Celastrol and triptolide, chemical compounds isolated from Tripterygium wilfordii hook (also known as thunder god vine), are effective against rheumatoid arthritis (RA). Celastrol targets numerous signaling pathways involving NF-κB, endoplasmic reticulum Ca2+-ATPase, myeloid differentiation factor 2, toll-like receptor 4, pro-inflammatory chemokines, DNA damage, cell cycle arrest and apoptosis. Triptolide, inhibits NF-κB, the receptor activator of NF-κB (RANK)/RANK ligand/osteoprotegerin signaling pathway, cyclooxygenase-2, matrix metalloproteases and cytokines. The present review examined the chemistry and bioavailability of celastrol and triptolide, and their molecular targets in treating RA. Clinical studies have demonstrated that T. wilfordii has several promising bioactivities, but its multi-target toxicity has restricted its application. Thus, dosage control and structural modification of T. wilfordii are required to reduce the toxicity. In this review, future directions for research into these promising natural products are discussed.
rheumatoid arthritisthunder god vineTripterygium wilfordii hookmolecular targetsmetabolismbioavailabilitycelastroltriptolidesignaling pathwayIntroduction
Rheumatoid arthritis (RA) is a complicated disease caused by environmental and genetic factors that involves a hyperactive immune system and synovial inflammation in multiple joints, which if left untreated irreversibly destroys joints and leads to severe disability (1). The common drugs used to treat RA, including methotrexate, cannot prevent the disease and cause severe complications in many patients (2); therefore, the development of safer, cost-effective therapeutics is required.
RA involves the action of pro-inflammatory cytokines and chemokines produced by synoviocytes and infiltrating immune cells (3), including interleukin (IL)-1, IL-2, IL-3, IL-4, IL-6, IL-8, IL-17, interferon (IFN)-α and IFN-β, tumor necrosis factor (TNF)-α, transforming growth factor β, granulocyte-macrophage colony-stimulating factor and macrophage inflammatory protein (MIP)-3α (2,4–7). These cytokines and chemokines are able to activate NF-κB, upregulate the expressions of cyclooxygenase-2 (COX-2) and nitric oxide synthase, and promote the production of prostaglandin E2 (PGE2) and nitric oxide. Moreover, these changes contribute to synovial inflammation accompanied by arthrosis, swelling, hyperplasia, angiogenesis, bone destruction and arthritic decay (8,9). Natural products that target these molecules are less likely to induce adverse effects may be used as therapeutic agents owing to their high therapeutic potential (2,10–13). For example, bioactive natural compounds extracted from plants, such as polyphenolic compounds, commonly exert multiple therapeutic effects (14–17).
Tripterygium wilfordii hook (also known as thunder god vine) is a common plant species, which has been used for a variety of purposes in traditional Chinese medicine (TCM) (18). Previous studies in the TCM literature suggest that T. wilfordii can treat several autoimmune and inflammatory conditions including RA, and improvements to its efficacy and safety have been made (14,19).
Currently, >380 secondary metabolites have been isolated from T. wilfordii, and ≥350 of these are structurally diverse terpenoids with a wide range of pharmacological activities, including anti-inflammatory, immunosuppressive and antineoplastic effects (20). It has been shown that two diterpenoid tri-epoxides, celastrol and triptolide (Fig. 1), are primarily responsible for the anti-inflammatory and immunosuppressive effects of T. wilfordii preparations (21,22). Furthermore, these two compounds are the most abundant and most pharmacologically active of the metabolites found in T. wilfordii extracts (23).
The present study critically reviews the chemistry, bioavailability, bioactivities, multi-target toxicities and molecular targets of celastrol and triptolide for the treatment of RA (Fig. 2; Table I). The present review also discussing future directions for research into the aforementioned promising natural products.
Metabolism and bioavailability
Oral administration of triptolide is recommended for to treat inflammation, autoimmune diseases and tumors (24). In rats, triptolide at a dose of 1 mg/kg exhibits a bioavailability of 81.6% after intravenous injection and 63.9% after oral administration (25). Moreover, it achieves a maximum concentration of 293.19±24.43 ng/ml within ~10 min. Triptolide distributes into the liver, followed by plasma, kidney, lung, spleen, heart and testicular tissue, and is quickly excreted through the biliary, urinary and fecal routes with a half-life of 0.42 h (26). Moreover, the metabolism and bioavailability of triptolide is not fully understood as clinical trials investigating the use of triptolide to treat RA have not been performed (27,28).
Celastrol has low aqueous solubility (13.25±0.83 µg/ml at 37°C) and poor intestinal absorption, which results in low oral bioavailability and limits its clinical application (29). To overcome these constraints, the compound can be delivered using solid lipid nanoparticles, liposomes, micelles or nanostructured lipid carriers (30,31).
Molecular targets of celastrolCelastrol inhibits activation of NF-κB by targeting inhibitor of NF-κB (IκB) kinase
NF-κB regulates the transcription of numerous genes that are involved in immune, inflammatory and anti-apoptotic responses (32). Furthermore, the function of NF-κB is regulated by rapid degradation of its endogenous inhibitory molecule IκB. Inflammatory stimuli, such as cytokines, initiate a signaling cascade that leads to the activation of two IκB kinases (IKK), IKK-1 and IKK-2, which then phosphorylate IκB at two N-terminal serine residues (33). The IKK complex is expressed in fibroblast-like synoviocytes (FLS) and is activated by IL-1 and TNF-α (34–36). These studies demonstrated that celastrol suppresses NF-κB activation by inhibiting IKK activity, possibly by targeting cysteine 179 in the activation loop of IKK (34,35,37). Moreover, celastrol inhibits the activation of NF-κB by targeting IκB kinase, which is not specific in the RA (38). It has been revealed that the NF-κB signaling pathway is involved in a number of diseases, including RA, systemic lupus erythematosus and ankylosing spondylitis (32,34–37). Moreover, myeloid differentiation factor 2 (MD2) and Toll-like receptor 4 (TLR4) are associated with RA, thus it is likely that celastrol targets MD2 (39).
