Abstract Sinomenine, a major active ingredient from traditional Chinese medicine Qingfengteng (Sinomenium acutum (Thunb.) Rehd.et Wils.), has been proven to have anti-inflammatory, analgesic, anti-tumor, immunomodulatory and other pharmacological effects, and is clinically used for various inflammatory and autoimmune diseases. However, due to complex molecular mechanisms and pathological characteristics in inflammatory and immune responses, the precise anti-inflammatory and immunological mechanisms of sinomenine are still unclear. This review summarizes the anti-inflammatory and immunoregulatory mechanisms of sinomenine during recent years in rheumatoid arthritis, respiratory system, nervous system, digestive system and organ transplant rejection. The molecular pharmacological mechanisms of sinomenine responsible for anti-inflammatory and immunosuppressive effects were in detail introduced based on 3 aspects including cytokines induction, signal pathways modulation and immune cells function regulation. Moreover, this review also raises some concerns and challenges in future sinomenine study, which will contribute to crucial theoretical and practical significance for in-depth development and utilization of sinomenine as medicinal resource.

1. Traditional Medicine Research
1
Submit a manuscript: https://www.tmrjournals.com/tmr
doi: 10.12032/TMR 20200814194
Traditional Chinese Medicine
Advances in anti-inflammatory and immunoregulatory mechanisms
of sinomenine
Xiao-Qing Zhou1
, Ke-Wu Zeng1*
1
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing
100191, China
*Corresponding to: Ke-Wu Zeng. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical
Sciences, Peking University, No. 38 Xueyuan Road, Haidian District, Beijing 100191, China. E-mail: ZKW@bjmu.edu.cn.
Highlights
This review has summarized the anti-inflammatory and immunosuppressive effects of sinomenine, a natural
isoquinoline alkaloid compound from dried roots and canes of Qingfengteng (Sinomenium acutum (Thunb.)
Rehd.et Wils.), in multiple diseases. Besides, the specific molecular pharmacological mechanisms have
been introduced based on three aspects including cytokines induction, signal pathways modulation and
immune cells function regulation.
Tradition
Zhiwu Mingshi Tukao (An Illustrated Book on Plants, written by Qijun Wu in 1848 C.E.), a well-known
botanical monograph in ancient China recorded that Qingfengteng (Sinomenium acutum (Thunb.) Rehd.et
Wils.) had “dispelling-wind” effect, which is similar to the anti-inflammatory and analgesic effect in
modern pharmacology. Sinomenine (C19H23NO4), a molecular structure similar to morphine, has been used
clinically for rheumatoid arthritis in the past few decades and has fewer cardiovascular and gastrointestinal
side effects compared with commonly used non-steroidal anti-inflammatory drugs. Clinically, there are
various sinomenine-orientated preparations such as the Chinese patent medicine Zhengqing Fengtongning
tablets (China Food and Drug Administration approval number Z43020278) and the Chinese patent
medicine Yansuanqingtengjian Changrongpian tablets (China Food and Drug Administration approval
number H41025114).

2. REVIEW
2
doi: 10.12032/TMR20200814194
Submit a manuscript: https://www.tmrjournals.com/tmr
Abstract
Sinomenine, a major active ingredient from traditional Chinese medicine Qingfengteng (Sinomenium acutum
(Thunb.) Rehd.et Wils.), has been proven to have anti-inflammatory, analgesic, anti-tumor, immunomodulatory and
other pharmacological effects, and is clinically used for various inflammatory and autoimmune diseases. However,
due to complex molecular mechanisms and pathological characteristics in inflammatory and immune responses, the
precise anti-inflammatory and immunological mechanisms of sinomenine are still unclear. This review summarizes
the anti-inflammatory and immunoregulatory mechanisms of sinomenine during recent years in rheumatoid arthritis,
respiratory system, nervous system, digestive system and organ transplant rejection. The molecular
pharmacological mechanisms of sinomenine responsible for anti-inflammatory and immunosuppressive effects
were in detail introduced based on 3 aspects including cytokines induction, signal pathways modulation and
immune cells function regulation. Moreover, this review also raises some concerns and challenges in future
sinomenine study, which will contribute to crucial theoretical and practical significance for in-depth development
and utilization of sinomenine as medicinal resource.
Keywords: Sinomenine, Sinomenium acutum (Thunb.) Rehd.et Wils., Anti-inflammatory, Immunosuppression,
Molecular mechanism, Immunocyte
Author contributions:
Ke-Wu Zeng contributed to conceive the research; Xiao-Qing Zhou and Ke-Wu Zeng contributed to write the
manuscript.
Competing interests:
The authors declare no conflicts of interest.
