Skip to main content

REVIEW article

Front. Chem., 17 November 2022
Sec. Analytical Chemistry
Volume 10 - 2022 | https://doi.org/10.3389/fchem.2022.1023779

Epimedii Herba: An ancient Chinese herbal medicine in the prevention and treatment of rheumatoid arthritis

www.frontiersin.orgLiu-Bo Zhang1,2 www.frontiersin.orgYu Yan1 www.frontiersin.orgJun He1 www.frontiersin.orgPei-Pei Wang2 www.frontiersin.orgXin Chen3 www.frontiersin.orgTian-Yi Lan1,2 www.frontiersin.orgYu-Xuan Guo1,2 www.frontiersin.orgJin-Ping Wang1 www.frontiersin.orgJing Luo1 www.frontiersin.orgZe-Ran Yan1 www.frontiersin.orgYuan Xu1* www.frontiersin.orgQing-Wen Tao1*
  • 1Department of TCM Rheumatism, Department of Pharmacy, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
  • 2China-Japan Friendship Clinical Medical College & School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
  • 3School of Chinese Medicine, Shenyang Pharmaceutical University, Shenyang, China

Rheumatoid arthritis (RA) is a chronic, progressive inflammatory and systemic autoimmune disease resulting in severe joint destruction, lifelong suffering and considerable disability. Diverse prescriptions of traditional Chinese medicine (TCM) containing Epimedii Herba (EH) achieve greatly curative effects against RA. The present review aims to systemically summarize the therapeutic effect, pharmacological mechanism, bioavailability and safety assessment of EH to provide a novel insight for subsequent studies. The search terms included were “Epimedii Herba”, “yinyanghuo”, “arthritis, rheumatoid” and “Rheumatoid Arthritis”, and relevant literatures were collected on the database such as Google Scholar, Pubmed, Web of Science and CNKI. In this review, 15 compounds from EH for the treatment of RA were summarized from the aspects of anti-inflammatory, immunoregulatory, cartilage and bone protective, antiangiogenic and antioxidant activities. Although EH has been frequently used to treat RA in clinical practice, studies on mechanisms of these activities are still scarce. Various compounds of EH have the multifunctional traits in the treatment of RA, so EH may be a great complementary medicine option and it is necessary to pay more attention to further research and development.

Introduction

Rheumatoid arthritis (RA) is classified as a chronic, progressive inflammatory and systemic autoimmune disease that primarily manifests as a symmetric poly-arthritis in hands and feet (Cush, 2021), leading to severe joint destruction, lifelong suffering and considerable disability (Burmester and Pope, 2017). The global prevalence of RA is estimated at approximately 1% (van der Woude and van der Helm-van Mil, 2018). In case of inadequate treatment, RA can result in permanent cartilage degradation, bone abrasions, joint impairment, impaired movement, and even irreversible disability (Chakraborty et al., 2021). Consequently, the issue of prompt and targeted RA treatment has received considerable attention. Currently, the main classes of therapeutic medications against RA are glucocorticoid, nonsteroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs (DMARDs). Without doubt, those medications have greatly therapeutic effects, but they are related to harmful side effects, such as gastrointestinal bleeding, osteoporosis, stomatitis, fatigue and hepatotoxicity (Lin et al., 2020). Extensive research has shown that traditional Chinese medicine (TCM) has remarkable advantages of alleviation effectively of symptoms of RA and lowered side effects. Therefore, TCM is necessary to be seen as a complementary medicine strategy.

Epimedii Herba (EH), a classical herbal medicine, is the dried leaves originated from several plants of the genus Epimedium (Cho et al., 2017) including Epimedium brevicornu Maxim., Epimedium sagittatum (Sieb. EtZucc.) Maxim., Epimedium pubescens Maxim. and Epimedium koreanum Nakaias according to Chinese Pharmacopoeia (Figure 1). EH exerts osteoprotective effects by strengthening bones and muscle, dispelling wind chill and tonifying kidney in the Chinese medicine classics Shen Nong Ben Cao Jing (Yang et al., 2018a). EH alone, or combined within the TCM prescriptions has been used extensively to treat various disease including osteoporosis (Wang et al., 2016), cancer (Chen et al., 2016), chronic fatigue syndrome (Chi et al., 2017) and sexual dysfunction (Niu, 1989). Furthermore, in clinical practice, EH is one of the most frequently used herbs in a variety of traditional Chinese decoction for the treatment of RA, such as Bushen Quhan Zhiwang decoction (Wang G et al., 2021), Yishen Qubi Tongluo decoction (Luo. et al., 2019) and Bushen Jiedu Tongluo decoction (Yuan. et al., 2019). Additionally, EH is also a component of Chinese patent medicine for treating RA, including Wangbi tablet (Chen. et al., 2021), Kunxian capsule (Sun. and Chen., 2021) and Fugui Gutong capsule (Zhang. et al., 2020b). The prescriptions of TCM containing EH used by physicians for management of RA were shown in Table 1. EH had drawn increased attention and pharmacological research to explore material foundation and pharmacological mechanism for treating RA.

