Kapil Project

Download as pdf or txt
Download as pdf or txt
You are on page 1of 27

‘‘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


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

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
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

3
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

4
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 :-

5
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

6
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

7
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

8
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

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

9
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

10
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].

11
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].

Fig 4 :- Dry root of Aconitum kusnezoffii Reichb.

12
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].

13
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.

14
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.

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

15
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.

16
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).

17
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].

18
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].

19
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].

20
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].

21
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.

22
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]

23
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]

24
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]

25
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]

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]

26
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]

27

You might also like