‘‘A BRIEF REVIEW OF NATURAL PLANT

EXTRACTSAND COMPOUNDS FOR RHEUMATOID

ARTHRITISTHERAPY"

A Project topic Submitted In Partial Fulfillment Of

TheRequirementForDegreeofBachelorofPharmacyIn

Faculty of Science and

TechnologyRashtrasantTukdojiMaharajNagpurU

niversity,

Nagpur, Maharashtra,
IndiaSubmittedBy
Mr.KAPIL.B.KHANDAVE
B.Pharm VII

SemGuided By
MS.POONAMDHARPURE(Asst.Prof.)
Taywade College of
PharmacyMahadulaKorad
iNagpur

ShriSacchidanandSahikshanSanstha’s

TAYWADECOLLEGEOFPHARMACY 1
Koradi,Tah:Kamptee, 441111,Dist.Nagpur,Maharashtra, India2024-2025

2
 ShriSacchidanandShikshanSanstha’s
TAYWADECOLLEGE OFPHARMACY,KORADI
RashtrasantTukdojiMaharajNagpurUniversity,Nagpur2024-2025

Dr. C. A.
DoifodeDirector
Shri Sacchidanand Shikshan

Sanstha’sTaywade College Of

Pharmacy,Koradi,Nagpur

CERTIFICATE
This is to certify that the project entitled,“A BRIEF REVIEW OF
NATURALPLANTEXTRACTSANDCOMPOUNDSFORRHEUMATOIDARTHRITISTHE
RAPY
” was done by Mr. KAPIL .B.KHANDAVE of B. PharmFinal Year
(VIISem),ShriSacchidanandShikshan Sanstha’sTaywade College Of Pharmacy, Koradi,
R.T.M.NagpurUniversity, Nagpur under the guidance of Dr. C. A. Doifode sir in partial
fulfillment oftherequirement for the degree of Bachelor of Pharmacy in the Faculty Of
Medicine, R.T.M.NagpurUniversity, Nagpur forscrutiny.

Place :
KoradiDate:

Director

3
 ShriSacchidanandShikshanSanstha’s
TAYWADECOLLEGE OFPHARMACY,KORADI
RashtrasantTukdojiMaharajNagpurUniversity,Nagpur2024-2025

Dr.GEETALODHI
Principal
Shri Sacchidanand Shikshan

Sanstha’sTaywade College Of

Pharmacy,Koradi,Nagpur

CERTIFICATE
This is to certify that the project entitled,“A BRIEF REVIEW OF
NATURALPLANTEXTRACTSANDCOMPOUNDSFORRHEUMATOIDARTHRITISTHE
RAPY
” was done by Mr. KAPIL .B.KHANDAVE of B. PharmFinal Year
(VIISem),ShriSacchidanandShikshan Sanstha’sTaywade College Of Pharmacy, Koradi,
R.T.M.NagpurUniversity, Nagpur under the guidance of Dr. GEETA LODHI mam in
partial fulfillment ofthe requirement for the degree of Bachelor of Pharmacy in the Faculty
Of Medicine, R.T.M.NagpurUniversity, Nagpur forscrutiny.

Place:Koradi
Date: PRINCIPAL

4
 ShriSacchidanandShikshanSanstha’s
TAYWADECOLLEGEOFPHARMACY, KORADI
Rashtrasant Tukdoji Maharaj Nagpur University,
Nagpur2022-2023
MS.POONAMDHARPURE
Asst.Professor
Shri Sacchidanand Shikshan
Sanstha’sTaywade College Of
Pharmacy,Koradi,Nagpur
CERTIFICATE
This is to certify that the project entitled, ‘‘A BRIEF REVIEW OF
NATURALPLANTEXTRACTSANDCOMPOUNDSFORRHEUMATOIDARTHRITISTHE
RAPY
”wasdonebyMr.KAPIL.B.KHANDAVEB.PharmFinalYear(VIISem),ShriSacchidanand
Shikshan Sanstha’s Taywade College Of Pharmacy, Koradi, R. T .M. NagpurUniversity,
Nagpur under guidance of Ms. POONAM DHARPURE in partial fulfillment
oftherequirementforthedegreeofBachelorOfPharmacyintheFacultyOfMedicine,
R.T.M.NagpurUniversity,Nagpur.TheProjectis nowreadyforscrutiny.

