‘‘A BRIEF REVIEW OF NATURAL PLANT EXTRACTS

AND COMPOUNDS FOR RHEUMATOID ARTHRITIS

THERAPY "

A Project topic Submitted In Partial Fulfillment Of The

Requirement For Degree of Bachelor of Pharmacy In

Faculty of Science and Technology

Rashtrasant Tukdoji Maharaj Nagpur University,

Nagpur, Maharashtra, India

Submitted By
Mr.KAPIL .B. KHANDAVE
B.Pharm VII Sem

Guided By
MS. POONAM DHARPURE (Asst. Prof.)
Taywade College of Pharmacy
Mahadula Koradi Nagpur

Shri Sacchidanand Sahikshan Sanstha‟s

1
 Shri Sacchidanand Shikshan Sanstha‟s
TAYWADE COLLEGE OF PHARMACY, KORADI
Rashtrasant Tukdoji Maharaj Nagpur University, Nagpur 2024-2025

Dr. GEETA LODHI

Principal
Shri Sacchidanand Shikshan Sanstha’s

Taywade College Of Pharmacy,

Koradi, Nagpur

CERTIFICATE
This is to certify that the project entitled, “A BRIEF REVIEW OF NATURAL
PLANT EXTRACTS AND COMPOUNDS FOR RHEUMATOID ARTHRITIS THERAPY
” was done by Mr. KAPIL .B. KHANDAVE of B. Pharm Final Year (VIISem), Shri
Sacchidanand Shikshan Sanstha‟s Taywade College Of Pharmacy, Koradi, R.T.M. Nagpur
University, Nagpur under the guidance of MS. POONAM DHARPURE mam in partial
fulfillment of the requirement for the degree of Bachelor of Pharmacy in the Faculty Of
Medicine, R.T.M. Nagpur University , Nagpur for scrutiny.

Place : Koradi
Date :

PRINCIPAL

2
3
 TAYWADE COLLEGE OF PHARMACY
Koradi, Tah: Kamptee, 441111, Dist. Nagpur, Maharashtra, India 2024-2025

Shri Sacchidanand Shikshan Sanstha‟s

TAYWADE COLLEGE OF PHARMACY, KORADI
Rashtrasant Tukdoji Maharaj Nagpur University, Nagpur 2024-2025

Dr. GEETA LODHI

Principal
Shri Sacchidanand Shikshan Sanstha’s

Taywade College Of Pharmacy,

Koradi, Nagpur

CERTIFICATE
This is to certify that the project entitled, “A BRIEF REVIEW OF NATURAL
PLANT EXTRACTS AND COMPOUNDS FOR RHEUMATOID ARTHRITIS THERAPY
” was done by Mr. KAPIL .B. KHANDAVE of B. Pharm Final Year (VIISem), Shri
Sacchidanand Shikshan Sanstha‟s Taywade College Of Pharmacy, Koradi, R.T.M. Nagpur
University, Nagpur under the guidance of MS. POONAM DHARPURE mam in partial
fulfillment of the requirement for the degree of Bachelor of Pharmacy in the Faculty Of
Medicine, R.T.M. Nagpur University , Nagpur for scrutiny.

Place : Koradi
Date :

4
 PRINCIPAL

Shri Sacchidanand Shikshan Sanstha‟s

TAYWADE COLLEGE OF PHARMACY, KORADI
Rashtrasant Tukdoji Maharaj Nagpur University, Nagpur
2022-2023
MS. POONAM DHARPURE
Asso. Professor
Shri Sacchidanand Shikshan Sanstha’s
Taywade College Of Pharmacy,
Koradi, Nagpur
CERTIFICATE
This is to certify that the project entitled, „„A BRIEF REVIEW OF NATURAL
PLANT EXTRACTS AND COMPOUNDS FOR RHEUMATOID ARTHRITIS THERAPY
” was done by Mr. KAPIL .B. KHANDAVE B.Pharm Final Year (VII Sem), Shri
Sacchidanand Shikshan Sanstha‟s Taywade College Of Pharmacy, Koradi, R. T .M. Nagpur
University, Nagpur under my guidance in partial fulfillment of the requirement for the degree
of Bachelor Of Pharmacy in the Faculty Of Medicine, R.T.M. Nagpur University, Nagpur.
The Project is now ready for scrutiny.

Place : Koradi DR. GEETA LODHI

Date : Principle

5
 DECLARATION

I here declare that the project work entitled. „„A BRIEF REVIEW OF NATURAL
PLANT EXTRACTS AND COMPOUNDS FOR RHEUMATOID ARTHRITIS THERAPY
” is based on Literature Review Conducted. This has not been submitted for the award of any
Diploma or Degree of this or any other University.

This project is ready for evaluation.

Place : Koradi

DATE:_
Mr. KAPIL .B. KHANDAVE

6
 Acknowledgement

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

Sacchidanand Shikshan Sanstha‟s Taywade College Of Pharmacy, Koradi for Providing
excellent infrastructural facility for undertaking this project.

I am grateful to Dr. Geeta Lodhi, Principal, Shri Sacchidanand Shikshan

Sanstha‟s Taywade College of Pharmacy, Koradi, Nagpur for providing necessary facilities
required for this project work.

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

DR.GEETA LODHI And MS. POONAM DHARPURE mam Asso. Professor
Sacchidanand Shikshan Sanstha‟s Taywade College Of Pharmacy, Koradi, Nagpur for her
excellent guidance.

I am also thankful to l librarian of the institution and to store

department for providing me facilities for review work.

I would like to thanks all those who have helped me directly or

indirectly to complete this work successfully.