In RA, Ca2+ signaling mediates the expression of pro-inflammatory cytokines through autoreactive T- and B-lymphocytes after autoantigen stimulation (40). Various pumps maintain Ca2+ homeostasis, among which is the ER Ca2+-ATPase, which can be inhibited by celastrol (41). Therefore, celastrol may alter Ca2+ signaling pathways to downregulate inflammatory response genes (42) and promote Ca2+-mediated autophagic cell death (43,44), as shown by studies in RA-FLS. Thus, it is speculated that resistance of FLS to apoptosis may be a characteristic of RA.
Celastrol induces DNA damage, cell cycle arrest and apoptosis
Celastrol blocks RA-FLS at G2/M phase (45), which may be a potential mechanism for its ability to inhibit proliferation and induce apoptosis. It has also been demonstrated that celastrol inhibits cell cycle progression by blocking the association of cyclins with cyclin-dependent kinases (33). Furthermore, celastrol leads to an increase in cell division cycle protein 2 homolog (Cdc2) phosphorylation and downregulation of Cdc2 and Cyclin-b1, which may reduce the number of Cdk1-Cyclin-b1 complexes and arrest cells at the G2/M phase (45). Celastrol also increases phosphorylation of Cdc25, which may contribute to G2/M phase arrest (46).
It has been shown that celastrol activates cleaved caspases 3 and 9, as well as cleaved poly (ADP-ribose) polymerase, downregulates FasR and increases the Bax/Bcl-2 ratio (46). Therefore, celastrol may induce apoptosis in RA-FLS, which express a variety of death-inducing surface receptors of the TNF receptor family such as Fas/CD95, TNF-related apoptosis-inducing ligand-receptor (TRAIL-R1), TRAIL-R2 and TNF receptor 1 (47).
Celastrol targets MD2 and inhibits TLR4 activation
TLR4 exists as a complex with a co-receptor, MD2, in the plasma membrane of various immune cells (48). Celastrol blocks the most upstream step in TLR4 activation (49), and thus it likely targets MD2. Moreover, celastrol may function similar to the anti-inflammatory phytochemicals sulforaphane and caffeic acid phenethyl ester, which interfere with the interaction between lipopolysaccharide (LPS) and the TLR4/MD2 complex (50,51). Furthermore, it is speculated that celastrol may have intracellular targets, including MD2 and TLR4 (48,49).
Celastrol modulates pro-inflammatory chemokines
Chemokines are a superfamily of cytokines that are associated with cell migration and recruitment to sites of inflammation (5). Chemokines are categorized into four groups, CXC, CX3C, CC and C, based on the location of conserved cysteine residues (21). In inflammatory disorders such as RA, chemokines bind to their receptors leading to leukocyte trafficking into the joints, where leukocytes exacerbate inflammation and lead to pannus formation and tissue damage (4). Moreover, several chemokines have been implicated in RA and experimental arthritis, including T cell specific protein RANTES [RANTES; also known as C-C motif chemokine 5 (CCL5)], monocyte chemotactic protein-1 (MCP-1; also known as CCL2), MIP-1α (also known as CCL3) and growth-related oncogene/keratinocyte chemoattractant (GRO/KC) (51–53). It has been revealed that treating arthritic rats with celastrol significantly reduces expression levels of RANTES, MCP-1, MIP-1α and GRO/KC, as well as the pro-inflammatory cytokines TNF-α and IL-1β (54), and this may inhibit leukocyte migration into joints (55).
Molecular targets of triptolideTriptolide inhibits the NF-κB pathway
The NF-κB family comprises Rel domain-containing proteins that regulate inflammatory and immune responses (56). In resting cells, these proteins are retained in the cytosol by a group of inhibitory proteins, such as IκBα (57). Upon activation, IKKs, including IKK-1 and IKK-2, phosphorylate IκBα, which is subsequently ubiquitinated and destroyed by the proteasome. This liberates NF-κB to translocate into the nucleus, where it activates several genes associated with RA (56). It has been shown that triptolide regulates IKK-1 and IKK-2 activities induced by various stimuli (57). The purified T. wilfordii component PG490 inhibits both IKK-1 and IKK2 activities with similar potency (58). As NF-κB transcription factors upregulate the expression of several genes involved in inflammatory responses, the targeting of components of NF-κB signaling is a major therapeutic strategy for treating autoimmune diseases (59).
Similar to NF-κB, activating protein-1 (AP-1) transcription factors, comprising Jun and Fos family proteins, regulate cell proliferation, transformation and death, and may be potential therapeutic targets for the control of inflammation (60–62). Triptolide also inhibits mitogen-activated protein kinase (MAPK)/AP-1 signaling pathways, effectively suppressing MAP kinases, including JNK, p38 and ERK activities (59). Therefore, triptolide is a promising candidate immunomodulatory drug for autoimmune disorder therapy (63,64).