Acknowledgments:
This research was funded by National Natural Science Foundation of China (No. 81973505) and The National
Key Research and Development Program of China (No. 2019YFC1708902, 2019YFC1711000).
Abbreviations:
Sin, sinomenine; RA, rheumatoid arthritis; AR, allergic rhinitis; ICH, intracerebral hemorrhage; MAPKs,
mitogen-activated protein kinases; TGF, transforming growth factor; Treg cells, regulatory T cells; Th17 cells, T
helper type 17 cells; AhR, aromatic hydrocarbon receptor; CIA, collagen induced arthritis; Nrf2, nuclear factor
NF-E2 related factor 2; LPS, lipopolysaccharide; STAT3, signal transducer and activator of transcription 3,
TNF-α, tumor necrosis factor-α; α7nAChR, α7 nicotinic acetylcholine receptor; mPGES-1, microsomal
prostaglandin E synthase-1; PG, prostaglandin; DCs, dendritic cells.
Citation:
Zhou XQ, Zeng KW. Advances in anti-inflammatory and immunoregulatory mechanisms of sinomenine. Tradit
Med Res. 2021; 6(1): 6. doi: 10.12032/TMR 20200814194.
Executive editor: Yu-Ping Shi.
Submitted: 22 June 2020, Accepted: 14 August 2020, Online: 26 August 2020.
© 2021 By Authors. Published by TMR Publishing Group Limited. This is an open access article under the CC-BY
license (http://creativecommons.org/licenses/BY/4.0/).

3. Traditional Medicine Research
3
Submit a manuscript: https://www.tmrjournals.com/tmr
doi: 10.12032/TMR 20200814194
Introduction
Qingfengteng (Sinomenium acutum (Thunb.) Rehd.et
Wils.) is a traditional Chinese medicine with
anti-inflammatory and analgesic effects (Figure 1) [1].
The earliest engraved herbal atlas in China, Bencao
Tujing (Atlas of Materia Medica, written by Song Su et
al. in 1061 C.E.) reported that Sinomenium acutum
(Thunb.) Rehd.et Wils. could be used in Chinese
medicine. Zhiwu Mingshi Tukao (An Illustrated Book
on Plants, written by Qijun Wu in 1848 C.E.), a
well-known botanical monograph in ancient China
recorded that Sinomenium acutum (Thunb.) Rehd.et
Wils. had “dispelling-wind” effect, which is similar to
the anti-inflammatory and analgesic effect in modern
pharmacology. Moreover, the famous Chinese medical
book, Bencao Gangmu (Compendium of Materia
Medica, written by Shizhen Li in 1590 C.E.)
demonstrated that Sinomenium acutum (Thunb.)
Rehd.et Wils. could be applied for treating rheumatic
diseases.
Sinomenine (Sin, C19H23NO4) is a natural
isoquinoline alkaloid compound from dried roots and
canes of Sinomenium acutum (Thunb.) Rehd.et Wils.,
with a molecular structure similar to morphine [2]. Sin
has been found to show wide pharmacological
activities including anti-inflammatory, analgesic,
anti-tumor, and immunosuppressive effects [3]. Sin has
been used clinically for rheumatoid arthritis (RA) in
the past few decades and has fewer cardiovascular and
gastrointestinal side effects compared with commonly
used non-steroidal anti-inflammatory drugs [4].
Moreover, Sin also has kidney protective effect [5] and
has recently been used in transplantation immunology
research [6]. Clinically, there are various
Sin-orientated preparations such as the Chinese patent
medicine Zhengqing Fengtongning tablets (China
Food and Drug Administration approval number
Z43020278) and the Chinese patent medicine
Yansuanqingtengjian Changrongpian tablets (China
Food and Drug Administration approval number
H41025114). However, meanwhile, Sin possesses a
short half-life, low efficacy and large administration
dose [7], thus limiting its wide application. Notably,
precise pharmacological mechanism of Sin is still
largely unexplored. Therefore, systematic literature
summary of Sin pharmacological studies has become
an urgent need to promote Sin further development.
This review aims to summarize the
anti-inflammatory and immunoregulatory mechanisms
of Sin, to provide a theoretical reference for the
in-depth development and utilization of Sin.