Place : Koradi: Mr. KAPIL .B.

KHANDAVE

Date :-

7
Sr.no. INDEX Page no.

07
1. Abstract

2. Introduction 08

3. Natural Plant Extract 09

4. Treatment of RA with Mixed Herbal Compound 20

5. Conclusions 21

6. Reference 22

8
Abstract :

Natural plant extracts and compounds (NPECs), which originate from herbs
or plants, have been used in the clinical treatment of rheumatoid arthritis
(RA) for many years. Over the years, many scientists have carried out a
series of studies on the treatment of RA by NPEC. They found a high
quantity of active NPECs with broad application prospects. In view of
various complex functions of these NPECs, exploring their potential as
medicines for RA treatment will be beneficial for RA patients. Thus, to help
advance the development of high-quality NPECs for RA, we herein aimed to
review the research progress of NPECs in the treatment of RA in recent
years. Our findings showed that, from the pharmacological perspective,
natural plant extracts or mixed herbal compounds effectively regulate the
immune system to alleviate RA by inhibiting pro-inflammatory cytokines.
Further, individualized medication can be applied according to each
patient’s physical condition. However, the pathogenesis of RA and its
immune mechanism has not been fully understood and requires further
studies.

Keywords: natural plant; rheumatoid arthritis; therapy

9
1. Introduction

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

joint [1]. Systemic autoimmune disease affects many non-joint organs, such as the skin,
eyes, lungs, heart, kidneys, salivary glands, nerve tissue, bone marrow, and blood vessels
[2]. However, RA mainly attacks the joints. This common immunological disease hinders the
activity and function of the joints, affecting the health and quality of life of afflicted patients.
According to epidemiological statistics, the incidence of RA is approximately 1% of the
worldwide population; that is, nearly 700 million people worldwide have RA, and more than
80% of the patients are women [3].
Inflammatory cytokines play an essential role in the occurrence and development of RA. For
example, TNF-α is a pro-inflammatory factor that causes the activation and aggregation of
the cell inflammasome. This induces the release of other inflammatory mediators and
aggravates the inflammatory response [4]. IL-2 is secreted by activated Th1 cells, which
helps lymphocyte and T cell proliferation as well as inducing local inflammatory response
[5]. IL-13 is produced by Th2 cells and promotes eosinophil production [6]. Recent studies
have shown that antigen-activated CD4+ T cells, monocytes, macrophages, and synovial
fibroblasts can produce many inflammatory factors, including TNF-α, IL-1, and IL-6, leading
to the secretion of metalloproteinases by chondrocytes, fibroblasts, and osteoclasts [4].
Subsequently, the erosion of bone and cartilage causes the gradual destruction and
functional loss of the joints [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]. In
recent years, preclinical trials have proved that natural plant extracts and compounds
(NPECs) can significantly alleviate RA [10]. Considering that NPEC medicines for the
treatment of RA present various complex functions, exploring the potential of NPECs as
medicines for RA treatment will be beneficial for RA patients. Therefore, we herein review
the recent research progress of NPECs as a treatment of RA. This article will help advance
the development of high-quality NPECs for R

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2. Natural Plant Extract (NPE)

2.1. Cinnamomum cassia Presl

Cinnamomum cassia Presl, also known as cassia or cinnamon, is a tropical aromatic

evergreen tree of the Lauraceae family, commonly used in traditional Oriental medicine.
More than 160 chemicals have been identified from C. cassia. The main constituents are
terpenoids, phenylpropanoids, and glycosides [11]. The main components of C. cassia have a
wide 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, and anti-tyrosinase
activities [11,12].
Terpenoids, phenylpropanoids, and glycosides in C. cassia have immunomodulatory ability
and can reduce the levels of inflammatory mediators, such as interleukin (IL)-1β,
transforming growth factor-α (TGF-α), and prostaglandin E2 (PGE2) in the synovial fluid [13].
Western blotting analysis revealed that the expression of cyclooxygenase (COX)-2 and
inducible nitric oxide synthase (iNOS) was significantly reduced by C. cassia, indicating the
suppression of immune responses and alleviation of joint inflammation [13].

Fig 1:- Cinnamomum cassia Presl and it's bark

11
In a recent study, cinnamaldehyde (CA) in C. cassia extract was shown to exert anti-
inflammatory effects against RA. The therapeutic effects of CA were revealed in in vitro
experiments using activated macrophages (Raw246.7 cells) and in a rat model of adjuvant
arthritis (AA) in vivo [14]. CA is an α,β-unsaturated aromatic aldehyde that can be used as a
flavoring agent (Figure 1). It is the principal flavor component of cinnamon oil. The
researchers concluded that CA is a potential therapeutic compound that can inhibit RA
progression by suppressing IL-1β by modulating the succinate/HIF-1α axis and inhibiting
NLRP3 [14]. Moreover, CA significantly reduced synovial inflammation in AA rats and in the
peripheral blood mononuclear cells of RA patients by inhibiting the expression of pro-
inflammatory cytokines (IL-1β, TNF-α, and IL-6) [15,16]. The binding of CA on the residues of
TNF-α and IL-6 was described using a molecular docking experiment [16].

Fig 2:- Chemical structure of cinnamaldehyde.

