International Immunopharmacology 14 (2012) 27–31

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Review

Mechanisms involved in the therapeutic effects of Paeonia lactiflora Pallas inrheumatoid arthritis

Wei Zhang a, Sheng-Ming Dai b,⁎a Wei Zhang, MD, PhD: Department of Orthopedics, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, Chinab Sheng-Ming Dai, MD, PhD: Department of Rheumatology & Immunology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China

Abbreviations: AA, complete Freund's adjuvant-indinduced arthritis; ConA, concanavalin A; ERK, extracelHMEC-1, human dermal microvascular endothelial cellcal vein endothelial cells; IκB, inhibitor of κB; IL, interleMMPs, matrix metalloproteinases; NF-κB, nuclear facttis; TGP, total glycosides of paeony; TNF, tumor necrosithelial growth factor.⁎ Corresponding author at: Department of Rheumato

Hospital, Second Military Medical University, 168 ChanChina. Tel.: +86 21 81873314; fax: +86 21 65270409.

E-mail address: dsm@medmail.com.cn (S.-M. Dai).

1567-5769/$ – see front matter © 2012 Elsevier B.V. Alldoi:10.1016/j.intimp.2012.06.001

a b s t r a c t

a r t i c l e i n f o

Article history:Received 30 March 2012Received in revised form 29 May 2012Accepted 1 June 2012Available online 21 June 2012

Keywords:Paeonia lactiflora PallasRheumatoid arthritisChinese herbAnalgesicAnti-inflammationJoint destruction

Paeonia lactiflora Pallas, also named Chinese Paeony, is a Chinese herb. A decoction of its root has been used totreat painful or inflammatory disorders in traditional Chinese medicine. A water/ethanol extract of RadixPaeoniae is known as total glycosides of paeony (TGP), of which paeoniflorin is the major active component.Preclinical studies show that TGP/paeoniflorin is able to diminish pain, joint swelling, synovial hypertrophy,and the severity of bone erosion and cartilage degradation in experimental arthritis. TGP/paeoniflorin sup-presses inflammatory process by reducing the production of prostaglandin E2, leukotriene B4, nitric oxide,reactive oxygen species, proinflammatory cytokines and chemokines. TGP/paeoniflorin also inhibits the pro-liferation of lymphocytes and fibroblast-like synoviocytes, the formation of new blood vessels, and the pro-duction of matrix metalloproteinases. Clinical data show that TGP is effective to relieve the symptoms andsigns of rheumatoid arthritis without significant adverse effects. Recently, TGP is widely used to treat rheu-matoid arthritis in China.

© 2012 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272. Analgesic effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283. Anti-inflammatory effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

3.1. Inhibitory effects on the production of prostaglandin E2 and leukotriene B4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293.2. Inhibitory effect on the production of nitric oxide and antioxidant effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293.3. Inhibitory effects on the production of proinflammatory cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293.4. Inhibitory effects on the production of chemokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293.5. Inhibitory effects on the proliferation of lymphocytes in arthritis models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303.6. Inhibitory effect on activation of neutrophils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

4. Inhibition of synovial hypertrophy and neovascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305. Protective effects on joint destruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306. Clinical aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

uced arthritis; CIA, collagen-lular signal-regulated kinase;line; HUVECs, human umbili-ukin; LPS, lipopolysaccharide;or-κB; RA, rheumatoid arthri-s factor; VEGF, vascular endo-

logy & Immunology, Changhaighai Road, Shanghai 200433,

rights reserved.

1. Introduction

Paeonia lactiflora Pallas (family Ranunculaceae), also namedChinese Paeony, is a herbaceous perennial herb and is also widelygrown as an ornamental plant in gardens, with several hundred se-lected cultivars; many of the cultivars have double flowers, with thestamens modified into additional petals. It flowers in the late spring.The flowers are very beautiful with various colours (Figs. 1A-E), sothey are awarded the fame of “love flower” in China.

Fig. 1. Chinese herb Paeonia lactiflora Pallas. A–E, plant of P. lactiflora Pallas with different colors of flowers. F, the dried root of P. lactiflora Pallas (Radix Paeoniae). G, slices of the root.H, molecular structure of paeoniflorin, a major active component extracted from the root.