Place:Koradi Ms.POONAMDHARPURE

Date: Asst. Prof

5
 DECLARATION

I here declare that the project work entitled. ‘‘A BRIEF REVIEW OF
NATURALPLANTEXTRACTSANDCOMPOUNDSFORRHEUMATOIDARTHRITISTH
ERAPY
” is based on Literature ReviewConducted. This has not been submitted for the award of
anyDiplomaorDegreeofthisoranyotherUniversity.

Thisprojectis readyforevaluation.

Place:Koradi

DATE:_
Mr.KAPIL.B.KHANDAVE

6
 Acknowledgement

I express my deep sense of gratitude to Dr. B. B. Taywade, Chairman

ShriSacchidanand Shikshan Sanstha’s Taywade College Of Pharmacy, Koradi
forProvidingexcellent infrastructuralfacilityforundertakingthisproject.

I am grateful to Dr.C.A. Doifode, Director and Dr. Geeta Lodhi, Principal,

Shri Sacchidanand ShikshanSanstha’s Taywade College of Pharmacy, Koradi, Nagpur for
providingnecessary facilitiesrequiredforthis projectwork.

It gives me deep seated pleasure to express my sense of gratitude tomy guide

MS.POONAMDHARPUREmamAsst.ProfessorSacchidanand Shikshan Sanstha’s
TaywadeCollege Of Pharmacy, Koradi, Nagpur for herexcellent guidance.

Iamalsothankfultollibrarianoftheinstitutionandtostoredepartmentfo
rprovidingmefacilitiesforreviewwork.

Iwould like to thanks all those who have helped me directly

orindirectlytocompletethisworksuccessfully.

Place:Koradi Mr.KapilBKhandave

Date:-

7
Sr.no. INDEX Pageno.

08
1. Abstract

2. Introduction 09

3. NaturalPlantExtract 10

4. CinnamomumcassiaPresl 10

5. LigusticumchuanxiongHort 12

6. AconitumkusnezoffiiReichb. 13

7. Tripterygiumwilfordii HookF 14

8. CurcumaeLongaeRhizoma 16

9. PaeonialactifloraPallas 18

10. AstragalusmembranaceusBunge 20

11. AchyranthesbidentataBlume 21

12. TreatmentofRAwith MixedHerbalCompound 22

13. Conclusions 23

14. Reference 24

8
Abstract:

Naturalplantextractsandcompounds (NPECs), which originate from

herbsorplants,havebeenusedinthe clinical treatment of rheumatoid
arthritis(RA)formanyyears.Overthe years, many scientists have carried out
aseriesofstudiesonthe treatment of RA by NPEC. They found a
highquantityofactive NPECs with broad application prospects. In view
ofvariouscomplexfunctionsoftheseNPECs,exploringtheirpotential asmedicines
for RA treatment will be beneficial for RA patients. Thus, to helpadvance the
development of high-quality NPECs for RA, we herein aimed
toreviewtheresearchprogressofNPECs in the treatment of RA in
recentyears.Ourfindingsshowedthat, from the pharmacological
perspective,naturalplantextractsormixedherbalcompoundseffectivelyregulateth
eimmunesystemtoalleviateRAbyinhibitingpro-inflammatorycytokines.Further,
individualized medication can be applied according to
eachpatient’sphysicalcondition. However, the pathogenesis of RA and
itsimmunemechanismhasnotbeenfullyunderstoodand requires furtherstudies.