Further studies have found that CA inhibited the activity of HIF-1α by inhibiting the accumulation of
succinate in the cytoplasm [15]. To the best of our knowledge, the reduction of HIF-1α nuclear
location slows down the production of IL-1β through inhibition of the NLRP3 assembly of
inflammasome [14]. In addition, CA inhibited the expression of the sucinate receptor GPR91, thereby
inhibiting the activation of HIF-1α

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2.2. Ligusticum chuanxiong Hort

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

herb 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 (ligustrazine or chuanxiongzine), palmitic acid, carotene, and β-
sitosterol. Many biomedical and clinical studies have shown the antioxidant,
neuroprotective, anti-fibrosis, antinociceptive, anti-inflammatory, and antineoplastic

activities of L. chuanxiong [18,19,20].

Fig 3:- The Chuanxiong plant and the chemical structures of its major extract constituents.

Chuan-Xian Mu et al. (2014) showed that ligustrazine can significantly inhibit swelling in a
rat 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 results
suggested that ligustrazine inhibited RA by elevating the levels of anti-inflammatory
cytokines and maintaining the balance of the inflammatory cytokine network [21]. More
importantly, treatment using a combination of leflunomide, a disease-modifying
antirheumatic drug (DMARD) for RA, and ligustrazine attenuated bone erosion in RA
patients [22].

13
2.3. Aconitum kusnezoffii Reichb.

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

Recent research showed that benzoylaconitine (BAC) from the root of A. kusnezoffii has
potent anti-inflammatory effects (it inhibits the production of IL-6 and IL-8 in human
synovial cells) [24,25]. Encapsulated mPEG-PLGA NPs (NP/BAC) with improved bioavailability
provide a promising RA therapy strategy, exhibiting high cytocompatibility for activated
macrophages. NP/BAC significantly inhibited the secretion of the pro-inflammatory
cytokines TNF-α and IL-1β (60–70%) by inhibiting the NF-κB signaling pathway [25,26].
NP/BAC also attenuated ear (69.8%) and paw (87.1%) swelling in an in vivo CIA model
[25,26].

Pharmacological researchers believe that Aconiti Kusnezoffii Radix (caowu) exerts an

inhibitory effect on the immune response and an antioxidant effect. Caowu reduces painful
obstruction syndrome, relieves pain and is widely used in RA treatment to alleviate
arthralgia and pain [27].

14
2.4. Tripterygium wilfordii Hook F

Tripterygium wilfordii Hook F (TWHF) has a long history of use for ameliorating RA
symptoms. TWHF has various pharmacological activities, such as antitumor, anti-
inflammatory, and immune system-regulatory activities [28].

Fig 5:- Tripterygium wilfordii Hook F

The chemical composition of TWHF is complex, and many biologically active substances
have been isolated. The identified compounds include sesquiterpenes, diterpenes
(triptolide, tripdiolide, and triptonide), triterpenes (celastrol, pristimerin, and wilforlide A),
lignans, glycosides, and alkaloids [28,29,30]. Triptolide and celastrol are considered the
representative active components of TWHF, with higher percentages of content and clinical
application prospects.
In a recent clinical follow-up study by Zhou et al., patients with RA were treated with TWHF
for two consecutive years [31]. Clinical indexes and radiographic data were collected for 2
years and compared using intent-to-treat and per-protocol analyses. A total of 109 patients
completed the test during the two-year therapy period. The research concluded that TWHF
monotherapy was not inferior to methotrexate monotherapy in patients with RA [31].

15
Triptolide treatment inhibited serum inflammatory cytokine levels in rats with CIA-induced
RA [32]. TWHF significantly inhibited increases in IL-1β and TNF-α levels and significantly
decreased the levels of the pro-inflammatory cytokines IL-17 and IL-8 [33]. Moreover, the
expression of vascular endothelial growth factor (VEGF) and toll-like receptor 2 (Tie2) in rat
synovial 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 results
showed that triptolide improved the severity of CIA-induced RA by inhibiting the RANKL-
mediated ERK/AKT signaling pathway in rat synovial cells [34]. Triptolide regulates the
proportion of CD4+ and CD8+ populations and suppresses T and B lymphocytes [35].
Furthermore, triptolide attenuates the expression of TCR receptors in rats with CIA [36]. In
addition, celastrol treatment decreased Th17 population, but increased Treg population in
arthritic joints [37]. These results suggested that triptolide and celastrol can suppress the
immunological function of RA rat models.

Figure 6:- Schematic summary of triptolide potential medical applications.

16
2.5. Curcumae Longae Rhizoma

Curcumae Longae Rhizoma (CLR) is a traditional herbal medicine that has been used for
many years, and mainly contains volatile oil and phenolic substances [38]. Several
components have been identified in the volatile oils of CLR, mostly terpenoids, curcumone,
and gingerene. The main phenolic component of CLR is curcumin [38,39]. CLR also contains
a new turmeric ketone, 3-sitosterol, 3-sitosterol-3-O-carotene, and turmeric polysaccharides
[39,40]. Pharmacological studies have shown that CLR protects the liver and exerts
choleretic, antibacterial, anti-inflammatory, antitumor, blood lipid-lowering, and anti-
pathogenic microorganism effects [41]. It also protects the digestive system, enhances
immune function, and improves coronary blood flow in the heart [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 of
human RA fibroblast-like synoviocytes in a concentration-dependent manner [46]. β-
Elemene significantly decreased mitochondrial membrane potential and cytochrome c
accumulation in the cytosol, as well as increased caspase-9 and caspase-3 activities [47]. All
of these activities are related to apoptosis signaling, and this phenomenon was reversed by
pretreatment with the p38 inhibitor SB203580 or the reactive oxygen species (ROS) inhibitor
N-acetyl-l-cysteine [47]. β-Elemene effectively induces mitochondrial apoptosis in
fibroblast-like synoviocytes, and this effect is mediated via induction of ROS formation and
p38 mitogen-activated protein kinase (MAPK) activation [48]. This result suggested that β-
elemene has therapeutic potential against RA [48].