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Radix Paeoniae is the dried root of P. lactiflora Pallas, which is cylindri-cal, straight, or slightly curved, 5–20 cm long and 1–2.5 cm in diameter(Figs. 1F-G). It is used as amedicinal herb in traditional Chinesemedicine,where it is called (pinyin: sháo yào; literally: “Paeony Medicine”).Radix Paeoniae is categorized into two classes: Radix Paeoniae Alba(pinyin: Bái Sháo; literally: “White Paeony”), the dried root withoutbark, usually collected from the cultivated P. lactiflora Pallas; and RadixPaeoniae Rubra (pinyin: Chì Sháo; literally: “Red Paeony”), the driedroot with bark, usually collected from the wild P. lactiflora Pallas. Re-cently, Radix Paeoniae Alba is used much more widely than RadixPaeoniae Rubra in China.

Awater/ethanol extract of Radix Paeoniae Alba is known as total glyco-sides of paeony (TGP), of which paeoniflorin (structure shown in Fig. 1H)is the major active component [1–3]. Paeoniflorin (C23H28O11, with a mo-lecular weight of 480.45) is a water-soluble monoterpene glycoside, thecontent of which constitutes>90% of TGP and 0.05–6.01% of RadixPaeoniae Alba. The content of paeoniflorin is used for the standardizationof the dosage of TGP in modern medicine. Orally administeredpaeoniflorin is metabolized into three metabolites, paeonimetabolin I–III,by intestinal bacteria [4]. Paeonimetabolin-I, a major metabolite, is dem-onstrated to be a potent anticonvulsant [5].

A decoction of Radix Paeoniae has been used in the treatment ofheadaches, dizziness, costal and abdominal pain, spasmodic pain ofthe limbs, anemia, menstrual disorders, spontaneous sweating andnight sweating in traditional Chinese medicine with a long history. Inrecent decades, Radix Paeoniae Alba is found to be effective in the treat-ment of rheumatoid arthritis (RA), systemic lupus erythematosus, hep-atitis, and other inflammatory/autoimmune diseases. The mainpathological change of RA is characterized by hyperplasia of synovialmembrane, infiltration of inflammatory cells, and neovascularization,which finally lead to cartilage erosion and articular destruction. Inrecent years, a lot of studies describing the analgesic, anti-inflammatory, and immunomodulatory effects of TGP or paeoniflorinhave been published. Here, we briefly reviewed the possible mecha-nisms responsible for the therapeutic effects of TGP in RA.

2. Analgesic effects

Pain is the commonest symptom of RA. In several models of pain,Radix Paeoniaewas demonstrated to relieve the pain effectively [6–9].Intramuscular injection of TGP suppressed writhing induced by intra-peritoneal injection of acetic acid, squeak induced by footpad stimula-tion with electricity and hot-plate reaction of mice (5–40 mg/kg)and/or rats (50–125 mg/kg) in a dose-dependant manner. Further-more, intra-gastric administration of TGP was demonstrated to in-crease the threshold of feeling the pain in mice [8]. Anticholinergicaction may be responsible for the analgesic effect of TGP [3]. Recently,it was demonstrated that intraperitoneal injection of paeoniflorin, achief active ingredient in Radix Paeoniae, is effective in relieving vis-ceral pain, which is mediated, at least in part, by adenosine A1 recep-tors [10]. Centrally administered paeoniflorin (4.5 mg/kg i.c.v) alsoproduced a significant analgesic effect, which may be mediated byκ-opioid receptors and α2-adrenoceptors in the central nervous sys-tem [11]. Taken together, multiple pathways may be involved in theanalgesic effect of Radix Paeoniae.