Keywords:naturalplant;rheumatoidarthritis;therapy

9
1. Introduction

Rheumatoid arthritis (RA) is a chronic systemic inflammatory autoimmune disease of

thejoint [1]. Systemic autoimmune disease affects many non-joint organs, suchas the
skin,eyes,lungs, heart,kidneys,salivaryglands, nervetissue, bone marrow,
andbloodvessels[2]. However, RA mainly attacks the joints. This common immunological
disease hinders theactivity and function of the joints, affecting the health and quality of life
of afflicted
patients.Accordingtoepidemiologicalstatistics,theincidenceofRAisapproximately1%oftheworl
dwide population; that is, nearly 700 million people worldwide have RA, and more
than80%ofthepatientsarewomen[3].
Inflammatory cytokines play an essential role in the occurrence and development of RA.
Forexample, TNF-α is a pro-inflammatory factor that causes the activation and aggregation
ofthecellinflammasome.Thisinducesthereleaseofotherinflammatorymediatorsandaggravates
theinflammatory response [4].IL-2 issecreted by activatedTh1 cells, whichhelps
lymphocyteand T cellproliferationas wellas inducinglocal inflammatory response[5]. IL-13 is
produced by Th2 cells and promotes eosinophil production [6]. Recent studieshave shown
that antigen-activated CD4+ T cells, monocytes, macrophages, and synovialfibroblasts
canproduce many inflammatory factors,including TNF-α, IL-1,and IL-6, leadingto the
secretion of metalloproteinases by chondrocytes, fibroblasts, and osteoclasts
[4].Subsequently,theerosionofboneandcartilagecausesthegradualdestructionandfunctional
lossofthejoints[7].
RA patients are required to change their lifestyle [8]. Medication for RA mainly involves non-
steroidal anti-inflammatory drugs, anti-rheumatism drugs, and glucocorticoid drugs [9].
Inrecentyears,preclinicaltrialshaveprovedthatnaturalplantextractsandcompounds(NPECs)can
significantlyalleviateRA[10].ConsideringthatNPECmedicinesforthetreatment of RA present
various complex functions, exploring the potential of NPECs asmedicines for RA treatment
will be beneficial for RA patients. Therefore, we herein
reviewtherecentresearchprogressofNPECsasatreatmentofRA.Thisarticlewillhelpadvancethed
evelopment ofhigh-qualityNPECsforR

10
2. NaturalPlantExtract(NPE)

2.1. CinnamomumcassiaPresl

CinnamomumcassiaPresl,alsoknownascassiaorcinnamon,isatropicalaromaticevergreen tree
of the Lauraceae family, commonly used in traditional Oriental medicine.More than 160
chemicals have been identified from C. cassia. The main constituents areterpenoids,
phenylpropanoids, and glycosides [11]. The main components of C. cassia have awide range
of pharmacological effects, including anti-platelet aggregation, antithrombotic,pro-
angiogenesis, vasodilating, and microcirculation-improving effects [12]. In addition, C.cassia
has antitumor, anti-inflammatory, analgesic, antibacterial, antiviral, cardiovascular-
protective,cytoprotective,neuroprotective,immunomodulatory,andanti-
tyrosinaseactivities[11,12].
Terpenoids, phenylpropanoids, and glycosides in C. cassia have immunomodulatory
abilityandcanreducethelevelsofinflammatorymediators,suchasinterleukin(IL)-
1β,transforming growth factor-α (TGF-α), and prostaglandin E2 (PGE2) in the synovial fluid
[13].Westernblottinganalysisrevealedthattheexpressionofcyclooxygenase(COX)-
2andinducible nitric oxide synthase (iNOS) was significantly reduced by C. cassia, indicating
thesuppressionofimmuneresponsesand alleviation ofjointinflammation[13].

Fig1:-Cinnamomum cassiaPreslandit'sbark

11
Inarecentstudy,cinnamaldehyde(CA)inC.cassiaextractwasshowntoexertanti-inflammatory
effects against RA. The therapeutic effects of CA were revealed in in vitroexperiments using
activated macrophages (Raw246.7 cells) and in a rat model of adjuvantarthritis (AA) in vivo
[14]. CA is an α,β-unsaturated aromatic aldehyde that can be used as
aflavoringagent(Figure1).Itistheprincipalflavorcomponentofcinnamonoil.Theresearchers
concluded that CA is a potential therapeutic compound that can inhibit RAprogression by
suppressing IL-1β by modulating the succinate/HIF-1α axis and inhibitingNLRP3 [14].
Moreover, CA significantly reduced synovial inflammation in AA rats and in
theperipheralbloodmononuclearcellsofRApatientsbyinhibitingtheexpressionofpro-
inflammatory cytokines (IL-1β, TNF-α, and IL-6) [15,16]. The binding of CA on the residues
ofTNF-αandIL-6wasdescribed usingamoleculardockingexperiment [16].