Fig 7 : Chemical structure of β-elemene.

17
Curcumin incorporates a seven-carbon linker and three major functional groups: an α,β-
unsaturated β-diketone moiety and an aromatic O-methoxy-phenolic group (Figure 9).
Curcumin from CLR can reduce Complete Freund’s Adjuvant (CFA)-induced glial cell
activation and inflammatory mediator levels IL-1β, monocyte chemotactic protein-1 (MCP-
1), and monocyte inflammatory protein in the spinal cord-1 (MIP-1α)] [49,50]. Curcumin
also reduces the production of IL-1β, TNF-α, MCP-1, and MIP-1α in lipopolysaccharide (LPS)-
stimulated astrocytes and microglia cells [49,51]. Curcumin alleviates arthritis pain by
inhibiting the activation of glia and the production of inflammatory mediators in the spinal
cord 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 (twice
daily for 90 days) showed significantly improved clinical symptoms via the American College
of Rheumatology response, visual analog scale, C-reactive protein, Disease Activity Score 28,
erythrocyte sedimentation rate, and rheumatoid factor values, compared with those who
received placebo, without any side effects [52]. The weight of the immune organ of rat RA
models indicated the immunological inhibition effects of curcumin [53]. These findings
suggest that curcumin treatment attenuates the clinical symptoms of RA patients and
therefore has a therapeutic potential against RA [52,54].

Fig 9 : Chemical structures of curcumin.

18
2.6. Paeonia lactiflora Pallas

Paeonia lactiflora Pallas is a traditional Oriental natural plant medicine that has been used
for 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 the
Chinese Experience Medicine book, ―Treatise on Cold Pathogenic‖ and ―Synopsis of Golden
Chamber‖ [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, and benzoyl-paeoniflorin (Figure 10) [57]. The first clinical trial of TGP was
conducted in 1993 with 450 RA patients [58]. Therapeutic response was achieved in 71.7%
of TGP-treated patients. Following the clinical trial of TGP for RA patients, a phase III trial
was conducted with 1016 patients [59]. Based on these clinical trials, TGP was approved by
the State Food and Drug Administration of China to enter the market as a disease-modifying
drug for RA in 1998 [58]. Furthermore, a combined treatment with TGP and methotrexate
showed a favorable effect on RA, with less side-effect [57]. TGP-treated RA patients showed
decreased erythrocyte sedimentation rate and C-reactive protein level, along with a
decrease in the population of IFN-γ- and IL-17-producing cells [60,61].

Fig 10 :- Structures of the principal constituents in total glycoside of paeony (TGP).

19
Paeoniflorin, a monoterpene glucoside, is a major active component of TGP, constituting
over or equal to 40% of the total components. Paeoniflorin has been reported to possess
extensive anti-inflammatory and immunoregulatory effects [57,62]. Paeoniflorin can
diminish pain, joint swelling, synovial hypertrophy, bone erosion, and cartilage degradation
in experimental arthritis [63,64]. It has been reported that paeoniflorin alleviated AA in rats
by inhibiting DC maturation and activation [65]. Paeoniflorin also regulates immune function
by affecting splenic T cells in rats with AA [66]. Clinical trials of paeoniflorin in the treatment
of RA have been conducted in many hospitals in China. For example, paeoniflorin was
shown to be a safer option to substitute DMARDs for long-term RA treatment [67]. As a
result, paeoniflorin was approved for RA treatment and marketing in 1998 by the China
Food and Drug Administration [68,69]. Clinical data have shown that paeoniflorin effectively
relieves the symptoms and signs of RA without causing significant adverse effects [58].

In one study, 92 children with juvenile idiopathic arthritis hospitalized at Zhengzhou

Children’s Hospital from March 2017 to March 2019 were treated with paeoniflorin. They
were 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 those
in the control group [70]. Paeoniflorin is also recommended for the treatment of other
autoimmune diseases, such as systemic lupus erythematosus, psoriasis, diabetes mellitus,
diabetic nephropathy, ankylosing spondylitis, and immune liver injury [71,72,73,74].

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2.7. Astragalus membranaceus Bunge

Radix Astragali (Astragalus membranaceus Bunge) is one of the most famous Oriental
traditional medicines that has been used for many years [75]. It is sold worldwide as dietary
supplements in the form of tea, beverages, soup, trail mix, and capsule [75,76]. Radix
Astragali has been reported to exert hepatoprotective, antioxidative, antiviral, anti-
hypertensive, and immunostimulatory properties [77,78]. It has also been reported to
strengthen superficial resistance, drainage action, and new tissue growth [79,80]. Total
flavonoids of astragalus (TFA) are the main active components isolated from A.
membranaceus [77]. Jinxia et al. (2018) showed the immunomodulatory and anti-
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 macrophages
after treatment with TFA. The protein expression levels of iNOS, COX-2, MAPK, and nuclear
factor (NF-kB) in LPS-stimulated RAW 264.7 macrophages were measured by western
blotting. The results showed that TFA significantly decreased TNF-α, IL-1β, IL-6, iNOS, and
COX-2 mRNA levels and increased IL-10 mRNA levels in LPS-stimulated RAW 264.7 cells in a
dose-dependent manner [81]. Further studies revealed that TFA significantly inhibited the
protein expression of iNOS and COX-2 as well as the phosphorylation of MAPKs (p38 and
JNK) and NF-κB (IKKα/β, IκBα, NF-κB p65) in LPS-stimulated RAW 264.7 cells [81]. These
results suggest that TFA exerts immunomodulatory and anti-inflammatory effects by
regulating the MAPK and NF-κB signaling pathways in RAW 264.7 macrophages.