3. Anti-inflammatory effects

Chronic and persistent inflammation in the synovial membrane isthe pathological basis of RA. The direct anti-inflammatory effects ofTGP were observed in various animal models of both acute andchronic inflammation, such as dimethylbenzene-induced ear swell-ing, carrageenan-induced paw edema, subcutaneous tampon-induced granuloma, complete Freund's adjuvant-induced arthritis(AA), and collagen-induced arthritis (CIA) [7,8,12–15]. In both AArats [12,13,15,16] and CIA rats [14,17,18], intra-gastric administra-tion of TGP (25–100 mg/kg/d) for 7–14 days significantly diminishedthe severity of hind paw swelling and the scores of polyarthritis in adose-dependent manner. Histological examination demonstrated thatthe synovial infiltration of lymphocytes was also markedly inhibited byTGP [12,14,16,18]. Similar effects of paeoniflorin on the severity of hind

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paw swelling and the scores of polyarthritis were also confirmed in therats with experimental arthritis [19–21]. In addition, intraperitoneal in-jection of paeoniflorin inhibited the severity of intratracheal instillationof lipopolysaccharide (LPS)-induced acute lung injury in mice by sup-pressing inflammatory cell infiltration and lowing microvascular per-meability [22]. Subcutaneous injection of TGP also inhibited capillarypermeability associated with inflammation induced by intraperitonealinjection of acetic acid in mice [23]. These data support that RadixPaeoniae suppresses both acute and chronic inflammation by lowingmicrovascular permeability and inhibiting the infiltration of inflamma-tory cells. Further evidences indicate that TGP or paeoniflorin exertsanti-inflammatory effect by inhibiting the production of inflammatorymediators, such as prostaglandin E2, leukotriene B4, nitric oxide, reac-tive oxygen species and proinflammatory cytokines.

3.1. Inhibitory effects on the production of prostaglandin E2 andleukotriene B4

In vitro, TGP (0.001–100 μg/ml) inhibited the production of leuko-triene B4 and prostaglandin E2 by calcimycin A23187-stimulatedperitoneal macrophages in a dose-dependent manner [24,25]. TheA23187-induced increase of intracellular calcium ion concentration([Ca2+]i) in macrophages was also inhibited by TGP [25]. In vivo studiesalso showed that oral administration of TGP inhibited the production ofprostaglandin E2 by peritoneal macrophages and macrophage-likesynoviocytes of AA rats [12,25]. TGP significantly decreased the produc-tion of prostaglandin E2 from cultured fibroblast-like synoviocytes ofCIA rats, in response to interleukin (IL)-1α- or tumor necrosis factor(TNF) α-stimulation [26]. TGP elevated the intracellular cAMP level inboth macrophage-like synoviocytes and fibroblast-like synoviocytes[13,26], which may be involved in inhibiting the production of inflam-matory mediators. Recently, paeoniflorin was also demonstrated to beeffective in inhibiting the production of prostaglandin E2 from LPS-stimulated RAW 264.7 macrophages [27]. Paeoniflorin also suppressedthe production of prostaglandin E2 from IL-1α-stimulated or TNFα-stimulated fibroblast-like synoviocytes of CIA rats [28,29]. Moreover,oral treatment with paeoniflorin suppressed the base-line production ofprostaglandin E2 from fibroblast-like synoviocytes in CIA rats [21].These data imply that Radix Paeoniae inhibits prostaglandin E2 and leuko-triene B4 production frommacrophages and fibroblast-like synoviocytesby decreasing intracellular calcium ion concentration and increasing in-tracellular cAMP level.

3.2. Inhibitory effect on the production of nitric oxide and antioxidanteffect

In vitro, TGP markedly suppressed LPS-induced nitric oxide pro-duction and inducible nitric oxide synthase expression in rat perito-neal macrophages [30]. In addition, the production of reactiveoxygen species from LPS-stimulated macrophages was inhibited byhigher concentrations (11.25–125 μg/ml) but enhanced by lowerconcentrations (0.09–11.25 μg/ml) of TGP in a dose-dependent man-ner [31]. It was also reported TGP protected cells from harmful effectsof oxidative stress [32].

Recently, paeoniflorin was also demonstrated to be effective ininhibiting the production of nitric oxide from LPS-stimulated RAW264.7 macrophages [27]. In vitro studies also demonstrated the protec-tive effects of paeoniflorin against hydrogen peroxide (H2O2)-inducedoxidative damage in human umbilical vein endothelial cells (HUVECs)by decreasing the production of intracellular reactive oxygen speciesand increasing the production of endogenous antioxidants [33]. Theantioxidative effect of paeoniflorin on the LPS-induced liver inflamma-tory reactions was confirmed by in vivo studies [34]. The LPS-induceddecreases in antioxidant levels of superoxide dismutase, catalase, andglutathione peroxidase could be reversed by paeoniflorin [34].