Fig2:-Chemicalstructureofcinnamaldehyde.

Further studies have found that CA inhibited the activity of HIF-1α by inhibiting the accumulation
ofsuccinate in the cytoplasm [15]. To the best of our knowledge, the reduction of HIF-1α
nuclearlocationslowsdowntheproductionofIL-
1βthroughinhibitionoftheNLRP3assemblyofinflammasome [14]. In addition, CA inhibited the
expression of the sucinate receptor GPR91, therebyinhibitingthe activation ofHIF-1α

12
2.2. LigusticumchuanxiongHort

Ligusticum chuanxiong Hort (Umbelliferae), also called Chuanxiong Rhizoma, is a

medicinalherb that has been extensively applied to treat various diseases. The main
components of L.chuanxiong are ligustilide, 3-butyrolactone, and cypressene [17]. It also
contains ferulic acid,tetra-
methylpyrazine(ligustrazineorchuanxiongzine),palmiticacid,carotene,andβ-
sitosterol.Manybiomedicalandclinicalstudieshaveshowntheantioxidant,neuroprotective,anti-
fibrosis,antinociceptive,anti-
inflammatory,andantineoplasticactivitiesofL.chuanxiong[18,19,20].

Fig3:-TheChuanxiongplantandthechemicalstructuresofitsmajorextract constituents.

Chuan-XianMuetal.(2014)showedthatligustrazinecansignificantlyinhibitswellinginarat model
of collagen-induced arthritis (CIA) [21]. Serum IL-1 and IL-6 levels were decreased,whereas
serum IL-2 levels were increased by treatment with ligustrazine [21]. The
resultssuggestedthatligustrazineinhibitedRAbyelevatingthelevelsofanti-
inflammatorycytokines and maintaining the balance of the inflammatory cytokine network
[21]. Moreimportantly,treatmentusingacombinationofleflunomide,adisease-
modifyingantirheumaticdrug(DMARD)forRA,andligustrazineattenuatedboneerosioninRApati
ents[22].

13
2.3. AconitumkusnezoffiiReichb.

The dry root of Aconitum kusnezoffii Reichb. (caowu) has been used to treat RA and
jointpain for many years owing to its anti-inflammatory properties. Pharmacological studies
haveshown that diterpenoid alkaloids, including aconitine, mesaconitine, hypaconitine,
neoline,talatizamine beiwutine, and deoxy-aconitine, are responsible for the main bioactive
effectsofA. kusnezoffii[23].

Recent research showed that benzoylaconitine (BAC) from the root of A. kusnezoffii
haspotentanti-inflammatoryeffects(itinhibitstheproductionofIL-6andIL-8inhumansynovial
cells) [24,25]. Encapsulated mPEG-PLGA NPs (NP/BAC) with improved bioavailabilityprovide
a promising RA therapy strategy, exhibiting high cytocompatibility for
activatedmacrophages.NP/BACsignificantlyinhibitedthesecretionofthepro-
inflammatorycytokinesTNF-αandIL-1β(60–70%)byinhibitingtheNF-
κBsignalingpathway[25,26].NP/BAC also attenuated ear (69.8%) and paw (87.1%) swelling in
an in vivo CIA model[25,26].

PharmacologicalresearchersbelievethatAconitiKusnezoffiiRadix(caowu)exertsaninhibitory
effect on the immune response and an antioxidant effect. Caowu reduces
painfulobstructionsyndrome,relievespainandiswidelyusedinRAtreatmenttoalleviatearthralgi
a andpain [27].

14
2.4. Tripterygium wilfordiiHookF

TripterygiumwilfordiiHookF(TWHF)hasalonghistoryofuseforamelioratingRAsymptoms.TWHF
hasvariouspharmacologicalactivities,suchasantitumor,anti-
inflammatory,andimmunesystem-regulatory activities[28].