TFA significantly inhibited serum TNF-α, IL-1β, PGE2, and the receptor activator of nuclear
factor-κB ligand (RANKL) production [82]. Serum osteo-protegerin (OPG) production and
OPG/RANKL ratio in rats were induced by Freund’s complete adjuvant (FCA) [82].
Histopathological examination indicated that TFA significantly attenuated inflammatory cell
infiltration, synovial hyperplasia, pannus formation, and bone/cartilage damage [82]. In
addition, the immunohistochemical assay showed that TFA inhibited NF-κB p65 expression
in the synovial tissues of rats induced by FCA [82].

21
2.8. Achyranthes bidentata Blume

Achyranthes bidentata Blume (ABB) is a species of flowering plant in the amaranth family.
Amaranthaceae plants are traditional Oriental medicines that contain polysaccharides,
triterpene saponins, sterones, and other active ingredients. The main pharmacological
effects of ABB are antitumor, antiviral, anti-inflammatory, and analgesic [83]. ABB also
exerts protective effect on rabbit knee joint cartilage and can inhibit cytokine IL-1β
expression, increase TGF-β1 expression, and alleviate cartilage degeneration [84]. ABB
treatment significantly reduced paw swelling, inflammatory cell proliferation, and bone
degradation in CIA model rats [85]. The levels of fibrinogen, procollagen, protein disulfide
isomerase A3, and apolipoprotein A-I were elevated in inflamed synovial tissue; however,
the RA phenotypes were significantly reduced by ABB treatment [85]. In addition, α-1-
antiprotease and manganese superoxide dismutase levels were increased in ABB-treated
synovial tissues [85].

22
3. Treatment of RA with Mixed Herbal Compound
In recent years, researchers have confirmed that mixed herbal compound decoction can
control RA by strengthening or inhibiting the production of anti-inflammatory factors, and
regulating the immune and endocrine systems.

3.1. Wutou Decoction

Wutou decoction originates from ―The Synopsis of the Golden Chamber‖ and is composed
of ephedra, peony, astragalus, licorice, and Sichuan aconite. It has the functions of dispelling
cold and dampness, removing numbness, and relieving pain in knee osteoarthritis [86]. A
study found that Wutou decoction can inhibit synovial inflammation in knee osteoarthritis
by regulating the TLR4/NF-κB signaling pathway [86]. In the study, using the random
number table method, Wutou decoction was shown to effectively inhibit the expression of
iNOS, TNF-α, and IL-6 [86]. Moreover, real-time PCR results showed that Wutou decoction
inhibited TLR4, MyD88, TRAF6, and NF-κB p65 mRNA expression [86]. Western blotting
results were consistent with real-time PCR results, in which Wutou decoction inhibited TLR4,
MyD88, TRAF6, and NF-κB p65 protein expression [86].

3.2. GuiZhi ShaoYao ZhiMu Decoction

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 composed
of Ramulus Cinnamomi, P. lactiflora root, Radix Glycyrrhizae Preparata, Ephedra sp.,
Anemarrhena asphodeloides Bunge root, Atractylodes macrocephala, and Zingiber
officinale. In CIA model rats (AA models induced by acetic acid-soluble type II collagen and
Freund’s complete adjuvant), GSZD increased Fas antigen expression and decreased Bcl-2
and p53 protein expression [87]. GSZD accelerated the clearance of synovial cells and
significantly reduced synovial proliferation pathology in the CIA model [87]. GSZD
attenuates RA by reversing the inflammation–immune system imbalance [88]. Combination
treatment with GSZD and methotrexate was more efficacious and safer than methotrexate
alone for treating RA [89]. This conclusion was based on 14 randomized controlled trials
with 1224 RA patients [89]. Moreover, it has been reported that the effectiveness and safety
of GSZD in treating RA are equal or superior to those of Western RA drugs [90].

23
4. Conclusions

Specific research and clinical data are available on the use of natural plant extracts or mixed
herbal compounds (NPEMHCs) as a treatment of RA. From the pharmacological point of
view, NPEMHCs effectively regulate the immune system to alleviate RA by inhibiting mainly
pro-inflammatory cytokines. In addition, NPEMHCs attenuate the potential side effects of
currently available drugs. Further, individualized medication can be applied according to the
physical condition of each individual patients. However, thus far, the pathogenesis of RA
and its immune mechanism has not been fully understood. Therefore, the treatment of RA
by NPEMHC needs more basic research support, and a clinical study involving a large group
of patients will help advance the development of NPEMHCs as drugs for RA treatment.