Triptolide alters RANKL/RANK/OPG signaling
Osteoclasts are the primary bone resorptive cells, and are located mainly in the synovial inflammatory tissue; RANKL stimulates osteoclast-mediated bone destruction in RA by binding to its receptor RANK (65). Under physiological conditions, osteoblasts and activated T cells express RANKL, which binds to RANK on osteoclasts to trigger osteoclast maturation and bone resorption. Osteoblasts counteract the action of osteoclasts in the balance between bone formation and destruction; osteoblasts express osteoprotegerin (OPG), which ‘mops up’ RANKL and prevents it from binding to RANK, thus inhibiting bone resorption (66). However, under pathological conditions such as RA, this balance is shifted toward bone destruction (67). In mice with collagen-induced arthritis, triptolide significantly reduces the number of osteoclasts in areas of bone destruction by downregulating RANKL and RANK, and upregulating OPG (68).
Triptolide inhibits COX-2 and matrix metalloproteinases (MMPs)
It has been revealed that injury, tumorigenesis and invasion from the joint into multiple organs upregulate COX-2 via NF-κB to produce prostaglandins, which induce inflammation and increase capillary permeability (69). Moreover, triptolide downregulates COX-2 and PGE2, thus alleviating LPS-induced inflammation (70).
MMPs participate in tumorigenesis, tumor metastasis and inflammatory diseases such as RA (57,71–75). In human synovial fibroblasts and mouse macrophages, triptolide inhibits IL-1α-induced phosphorylation of MMP-1 and LPS-induced phosphorylation of MMP-3. By inhibiting MMP-3 and MMP-13, triptolide slows the degradation of extracellular matrix and cartilage degeneration in mice with collagen-induced arthritis, as well as in primary human osteoarthritis and bovine chondrocytes (26,76–79).
Triptolide inhibits cytokines
Antigen-presenting cells produce IL-12 and IL-23, which are heterodimeric cytokines sharing a p40 subunit; these cytokines stimulate the generation and functions of T helper (Th)1 and Th17 cells, respectively. These cytokines are involved in the pathogenesis of several autoimmune disorders, including RA and systemic lupus erythematosus (80). Triptolide downregulates p40, in part, by activating the expression and phosphorylation of CCAAT/enhancer binding protein-α (C/EBPα) via the kinases ERK1/2 and AKT-glycogen synthase kinase 3β (81). This phosphorylation allows C/EBPα to bind antagonistically to the p40 promoter (81). Furthermore, programmed cell death 5 enhances the ability of triptolide to induce FLS apoptosis in RA, and therefore may be a potential therapeutic target in RA (29,82,83).
VEGF-driven angiogenesis promotes RA progress by allowing inflammatory cell infiltration of the synovial membrane (5). Triptolide prevents the formation of new blood vessels in vitro and in vivo, and it inhibits several downstream effects of IL-1β, including cell adhesion of human FLS in RA and human umbilical vein endothelial cells (HUVECs) (84). Furthermore, triptolide upregulates several angiogenic activators, including TNF-α, IL-17, VEGF, VEGFR, Angiopoietin (Ang)-1, Ang-2 and Tie2, and activates the MAPK signaling pathway involving phosphorylated (p)-ERK, p-p38 and p-JNK (85). Moreover, triptolide disrupts tube formation in HUVECs on Matrigel, and suppresses VEGF-induced chemotactic migration of HUVECs and human FLS in RA (86).
Adverse effects of T. wilfordii
T. wilfordii is a Chinese herb that has been traditionally used in clinics for RA treatment (3). Numerous preclinical studies have demonstrated that extracts from T. wilfordii roots inhibit the expression levels of RA-related inflammatory factors secreted by macrophages, lymphocytes, synovial fibroblasts and chondrocytes (87–91). Moreover, T. wilfordii suppresses lymphocytes and synovial fibroblast proliferation by inducing apoptosis (46). The anti-angiogenesis property of synovial fibroblasts has been shown in a previous study (83). Although T. wilfordii has several promising bioactivities in vivo and in vitro, its multi-target toxicity has restricted its clinical application (88). Data from the China Food and Drug Administration catalogue at least 633 instances of adverse reactions (53 severe) involving reproductive organ, liver and renal toxicity. Furthermore, clinical studies have concluded that T. wilfordii can damage the digestive system, including liver injury and stomachache, as well as the endocrine and reproductive systems (30,32,92). Moreover, 271 patients with RA have reported digestive tract symptoms and irregular menstruation. As a compound of T. wilfordii, triptolide-induced toxicity was shown to be dependent on dosage and administration times (30,93). To avoid toxicity, previous studies have attempted to alter the dosage and structure, and to assess its compatibility with other drugs (34). For example, Freag et al (94) developed self-assembled celastrol phytosomal nanocarriers (celastrol-PHY) to improve celastrol solubility and oral bioavailability; these were confirmed through an in vitro release study and a pharmacokinetic study in rabbits (94). Structural modification and alternation of triptolide can produce derivatives of triptolide with lower toxicity and relative higher activity. Apart from structural alterations, the development of novel triptolide delivery systems is a valuable strategy to improve water solubility, and the efficiency of absorption and metabolism, and to reduce toxicity (95).
Conclusions
Celastrol and triptolide from T. wilfordii are effective against RA; they target numerous signaling pathways, proteases and cytokines. The present review examined the chemistry and bioavailability of celastrol and triptolide, and their molecular targets in treating RA, which may be potential effective drugs. However, owing to the strong toxicity of T. wilfordii, novel approaches are required for the safe application of this TCM. These may include investigating new triptolide formulations or its combination with other drugs. Furthermore, defining early toxicity markers, investigating dosage ranges for different target organs and establishing a toxicity warning system are required.