Fig5:-Tripterygiumwilfordii HookF

Thechemicalcompositionof TWHFiscomplex,andmany
biologicallyactivesubstanceshavebeenisolated.Theidentifiedcompoundsincludesesquiterpen
es,diterpenes(triptolide, tripdiolide, and triptonide), triterpenes (celastrol, pristimerin, and
wilforlide A),lignans, glycosides,andalkaloids
[28,29,30].Triptolideandcelastrolareconsideredtherepresentative active components of
TWHF, with higher percentages of content and clinicalapplicationprospects.
In a recent clinical follow-up study by Zhou et al., patients with RA were treated with
TWHFfor two consecutive years [31]. Clinical indexes and radiographic data were collected
for 2years and compared using intent-to-treat and per-protocol analyses. A total of 109
patientscompleted the test during the two-year therapy period. The research concluded
that TWHFmonotherapywasnotinferiortomethotrexatemonotherapyinpatients with RA[31].

15
Triptolide treatment inhibited serum inflammatory cytokine levels in rats with CIA-
inducedRA [32]. TWHF significantly inhibited increases in IL-1β and TNF-α levels and
significantlydecreased the levels of the pro-inflammatory cytokines IL-17 and IL-8 [33].
Moreover, theexpression of vascular endothelial growth factor (VEGF) and toll-like receptor
2 (Tie2) in ratsynovial cells was downregulated by triptolide [34]. The expression of
angiogenin-1 (Ang-1)and Ang-2 was also markedly decreased by triptolide in CIA-induced RA
rats [34]. The resultsshowed that triptolide improved the severity of CIA-induced RA by
inhibiting the RANKL-
mediatedERK/AKTsignalingpathwayinratsynovialcells[34].Triptolideregulatestheproportionof
CD4+andCD8+populationsandsuppressesTandBlymphocytes[35].Furthermore, triptolide
attenuates the expression of TCR receptors in rats with CIA [36]. Inaddition, celastrol
treatment decreased Th17 population, but increased Treg population inarthritic joints [37].
These results suggested that triptolide and celastrol can suppress theimmunological
functionofRArat models.

Figure6:-Schematicsummaryoftriptolidepotentialmedicalapplications.

16
2.5. CurcumaeLongaeRhizoma

Curcumae Longae Rhizoma (CLR) is a traditional herbal medicine that has been used
formanyyears,andmainlycontainsvolatileoilandphenolicsubstances[38].Severalcomponents
have been identified in the volatile oils of CLR, mostly terpenoids,
curcumone,andgingerene.ThemainphenoliccomponentofCLRiscurcumin[38,39].CLRalsocont
ainsa new turmeric ketone, 3-sitosterol, 3-sitosterol-3-O-carotene, and turmeric
polysaccharides[39,40].PharmacologicalstudieshaveshownthatCLRprotectstheliverandexerts
choleretic,antibacterial,anti-inflammatory,antitumor,bloodlipid-lowering,andanti-
pathogenicmicroorganismeffects[41].Italsoprotectsthedigestivesystem,enhancesimmunefun
ction,and improves coronarybloodflowintheheart[40,41,42,43,44,45].
β-Elemene is a natural compound extracted from CLR. Elemenes, which include α-, β-, γ-
,and δ-elemene, are structural isomers of each other and are classified as
sesquiterpenes(Figure 7). β-Elemene significantly inhibited the viability and promoted the
apoptosis ofhumanRAfibroblast-likesynoviocytesinaconcentration-dependentmanner[46].β-
Elemenesignificantlydecreasedmitochondrialmembranepotentialandcytochromecaccumulati
on in the cytosol, as well as increased caspase-9 and caspase-3 activities [47]. Allof these
activities are related to apoptosis signaling, and this phenomenon was reversed
bypretreatment with the p38 inhibitor SB203580 or the reactive oxygen species (ROS)
inhibitorN-acetyl-l-cysteine[47].β-
Elemeneeffectivelyinducesmitochondrialapoptosisinfibroblast-like synoviocytes, and this
effect is mediated via induction of ROS formation andp38 mitogen-activated protein kinase
(MAPK) activation [48]. This result suggested that β-elemene has
therapeuticpotentialagainstRA[48].