Anti-inflammatory and immunological
activities of Sin
Sin for RA
RA is a common autoimmune disease characterized by
chronic arthritis accompanied with various symptoms
[8]. The pathogenesis of RA is not completely clear,
but it is generally considered to be associated with
disorders of autoimmune and cytokine networks,
resulting in persistent immunocyte activation. Wang et
al. reported that acupoint application of Sin had good
therapeutic effect on RA [9]. Moreover, Feng et al.
studied the inhibitory effect of Sin on angiogenesis in a
collagen-induced arthritis mouse model and found that
Sin (30 mg/kg) could significantly improve swelling
and erythema prolongation, decrease arthritis index,
and reduce cartilage damage and bone erosion. Sin
also showed inhibitory effect on CD31 positive cells
number on synovium [10]. In addition, Qian et al.
reported that Sin (30 mg/kg) improved synovial cell
hyperplasia and synovial swelling in collagen induced
arthritis (CIA) rats, thus significantly improving joint
pathological damage in RA [11]. Furthermore, Liu et
al. evaluated Sin effect on CIA mice and RA patients,
and results suggested that Sin could regulate tumor
necrosis factor-α (TNF-α), IL-1α, IL-1β, IL-6, IL-10,
IL-12 p40, monocyte chemotactic protein-1, Eotaxin-2,
M-CSF, chemokine (C-X-C motif) ligand 1 and
RANTES secretion to suppress RA progression [12].
Thus, these studies provide a reliable experimental
basis for Sin treatment of RA.
Figure 1 Sinomenium acutum whole plant, rhizome slices and its main component Sin. Sin, sinomenine.

4. REVIEW
4
doi: 10.12032/TMR20200814194
Submit a manuscript: https://www.tmrjournals.com/tmr
Sin for respiratory inflammation
Bronchial asthma is a hyperresponsive disease caused
by a variety of immune cells responsible for chronic
airway inflammation. Bao et al. showed that Sin
significantly reduced asthmatic mice smooth muscle
thickness, mucinous gland hypertrophy, goblet cell
hyperplasia, collagen deposition and eosinophil
inflammatory response in a dose-dependent manner.
Sin (25 mg/kg) also significantly inhibited
malondialdehyde production and myeloperoxidase
activity in asthmatic mice lung tissue [13]. Moreover,
allergic rhinitis (AR) is a chronic allergic airway
disease in nasal mucosa. Chen et al. found that Sin
(100 mg/kg) effectively improved AR symptom by
decreasing eosinophils, anti-ovalbumin specific IgE
and IL-4 levels in an AR mouse model [14]. Therefore,
Sin exhibited a significant effect on respiratory
inflammation such as bronchial asthma and AR.
Sin for neuroinflammation
Epilepsy is a neurological disorder that is currently not
well controlled by available drugs. Neuroinflammation
is considered to be a key risk factor for epilepsy. Gao
et al. established a chronic epilepsy model induced by
pentylenetetrazole and found Sin reduced epilepsy
incidence and complete seizure, and increased rat
seizuresin latency. Meanwhile, Sin could block
hippocampal neurons injury and minimize spatial
learning and memory loss. In addition, Sin (20 mg/kg)
showed inhibitory effect on NLRP1 inflammatory
complexes and inflammatory cytokines production
including IL-1β, IL-18, IL-6 and TNF-α in
pentylenetetrazole kindled rats [15]. Notably,
microglial polarization plays an important role in
neuroinflammation after intracerebral hemorrhage
(ICH), whose exact mechanism remains unclear. Shi et
al. reported that Sin (100 mg/kg) could protect
hippocampal neurons against ICH-induced microglial
cytotoxicity and inhibit matrix metalloproteinase-3/9
expressions and neurological deficits in C57/BL6 mice
ICH model [16]. Therefore, Sin is considered to
protect brain function by inducing microglial M2
phenotype and inhibiting MMP-3/9 expressions, which
is a promising therapeutic strategy for
neuroinflammation.
Sin for digestive system inflammation
Ulcerative colitis is a major clinical digestive system
disease, which is associated with autoimmune
dysfunction. Zhou et al. found that Sin (100 mg/kg)
significantly inhibited disease activity index and
improved colon histological damage in sodium dextran
sulfate-induced colitis mouse model. Moreover, Sin
markedly down-regulated TNF-α, IL-6 and inducible
nitric oxide synthase levels, and promoted nuclear
factor NF-E2 related factor 2 (Nrf2), heme
oxygenase-1 and NQO-1 expressions, suggesting that
Nrf2/NQO-1 may be a key signaling pathway for
colitis therapy [17]. Additionally, Xiong et al.
confirmed the effect of Sin on inflammatory bowel
disease. Result showed that Sin (30 mg/kg)
significantly decreased TLR4, MyD88, NF-κB p65 and
pro-inflammatory cytokines expression in a
dose-dependent manner in mouse model of colitis
employs dextran sodium sulfate, indicating Sin may
regulate TLR/NF-κB signaling pathway for
inflammatory bowel disease [18]. Therefore, Sin plays
an important therapeutic role in digestive system
inflammation.