Inflammation induces oxidative stress by producing oxidants like re-active oxygen species and nitric oxide. Nitric oxide is also a potentmedi-ator of inflammation. Radix Paeoniae may relieve inflammatory processby increasing the production of endogenous antioxidants and decreasingthe production of nitric oxide.

3.3. Inhibitory effects on the production of proinflammatory cytokines

In vitro, dual effects of TGP on IL-1 and IL-2 production were noted[35,36]. TGP enhanced IL-1 production by LPS-stimulated mousespleen lymphocytes at lower concentrations (0.5–12.5 μg/ml) butinhibited IL-1 production at higher concentrations (12.5–312.5 μg/ml)[35]. TGP enhanced IL-1 production by LPS-stimulated macrophages,and IL-2 production by concanavalin A (ConA)-stimulatedmouse spleenlymphocytes at lower concentrations (0.5–12.5 μg/ml). However, itinhibited their production at higher concentrations (12.5–62.5 μg/ml)[31,36]. Oral administration of TGP in CIA rats inhibited both the produc-tion of IL-2 from spleen lymphocytes upon ConA stimulation and theproduction of IL-1 from peritoneal macrophage upon LPS stimulation[37]. Moreover, in macrophage-like synoviocytes isolated from both AArats and CIA rats, the increased production of IL-1, IL-6 and TNFα couldbe inhibited by treatment with oral TGP [13,14]. In AA rats, treatmentwith oral TGP significantly down-regulated the serum levels of TNFαand soluble ICAM-1 [16]. In addition, in rats with experimental colitis,serum levels of IL-6, IL-17 and IL-23 were lowered by treatment withintra-gastric administration of TGP [38]. Furthermore, in vitro studiesdemonstrated that TGP decreased the production of IL-1 from culturedfibroblast-like synoviocytes, which were isolated from RA patients [39].

Paeoniflorin attenuated the production of TNFα, IL-6 and high-mobility group-box 1 protein in LPS-stimulated RAW264.7 macrophagesin a concentration-dependent manner, and inhibited the activation of in-hibitor of κB (IκB)/nuclear factor (NF)-κB pathway [40]. In LPS-challenged mice, intra-gastric administration of paeoniflorin reducedserum levels of TNFα, IL-1β, IL-6, and high-mobility group-box 1 protein,while increased serum level of IL-10 [40,41]. In mesenteric lymph nodelymphocytes isolated from AA rats, the increased production of IL-2and the decreased production of IL-4 and transforming growth factor(TGF)-β1 were suppressed by treatment with oral paeoniflorin(50–100 mg/kg/d) [20]. These data suggest that paeoniflorin exerts theanti-inflammatory and immunomodulatory effects by balancing thefunction of Th1 cells and Th2 cells. Infibroblast-like synoviocytes isolatedfrom CIA rats, the increased production of IL-1 and TNFαwas also atten-uated by treatment with oral paeoniflorin (50–100 mg/kg/d) [21,28].The increased expression levels of IL-1, IL-6 and GM-CSF in synovialhomogenates of AA rats were down-regulated by treatment withoral paeoniflorin [19]. Both in vitro and in vivo studies support thatRadix Paeoniae inhibited RA synovitis by balancing the differentia-tion and function of Th1 and Th2 cells and suppressing the produc-tion of proinflammatory cytokines from lymphocytes, macrophagesand fibroblast-like synoviocytes.