Acknowledgements
Not applicable.
Funding
The present study was supported by The National Natural Science Foundation of China (grant no. U1804179), The Key Scientific and Technological Projects in Henan Province (grant no. 202102310190), The Henan Science and Technology Innovation Team, Investigation on Plant Resources in Dabie Mountains and The Study and Utilization of Active Components of Special Plants (grant no. 2017083), and The Nanhu Scholars Program for Young Scholars of Xinyang Normal University (grant no. 2018001).
Availability of data and materials
Not applicable.
Authors' contributions
XS conceived and designed the study, and wrote the manuscript. YZ and ED analyzed the data. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
ReferencesDeaneKDHolersVMThe natural history of rheumatoid arthritisClin Ther4112561269201910.1016/j.clinthera.2019.04.02831196652BurmesterGRPopeJENovel treatment strategies in rheumatoid arthritisLancet38923382348201710.1016/S0140-6736(17)31491-528612748RidgleyLAAndersonAEPrattAGWhat are the dominant cytokines in early rheumatoid arthritis?Curr Opin Rheumatol30207214201810.1097/BOR.000000000000047029206659NoackMMiossecPSelected cytokine pathways in rheumatoid arthritisSemin Immunopathol39365383201710.1007/s00281-017-0619-z28213794KangSTanakaTNarazakiMKishimotoTTargeting interleukin-6 signaling in clinicImmunity5010071023201910.1016/j.immuni.2019.03.02630995492SioutiEAndreakosEThe many facets of macrophages in rheumatoid arthritisBiochem Pharmacol165152169201910.1016/j.bcp.2019.03.02930910693YasudaKTakeuchiYHirotaKThe pathogenicity of Th17 cells in autoimmune diseasesSemin Immunopathol41283297201910.1007/s00281-019-00746-330891627ArleevskayaMILarionovaRVBrooksWHBettacchioliERenaudineauYToll-like receptors, infections, and rheumatoid arthritisClin Rev Allergy ImmunolMay292019(Epub ahead of print)6411459AlamJJantanIBukhariSNARheumatoid arthritis: Recent advances on its etiology, role of cytokines and pharmacotherapyBiomed Pharmacother92615633201710.1016/j.biopha.2017.05.05528582758SilvagniEDi BattistaMBonifacioAFZucchiDGovernatoGScirèCAOne year in review 2019: Novelties in the treatment of rheumatoid arthritisClin Exp Rheumatol37519534201931140394ConigliaroPTriggianesePDe MartinoEFontiGLChimentiMSSunziniFViolaACanofariCPerriconeRChallenges in the treatment of rheumatoid arthritisAutoimmun Rev18706713201910.1016/j.autrev.2019.05.00731059844CecchiIArias de la RosaIMenegattiERoccatelloDCollantes-EstevezELopez-PedreraCBarbarrojaNNeutrophils: Novel key players in rheumatoid arthritis. Current and future therapeutic targetsAutoimmun Rev1711381149201810.1016/j.autrev.2018.06.00630217550CheungTTMcInnesIBFuture therapeutic targets in rheumatoid arthritis?Semin Immunopathol39487500201710.1007/s00281-017-0623-3284517875486796HouWLiuBXuHTriptolide: Medicinal chemistry, chemical biology and clinical progressEur J Med Chem176378392201910.1016/j.ejmech.2019.05.03231121546DongYChenHGaoJLiuYLiJWangJBioactive ingredients in Chinese herbal medicines that target non-coding RNAs: Promising new choices for disease treatmentFront Pharmacol10515201910.3389/fphar.2019.00515311787216537929HuangYMaSWangYYanRWangSLiuNChenBChenJLiuLThe role of traditional Chinese herbal medicines and bioactive ingredients on ion channels: A brief review and prospectCNS Neurol Disord Drug Targets18257265201910.2174/187152731766618102616540030370864DongYWangPFengXLiBWangZLiHThe role of Chinese herbal medicines and bioactive ingredients targeting myocardial KCa and KATP Channels in cardiovascular diseasesCurr Pharm Des2310701076201710.2174/138161282366616112214175527875972LvHJiangLZhuMLiYLuoMJiangPTongSZhangHYanJThe genus Tripterygium: A phytochemistry and pharmacological reviewFitoterapia137104190201910.1016/j.fitote.2019.10419031163199VenkateshaSHDudicsSAstryBMoudgilKDControl of autoimmune inflammation by celastrol, a natural triterpenoidPathog Dis74piiftw059201610.1093/femspd/ftw059274054855985506TuLSuPZhangZGaoLWangJHuTZhouJZhangYZhaoYLiuYGenome of Tripterygium wilfordii and identification of cytochrome P450 involved in triptolide biosynthesisNat Commun11971202010.1038/s41467-020-14776-1320801757033203LinNSatoTItoATriptolide, a novel diterpenoid triepoxide from Tripterygium wilfordii Hook. f., suppresses the production and gene expression of pro-matrix metalloproteinases 1 and 3 and augments those of tissue inhibitors of metalloproteinases 1 and 2 in human synovial fibroblastsArthritis Rheum4421932200200110.1002/1529-0131(200109)44:9<2193::AID-ART373>3.0.CO;2-511592385AstryBVenkateshaSHLaurenceAChristensen-QuickAGarzino-DemoAFriemanMBO'SheaJJMoudgilKDCelastrol, a Chinese herbal compound, controls autoimmune inflammation by altering the balance of pathogenic and regulatory T cells in the target organClin Immunol157228238201510.1016/j.clim.2015.01.011256609874410084DiYMZhouZWGuang