Sin for organ transplant rejection
Sin has also been tested on potential therapeutic effect
on organ transplant rejection. Cai et al. investigated
immunosuppressive effect of Sin on the orthotropic
liver transplantation rats and found that Sin (40 mg/kg)
showed inhibitory effect on immune rejection and
reduced transplant liver damage in rats [19]. Moreover,
Xiong et al. reported that Sin (30 mg/kg) together with
cyclosporine could effectively protect kidney
transplant rats [20]. Similarly, Wang et al. found that
Sin (15 mg/kg) could significantly prolong rat survival
time of high-risk corneal graft, and combination of Sin
with cyclosporine A showed a better therapeutic effect
[21]. These studies suggest that Sin can exert obvious
synergistic effect with cyclosporine A to alleviate
adverse reactions and enhance curative effect. Thus,
Sin can be used as an adjuvant agent of
immunosuppressive agents for acute or chronic
transplant rejection.
Other therapeutic effects of Sin
Wang et al. studied Sin effect on type 1 diabetes in
non-obese diabetic mice and found that Sin (25 mg/kg)
significantly reduced diabetes incidence and improved
glucose tolerance. Meanwhile, Sin decreased serum
IFN-​ γ and IL-​ 2 levels and down-regulated IFN-γ
and IL-2 expressions in pancreas. These results
suggested that Sin might have a preventive effect on
diabetes development in non-obese diabetic mice [22].
Moreover, Zhao et al. reported that Sin (200 mg/kg)
could attenuate serum creatinine and blood urea
nitrogen levels and inhibit renal tubular cell apoptosis;
thereby alleviating inflammatory response in
ischemia-reperfusion-induced mice kidney injury [23].
Anti-inflammatory and immunomodulatory
mechanisms of Sin
Cytokines regulation
Cytokines are soluble low molecular weight proteins
secreted by immune cells and non-immune cells,
which have various functions such as regulating innate
and adaptive immunity, hematopoiesis, cell growth and
tissue repair. Cytokines can be divided into
pro-inflammatory and anti-inflammatory categories

5. Traditional Medicine Research
5
Submit a manuscript: https://www.tmrjournals.com/tmr
doi: 10.12032/TMR 20200814194
according to their effects on inflammation. Numerous
studies have shown that Sin exerts anti-inflammatory
and immunosuppressive effects by regulating the
levels of different cytokines.
Pro-inflammatory cytokines. Pro-inflammatory
cytokines can promote inflammatory reactions,
including TNF-α, serotonin (5-hydroxytryptamine),
and most interleukins such as IL-1β, IL-2, IL-6, IL-8.
Shen et al. studied Sin effect on ankle fracture and
found that Sin could effectively inhibit IL-1β, IL-6,
TNF-α, p-p38 and p-NF-κB increases and balance
antioxidants and detoxifying enzymes, indicating that
Sin could treat ankle fracture by reducing
inflammation and oxidative stress [24]. Moreover, Lin
et al. established an in vitro model of atopic dermatitis
by stimulating RAW264.7 cells with
lipopolysaccharide (LPS), and found that Sin
remarkably inhibited TNF-α, IL-1β and IL-6
production against LPS in a dose-dependent manner.
Besides, Sin significantly reduced inducible nitric
oxide synthase and COX2 expressions [25], indicating
that Sin may play an anti-inflammatory role by
suppressing pro-inflammatory cytokines production.
Anti-inflammatory cytokines. Anti-inflammatory
cytokines including IL-4, IL-10, IL-13 and
transforming growth factor (TGF), are mainly
produced by activated T cells and can regulate
biological functions of B cells, T cells and monocytes.
Chen et al. previously established AR mouse model to
study Sin effect in AR treatment as well as potential
mechanism. It was found that Sin significantly
down-regulated serum anti-OVA specific IgE and IL-4,
and increased TGF-β expression in serum and nasal
mucosa of AR mice. It is suggested that the
immunosuppressive effect of Sin on AR may be due to
TGF-β induction [14].
Signaling pathways regulation
Nrf2 pathway. Nrf2 is a key transcription factor
regulating oxidation/reduction balance and
inflammatory response. Qin et al. found that Sin
prominently reduced Nrf2 inhibitor Keap1 through
PKC-sensitive ubiquitination-proteasome degradation
and was an activator of Nrf2. Thus, Sin significantly
increased Nrf2 level and promoted Nrf2 nuclear
translocation for anti-inflammatory effect. Moreover,
Sin can regulate M1/M2 polarization of macrophages
and inhibit IκBα phosphorylation and NF-κB nuclear
translocation through regulating Nrf2 [5]. Furthermore,
Zhang et al. investigated Sin effect on motor
dysfunction and neuropathology of traumatic spinal
cord injury, and discovered that Sin could promote
Nrf2 translocation from cytoplasm to nucleus as well
as Nrf2-mediated transactivation, thereby inhibiting
inflammation and oxidative stress. Notably,
Sin-mediated anti-inflammatory effect was
significantly reversed by siRNA knockdown of Nrf2
expression [26]. In addition, Qin et al. also found that
Sin achieved inhibition of oxidative stress through the
Nrf2 pathway [5]. Collectively, these results indicate
that Sin inhibits inflammation and oxidative stress by
activating Nrf2.