3.4. Inhibitory effects on the production of chemokines

Chemokines are vital for directing the movement of circulatingleukocytes to the sites of inflammation. Paeoniflorin markedly atten-uated the mRNA expression levels of chemokines (including CCL2,CCL5, CCL20, CXCL8, CXCL16 and CX3CL1) in human dermal micro-vascular endothelial cell line (HMEC-1) stimulated by TNFα.Paeoniflorin also reduced the secretion of these chemokines into cul-ture medium. Furthermore, Western blotting analysis revealed thatpaeoniflorin inhibited TNFα-upregulated phosphorylation of bothIκB-α and extracellular signal-regulated kinase (ERK)1/2. Further-more, paeoniflorin inhibited TNFα-induced nuclear translocation ofNF-κB to the nucleus. These data suggest that the anti-inflammatoryeffect of paeoniflorin involves the inhibition of chemokine productionand leukocyte migration [42].

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3.5. Inhibitory effects on the proliferation of lymphocytes in arthritismodels

In vitro, TGP (2.5–62.5 μg/ml) inhibited the proliferation of LPS-stimulated B cells and ConA-stimulated T cells, which were isolatedfrom the spleen of CIA rats [37]. In CIA rats, oral treatment with TGPin vivo inhibited the in vitro proliferation of both B cells respondingto LPS stimulation and T cells responding to ConA stimulation [37].Paeoniflorin also inhibited the proliferation of IL-1α-stimulated thy-mocytes and IL-1α-stimulated splenocytes, which were isolatedfrom CIA rats [28]. In AA rats, oral administration of paeoniflorinalso significantly inhibited the proliferation of mesenteric lymphnode lymphocytes [20]. In addition, paeoniflorin induced apoptosisin murine T lymphocytes and Jurkat human T cell leukemia cellsthrough a redox-linked mechanism [43]. All these data show thatboth TGP and paeoniflorin suppress the proliferation of lymphocytesand induce apoptosis of lymphocytes in experimental arthritis.

3.6. Inhibitory effect on activation of neutrophils

Neutrophils play an important role in nonspecific immunity. Acti-vation of these cells results in a respiratory burst (release of oxygenfree radicals) and degranulation (release of elastase), which contrib-ute to inflammation. TGP significantly inhibited the production of ox-ygen free radicals and the release of elastase from culturedneutrophils, suggesting TGP inhibits the activation of neutrophils[23].

4. Inhibition of synovial hypertrophy and neovascularization

In both AA and CIA rats given TGP intragastrically, the hypertrophyof synovial membrane and formation of new blood vessels and pannuswere significantly alleviated [12,14,19]. In vitro, the proliferation offibroblast-like synoviocytes isolated from both CIA and AA rats in-creased significantly compared with those isolated from normal rats[26,29]. TGP (0.8–25.6 μg/ml) significantly suppressed the proliferationof synovial fibroblast-like cells isolated from AA or CIA animal modelsin a dose-dependant manner [18,26,44]. The supernatants of culturedmacrophage-like synoviocytes, which were isolated from CIA and AArats, were more powerful than those from normal rats to stimulatethe proliferation of fibroblast-like synoviocytes. TGP also inhibited theproliferation of fibroblast-like synoviocytes stimulated by the superna-tants of cultured CIA macrophage-like synoviocytes [14]. Other studiesconfirmed the inhibitory effects of TGP/paeoniflorin on the TNFα- orIL-1α-induced proliferation of fibroblast-like synoviocytes, whichwere isolated fromAA rats, CIA rats and RA patients [28,29,39]. Further-more, oral treatment with TGP significantly suppressed the prolifera-tion of synoviocytes in AA rats [13]. Taken together, TGP/paeoniflorintreatment may relieve the synovial hypertrophy by inhibiting the pro-liferation of fibroblast-like synoviocytes and the infiltration of inflam-matory cells.

Angiogenesis is highly dependent on the proliferation, motilityand invasion of endothelial cells. TGP significantly inhibited the pro-liferation of HUVECs [45]. Flow cytometric analysis showed that TGParrested the HUVECs in the G0/G1 phase of the cell cycle. TGP signif-icantly inhibited the migration of HUVECs toward vascular endothe-lial growth factor (VEGF)-containing media in a dose-dependentmanner. TGP also inhibited VEGF-induced tube formation of HUVECsin a three-dimensional Matrigel. In vivo data further demonstratedthat TGP inhibited angiogenesis by using the chick chorioallantoicmembrane assay [45]. The increased expression level of VEGF, a stim-ulator of neovascularization, in synovial homogenates of AA and CIArats was down-regulated by oral treatment with TGP or paeoniflorin[14,19]. These data suggest that TGP treatment may inhibit synovialneovascularization in RA by decreasing the production of VEGF andthen the proliferation of endothelial cells and angiogenesis.