FIGURE 1
www.frontiersin.org

FIGURE 1. Epimedii Herba (A) (https://www.daquan.com/) is the dried leaves originated from several plants of the genus Epimedium, including Epimedium brevicornu Maxim (B), Epimedium sagittatum (Sieb. EtZucc.) Maxim (C), Epimedium pubescens Maxim (D) and Epimedium koreanum Nakaias (E) (Cited from plant photo bank of China at http://ppbc.iplant.cn/).

TABLE 1
www.frontiersin.org

TABLE 1. The prescriptions of TCM containing EH used by physicians for management of RA.

Sze et al. have reviewed anti-oxidative properties of EH (Sze et al., 2010). However, the study did not review anti-inflammatory, immunoregulatory, osteoprotective and antiangiogenic activities. Consequently, the information of EH was searched to review the current research status. In detail, the literatures on compounds from EH were obtained using Web of Science, Google Scholar, Pubmed, and CNKI. Subsequently, the literatures on compounds involved in RA treatment were further filtered (Figure 2). Based on various pathological mechanism of RA including inflammation of the synovial membrane, oxidation, angiogenesis and bone destruction, this article systematically summarizes anti-RA activities of EH and further explores material basis and mechanism of these activities, so as to provide novel insight in the treatment of RA.

FIGURE 2
www.frontiersin.org

FIGURE 2. Articles were identified and screened for eligibility.

Effects of EH on RA

EH and its total flavonoids

In vivo studies were performed on adjuvant-induced arthritis (AIA) mice to investigate the anti-RA effects after an oral administration of EH and the results showed that compared with Tripterygii Radix, paw thickness was lower after oral administration of EH combined with Tripterygii Radix (Du. et al., 2019). It was reported that total flavonoids of EH can inhibit differentiation and bone resorption of osteoclasts (Zhang et al., 2012). Furthermore, total flavonoids of EH were found to promote osteogenic differentiation via the bone morphogenetic protein and Wnt/β-catenin signaling pathways (Zhang et al., 2010).

Components of EH

293 compounds from EH were searched in different database (Ma et al., 2011; Jin et al., 2014; Li F. et al., 2017; Pang et al., 2018; Ren et al., 2018; Su et al., 2018; Zhang et al., 2020; Hu. et al., 2021). Then, the studies of the compounds against RA were further searched in the database and 15 compounds for the treatment of RA have been reported, including icariin, quercetin, kaempferol, apigenin, luteolin, kaempferitrin, astragalin, hyperoside, ikarisoside A, tricin, isoliquiritigenin, emodin, β-sitosterol, magnoflorine and chlorogenic acid (Figure 3). Icariin is the most abundant constituent in EH and one of chemical markers for quality control of EH. Other compounds extracted from EH may have positive effects for the treatment of RA. The overview of the compounds for the treatment of RA was shown in Table 2.

FIGURE 3
www.frontiersin.org

FIGURE 3. Structure of compounds from EH against RA.

TABLE 2
www.frontiersin.org

TABLE 2. Compounds from EH for the treatment of RA.

