠的关节炎症程度采用关节炎指数进行评价。在对除正常组的大鼠进行初次免疫前观察一次,之后每周对大鼠的足趾部和关节变化情况及记录一次。采用国际通用5级评分标准[15]见表1。
2.3.3 计算大鼠脾脏指数、胸腺指数
待末次给药后,用质量分数20%氨基甲酸乙酯麻醉大鼠,腹主动脉采集血液完成后处死大鼠并解剖,取出脾和胸腺洗后称重并记录,然后计算脏器指数(公式2)。
脏器指数(%)=脏器质量(g)/解剖当日大鼠体质量(g)×100%[16]
2.4 关节组织采集
处死大鼠后,取下踝关节和膝关节组织,用生理盐水清洗后,一部分储存在多聚甲醛里,一部分放-80 ℃冰箱保存备用。
2.5 酶联免疫法(ELISA)法检测血清中氧化应激指标
将“2.3.3”项下取得的血样在室温下1 400 g离心20 min后取上清,严格按照ELISA检测试剂盒说明书检测血清中CAT、SOD、MDA及GSH-Px的水平。
2.6 组织病理学观察
将大鼠膝关节浸泡于体积分数4%多聚甲醛中固定48 h脱钙、固定。然后依次进行冲水、脱水、透明、浸蜡、包埋、切片等操作,部分切片使用HE染色,部分切片使用番红O-固绿染色,显微镜下观察膝关节滑膜组织病理形态。
2.7 实时荧光定量PCR(qPCR)法检测PI3K、Akt、Nrf2、血红素加氧酶1(HO-1)mRNA在大鼠滑膜组织中表达情况
用总RNA提取试剂盒提取大鼠滑膜组织总RNA。检测其浓度和完整性后,反转录合成cDNA,随后准备1个10 μL的反应混合物,包括0.2 μL的每个上游和下游引物、0.8 μL的目标DNA、5 μL的TB Green Premix Ex Taq,并用无核酸酶水补足到10 μL用于qPCR反应。引物由生工生物公司合成,引物序列见表2,β-actin为内参。
2.8 Western blot法检测p-PI3K、PI3K、p-Akt、Akt、Nrf2、HO-1蛋白在大鼠滑膜中的表达情况
用含体积分数1%蛋白酶抑制剂(PMSF)的RIPA裂解液提取各组大鼠滑膜组织总蛋白。BCA法检测蛋白浓度。等量的待测蛋白经SDS-聚丙烯酰胺凝胶孔道电泳,在聚偏二氟乙烯膜(PVDF)膜上转膜、封闭,于一抗中4℃孵育过夜。一抗浓度分别为:p-PI3K(1∶1 000)、PI3K(1∶2 000)、p-Akt(1∶5 000)、Akt(1∶1 000)、Nrf2(1∶2 000)、HO-1(1∶1 000)、β-actin(1∶1 000)。第二天洗膜后放入提前配制好的二抗(1∶1 000)中,室温下摇床孵育1 h后再次洗膜。用ECL试剂显色条带并显影,再利用Image J软件进行灰度值计算。以目标蛋白质条带的灰度值与内参β-actin条带灰度值的比值作为相对表达量。
2.9 数据分析
应用GraphPad Prism 9.5软件进行数据分析,P<0.05认为差异有统计学意义。多组间比较采用单因素方差分析(One-way ANOVA),结果以均$\bar{x}±s$表示。
3 结 果
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3.1 各组大鼠一般情况、体质量、踝关节肿胀率
正常组大鼠始终一般状态良好,精神正常、活动敏捷、饮食正常、体质量持续增加、四肢关节形态正常。模型组大鼠精神萎靡、食量及饮水量减少、体重增长缓慢、关节红肿明显、活动受限甚至跛行。与模型组比较,各给药组大鼠在开始给药后上述情况有不同程度改善,其中雷公藤多苷组和当归补血汤水煎液中、高剂量组体质量平缓增长,表现出明显差异(P<0.05)(图1A、D)。
与正常组相比,模型组和其余各给药组大鼠初次免疫后第7天开始足关节出现明显红肿症状,且模型组大鼠随着时间延长红肿症状逐渐加重,关节肿胀率升高(P<0.05);与模型组比较,给药28 d后雷公藤多苷组明显减轻大鼠的关节红肿、畸形,当归补血汤水煎液各组关节红肿、变形也均有不同程度的减轻,关节肿胀率下降(P<0.05)(图1B)。