24
 References
1.Scott D.L., Wolfe F., Huizinga T.W. Rheumatoid arthritis. Lancet. 2010;376:1094–1108. doi:
10.1016/S0140-6736(10)60826-4. [DOI] [PubMed] [Google Scholar]
2.McInnes I.B., Schett G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med.
2011;365:2205–2219. doi: 10.1056/NEJMra1004965. [DOI] [PubMed] [Google Scholar]
3.Petsch C., Araujo E.G., Englbrecht M., Bayat S., Cavallaro A., Hueber A.J., Lell M., Schett G.,
Manger B., Rech J. Prevalence of monosodium urate deposits in a population of rheumatoid
arthritis patients with hyperuricemia. Semin. Arthritis Rheum. 2016;45:663–668. doi:
10.1016/j.semarthrit.2015.11.014. [DOI] [PubMed] [Google Scholar]
4.Kany S., Vollrath J.T., Relja B. Cytokines in Inflammatory Disease. Int. J. Mol. Sci.
2019;20:6008. doi: 10.3390/ijms20236008. [DOI] [PMC free article] [PubMed] [Google
Scholar]
5.Ross S.H., Cantrell D.A. Signaling and Function of Interleukin-2 in T Lymphocytes. Annu.
Rev. Immunol. 2018;36:411–433. doi: 10.1146/annurev-immunol-042617-053352. [DOI]
[PMC free article] [PubMed] [Google Scholar]
6.Shamriz O., Nussinovitch U., Rose N.R. Chapter 1—Pathophysiology of Autoimmunity and
Immune-Mediated Mechanisms in Cardiovascular Diseases. In: Nussinovitch U., editor. The
Heart in Rheumatic, Autoimmune and Inflammatory Diseases. Academic Press; Cambridge,
MA, USA: 2017. pp. 3–23. [DOI] [Google Scholar]
7.Summers K.M., Kockler D.R. Rituximab treatment of refractory rheumatoid arthritis. Ann.
Pharmacother. 2005;39:2091–2095. doi: 10.1345/aph.1G311. [DOI] [PubMed] [Google
Scholar]
8.Lau C.S., Chia F., Dans L., Harrison A., Hsieh T.Y., Jain R., Jung S.M., Kishimoto M., Kumar
A., Leong K.P., et al. 2018 update of the APLAR recommendations for treatment of
rheumatoid arthritis. Int. J. Rheum. Dis. 2019;22:357–375. doi: 10.1111/1756-185X.13513.
[DOI] [PubMed] [Google Scholar]
9.Ferro F., Elefante E., Luciano N., Talarico R., Todoerti M. One year in review 2017:
Novelties in the treatment of rheumatoid arthritis. Clin. Exp. Rheumatol. 2017;35:721–734.
[PubMed] [Google Scholar]
10.Xu T., Liu S., Zhao J., Feng G., Pi Z., Song F., Liu Z. A study on the effective substance of
the Wu-tou formula based on the metabonomic method using UPLC-Q-TOF-HDMS. Mol.
Biosyst. 2015;11:3081–3091. doi: 10.1039/C5MB00454C. [DOI] [PubMed] [Google Scholar]
11.Zhang C., Fan L., Fan S., Wang J., Luo T., Tang Y., Chen Z., Yu L. Cinnamomum cassia Presl:
A Review of Its Traditional Uses, Phytochemistry, Pharmacology and Toxicology. Molecules.
2019;24:3473. doi: 10.3390/molecules24193473. [DOI] [PMC free article] [PubMed] [Google
Scholar]

25
12.Yang Y.L., Luo B., Zhang H., Zheng W.J., Wu M.L., Li S.Y., Gao H.Y., Li Q., Ge Y.W., Yang Q.
Advances in quality research of Cinnamomum cassia. Zhongguo Zhong Yao Za Zhi.
2020;45:2792–2799. doi: 10.19540/j.cnki.cjcmm.20191106.202. [DOI] [PubMed] [Google
Scholar]
13.Sun L., Zong S.B., Li J.C., Lv Y.Z., Liu L.N., Wang Z.Z., Zhou J., Cao L., Kou J.P., Xiao W. The
essential oil from the twigs of Cinnamomum cassia Presl alleviates pain and inflammation in
mice. J. Ethnopharmacol. 2016;194:904–912. doi: 10.1016/j.jep.2016.10.064. [DOI]
[PubMed] [Google Scholar]
14.Liu P., Wang J., Wen W., Pan T., Chen H., Fu Y., Wang F., Huang J.H., Xu S.
Cinnamaldehyde suppresses NLRP3 derived IL-1β via activating succinate/HIF-1 in
rheumatoid arthritis rats. Int. Immunopharmacol. 2020;84:106570. doi:
10.1016/j.intimp.2020.106570. [DOI] [PubMed] [Google Scholar]
15.Braddock M., Quinn A., Canvin J. Therapeutic potential of targeting IL-1 and IL-18 in
inflammation. Expert Opin. Biol. Ther. 2004;4:847–860. doi: 10.1517/14712598.4.6.847.
[DOI] [PubMed] [Google Scholar]
16.Mateen S., Rehman M.T., Shahzad S., Naeem S.S., Faizy A.F., Khan A.Q., Khan M.S.,
Husain F.M., Moin S. Anti-oxidant and anti-inflammatory effects of cinnamaldehyde and
eugenol on mononuclear cells of rheumatoid arthritis patients. Eur. J. Pharmacol.
2019;852:14–24. doi: 10.1016/j.ejphar.2019.02.031. [DOI] [PubMed] [Google Scholar]
17.Li W., Tang Y., Chen Y., Duan J.A. Advances in the chemical analysis and biological
activities of chuanxiong. Molecules. 2012;17:10614–10651. doi:
10.3390/molecules170910614. [DOI] [PMC free article] [PubMed] [Google Scholar]
18.Yuan X., Han B., Feng Z.M., Jiang J.S., Yang Y.N., Zhang P.C. Chemical constituents of
Ligusticum chuanxiong and their anti-inflammation and hepatoprotective activities. Bioorg.
Chem. 2020;101:104016. doi: 10.1016/j.bioorg.2020.104016. [DOI] [PubMed] [Google
Scholar]
19.Du J.C., Xie X.F., Xiong L., Sun C., Peng C. Research progress of chemical constituents and
pharmacological activities of essential oil of Ligusticum chuanxiong. Zhongguo Zhong Yao Za
Zhi. 2016;41:4328–4333. doi: 10.4268/cjcmm20162306. [DOI] [PubMed] [Google Scholar]
20.Huang C., Cao X., Chen X., Fu Y., Zhu Y., Chen Z., Luo Q., Li L., Song X., Jia R., et al. A pectic
polysaccharide from Ligusticum chuanxiong promotes intestine antioxidant defense in aged
mice. Carbohydr. Polym. 2017;174:915–922. doi10.1016/j.carbpol.2017.06.122. [DOI]
[PubMed] [Google Scholar]

