Abstract
Triptolide (TP), a major extract of the herb Tripterygium wilfordii Hook F (TWHF), has been shown to exert potent pharmacological effects, especially an immunosuppressive effect in the treatment of rheumatoid arthritis (RA). However, its multiorgan toxicity prevents it from being widely used in clinical practice. Recently, several attempts are being performed to reduce TP toxicity. In this review, recent progress in the use of TP for RA, including its pharmacological effects and toxicity, is summarized. Meanwhile, strategies relying on chemical structural modifications, innovative delivery systems, and drug combinations to alleviate the disadvantages of TP are also reviewed. Furthermore, we also discuss the challenges and perspectives in their clinical translation.
Highlights
Rheumatoid arthritis (RA) is an immune-related disease that generally gives rise to continuous joint destruction, decreased expectancy of life and work ability, considerable disability, and even raised mortality [1]
Our study indicated that TP could significantly inhibit Triggering receptor expressed on myeloid cells (TREM)-1 expressions in collagen-induced arthritis (CIA) rats, as well as decrease the production of TREM-1 in LPS-stimulated U937 cells, which demonstrated that TP could modulate the TREM-1 signaling pathway to inhibit the inflammatory response in RA [5]
Xu et al reported that TP could enhance the expression of IL-10 in regulatory T cells (Tregs) and further suppress osteoclast formation and bone resorption [6], and in vivo data revealed that the level of IL-10 was increased in the TP treatment group compared with the CIA group [13]
Summary
Rheumatoid arthritis (RA) is an immune-related disease that generally gives rise to continuous joint destruction, decreased expectancy of life and work ability, considerable disability, and even raised mortality [1]. Disease-modifying anti-rheumatic drugs (DMARDs), such as conventional synthetic DMARDs (csDMARDs) and biological DMARDs (bDMARDs), are currently the most commonly used drugs for treating RA. These drugs can not cure RA completely and often bring about severe side effects, such as infection and malignancies. BDMARDs have low cost-effectiveness and bring a huge financial burden to the patients. As the main active ingredient in Tripterygium glycosides, Triptolide (TP, a dierpene triepoxide in chemical structure, see Figure 1) has been considered as a promising anti-RA drug [4]. TP can significantly alleviate the severity of collagen-induced arthritis (CIA) in rats, with a potent anti-inflammatory effect and the ability to prevent bone destruction [5,6]. ThMe aIPn:ti-mRfaAcctroporp-rκohBpalegigreatniedins; fOloaPfmGT:mPosathetoaprvyreotepbgreeoertine;inaTt;GtFrM:ibtrCuanPtes:fdomrmtooinnigtosgcryiomtwemthcufhanectmoosro.uapttrreascstaivnet apnrdoteainnt;ipRroAlNifeTrEaSti:ve effreecgt.uMlatIePd: mupaocnroapchtiavgaetioinflnaomrmmaaltTorcyelplreoxtperines;sMedCaPn:dmsoencroectyedte; cIPh:eimntoearftetraocnt-ainndt upcreodtepinro; tReiAnN; ITL:ES: reginutleartleedukuipn;oVnEaGctFiv: avtaisocnulnaor remndaol tThecleialll egxrpowretshsefdacatonrd; VseEcGreFtRe:dv; aIsPc:uilnatreerfnedrotnh-einliadlugcreodwpthroftaecitno;rIL: intreercleputkoirn; ; AVnEgG: Fa:nvgaiospcuoileatrine;nTdNotFh:eltiuaml goronwetchrofsaicstofarc; tVorE;GCFCRR::vCas-Cculcahremenodkointheerleiaclepgtroorw; tMhMfaPc:tor recmepatorirx; Amnegt:alalnopgiroopteoinieatsine; TCNOFX::tucmycolroonxeycgroensiassfea;ctPoGr;: CpCroRs:tCag-Clancdhienm; oNkOin:e nreitcreipc torx;idMeM; TPR: mEMat:rix mettraigllgoeprirnogteirneacesep;toCrsOXex:pcryecslsoeodxyognenmayseel;oiPdGc: epllrso-1s;taTgLlaRn:dtionl;l-lNikOe : rneciterpictoor;xiBdMe;DT:RbEoMne: tmriigngeerrailng recdeepntsoirtsy;exRpArNesKse: dreocnepmtoyrelaocitdivcaetollrs-1o;f TnLuRcl:etaorll-flaickteorr-eκcBe;pRtoNr;ABKML:D:rebcoenpetomr iancetirvaaltdorenosfityn;uRclAeaNr K: recfeapcttoorr-κaBctilivgaatnodr;oOf PnGu:cloesaterofpacrototerg-κeBri;nR; TNGAFK: tLra: nresfcoerpmtoinrgacgtriovwattohrfaocftnoru.clear factor-κB ligand; OPG: osteoprotegerin; TGF: transforming growth factor
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