TGP may also suppress the hypertrophy of synovial tissue by in-ducing cell apoptosis, because oral administration of TGP for 14 daysdownregulated the expression of anti-apoptotic factor Bcl-2 whileupregulated the expression of pro-apoptotic factor Bax in the synovialtissue of CIA rats [17].

5. Protective effects on joint destruction

Histological examination demonstrated that the severity of boneerosion and cartilage degradation in AA and CIA rats was alleviatedby TGP treatment [12,14,16,17]. The protective effect of paeoniflorintreatment on the destruction of articular cartilage in AA rats wasalso confirmed [19]. The primary enzymes responsible for the degra-dation of cartilage are the matrix metalloproteinases (MMPs). In vitro,TGP inhibited the production of MMP-1 and MMP-3 from fibroblast-like synoviocytes [12,14]. Although the limited data from arthritismodels support that TGP treatment is able to retard the progressionof cartilage destruction, the protective effect of TGP needs to be veri-fied by clinical evidences in RA patients.

6. Clinical aspects

There have been numerous clinical reports on the efficacy and safetyof TGP in various diseases. Unfortunately, few of them have been sub-stantiated by randomized controlled trials with large sample size. Thefirst prospective, double-blind trial of TGP was conducted in 1993, and450 patients with RA were randomized to receive oral TGP (1.8 g/d)or methotrexate (10 mg/w) for 12 weeks. Therapeutic response wasachieved in 71.7% of TGP-treated patients and 81.7% of methotrexate-treated patients, respectively. The side effects of TGP occurred in13.3% patients, and most of them were gastrointestinal tract distur-bances, especially mild diarrhea. They will be self-resolved in1–2 weeks. No adverse effects on hepatic, renal and hematologicaltestswere found. The similar resultswere observed in a phase III clinicaltrial of 1016 patients with RA [46]. A preparation of TGP was approvedby State Food and Drug Administration of China to enter market as adisease-modifying drug for RA in 1998. However, there is no reportavailable to show whether TGP treatment retard the radiographic pro-gression of the disease. Somepilot studies also showed therapeutic ben-efits of TGP in systemic lupus erythematosus [47], Sjögren syndrome[48], ankylosing spondylitis [49], chronic urticaria [50], et al. Reportsof traditional use indicate that Radix Paeoniae may have abortifacientactivity, so the use of Radix Paeoniae is contraindicated in pregnancy.

7. Summary

Radix Paeoniae is the dried root of P. lactiflora Pallas, which is wide-ly used in traditional Chinese medicine. Paeoniflorin is the majorcomponent of the active monoterpene glycosides extracted fromRadix Paeoniae. Numerous preclinical studies have demonstrated theanalgesic, antiinflammatory, immunomodulatory and cartilage pro-tective effects of TGP/paeoniflorin in vitro and in vivo. It exerts anti-inflammatory effect by inhibiting the production of inflammatorymediators, such as prostaglandin E2, leukotriene B4, nitric oxide, re-active oxygen species and proinflammatory cytokines, from lympho-cytes, macrophages and fibroblast-like synoviocytes. It also inhibitschemokine production from endothelial cells, induces the productionof antioxidants and decreases the micro-vascular permeability. It bal-ances the differentiation and function of Th1 and Th2 cells, inhibitsthe proliferation of lymphocytes, and induces apoptosis of lympho-cytes. It also inhibits the activation of neutrophils. TGP/paeoniflorinmay alleviate the synovial hypertrophy and joint destruction ofRA by anti-inflammation, anti-proliferation of synoviocytes, anti-neovascularization and reduction of cartilage-degradation enzymes.Clinical data support the therapeutic efficacy of TGP in RA without

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severe adverse effects, but no evidence demonstrates whether TGPretards the radiographic progression of RA.

Acknowledgment

This study was supported in part by the grants from the NationalNatural Science Foundation of China (Nos. 30972729 and 81172852).

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