LiCZhouSFCurrent and future therapeutic targets of rheumatoid arthritisAntiinflamm Antiallergy Agents Med Chem1092120201110.2174/187152301110702009225182058LiuJZhouXChenXYZhongDFExcretion of [3H]triptolide and its metabolites in rats after oral administrationActa Pharmacol Sin35549554201410.1038/aps.2013.192246328434813726LiuQTriptolide and its expanding multiple pharmacological functionsInt Immunopharmacol11377383201110.1016/j.intimp.2011.01.01221255694LiXJJiangZZZhangLYTriptolide: Progress on research in pharmacodynamics and toxicologyJ Ethnopharmacol1556779201410.1016/j.jep.2014.06.00624933225ChengYChenGWangLKongJPanJXiYShenFHuangZTriptolide-induced mitochondrial damage dysregulates fatty acid metabolism in mouse sertoli cellsToxicol Lett292136150201810.1016/j.toxlet.2018.04.03529723566XiCPengSWuZZhouQZhouJToxicity of triptolide and the molecular mechanisms involvedBiomed Pharmacother90531541201710.1016/j.biopha.2017.04.00328402922SongJShiFZhangZZhuFXueJTanXZhangLJiaXFormulation and evaluation of celastrol-loaded liposomesMolecules1678807892201110.3390/molecules16097880221435486264578QiJLuYWuWAbsorption, disposition and pharmacokinetics of solid lipid nanoparticlesCurr Drug Metab13418428201210.2174/13892001280016652622443536PengXWangJSongHCuiDLiLLiJLinLZhouJLiuYOptimized preparation of celastrol-loaded polymeric nanomicelles using rotatable central composite design and response surface methodologyJ Biomed Nanotechnol8491499201210.1166/jbn.2012.139822764419CascaoRFonsecaJEMoitaLFCelastrol: A spectrum of treatment opportunities in chronic diseasesFront Med (Lausanne)469201710.3389/fmed.2017.00069286641585471334VenkateshaSHMoudgilKDCelastrol and its role in controlling chronic diseasesAdv Exp Med Biol928267289201610.1007/978-3-319-41334-1_1227671821ShenYFZhangXWangYCaoFFUzanGPengBZhangDHCelastrol targets IRAKs to block Toll-like receptor 4-mediated nuclear factor-κB activationJ Integr Med14203208201610.1016/S2095-4964(16)60257-127181127LeeJHKooTHYoonHJungHSJinHZLeeKHongYSLeeJJInhibition of NF-κB activation through targeting I kappa B kinase by celastrol, a quinone methide triterpenoidBiochem Pharmacol7213111321200610.1016/j.bcp.2006.08.01416984800MercurioFZhuHMurrayBWShevchenkoABennettBLLiJYoungDBBarbosaMMannMManningARaoAIKK-1 and IKK-2: Cytokine-activated IkappaB kinases essential for NF-kappaB activationScience278860866199710.1126/science.278.5339.8609346484SalminenALehtonenMPaimelaTKaarnirantaKCelastrol: Molecular targets of thunder God vineBiochem Biophys Res Commun394439442201010.1016/j.bbrc.2010.03.05020226165RigoglouSPapavassiliouAGThe NF-κB signalling pathway in osteoarthritisInt J Biochem Cell Biol4525802584201310.1016/j.biocel.2013.08.01824004831SamarpitaSKimJYRasoolMKKimKSInvestigation of toll-like receptor (TLR) 4 inhibitor TAK-242 as a new potential anti-rheumatoid arthritis drugArthritis Res Ther2216202010.1186/s13075-020-2097-2319737526979396BerridgeMJCalcium signalling remodelling and diseaseBiochem Soc Trans40297309201210.1042/BST2011076622435804ClaphamDECalcium signalingCell13110471058200710.1016/j.cell.2007.11.02818083096WongVKWQiuCXuSWLawBYKZengWWangHMichelangeliFDiasIRSRQuYQChanTWCa2+ signalling plays a role in celastrol-mediated suppression of synovial fibroblasts of rheumatoid arthritis patients and experimental arthritis in ratsBr J Pharmacol17629222944201910.1111/bph.14718311241396637043YooSAParkBHParkGSKohHSLeeMSRyuSHMiyazawaKParkSHChoCSKimWUCalcineurin is expressed and plays a critical role in inflammatory arthritisJ Immunol17726812690200610.4049/jimmunol.177.4.268116888030VillaloboAIshidaHVogelHJBerchtoldMWCalmodulin as a protein linker and a regulator of adaptor/scaffold proteinsBiochim Biophys Acta Mol Cell Res1865507521201810.1016/j.bbamcr.2017.12.00429247668XuZWuGWeiXChenXWangYChenLCelastrol induced DNA damage, cell cycle arrest, and apoptosis in human rheumatoid fibroblast-like synovial cellsAm J Chin Med41615628201310.1142/S0192415X1350043223711145FanXXLiNWuJLZhouYLHeJXLiuLLeungELCelastrol induces apoptosis in gefitinib-resistant non-small cell lung cancer cells via caspases-dependent pathways and Hsp90 client protein degradationMolecules1935083522201410.3390/molecules19033508246620706271537XuLMZhengYJWangYYangYCaoFFPengBXuXFAnHZZhengAXZhangDHCelastrol inhibits lung infiltration in differential syndrome animal models by reducing TNF-α and ICAM-1 levels while preserving differentiation in ATRA-induced acute promyelocytic leukemia cellsPLoS One9e105131201410.1371/journal.pone.0105131251161254130635FangZHeDYuBLiuFZuoJLiYLinQZhouXWangQHigh-throughput study of the effects of celastrol on activated fibroblast-like synoviocytes from patients with rheumatoid arthritisGenes (Basel)8piiE221201710.3390/genes809022128878153MukherjeeSHudaSSinha BabuSPToll-like receptor polymorphism in host immune