3.2 各组大鼠关节炎评分
与正常组相比,模型组和各治疗组在给药前关节红肿甚至变形,说明造模成功。与模型组比较,各治疗组在给药后关节炎指数均降低,且随着给药时间延长,关节炎指数显著降低(P<0.05),见图1C。
3.3 各组大鼠胸腺指数和脾脏指数
与正常组比较,模型组大鼠胸腺及脾指数显著升高(P<0.05);与模型组比较,各治疗组大鼠胸腺和脾脏指数均有不同程度降低(P<0.05)。这表明DBD具有一定的免疫调节作用,见表3。
3.4 各组大鼠血清氧化应激相关指标(SOD、MDA、GSH-Px、CAT)水平比较
与正常组相比,模型组大鼠血清MDA显著升高,CAT、SOD、GSH-Px显著降低(P<0.05);与模型组比较,雷公藤多苷组和当归补血汤水煎液各组大鼠血清MDA显著降低,CAT、SOD、GSH-Px显著升高(P<0.05),见表4。
3.5 各组大鼠膝关节组织病理变化情况
HE染色结果显示,正常组大鼠关节结构正常,滑膜细胞排列规律、无滑膜增生,未见炎性细胞浸润及血管翳。与正常组比较,模型组大鼠关节滑膜细胞排列杂乱无序、异常增殖,炎性细胞浸润明显、有血管翳形成。与模型组比较,各给药组不同程度改善了大鼠滑膜组织病理改变,炎性细胞浸润、血管翳生成均减少,见图2A。
番红O-固绿染色结果显示,正常组大鼠关节软骨与番红O结合呈均匀红色,软骨结构完整,细胞形态正常,骨组织同固绿结合呈绿色或蓝色。与正常组比较,模型组大鼠关节软骨严重受损,导致番红O淡染或不着色,软骨基质减少,软骨细胞簇集,排列紊乱。与模型组比较,各给药组不同程度减轻了软骨病变,软骨面较平整,软骨细胞排列较规整,见图2B。
3.6 各组大鼠滑膜组织中PI3K、Akt、Nrf2、HO-1mRNA表达情况
与正常组比较,模型组大鼠滑膜组织中PI3K、Akt、Nrf2、HO-1mRNA表达显著降低(P<0.05);与模型组比较,雷公藤多苷组和当归补血汤水煎液各组大鼠滑膜组织中PI3K、Akt、Nrf2、HO-1mRNA表达有不同程度升高(P<0.05),见表5。
3.7 各组大鼠滑膜组织p-PI3K、PI3K、p-Akt、Akt、Nrf2、HO-1蛋白水平
与正常组相比,模型组大鼠滑膜组织中p-PI3K/PI3K、p-Akt/Akt比值降低,Nrf2、HO-1蛋白水平显著降低(P<0.05);与模型组比较,雷公藤多苷组和当归补血汤水煎液各组大鼠滑膜组织中p-PI3K/PI3K、p-Akt/Akt比值和Nrf2、HO-1蛋白水平明显升高(P<0.05),见图3。
4 讨论
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RA是一种慢性自身免疫性疾病,病变主要集中在关节部位,表现为关节软骨的进行性破坏[17]。氧化应激已被证明是参与RA疾病发生、发展的关键因素之一。在RA病程中,自身免疫与内源性或外源性抗原之间的相互作用可诱导ROS等自由基的过度产生,过多的自由基会使机体氧化与抗氧化系统失衡并升高机体氧化应激水平,从而对机体造成更大的损伤[18]。SOD、CAT、GSH-Px是体内重要的抗氧化酶,其水平可间接反映机体抗氧化能力的强弱[19]。脂质过氧化的产物MDA反映机体氧自由基代谢水平,据其可推断机体的氧化应激水平变化[20]。有研究显示RA患者血清中,MDA含量显著升高,SOD、GSH-Px等含量明显降低,表现为氧化应激状态[21]。因此,降低氧化应激水平,提高机体抗氧化能力对RA的治疗具有重要意义。