Fig7: Chemicalstructureofβ-elemene.

17
Curcumin incorporates a seven-carbon linker and three major functional groups: an α,β-
unsaturatedβ-diketonemoietyandanaromaticO-methoxy-
phenolicgroup(Figure9).CurcuminfromCLRcanreduceCompleteFreund’sAdjuvant(CFA)-
inducedglialcellactivation and inflammatory mediator levels IL-1β, monocyte chemotactic
protein-1 (MCP-1),andmonocyteinflammatoryproteininthespinalcord-1(MIP-
1α)][49,50].Curcuminalso reduces the production of IL-1β, TNF-α, MCP-1, and MIP-1α in
lipopolysaccharide (LPS)-
stimulatedastrocytesandmicrogliacells[49,51].Curcuminalleviatesarthritispainbyinhibiting
the activation of glia and the production of inflammatory mediators in the spinalcord in a rat
model of mono-arthritis and thus has a potential for treating arthritis pain [51].RA patients
who received either a low (250 mg) or high (500 mg) dose of curcumin (twicedaily for 90
days) showed significantly improved clinical symptoms via the American Collegeof
Rheumatology response, visual analog scale, C-reactive protein, Disease Activity Score
28,erythrocyte sedimentation rate, and rheumatoid factor values, compared with those
whoreceived placebo, without any side effects [52]. The weight of the immune organ of rat
RAmodelsindicatedtheimmunologicalinhibitioneffectsofcurcumin[53].Thesefindingssuggestt
hatcurcumintreatmentattenuatestheclinicalsymptomsofRApatientsandthereforehasatherap
euticpotentialagainstRA[52,54].

Fig9:Chemicalstructuresofcurcumin.

18
2.6. Paeonia lactifloraPallas

Paeonia lactiflora Pallas is a traditional Oriental natural plant medicine that has been
usedfor thousands of years in China for its analgesic, anti-inflammatory, and immune
system-improving efficacies. The therapeutic effects of P. lactiflora have been recognized by
theChinese Experience Medicine book, “Treatise on Cold Pathogenic” and “Synopsis of
GoldenChamber” [55,56]. Total glycoside of paeony (TGP) is extracted from the root of P.
lactiflora.TGP contains beneficial components, such as paeoniflorin, hydroxy-paeoniflorin,
paeonin,albiflorin,andbenzoyl-
paeoniflorin(Figure10)[57].ThefirstclinicaltrialofTGPwasconducted in 1993with 450 RA
patients [58]. Therapeutic response was achieved in 71.7%of TGP-treated patients.Following
the clinical trialof TGP for RA patients,a phase III trialwas conducted with 1016 patients [59].
Based on these clinical trials, TGP was approved bythe State Food and Drug Administration
of China to enter the market as a disease-modifyingdrug for RA in 1998 [58]. Furthermore, a
combined treatment with TGP and methotrexateshowed a favorable effect on RA, with less
side-effect [57]. TGP-treated RA patients
showeddecreasederythrocytesedimentationrateandC-
reactiveproteinlevel,alongwithadecrease inthepopulationofIFN-γ- andIL-17-producingcells
[60,61].

Fig10:-Structuresoftheprincipal constituentsintotalglycosideofpaeony(TGP).

19
Paeoniflorin, a monoterpene glucoside, is a major active component of TGP,
constitutingover or equal to 40% of the total components. Paeoniflorin has been reported to
possessextensiveanti-
inflammatoryandimmunoregulatoryeffects[57,62].Paeoniflorincandiminish pain, joint
swelling, synovial hypertrophy, bone erosion, and cartilage degradationin experimental
arthritis [63,64]. It has been reported that paeoniflorin alleviated AA in ratsby inhibiting DC
maturation and activation [65]. Paeoniflorin also regulates immune functionby affecting
splenic T cells in rats with AA [66]. Clinical trials of paeoniflorin in the treatmentofRA have
beenconductedinmany hospitals inChina. Forexample,paeoniflorin wasshown to be a safer
option to substitute DMARDs for long-term RA treatment [67]. As aresult, paeoniflorinwas
approved for RA treatmentand marketing in 1998 by the ChinaFood and Drug
Administration [68,69]. Clinical data have shown that paeoniflorin
effectivelyrelievesthesymptoms and signs of RA
withoutcausingsignificantadverseeffects[58].