Mitogen-activated protein kinases pathway.
Mitogen-activated protein kinases (MAPKs) are key
signaling pathways mediating inflammatory reactions
including ERKs, JNKs and p38 MAPKs. Liu et al.
found that Sin could not only inhibit IL-6, IL-8 and
TNF-α expressions induced by LPS, but also promote
mitogen-activated protein kinase phosphatase-1
expression by down-regulating miRNA-101, thereby
blocking JNK signaling pathway to exert
anti-inflammatory effect in vivo [27]. Xu et al. found
Sin combined with acupuncture obviously effectively
reduced serum TNF-α, IL-6, IL-1β and IL-8 levels, and
increased superoxide dismutase production by
regulating p38 MAPK expression in arthritis rats [28].
These results indicate that MAPK signaling pathway
play an important role in Sin treatment of arthritis.
Janus kinase-signal transduction and transcription
activator pathway. Janus kinase-signal transduction
and transcription activator pathway can rapidly
transmit signal from membrane to nucleus and is
widely involved in various physiological and
pathological processes, such as cell proliferation,
differentiation, apoptosis and inflammation. Qiu et al.
studied protective effect of Sin on astrocyte-mediated
neuroinflammation and revealed that Sin remarkably
inhibited astrocyte activation and signal transducer and
activator of transcription 3 (STAT3) phosphorylation.
Further studies showed that dopamine D2 receptor or
αB-crystallin (encoded by CRYAB gene) knockdown
could obviously antagonize Sin-dependent suppressive
effect on STAT3. Moreover, it was found that Sin
induced CRYAB up-regulation and nuclear
translocation in astrocytes, and enhanced CRYAB
interaction with STAT3, thus exhibiting a
neuroimmune regulatory characteristic [29].
α7 nicotinic acetylcholine receptor pathway. α7
nicotinic acetylcholine receptor (α7nAChR) is a
member of nicotinic acetylcholine receptor and is a
ligand-gated ion channel composed of homologous
pentamers. α7nAChR belongs to neuronal
acetylcholine receptor and plays an important role in
anti-inflammatory pathway. Yue et al. found that Sin
may bind directly to α7nAChR by targeting Tyr184
and Tyr191 residues to activate PI3K/Akt/mTOR
pathway, thereby specifically enhancing vasoactive
intestinal polypeptide production [30]. Moreover, Yi et
al. found that α7nAChR was involved in
TNF-α-induced invasive proliferation of fibroblast-like
synoviocyte, and Sin could reduce the α7nAChR
expression and the fibroblast-like synoviocyte
proliferation, exerting an anti-arthritic effect [31].
Furthermore, Zhu et al. reported that Sin inhibited
CD14/TLR4 expression via targeting α7nAChR to
decrease intracellular free calcium level [32].

6. REVIEW
6
doi: 10.12032/TMR20200814194
Submit a manuscript: https://www.tmrjournals.com/tmr
Microsomal prostaglandin E synthase-1 pathway.
Microsomal prostaglandin E synthase-1 (mPGES-1) is
a promising anti-inflammatory target, which plays an
anti-inflammatory role without adverse effects caused
by non-steroidal anti-inflammatory drugs. Zhou et al.
found that Sin could selectively decrease mPGES-1
expression and reduce prostaglandin (PG) E2 level
without affecting PG I2 and thromboxane A2
synthesis. Meanwhile, mPGES-1 expression was
effectively reduced by Sin in carrageenan-induced
edema rat model and CIA mouse model. Furthermore,
Sin could block NF-κB binding to DNA, thereby
inhibiting mPGES-1 expression, which represents a
new direction for anti-inflammatory agent discovery
[4]. In addition, scholars found that Sin inhibited the
production of another type of PG D2 [33], but no effect
of Sin on PG F2α was reported.
Immunocytes regulation
Regulatory T cells and T helper type 17 cells. As a
subset of T cells, regulatory T cells (Treg cells) play a
valuable role in maintaining immune homeostasis
mainly by secreting IL-10 and TGF-β1. T helper type
17 cells (Th17 cells) can produce IL-17 and effectively
mediate the stimulating process of neutrophil
mobilization, thereby mediating the pre-inflammatory
response. The balance between Treg and Th17 cell
numbers is highly associated with autoimmune
diseases. Tong et al. used collagen-induced arthritis
mouse model to evaluate Sin effect on Treg and Th17
cells in autoimmune arthritis and indicated that Sin
increased Treg cells frequency while decreased Th17
cells frequency [34]. Further studies showed Sin
promoted aromatic hydrocarbon receptor (AhR)/Hsp90
dissociation and nuclear translocation of AhR by
inducing AhR expression, demonstrating that Sin may
be a potential AhR agonist. In addition, resveratrol, an
AhR antagonist, could obviously inhibit intestinal Treg
cells function and attenuate anti-arthritis effect of Sin.