26
21.Mu C.X., Liu G.L., Tian H., Li Y.C., Huang Y.L. Effect of Tetramethyl pyrazine on serum
levels of IL-1beta, IL-6, and IL-2, and NO and PGE2 in the synovial fluid of CIA rats: An
experimental research. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2014;34:214–217. [PubMed]
[Google Scholar]
22.Zhang C., Guan D., Jiang M., Liang C., Li L., Zhao N., Zha Q., Zhang W., Lu C., Zhang G., et
al. Efficacy of leflunomide combined with ligustrazine in the treatment of rheumatoid
arthritis: Prediction with network pharmacology and validation in a clinical trial. Chin. Med.
2019;14:26. doi: 10.1186/s13020-019-0247-8. [DOI] [PMC free article] [PubMed] [Google
Scholar]
23.Sun H., Wang M., Zhang A., Ni B., Dong H., Wang X. UPLC-Q-TOF-HDMS analysis of
constituents in the root of two kinds of Aconitum using a metabolomics approach.
Phytochem. Anal. 2013;24:263–276. doi: 10.1002/pca.2407. [DOI] [PubMed] [Google
Scholar]
24.Song B., Jin B., Li Y., Wang F., Yang Y., Cui Y., Song X., Yue Z., Liu J. C19-Norditerpenoid
Alkaloids from Aconitum szechenyianum. Molecules. 2018;23:1108. doi:
10.3390/molecules23051108. [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Yu H.H., Li M., Li Y.B., Lei B.B., Yuan X., Xing X.K., Xie Y.F., Wang M., Wang L., Yang H.J., et
al. Benzoylaconitine Inhibits Production of IL-6 and IL-8 via MAPK, Akt, NF-κB Signaling in IL-
1β-Induced Human Synovial Cells. Biol. Pharm. Bull. 2020;43:334–339. doi:
10.1248/bpb.b19-00719. [DOI] [PubMed] [Google Scholar]
26.Gai W., Hao X., Zhao J., Wang L., Liu J., Jiang H., Jin H., Liu G., Feng Y. Delivery of
benzoylaconitine using biodegradable nanoparticles to suppress inflammation via regulating
NF-κB signaling. Colloids Surf. B Biointerfaces. 2020;191:110980. doi:
10.1016/j.colsurfb.2020.110980. [DOI] [PubMed] [Google Scholar]
27.Zhang X.M., Lin Z.J., Zhang B., Li A. Traditional prescription rules of Aconitum herbs in
treatment of Bi syndrome. Zhongguo Zhong Yao Za Zhi. 2018;43:211–215. doi:
10.19540/j.cnki.cjcmm.20171106.008. [DOI] [PubMed] [Google Scholar]
28.Bao J., Dai S.M. A Chinese herb Tripterygium wilfordii Hook F in the treatment of
rheumatoid arthritis: Mechanism, efficacy, and safety. Rheumatol. Int. 2011;31:1123–1129.
doi: 10.1007/s00296-011-1841-y. [DOI] [PubMed] [Google Scholar]
29.Li C.J., Xie F.G., Yang J.Z., Luo Y.M., Chen X.G., Zhang D.M. Two sesquiterpene pyridine
alkaloids and a triterpenoid saponin from the root barks of Tripterygium hypoglaucum. J.
Asian Nat. Prod. Res. 2012;14:973–980. doi: 10.1080/10286020.2012.729049. [DOI]
[PubMed] [Google Scholar]
30.Wang C., Li C.J., Yang J.Z., Ma J., Chen X.G., Hou Q., Zhang D.M. Anti-inflammatory
sesquiterpene derivatives from the leaves of Tripterygium wilfordii. J. Nat. Prod.
2013;76:85–90. doi: 10.1021/np300759u. [DOI] [PubMed] [Google Scholar]