response to infectious diseases: A reviewScand J Immunol90e12771201910.1111/sji.1277131054156ZhangXWangYGeHYGuYJCaoFFYangCXUzanGPengBZhangDHCelastrol reverses palmitic acid (PA)-caused TLR4-MD2 activation-dependent insulin resistance via disrupting MD2-related cellular binding to PAJ Cell Physiol23368146824201810.1002/jcp.2654729667734KhanMAKhuranaNAhmedRSUmarSMd G SarwarAHAlamQKamalMAAshrafGMChemokines: A potential therapeutic target to suppress autoimmune arthritisCurr Pharm Des2529372946201910.2174/138161282566619070920502831580792EustaceADMcNaughtonEFKingSKehoeOKunglAMatteyDNobbsAHWilliamsNMiddletonJSoluble syndecan-3 binds chemokines, reduces leukocyte migration in vitro and ameliorates disease severity in models of rheumatoid arthritisArthritis Res Ther21172201910.1186/s13075-019-1939-2313000046625118BahlasSDamiatiLDandachiNSaitHAlsefriMPushparajPNRapid immunoprofiling of cytokines, chemokines and growth factors in patients with active rheumatoid arthritis using luminex multiple analyte profiling technology for precision medicineClin Exp Rheumatol37112119201929998825LeeJYLeeBHKimNDLeeJYCelastrol blocks binding of lipopolysaccharides to a Toll-like receptor4/myeloid differentiation factor2 complex in a thiol-dependent mannerJ Ethnopharmacol172254260201510.1016/j.jep.2015.06.02826116162LiGLiuDZhangYQianYZhangHGuoSSunagawaMHisamitsuTLiuYCelastrol inhibits lipopolysaccharide-stimulated rheumatoid fibroblast-like synoviocyte invasion through suppression of TLR4/NF-κB-mediated matrix metalloproteinase-9 expressionPLoS One8e68905201310.1371/journal.pone.0068905238619493701694VenkateshaSHAstryBNanjundaiahSMYuHMoudgilKDSuppression of autoimmune arthritis by celastrus-derived celastrol through modulation of pro-inflammatory chemokinesBioorg Med Chem2052295234201210.1016/j.bmc.2012.06.050228541933449088LiGQLiuDZhangYQianYYZhuYDGuoSYSunagawaMHisamitsuTLiuYQAnti-invasive effects of celastrol in hypoxia-induced fibroblast-like synoviocyte through suppressing of HIF-1α/CXCR4 signaling pathwayInt Immunopharmacol1710281036201310.1016/j.intimp.2013.10.00624144813ParkBSungBYadavVRChaturvediMMAggarwalBBTriptolide, histone acetyltransferase inhibitor, suppresses growth and chemosensitizes leukemic cells through inhibition of gene expression regulated by TNF-TNFR1-TRADD-TRAF2-NIK-TAK1-IKK pathwayBiochem Pharmacol8211341144201110.1016/j.bcp.2011.07.062218204223191321YangYYeYQiuQXiaoYHuangMShiMLiangLYangXXuHTriptolide inhibits the migration and invasion of rheumatoid fibroblast-like synoviocytes by blocking the activation of the JNK MAPK pathwayInt Immunopharmacol41816201610.1016/j.intimp.2016.10.00527816728FanDHeXBianYGuoQZhengKZhaoYLuCLiuBXuXZhangGLuATriptolide modulates TREM-1 signal pathway to inhibit the inflammatory response in rheumatoid arthritisInt J Mol Sci17498201610.3390/ijms17040498270493844848954HoLJChangWLChenAChaoPLaiJHDifferential immunomodulatory effects by Tripterygium wilfordii Hook f-derived refined extract PG27 and its purified component PG490 (triptolide) in human peripheral blood T cells: Potential therapeutics for arthritis and possible mechanisms explaining in part Chinese herbal theory ‘Junn-Chenn-Zuou-SS’J Transl Med11294201310.1186/1479-5876-11-294242567694222270RulandJReturn to homeostasis: Downregulation of NF-κB responsesNat Immunol12709714201110.1038/ni.205521772279KanarekNBen-NeriahYRegulation of NF-κB by ubiquitination and degradation of the IκBsImmunol Rev2467794201210.1111/j.1600-065X.2012.01098.x22435548CriswellLAGene discovery in rheumatoid arthritis highlights the CD40/NF-kappaB signaling pathway in disease pathogenesisImmunol Rev2335561201010.1111/j.0105-2896.2009.00862.x20192992SchonthalerHBGuinea-ViniegraJWagnerEFTargeting inflammation by modulating the Jun/AP-1 pathwayAnn Rheum Dis70(Suppl 1)i109i112201110.1136/ard.2010.14053321339212XiaoCZhouJHeYJiaHZhaoLZhaoNLuAEffects of triptolide from radix Tripterygium wilfordii (Leigongteng) on cartilage cytokines and transcription factor NF-kappaB: A study on induced arthritis in ratsChin Med413200910.1186/1749-8546-4-13195702402709898BezerraMCCarvalhoJFProkopowitschASPereiraRMRANK, RANKL and osteoprotegerin in arthritic bone lossBraz J Med Biol Res38161170200510.1590/S0100-879X200500020000415785827HoTYSantoraKChenJCFrankshunALBagnellCAEffects of relaxin and estrogens on bone remodeling markers, receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG), in rat adjuvant-induced arthritisBone4813461353201110.1016/j.bone.2011.03.68421419242GeusensPThe role of RANK ligand/osteoprotegerin in rheumatoid arthritisTher Adv Musculoskelet Dis4225233201210.1177/1759720X12438080228599213403250LiuQChenTChenGShuXSunAMaPLuLCaoXTriptolide impairs dendritic cell migration by inhibiting CCR7 and COX-2 expression through PI3-K/Akt and NF-kappaB pathwaysMol