Thus, it can be concluded that Sin can regulate Treg
cells function through AhR for its anti-arthritic effect
[35].
Dendritic cells. Dendritic cells (DCs) are the most
important antigen-presenting cells. DCs are classified
into 2 types: mature DCs and immature DCs. Mature
DCs are highly responsive to allogeneic T lymphocytes
and are crucial to transplant rejection. Meanwhile,
immature DCs can induce allogeneic lymphocytes
hyporesponse and reduce T cell-mediated cellular
immune response. Wang et al. observed the effect of
Sin on DC2.4 DCs stimulated by LPS and found that
TNF-α, CD80, IFN-γ, IL-6 and IL-12 decreased after
Sin treatment, indicating that Sin could inactivate
DC2.4 cells and reduce inflammatory factors secretion
of DC [36]. Moreover, Li et al. used Sin to block
donor-derived DCs before kidney transplantation and
found donor-derived DCs maturation could be
markedly inhibited by Sin pretreatment, further leading
to Treg cells increase in recipient spleen after kidney
transplantation [37]. Collectively, these observations
suggest that Sin can regulate DCs before allograft
transplantation, thereby increasing immune tolerance
to allograft.
Current problems and challenges in Sin
research
As a major active ingredient of Sinomenium acutum
(Thunb.) Rehd.et Wils., Sin has been proved to be a
promising immunoregulatory agent, which has been
used for treatment of various inflammatory diseases.
Although, during recent years, some progresses have
been made in Sin research, there are still some
problems that require further investigation. Notably,
though some potential anti-inflammatory and
immunosuppressive signaling pathways have been
discovered, the direct pharmacological targets
identification of Sin is still lacking. Thus, it is
recommended to pay more attentions to explore the
potential molecular target of Sin in vivo for
anti-inflammatory and immunosuppressive effects, to
reveal potential pharmacological mechanism of Sin
and guide its clinical precision medication.
Furthermore, although Sin has a wide range of
pharmacological activities, the clinical dose is still
high resulting in some side effects. Therefore, it is
necessary to advance investigations on Sin toxicology
and pharmacokinetic studies. Therefore, structural
modification coupled with activity screening of Sin as
a lead compound may discovery some high-efficiency
and low-toxic Sin derivatives, which promote Sin
development in the future. In fact, multiple studies on
the structural modification of Sin and the
anti-inflammatory activity screening of Sin derivatives
have been carried out. Zhao et al. tested the
anti-inflammatory activity of 6 Sin derivatives in 3
murine inflammation models and screened out an
anti-inflammatory drug candidate S1a, the 1, 4 bits on
the A ring of which had been changed [7]. Jin et al.
synthesized various Sin derivatives and evaluated their
anti-inflammatory activity in vivo and in vitro and
found derivative 3g had powerful anti-inflammatory
effect [38]. The structural modifications of Sin have
been mostly carried out in A, B, C, and D 4 rings [39],
while these 4 rings have not shown the regularity
affecting the anti-inflammatory activity of Sin
derivatives. Moreover, the anti-inflammatory and
immunomodulatory activities of these synthesized Sin
derivatives still need to be confirmed by further
studies. In addition, current Sin agents mainly include
tablets, injections, capsules and patches, but low
absorption demands further development of novel
pharmaceutical dosage forms.
Concluding remarks

7. Traditional Medicine Research
7
Submit a manuscript: https://www.tmrjournals.com/tmr
doi: 10.12032/TMR 20200814194
Figure 2 Anti-inflammatory and immuno-
modulatory mechanisms of Sin. Sin, sinomenine.
Broad biological effects of Sin, such as
anti-inflammatory, analgesic, anti-oxidant, anti-tumor,
et al., have been proved by a large number of
experimental and clinical studies. This article reviewed
anti-inflammatory and immunological
pharmacological mechanisms of Sin, including
pharmacological effects of Sin in RA, respiratory
system, nervous system and organ transplant rejection,
as well as associated molecular signaling pathways
(Figure 2). These contents can lay a solid foundation
for future research on pharmacological mechanisms
and therapeutic targets and promote innovative drugs
development of Sin for inflammatory and autoimmune
diseases.