27
31.Zhou Y.Z., Zhao L.D., Chen H., Zhang Y., Wang D.F., Huang L.F., Lv Q.W., Liu B., Li Z., Wei
W., et al. Comparison of the impact of Tripterygium wilfordii Hook F and Methotrexate
treatment on radiological progression in active rheumatoid arthritis: 2-year follow up of a
randomized, non-blinded, controlled study. Arthritis Res. Ther. 2018;20:70. doi:
10.1186/s13075-018-1563-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
32.Fan D., Guo Q., Shen J., Zheng K., Lu C., Zhang G., Lu A., He X. The Effect of Triptolide in
Rheumatoid Arthritis: From Basic Research towards Clinical Translation. Int. J. Mol. Sci.
2018;19:376. doi: 10.3390/ijms19020376. [DOI] [PMC free article] [PubMed] [Google
Scholar]
33.Tong L., Nanjundaiah S.M., Venkatesha S.H., Astry B., Yu H., Moudgil K.D. Pristimerin, a
naturally occurring triterpenoid, protects against autoimmune arthritis by modulating the
cellular and soluble immune mediators of inflammation and tissue damage. Clin. Immunol.
2014;155:220–230. doi: 10.1016/j.clim.2014.09.014. [DOI] [PMC free article] [PubMed]
[Google Scholar]
34.Gong Y., Huang X., Wang D., Li M., Liu Z. Triptolide protects bone against destruction by
targeting RANKL-mediated ERK/AKT signalling pathway in the collagen-induced rheumatoid
arthritis. Biomed. Res. 2017;28:4111–4116. [Google Scholar]
35.Liu C.-f., Lin N., Jia H.-w., Xiao C., Zhang L. Effect of Triptolide on Immunological Function
of Mice with Collagen II-induced Arthritis. Chin. J. Inf. TCM. 2004;7:602–604. [Google
Scholar]
36.Wang J., Wang A., Zeng H., Liu L., Jiang W., Zhu Y., Xu Y. Effect of triptolide on T-cell
receptor beta variable gene mRNA expression in rats with collagen-induced arthritis. Anat.
Rec. 2012;295:922–927. doi: 10.1002/ar.22479. [DOI] [PubMed] [Google Scholar]
37.Astry B., Venkatesha S.H., Laurence A., Christensen-Quick A., Garzino-Demo A., Frieman
M.B., O’Shea J.J., Moudgil K.D. Celastrol, a Chinese herbal compound, controls autoimmune
inflammation by altering the balance of pathogenic and regulatory T cells in the target
organ. Clin. Immunol. 2015;157:228–238. doi: 10.1016/j.clim.2015.01.011. [DOI] [PMC free
article] [PubMed] [Google Scholar]
38.Hosseini A., Hosseinzadeh H. Antidotal or protective effects of Curcuma longa (turmeric)
and its active ingredient, curcumin, against natural and chemical toxicities: A review.
Biomed. Pharmacother. 2018;99:411–421. doi: 10.1016/j.biopha.2018.01.072. [DOI]
[PubMed] [Google Scholar]
39.Drugs and Lactation Database (LactMed) National Library of Medicine (US); Bethesda,
MD, USA: 2006. Turmeric. [Google Scholar]
40.Dosoky N.S., Setzer W.N. Chemical Composition and Biological Activities of Essential Oils
of Curcuma Species. Nutrients. 2018;10:1196. doi: 10.3390/nu10091196. [DOI] [PMC free
article] [PubMed] [Google Scholar]

28
41.Kocaadam B., Şanlier N. Curcumin, an active component of turmeric (Curcuma longa),
and its effects on health. Crit. Rev. Food Sci. Nutr. 2017;57:2889–2895. doi:
10.1080/10408398.2015.1077195. [DOI] [PubMed] [Google Scholar]
42.Mau J.-L., Lai E.Y.C., Wang N.-P., Chen C.-C., Chang C.-H., Chyau C.-C. Composition and
antioxidant activity of the essential oil from Curcuma zedoaria. Food Chem. 2003;82:583–
591. doi: 10.1016/S0308-8146(03)00014-1. [DOI] [Google Scholar]
43.Wilson B., Abraham G., Manju V.S., Mathew M., Vimala B., Sundaresan S., Nambisan B.
Antimicrobial activity of Curcuma zedoaria and Curcuma malabarica tubers. J.
Ethnopharmacol. 2005;99:147–151. doi: 10.1016/j.jep.2005.02.004. [DOI] [PubMed]
[Google Scholar]
44.Angel G.R., Menon N., Vimala B., Nambisan B. Essential oil composition of eight starchy
Curcuma species. Ind. Crops Prod. 2014;60:233–238. doi: 10.1016/j.indcrop.2014.06.028.
[DOI] [Google Scholar]
45.Sundar Dhilip Kumar S., Houreld N.N., Abrahamse H. Therapeutic Potential and Recent
Advances of Curcumin in the Treatment of Aging-Associated Diseases. Molecules.
2018;23:835. doi: 10.3390/molecules23040835. [DOI] [PMC free article] [PubMed] [Google
Scholar]
46.Chen C., Long L., Zhang F., Chen Q., Chen C., Yu X., Liu Q., Bao J., Long Z. Antifungal
activity, main active components and mechanism of Curcuma longa extract against
Fusarium graminearum. PLoS ONE. 2018;13:e0194284. doi: 10.1371/journal.pone.0194284.
[DOI] [PMC free article] [PubMed] [Google Scholar]
47.An S., Jang E., Lee J.H. Preclinical Evidence of Curcuma longa and Its Noncurcuminoid
Constituents against Hepatobiliary Diseases: A Review. Evid. Based Complement. Altern.
Med. 2020;2020:8761435. doi: 10.1155/2020/8761435. [DOI] [PMC free article] [PubMed]
[Google Scholar]
48.Zou S., Wang C., Cui Z., Guo P., Meng Q., Shi X., Gao Y., Yang G., Han Z. β-Elemene
induces apoptosis of human rheumatoid arthritis fibroblast-like synoviocytes via reactive
oxygen species-dependent activation of p38 mitogen-activated protein kinase. Pharmacol.
Rep. 2016;68:7–11. doi: 10.1016/j.pharep.2015.06.004. [DOI] [PubMed] [Google Scholar]
49.Aggarwal B.B., Gupta S.C., Sung B. Curcumin: An orally bioavailable blocker of TNF and
other pro-inflammatory biomarkers. Br. J. Pharmacol. 2013;169:1672–1692. doi:
10.1111/bph.12131. [DOI] [PMC free article] [PubMed] [Google Scholar]
50.Nelson K.M., Dahlin J.L., Bisson J., Graham J., Pauli G.F., Walters M.A. The Essential
Medicinal Chemistry of Curcumin. J. Med. Chem. 2017;60:1620–1637. doi:
10.1021/acs.jmedchem.6b00975. [DOI] [PMC free article] [PubMed] [Google Scholar]

29