Immunol4426862696200710.1016/j.molimm.2006.12.00317223196LiuCZhangYKongXZhuLPangJXuYChenWZhanHLuALinNTriptolide prevents bone destruction in the collagen-induced arthritis model of rheumatoid arthritis by targeting RANKL/RANK/OPG signal pathwayEvid Based Complement Alternat Med20136260382013235731393610373BrinkerAMMaJLipskyPERaskinIMedicinal chemistry and pharmacology of genus Tripterygium (Celastraceae)Phytochemistry68732766200710.1016/j.phytochem.2006.11.02917250858XueMMcKelveyKShenKMinhasNMarchLParkSYJacksonCJEndogenous MMP-9 and not MMP-2 promotes rheumatoid synovial fibroblast survival, inflammation and cartilage degradationRheumatology (Oxford)5322702279201410.1093/rheumatology/keu25424982240GengYBlancoFJCornelissonMLotzMRegulation of cyclooxygenase-2 expression in normal human articular chondrocytesJ Immunol15579680119957608556MaekawaKYoshikawaNDuJNishidaSKitasatoHOkamotoKTanakaHMizushimaYKawaiSThe molecular mechanism of inhibition of interleukin-1beta-induced cyclooxygenase-2 expression in human synovial cells by Tripterygium wilfordii Hook F extractInflamm Res48575581199910.1007/s00011005050610598013FlowerRJThe development of COX2 inhibitorsNat Rev Drug Discov2179191200310.1038/nrd103412612644GengYFangMWangJYuHHuZYewDTChenWTriptolide down-regulates COX-2 expression and PGE2 release by suppressing the activity of NF-κB and MAP kinases in lipopolysaccharide-treated PC12 cellsPhytother Res26337343201221717513MaJDeyMYangHPoulevAPoulevaRDornRLipskyPEKennellyEJRaskinIAnti-inflammatory and immunosuppressive compounds from Tripterygium wilfordiiPhytochemistry6811721178200710.1016/j.phytochem.2007.02.02117399748LiaciniASylvesterJZafarullahMTriptolide suppresses proinflammatory cytokine-induced matrix metalloproteinase and aggrecanase-1 gene expression in chondrocytesBiochem Biophys Res Commun327320327200510.1016/j.bbrc.2004.12.02015629465LinNLiuCXiaoCJiaHImadaKWuHItoATriptolide, a diterpenoid triepoxide, suppresses inflammation and cartilage destruction in collagen-induced arthritis miceBiochem Pharmacol73136146200710.1016/j.bcp.2006.08.02717097618ZhangYMaXTriptolide inhibits IL-12/IL-23 expression in APCs via CCAAT/enhancer-binding protein alphaJ Immunol18438663877201010.4049/jimmunol.0903417201947242965075JiangJWangNGuanZHoushanLVProgrammed cell death 5 factor enhances triptolide-induced fibroblast-like synoviocyte apoptosis of rheumatoid arthritisArtif Cells Blood Substit Immobil Biotechnol383842201010.3109/1073119090349576920047520TasneemSLiuBLiBChoudharyMIWangWMolecular pharmacology of inflammation: Medicinal plants as anti-inflammatory agentsPharmacol Res139126140201910.1016/j.phrs.2018.11.00130395947ZiaeiSHalabyRImmunosuppressive, anti-inflammatory and anti-cancer properties of triptolide: A mini reviewAvicenna J Phytomed61491642016272228284877967KongXZhangYLiuCGuoWLiXSuXWanHSunYLinNAnti-angiogenic effect of triptolide in rheumatoid arthritis by targeting angiogenic cascadePLoS One8e77513201310.1371/journal.pone.0077513242048513810371ZhangWLiFGaoWTripterygium wilfordii inhibiting angiogenesis for rheumatoid arthritis treatmentJ Natl Med Assoc109142148201710.1016/j.jnma.2017.02.00728599756RamgolamVAngSGLaiYHLohCSYapHKTraditional Chinese medicines as immunosuppressive agentsAnn Acad Med Singapore291116200010748958CameronMGagnierJJChrubasikSHerbal therapy for treating rheumatoid arthritisCochrane Database Syst RevCD002948201121328257LipskyPETaoXLA potential new treatment for rheumatoid arthritis: Thunder god vineSemin Arthritis Rheum26713723199710.1016/S0049-0172(97)80040-69144848LvQWZhangWShiQZhengWJLiXChenHWuQJJiangWLLiHBGongLComparison of Tripterygium wilfordii Hook F with methotrexate in the treatment of active rheumatoid arthritis (TRIFRA): A randomised, controlled clinical trialAnn Rheum Dis7410781086201510.1136/annrheumdis-2013-20480724733191TaoXYoungerJFanFZWangBLipskyPEBenefit of an extract of Tripterygium Wilfordii Hook F in patients with rheumatoid arthritis: A double-blind, placebo-controlled studyArthritis Rheum4617351743200210.1002/art.1041112124856ZhaoQLiuFChengYXiaoXRHuDDTangYMBaoWMYangJHJiangTHuJPCelastrol protects from cholestatic liver injury through modulation of SIRT1-FXR signalingMol Cell Proteomics18520533201910.1074/mcp.RA118.000817306171576398203ZhangYJiangZXueMZhangSWangYZhangLToxicogenomic analysis of the gene expression changes in rat liver after a 28-day oral Tripterygium wilfordii multiglycoside exposureJ Ethnopharmacol141170177201210.1016/j.jep.2012.02.01522366672FreagMSSalehWMAbdallahOYSelf-assembled phospholipid-based phytosomal nanocarriers as promising platforms for improving oral bioavailability of the anticancer celastrolInt J Pharm5351826201810.1016/j.ijpharm.2017.10.05329102699XuHLiuBTriptolide-targeted delivery methodsEur J Med Chem164342351201910.1016/j.ejmech.2018.12.05830605832
Molecular structures of celastrol and triptolide.