References
1. Yi L, Luo JF, Xie BB, et al. α7 Nicotinic
acetylcholine receptor is a novel mediator of
sinomenine anti-Inflammation effect in
macrophages stimulated by lipopolysaccharide.
Shock 2015, 44: 188–195.
2. Sun YH, Zhu Q, Li JX. Research progress on
anti-inflammatory and anti-tumor effects of
sinomenine. Chin Pharm Bulletin 2015, 31:
1040–1043.
3. Liu WW, Zhu Y, Wang Y. Advance on active
ingredients and pharmacological effects of caulis
sinomenii alkaloid. J Liaoning Univ Tradit Chin
Med 2016, 43: 1765–1769.
4. Zhou H, Liu JX, Luo JF, et al. Suppressing
mPGES-1 expression by sinomenine ameliorates
inflammation and arthritis. Biochem Pharmacol
2017, 142: 133–144.
5. Qin T, Du RH, Huang FJ, et al. Sinomenine
activation of Nrf2 signaling prevents hyperactive
inflammation and kidney injury in a mouse model
of obstructive nephropathy. Free Radical Biol
Med 2016, 92: 90–99.
6. Li JJ, Chen XC, Tan SB, et al. Effect of CTLA4Ig
combined with sinomenine on survival time of
renal xenotransplantation. J Mod Med Health
2018, 34: 2276–2278.
7. Zhao ZJ, Xiao J, Wang JC, et al.
Anti-inflammatory effects of novel sinomenine
derivatives. Int Immunopharmacol 2015, 29:
354–360.
8. Kourilovitch M, Galarza-Maldonado C,
Ortiz-Prado E. Diagnosis and classification of
rheumatoid arthritis. J Autoimmun 2014, 48–49:
26–30.
9. Wang R, Yang J, Liu YX, et al. The effect of
acupoint application of sinomenine for
rheumatoid arthritis measured by microdialysis
and UPLC-MS/MS. Evid Based Complement
Alternat Med 2019, 2019: 5135692.
10. Feng ZT, Yang T, Hou XQ, et al. Sinomenine
mitigates collagen-induced arthritis mice by
inhibiting angiogenesis. Biomed Pharmacother
2019, 113: 108759–108765.
11. Qian X, Zhao ZM, Shang W, et al. Serum
proteomic analysis of the anti-arthritic effects of
sinomenine on rats with collagen-induced
arthritis. Mol Med Rep 2018, 18: 49–58.
12. Liu WW, Zhang YJ, Zhu WN, et al. Sinomenine
inhibits the progression of rheumatoid arthritis by
regulating the secretion of inflammatory
cytokines and monocyte/macrophage subsets.
Front Immunol 2018, 9: 2228.
13. Bao HR, Liu XJ, Li YL, et al. Sinomenine
attenuates airway inflammation and remodeling in
a mouse model of asthma. Mol Med Rep 2016,
13: 2415–2422.
14. Chen Z, Tao ZZ, Zhou XH, et al.
Immunosuppressive effect of sinomenine in an
allergic rhinitis mouse model. Exp Ther Med
2017, 13: 2405–2410.
15. Gao B, Wu Y, Yang YJ, et al. Sinomenine exerts
anticonvulsant profile and neuroprotective
activity in pentylenetetrazole kindled rats:
involvement of inhibition of NLRP1
inflammasome. J Neuroinflammation 2018, 15:
152–163.
16. Shi H, Zheng K, Su ZL, et al. Sinomenine
enhances microglia M2 polarization and
attenuates inflammatory injury in intracerebral
hemorrhage. J Neuroimmunol 2016, 299: 28–34.
17. Zhou Y, Liu HY, Song J, et al. Sinomenine
alleviates dextran sulfate sodium-induced colitis
via the Nrf2/NQO-1 signaling pathway. Mol Med
Rep 2018, 18: 3691–3698.
18. Xiong HF, Tian L, Zhao ZH, et al. The
sinomenine enteric-coated microspheres
suppressed the TLR/NF-κB signaling in
DSS-induced experimental colitis. Int
Immunopharmacol 2017, 50: 251–262.
19. Cai ZG, Yu ZJ, Wen S, et al. An experimental

8. REVIEW
8
doi: 10.12032/TMR20200814194
Submit a manuscript: https://www.tmrjournals.com/tmr
study on the effect of sinomenine on the acute
rejection after orthotropic liver transplantation in
rats. J Liaoning Univ Tradit Chin Med 2010, 12:
112–114.
20. Xiong L, Yang LY. Effects of alkaloid sinomenine
on levels of IFN-γ, IL-1β, TNF-α and IL-6 in a rat
renal allograft model. Immunotherapy 2012, 4:
785–791.