Inonestudy,92childrenwithjuvenileidiopathicarthritishospitalizedatZhengzhouChildren’s
Hospital from March 2017 to March 2019 were treated with paeoniflorin. Theywere
randomly divided into treatment and control groups (n = 46). The levels of IL-6, IL-1,and
TNF-α in both groups were significantly lower after treatment than before treatment.The
levels of IL-6, IL-1, and TNF-α in the treatment group were significantly lower than thosein
the control group [70]. Paeoniflorin is also recommended for the treatment of
otherautoimmune diseases, such as systemic lupus erythematosus, psoriasis, diabetes
mellitus,diabeticnephropathy,ankylosing spondylitis,andimmuneliverinjury [71,72,73,74].

20
2.7. AstragalusmembranaceusBunge

RadixAstragali(AstragalusmembranaceusBunge)isoneofthemostfamousOrientaltraditional
medicines that has been used for many years [75]. It is sold worldwide as
dietarysupplementsintheformoftea,beverages,soup,trailmix,andcapsule[75,76].RadixAstraga
lihasbeenreportedtoexerthepatoprotective,antioxidative,antiviral,anti-
hypertensive,andimmunostimulatoryproperties[77,78].Ithasalsobeenreportedtostrengthens
uperficialresistance,drainageaction,andnewtissuegrowth[79,80].Totalflavonoidsofastragalus
(TFA)arethemainactivecomponentsisolatedfromA.membranaceus[77].Jinxiaetal.(2018)show
edtheimmunomodulatoryandanti-inflammatory mechanisms of TFA [81]. The mRNA
expression levels of TNF-α, IL-6, IL-1β, IL-10, iNOS, and COX-2 were examined by RT-PCR in
LPS-stimulated RAW 264.7 macrophagesafter treatment with TFA. The protein expression
levels of iNOS, COX-2, MAPK, and nuclearfactor(NF-kB)inLPS-
stimulatedRAW264.7macrophagesweremeasuredbywesternblotting. The results showed
that TFA significantly decreased TNF-α, IL-1β, IL-6, iNOS, andCOX-2 mRNA levels and
increased IL-10 mRNA levels in LPS-stimulated RAW 264.7 cells in adose-dependent manner
[81]. Further studies revealed that TFA significantly inhibited theprotein expression of iNOS
and COX-2 as well as the phosphorylation of MAPKs (p38 andJNK) and NF-κB (IKKα/β, IκBα,
NF-κB p65) in LPS-stimulated RAW 264.7 cells [81].
TheseresultssuggestthatTFAexertsimmunomodulatoryandanti-
inflammatoryeffectsbyregulatingtheMAPKand NF-κB signalingpathwaysinRAW
264.7macrophages.

TFA significantly inhibited serum TNF-α, IL-1β, PGE2, and the receptor activator of
nuclearfactor-κB ligand (RANKL) production [82]. Serum osteo-protegerin (OPG) production
andOPG/RANKLratioinratswereinducedbyFreund’scompleteadjuvant(FCA)[82].Histopatholog
ical examination indicated that TFA significantly attenuated inflammatory
cellinfiltration,synovialhyperplasia,pannusformation,andbone/cartilagedamage[82].Inadditi
on,theimmunohistochemicalassayshowedthatTFAinhibitedNF-
κBp65expressioninthesynovialtissuesofrats induced by FCA [82].