Schematic of the molecular targets of celastrol and triptolide in the treatment of RA. Arrows indicate activating effects; horizontal lines indicate inhibitory effects. Celastrol targets numerous signaling pathways associated with RA, including those involving NF-κB, endoplasmic reticulum Ca2+-ATPase, MD2, TLR4, pro-inflammatory chemokines, DNA damage, cell cycle arrest and apoptosis. Triptolide inhibits NF-κB, RANKL/RANK/OPG signaling, COX-2, matrix metalloproteases and cytokines. AP-1, activating protein-1; C/EBPα, CCAAT/enhancer binding protein-α; cdc, cell division cycle protein; COX-2, cyclooxygenase-2; ER, endoplasmic reticulum; IκB, inhibitor of NF-κB; IKK, IκB kinase; IL, interleukin; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MD2, myeloid differentiation factor 2; MEK, MAPK/ERK kinase; MMP, matrix metalloproteinase; OPG, osteoprotegerin; p, phosphorylated; PARP, poly (ADP-ribose) polymerase; PDCD5, programmed cell death protein 5; PGE2, prostaglandin E2; RA, rheumatoid arthritis; RANK, receptor activator of NF-κB; RANKL, RANK ligand; TLR4, Toll-like receptor 4; VEGF, vascular endothelial growth factor.
Molecular targets, signaling pathways and potential biological effects of celastrol and triptolide in the treatment of rheumatoid arthritis.
A, Celastrol
Molecular targets
Signaling pathways
Potential biological effects
(Refs.)
IκB kinase
NF-κB
NF-κB function is regulated via rapid degradation of its endogenous inhibitory molecule IκB
(32–39)
Ca2+-ATPase
Ca2+ signaling
Alter Ca2+ signaling pathways to downregulate inflammatory response genes
(40–44)
Cyclins with CDKs
DNA damage, cell cycle arrest and apoptosis
Inhibit cell cycle progression by blocking the association of cyclins with cyclin-dependent kinases
(33,45–47)
MD2 or TLR4
Interaction between LPS and the TLR4/MD2 complex
Block the most upstream step in TLR4 activation, maybe targets MD2.
(48–51)
Pro-inflammatory chemokines
Reduces expression levels of RANTES, MCP-1, MIP-1α and GRO/KC, as well as the pro-inflammatory cytokines tumor necrosis factor-α and IL-1β
Inhibit leukocyte migration into joints
(4,5,51–55)
B, Triptolide
Molecular targets
Signaling pathways
Potential biological effects
(Refs.)
IκB kinase
NF-κB
Rapid degradation of its endogenous inhibitory molecule IκB
(56–64)
RANKL
RANKL/RANK/OPG signaling
Reduce the number of osteoclasts in areas of bone destruction by downregulating RANKL and RANK, and upregulating OPG
(65–68)
COX-2 and matrix metalloproteinases
NF-κB
Downregulate COX-2 and PGE2, and alleviate LPS-induced inflammation
(69–79)
Cytokines
Cytokines pathway
Inhibit cytokines
80–83
VEGF
Infiltration of the synovial membrane
Inhibit several downstream effects of IL1-β, including cell adhesion of human FLS, upregulate several angiogenic activators and activate MAPK signaling
(5,84–86)
MD2, myeloid differentiation factor 2; TLR4, Toll-like receptor 4; RANK, receptor activator of NF-κB; RANKL, RANK ligand; OPG, osteoprotegerin; COX-2, cyclooxygenase-2; IL, interleukin; IκB, inhibitor of NF-κB; RANTES, regulated upon activation, normally T cell expressed and secreted chemokine protein; VEGF, vascular endothelial growth factor; MAPK, mitogen-activated protein kinase; PGE2, prostaglandin E2; GRO/KC, growth-related oncogene/keratinocyte chemoattractant; MCP-1, monocyte chemotactic protein-1; MIP-1α, macrophage inflammatory protein-3α. LPS, lipopolysaccharide.