Anti-inflammatory activities

RA is an inflammatory disease and pro-inflammatory cytokines and chemokines are overproduced in synovial fluid and serum of RA patients (Shrivastava and Pandey, 2013; Jiang et al., 2021). It was reported that astragalin, hyperoside, kaempferol, icariin, apigenin and kaempferitrin treatment decreased arthritic score and incidence of arthritis in animal models (Chi et al., 2014; Li et al., 2016; Jin et al., 2017; Lee et al., 2018; Jia et al., 2019a; Wang and Zhao, 2019; Lei. et al., 2020; Jin. et al., 2021). Furthermore, arthritis symptoms including paw volume and paw thickness were reduced significantly with quercetin, astragalin, hyperoside, icariin, luteolin, kaempferol and kaempferitrin treatment in animal models of arthritis (Haleagrahara et al., 2017; Pan et al., 2018; Jia et al., 2019b; Wang and Zhao, 2019; Lei. et al., 2020; Ahmed and Abd Elkarim, 2021; Jin. et al., 2021; Liu Y et al., 2021). The anti-arthritis effect of compounds from EH in the animal models was shown in Table 3. Anti-arthritis mechanism of compounds extracted from EH may be related to inhibiting inflammatory mediators, such as cytokines, chemokines, Prostaglandin E2 (PGE2), cyclooxygenase (COX)-2, nitric oxide (NO) and inducible nitric oxide synthase (iNOS).

TABLE 3
www.frontiersin.org

TABLE 3. The anti-arthritis effect of compounds from EH for the treatment of RA in the animal models.

Effects on inflammatory cytokines

Proinflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β are responsible for the induction and maintenance of inflammatory milieu in the synovial tissue and articular destruction (Mateen et al., 2016b). Especially TNF-α, a central cytokine in RA pathophysiology (Feldmann et al., 1996), stimulates activation of leukocyte, endothelial, stromal-cell and chondrocyte, as well as expression of angiogenesis, nociception, chemokine (McInnes et al., 2016). Additionally, TNF-α directly increases osteocyte receptor activator of NF-κB ligand (RANKL) expression and induces formation of osteoclasts (Marahleh et al., 2019). Blocking bioactivity of TNF-α reduces production of IL-1, IL-1β, IL-6 and IL-8 (Brennan and McInnes, 2008). Consequently, TNF blockers are one of the most valuable agents to prevent bone erosion and loss in RA.

In vivo and in vitro studies showed that icariin, quercetin and kaempferitrin reduced the expression of IL-1β, IL-6 and TNF-α via PI3K/AKT/Mtor (Wang and Zhao, 2019; Xiang. et al., 2020), miR-223-3p/NLRP3 (Lei. et al., 2020; Wu et al., 2020), and NF-κB signaling pathway (Jia. et al., 2019a; Wang Z et al., 2019). Moreover, luteolin, tricin, kaempferol, isoliquiritigenin, emodin, astragalin and hyperoside inhibited proinflammatory cytokines including IL-1β, IL-6, TNF-α, IL-8, IL-17 and IL-1 (Kim et al., 2008; Hwang et al., 2013; Jin et al., 2016; Jia et al., 2019a; Zhu et al., 2019; Ji et al., 2021; Lin et al., 2021; Ling et al., 2021; Zhou et al., 2021). Apigenin suppressed bone marrow-derived dendritic cells (DCs) to produce cytokines including TNF-α, IL-12 p70 and IL-10, while increased the secretion of IL-1β (Li et al., 2016). Haque et al. reported that magnoflorine enhanced pro-inflammatory responses through producing of TNF-α and IL-1β (Haque et al., 2018). However, Shen et al. showed that magnoflorine attenuated inflammatory responses by reducing inflammatory cytokines, such as IL-6 and IL-8 (Shen et al., 2022). Further research is needed to confirm this opposite conclusion.

Effects on the production of chemokines

Previous research has confirmed that various chemokines are up-regulated in serum, synovial fluid and synovial tissue of patients with RA, compared with healthy controls (Miyabe et al., 2020). Furthermore, chemokines including CXCL13 and CXCL10 can be considered as biomarkers of RA disease activity (Meeuwisse et al., 2011; Pandya et al., 2017). In RA, chemokines boost neutrophils, T cells and the B cells recruitment into the joint (Lee et al., 2017; Miyabe et al., 2017; Armas-Gonzalez et al., 2018). Targeting chemokines might be a promising direction for RA therapies.

It was reported that quercetin suppressed expression of monocyte chemoattractant protein (MCP)-1 in the collagen-induced arthritis (CIA) and AIA mice (Gardi et al., 2015; Haleagrahara et al., 2017). Apigenin inhibited arthritis development through reducing the migration of DCs, which may be related to down-regulating the expression of chemokine receptor 4 (CXCR4) (Li et al., 2016).