21
2.8. AchyranthesbidentataBlume

Achyranthes bidentata Blume (ABB) is a species of flowering plant in the amaranth

family.AmaranthaceaeplantsaretraditionalOrientalmedicinesthatcontainpolysaccharides,trit
erpenesaponins,sterones,andotheractiveingredients.ThemainpharmacologicaleffectsofABBa
reantitumor,antiviral,anti-
inflammatory,andanalgesic[83].ABBalsoexertsprotectiveeffectonrabbitkneejointcartilageand
caninhibitcytokineIL-1βexpression,increaseTGF-
β1expression,andalleviatecartilagedegeneration[84].ABBtreatmentsignificantlyreducedpaws
welling,inflammatorycellproliferation,andbonedegradation in CIA model rats [85]. The levels
of fibrinogen, procollagen, protein disulfideisomerase A3, and apolipoprotein A-I were
elevated in inflamed synovial tissue; however,the RA phenotypesweresignificantly reduced
by ABB treatment [85].Inaddition, α-1-antiprotease and manganese superoxide dismutase
levels were increased in ABB-treatedsynovialtissues[85].

22
3. TreatmentofRAwithMixedHerbalCompound
In recent years, researchers have confirmed that mixed herbal compound decoction
cancontrol RA by strengthening or inhibiting the production of anti-inflammatory factors,
andregulatingtheimmune andendocrinesystems.

3.1. WutouDecoction
Wutou decoctionoriginates from “The Synopsis of the Golden Chamber”andis composedof
ephedra, peony, astragalus, licorice, and Sichuan aconite. It has the functions of
dispellingcold and dampness, removing numbness, and relieving pain in knee osteoarthritis
[86].
AstudyfoundthatWutoudecoctioncaninhibitsynovialinflammationinkneeosteoarthritisbyregu
latingtheTLR4/NF-κBsignalingpathway[86].Inthestudy,usingtherandomnumber table
method, Wutou decoction was shown to effectively inhibit the expression ofiNOS, TNF-α,
and IL-6 [86]. Moreover, real-time PCR results showed that Wutou decoctioninhibited TLR4,
MyD88, TRAF6, and NF-κB p65 mRNA expression [86]. Western blottingresults were
consistent with real-time PCR results, in which Wutou decoction inhibited
TLR4,MyD88,TRAF6,andNF-κB p65 proteinexpression[86].

3.2. GuiZhiShaoYaoZhiMuDecoction
Tian et al. confirmed that GuiZhi ShaoYao ZhiMu Decoction (GSZD) regulates synovial
cells[87]. GSZD, which also originates from “The Synopsis of the Golden Chamber,” is
composedofRamulusCinnamomi,P.lactifloraroot,RadixGlycyrrhizaePreparata,Ephedrasp.,An
emarrhenaasphodeloidesBungeroot,Atractylodesmacrocephala,andZingiberofficinale. In CIA
model rats (AA models induced by acetic acid-soluble type II collagen andFreund’s complete
adjuvant), GSZD increased Fas antigen expression and decreased Bcl-
2andp53proteinexpression[87].GSZDacceleratedtheclearanceofsynovialcellsandsignificantlyr
educedsynovialproliferationpathologyintheCIAmodel[87].GSZDattenuates RA by reversing
the inflammation–immune system imbalance [88]. Combinationtreatment with GSZD and
methotrexate was more efficacious and safer than methotrexatealone for treating RA [89].
This conclusion was based on 14 randomizedcontrolled trialswith 1224 RA patients [89].
Moreover, it has been reported that the effectiveness and safetyofGSZD
intreatingRAareequalor superiortothoseofWestern RA drugs[90].

23
4. Conclusions

Specific research and clinical data are available on the use of natural plant extracts or
mixedherbal compounds (NPEMHCs) as a treatment of RA. From the pharmacological point
ofview, NPEMHCs effectively regulate the immune system to alleviate RA by inhibiting
mainlypro-inflammatory cytokines. In addition, NPEMHCs attenuate the potential side
effects ofcurrently available drugs. Further, individualized medication can be applied
according to
thephysicalconditionofeachindividualpatients.However,thusfar,thepathogenesisofRAand its
immune mechanism has not been fully understood. Therefore, the treatment of RAby
NPEMHC needs more basic research support, and a clinical study involving a large
groupofpatientswill help advancethedevelopmentofNPEMHCs asdrugsfor RAtreatment.

24
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