中医认为RA由于营卫失调,致气血俱虚,使外邪有可乘之机[22]。DBD具有气血双补的功效。目前,临床上用DBD治疗RA已取得成效。《古今名医临证实录丛书·痹证》中治疗“痹证”的用药规律研究发现其常用方多在DBD等方的基础上化裁[23]。Luo等[24]用DBD治疗中老年女性RA扶正气以助祛邪,临床疗效颇好。另有研究认为[9],DBD气血双补而不壅遏病邪,具有补而不腻的特点,可作为RA缓解期反复发作的首选。Guo等[25]对3种风湿病关节炎处方用药规律的比较发现核心处方之一为DBD加减。现代药理学研究表明DBD具有抗氧化应激的作用[26-28]。Gong等[29]研究证明DBD中的抗氧化活性是由当归主要活性成分阿魏酸所介导。但对于DBD抑制RA中的氧化应激水平异常增高的作用机制仍有待进一步研究。课题组前期研究表明RA的发病及发展主要涉及PI3K/Akt等信号通路[14],提示调控PI3K/Akt/Nrf2信号通路可能成为DBD改善RA氧化应激状态的关键机制之一。
在RA的氧化应激状态下,PI3K/Akt/Nrf2信号通路主要起到维护细胞稳态、减轻氧化损伤等作用。近年有研究发现,氧化应激过度发生时机体的抗氧化功能下降,可能伴随着Nrf2表达下调,并与PI3K/Akt信号通路的磷酸化被抑制有关,这会导致Akt活性降低,进而影响Nrf2及其下游抗氧化基因HO-1的表达[30]。PI3K可被受体酪氨酸激酶(RTKs)和G蛋白偶联受体(GPCR)激活,激活后的PI3K可催化细胞膜磷脂的PI-4,5-二磷酸(PIP2)转化为PI-3,4,5-三磷酸(PIP3),PIP3将PIP3依赖性激酶-1(PDK1)活化并使其定位于细胞膜上进而催化Akt发生磷酸化,Akt在特定位点上完成激活并通过调节下游靶基因而发挥作用[31]。研究表明,Nrf2是PI3K途径的下游靶点,在诱导内源性抗氧化酶抗氧化应激过程中处于枢纽地位[32]。当氧化应激刺激机体,PI3K等蛋白激酶可直接磷酸化Nrf2,
综上,DBD可通过抑制氧化应激减轻RA的关节损伤。其机制可能与激活PI3K/Akt/Nrf2信号通路有关。本研究丰富了DBD治疗RA的作用机制,但没有使用RA经典治疗通路的相关抑制剂以排除这些通路对治疗效果的影响是本实验的不足之处,后续研究可从此角度深入开展,以明确DBD对RA氧化应激状态的具体分子机制。
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2024年第59卷第23期
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doi: 10.11669/cpj.2024.23.005
  • 接收时间：2024-05-24
  • 首发时间：2025-11-13
  • 出版时间：2024-12-08
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  • 收稿日期：2024-05-24
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    1 长春中医药大学中西医结合学院, 长春 130117
    2 长春中医药大学吉林省人参科学研究院, 长春 130117
    3 长春中医药大学附属医院风湿免疫科, 长春 130021

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* 王颖航,女,博士,教授 研究方向:风湿免疫疾病研究 Tel:(0431)86763807
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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