Effects on the production of PGE2 and COX

PGE2, a main mediator of inflammation in RA, contributes to the pathogenesis of RA. It can be produced by diverse immune cells upon the activation of COX enzymes and PGE synthases (Park et al., 2006). PGE2 increased IL-17 production and promoted the migration and antigen-presenting function of DCs (Okano et al., 2006; Sheibanie et al., 2007). Furthermore, PGE2 suppressed regulatory T (Treg) cells differentiation via the EP2-cAMP/PKA signaling pathway (Li H. et al., 2017).

Quercetin and kaempferol remarkably suppressed production of PGE2 in human rheumatoid arthritis fibroblast-like synoviocytes (RAFLS), and the mechanism might be related to the inhibition of COX1 and COX2 expression (Lee and Kim, 2010; Sung et al., 2012; Yoon et al., 2013). PGE2 and COX2 were suppressed by quercetin, emodin and icariin in RA mice (Zhu et al., 2013; Yang et al., 2018b; Guazelli et al., 2018; Liu T et al., 2021). Apigenin, isoliquiritigenin and luteolin treatment had an inhibitory effect on the expression of COX2 in lipopolysaccharide (LPS) induced RAW 264.7 macrophage cells (Kim et al., 2008; Lee and Kim, 2010).

Effects on the production of NO and iNOS

Overexpression of iNOS increases the levels of NO, which is an important mediator of synovial inflammation in RA (Li and Wan, 2013; Minhas et al., 2020).

Serum level of NO was effectively decreased in CIA mice with quercetin treatment (Choi et al., 2009). Additionally, apigenin, luteolin, quercetin and kaempferol had an inhibitory effect on NO production stimulated by LPS in RAW 264.7 macrophage cells (Lee and Kim, 2010). In vitro studies showed that magnoflorine, isoliquiritigenin, quercetin, kaempferol, luteolin and apigenin suppressed the level of iNOS (Sun et al., 2020; Lin et al., 2021) and the mechanism may be associated with PI3K/Akt/NF-κB signaling axis and the Keap1-Nrf2/HO-1 signaling pathway (Shen et al., 2022). Furthermore, iNOS was inhibited markedly by quercetin in CIA mice (Yang et al., 2018b) and suppressed by hyperoside in fibroblast-like synoviocytes (FLS) (Fu. et al., 2020).

Immunoregulatory activity

RA is a chronic autoimmune disease characterized as infiltration of the synovial membrane in multiple joints with immune cell such as T cells, B cells, macrophages and DCs (Aletaha and Smolen, 2018). Compounds from EH have immunoregulatory effects via regulating T cells, macrophages, neutrophils, DCs and B cells.

Under antigenic stimulation and cytokine signaling, naive CD4+ T cells activate and differentiate into various Th cell subsets, including Th1, Th2, Th17, follicular Th, and Treg cells. Th1/Th2 and Th17/Treg cells become disproportional in the pathogenesis of RA (Noack and Miossec, 2014; Wang Y et al., 2019). Th1 cells secrete pro-inflammatory factors including interferon-γ (IFN-γ) and TNF-α and Th2 cells secrete anti-inflammatory factors, such as IL-4, IL-10 and IL-13 (Srivastava et al., 2018). Th17 cells accelerate secretion of IL-17 that stimulates production of proinflammatory cytokines including TNF-α, IL-1β, IL-6, matrix metalloproteinases (MMPs) and chemokines (Jin et al., 2018). Treg cells exert anti-inflammatory effects via secreting IL-10 and transforming growth factor-β (TGF-β) (Jiang et al., 2021). Sun et al. found that luteolin and apigenin treatment significantly reduced levels of IFN-γ and IL-2 in concanavalin A -induced splenic T-lymphocyte (Sun et al., 2020). Recent studies have shown that apigenin and chlorogenic acid regulated Th1/Th2 cells balance by inhibiting cytokines of Th1 cells and elevating Th2 cytokines (You. et al., 2009; Chauhan et al., 2012; Zhang. et al., 2015). Quercetin and kaempferol modulated the balance between Th17 and Treg immune response by downregulating Th17 cells and upregulating Treg cells (Lin et al., 2015; Yang et al., 2018b; Lee et al., 2018). Icariin treatment reduced number of Th17 cells in mouse spleens and synovial and suppressed Th17 cell differentiation in vitro experiments via downregulating STAT3 activation (Chi et al., 2014).