21. Wang Y, Ma DL, Jie Y, et al. Sinomenine can
prolong high-risk corneal graft survival in a rat
model. Immunotherapy 2012, 4: 581–586.
22. Wang Y, Yang F, Xiang Y, et al. Preventive effects
of sinomenine on the development of diabetes in
NOD mice. Lat Am J Pharm 2014, 33: 87–92.
23. Zhao ZQ, Guan R, Song SH, et al. Sinomenine
protects mice against ischemia reperfusion
induced renal injury by attenuating inflammatory
response and tubular cell apoptosis. Int J Clin Exp
Pathol 2013, 6: 1702–1712.
24. Shen J, Yao R, Jing M, et al. Sinomenine
regulates inflammatory response and oxidative
stress via nuclear factor kappa B (NF-κB) and
NF-E2-related factor 2 (Nrf2) signaling pathways
in ankle fractures in children. Med Sci Monit
2018, 24: 6649–6655.
25. Lin SW, Wei ML, Zhu W. Molecular mechanisms
of the anti-inflammatory effect of sinomenine on
atopic dermatitis. Die Pharmazie 2018, 73:
474–476.
26. Zhang LL, Zhang WJ, Zheng BB, et al.
Sinomenine attenuates traumatic spinal cord
Injury by suppressing oxidative stress and
inflammation via Nrf2 pathway. Neurochem Res
2019, 44: 763–775.
27. Liu SM, Man YG, Zhao L. Sinomenine inhibits
lipopolysaccharide-induced inflammatory injury
by regulation of miR-101/MKP-1/JNK pathway
in keratinocyte cells. Biomed Pharmacother 2018,
101: 422–429.
28. Xu MM, Liu SF, Wan RJ, et al. Combined
treatment with sinomenine and acupuncture on
collagen-induced arthritis through the NF-κB and
MAPK signaling pathway. Oncol Lett 2018, 15:
8770–8776.
29. Qiu J, Yan ZJ, Tao K, et al. Sinomenine activates
astrocytic dopamine D2 receptors and alleviates
neuroinflammatory injury via the CRYAB/STAT3
pathway after ischemic stroke in mice. J
Neuroinflammation 2016, 13: 263.
30. Yue MF, Zhang XY, Dou YN, et al. Gut-sourced
vasoactive intestinal polypeptide induced by the
activation of α7 nicotinic acetylcholine receptor
substantially contributes to the anti-inflammatory
effect of sinomenine in collagen-induced arthritis.
Front Pharmacol 2018, 9: 675.
31. Yi L, Lyu YJ, Peng C, et al. Sinomenine inhibits
fibroblast-like synoviocyte proliferation by
regulating α7nAChR expression via ERK/Egr-1
pathway. Int Immunopharmacol 2018, 56: 65–70.
32. Zhu RL, Zhi YK, Yi L, et al. Sinomenine
regulates CD14/TLR4, JAK2/STAT3 pathway and
calcium signal via α7nAChR to inhibit
inflammation in LPS-stimulated macrophages.
Immunopharm Immunot 2019, 41: 172–177.
33. Oh YC, Kang OH, Choi JG, et al. Anti-allergic
effects of sinomenine by inhibition of
prostaglandin D2 and leukotriene C4 in mouse
bone marrow-derived mast cells. Immunopharm
Immunot 2011, 33: 266–270.
34. Tong B, Yu JT, Wang T, et al. Sinomenine
suppresses collagen-induced arthritis by
reciprocal modulation of regulatory T cells and
Th17 cells in gut-associated lymphoid tissues.
Mol Immunol 2015, 65: 94–103.
35. Tong B, Yuan XS, Dou YN, et al. Sinomenine
induces the generation of intestinal Treg cells and
attenuates arthritis via activation of aryl
hydrocarbon receptor. Lab Invest 2016, 96:
1076–1086.
36. Wang Z, Wang BB, Guan JM, et al. Sinomenine
inhibites biological activity of DC2.4 dendritic
cells and reduces secretion of inflammatory
cytokines. Chin J Cell Mol Immunol 2015, 31:
660–663.
37. L. Li, Z. Luo, Z. Song, et al. Pre-transplant
infusion of donor-derived dendritic cells
maintained at the immature stage by sinomenine
increases splenic Foxp3+ Tregs in recipient rats
after renal allotransplantation. Transpl Immunol
2017, 45: 22–28.
38. Jin J, Teng P, Liu HL, et al. Microfluidics assisted
synthesis and bioevaluation of sinomenine
derivatives as antiinflammatory agents. Eur J Med
Chem 2013, 62: 280–288.
39. Tang J, Raza A, Chen J, et al. A systematic review
on the sinomenine derivatives. Mini Rev Med
Chem 2018, 18: 906–917.