Macrophages are commonly divided into two distinct phenotypes, called M1-like macrophages and M2-like macrophages. M1 macrophages are considered as a pro-inflammatory phenotype via expressing pro-inflammatory cytokines and chemokines, while M2 macrophages release anti-inflammatory cytokines including IL-10 and TGF-β (Ross et al., 2021). The number of active M1 macrophages was increased in RA patients while the number of M2 type cells was decreased or inactive (Kennedy et al., 2011). Therefore, blocking M1 macrophage-derived cytokines and modulating the balance between M1 macrophages and M2 macrophages may contribute to the improvement of RA. Icariin and β-sitosterol suppressed M1 macrophage activation and increased M2 macrophage activation (Liu et al., 2019) and the mechanism may be related to inhibit mTOR/S6K1 and NF-κB signaling (Li et al., 2011). In vivo and in vitro studies showed that quercetin inhibited macrophage-derived NO, TNF-α, IL-1β and MCP-1 (Mamani-Matsuda et al., 2006).

In the absence of inflammation, healthy neutrophils circulate in the blood within several hours and undergo apoptosis (McCracken and Allen, 2014). In RA, however, neutrophils inappropriately activated by autoantibodies and inflammatory mediators are characterized by a delayed apoptotic process and migration into the joint (Cecchi et al., 2018). In addition, neutrophils produce reactive oxygen species (ROS) and release diverse cytokines and chemokines, contributing to inflammation and tissue damage (Fresneda Alarcon et al., 2021). The RA synovial microenvironment results in the formation of neutrophil extracellular traps (NETs) that are a source of citrullinated autoantigens and activate FLS, accelerating disease progression and joint damage in RA (Carmona-Rivera et al., 2017). Thus, NETs formation and neutrophil-produced cytokines, chemokines are considered as novel treatment targets (O'Neil and Kaplan, 2019). Quercetin suppressed neutrophil infiltration and NETs formation and increased the apoptosis of activated neutrophils in AIA mice (Yuan et al., 2020). Emodin reduced neutrophil infiltration in AIA mice and increased apoptosis and inhibited autophagy and NETs in vitro (Zhu et al., 2019).

DCs are antigen-presenting cells that link innate and adaptive immune responses. In RA, high concentrations of DCs are recruited in joint synovial fluid and tissues and DCs within the RA synovium are generally mature (Wehr et al., 2019). A recent study showed that synovial microenvironment in RA was responsible for DCs maturation and metabolic reprogramming via up-regulating STAT3 activation (Canavan et al., 2020). In addition, intracellular Zn2+ homeostasis and low oxygen state also impacted the maturation of DCs (Qiao et al., 2022). Inhibition of DCs maturation is an important treatment of DC-targeting in RA. In vivo and in vitro studies showed that apigenin efficiently inhibited DCs maturation and reduced cytokine secretion (Li et al., 2016).

The functions of B cells are closely associated with the pathogenesis of RA, such as antigen presentation, cytokine secretion and autoantibody production (Wu et al., 2021). B cells present autoantigens to T cells and secrete various cytokines including TNF-α, IFN-γ, IL-6, IL-1β, IL-17 and IL-10 (Yanaba et al., 2008). B-cell activating factor (BAFF), a member of the TNF superfamily, promoted the differentiation, proliferation, and activation of B cells via NF-κB signaling pathway (Zhang et al., 2021). Compared with healthy individuals, patients with RA had higher levels of BAFF in the peripheral blood and synovial fluid (Moura et al., 2011). Chlorogenic acid inhibited BAFF Expression in CIA mice and MH7A cells through the NF-κB pathway (Fu et al., 2019).

Osteoprotective activities

Bone and cartilage destruction can be evaluated by morphology, histology, X-ray, and computed tomography scan. Astragalin significantly reduced joint space widening and synovial vascularity by ultrasonography and color doppler and markedly diminished bone destruction of knee and ankle joints by the 3D reconstruction of a micro-CT analysis (Jia et al., 2019b). Icariin inhibited trabecular bone loss and increased bone mineral density in AIA rabbits by micro-CT analysis (Wei et al., 2016). Quercetin treatment attenuated level of 8F-FDG in the ankle and knee joints of CIA mice by 18F-FDG micro-PET imaging, suggesting it could reduce inflammation in joints (Shen et al., 2021). Furthermore, bone erosion and degradation were not serious and the narrowing of joint space was slight with quercetin treatment compared with the arthritis group in the X-ray examination (Haleagrahara et al., 2017). The compounds from EH play osteoprotective roles by decreasing formation and differentiation of osteoclasts, regulating of RANKL/osteoprotegerin (OPG) ratio and downregulating MMPs.

Effects on formation and differentiation of osteoclasts

Formation and differentiation of osteoclasts are the essential elements of bone degradation. Osteoclast differentiation is regulated by the molecular triad RANKL, receptor activator of nuclear factor-κB (RANK) and OPG (Aureal et al., 2020). RANKL-RANK signaling activates osteoclast differentiation and suppresses osteoclast apoptosis (Kitaura et al., 2020). OPG, a RANKL decoy receptor, can prevent RANKL-RANK binding (Boyle et al., 2003). The ratio of RANKL to OPG can be regarded as a marker of progression of osteoclast destruction (van Tuyl et al., 2010).

Ikarisoside A and isoliquiritigenin suppressed osteoclastogenesis in RANKL-stimulated RAW 264.7 cells and bone marrow-derived macrophages via MAPK and NF-κB pathways (Choi et al., 2010; Zhu et al., 2012). Furthermore, in vivo and in vitro studies showed that isoliquiritigenin had an anti-osteoclastogenic activity by suppressing NF-κB-dependent autophagy (Liu et al., 2016).

Emodin inhibited the osteoclast differentiation in bone marrow macrophages (Hwang et al., 2013). Quercetin attenuated IL-17-induced RANKL expression in RAFLS (Kim et al., 2019). Several in vivo models suggested that icariin decreased osteoclasts formation, mechanism of which might be relate to the regulation of RANKL/OPG ratio (Liu. et al., 2013; Wei et al., 2016). Apigenin and luteolin treatment regulated the RANKL/OPG ratio in CIA mice by inhibiting RANKL expression and elevating OPG expression (Liu and Li, 2018; Li et al., 2019).

Effects on cartilage protection

MMPs, belonging to the proteolytic enzymes, are intimately involved in degradation of extracellular matrix in cartilage (Itoh, 2017). Tissue inhibitor of metalloproteinases (TIMPs), a natural inhibitor, specifically inhibit MMPs (Alamgeer et al., 2020). In RA, cytokines promote chondrocytes to secret more cytokines and MMPs that degrade the cartilage and suppress generation of TIMPs (Fang et al., 2020). Furthermore, synovial tissue of RA patients produces diverse MMPs, such as MMP-1, -2, -3, -8, -9, -10, -12, -13 (Itoh, 2017). Previous studies have reported that the serum concentrations of MMP-3 can be considered as predictive marker of inflammation and joint destruction (Yamanaka et al., 2000; Shinozaki et al., 2007).

In vivo and in vitro studies showed that astragalin and quercetin inhibited the expression of MMPs via NF-κB pathway (Jia. et al., 2019b; Wang Z et al., 2019; Wang and Zhao, 2019) and Akt/mTOR pathways (Wang and Zhao, 2019). In vitro studies reported that MMPs were reduced by icariin (Chi et al., 2014), hyperoside (Fu. et al., 2020), kaempferitrin (Jia et al., 2019a), ikarisoside A, kaempferol, apigenin and luteolin treatment (Zhou et al., 2021) via NF-κB and MAPK signaling pathway (Choi et al., 2010; Choi and Lee, 2010; Yoon et al., 2013; Jin et al., 2016) and PI3K/Akt pathways (Hou et al., 2009). MMPs were suppressed with emodin treatment in CIA mice through NF-κB pathway (Hwang et al., 2013).

Effects on FLS proliferation, migration and apoptosis

In RA, FLS results in hyperplasia of the synovial lining, pannus formation, joint destruction through producing cytokines, chemokines, and matrix-degrading molecules and migrating and invading joint cartilage (Bustamante et al., 2017). RAFLS are resistant to apoptosis resulting from up-regulation of anti-apoptotic mediators including Bcl-2, Mcl-2, and FLICE-inhibitory protein (FLIP) and down-regulation of pro-apoptotic proteins including tumor necrosis factor-related apoptosis-inducing ligand and p53 up-regulated modulator of apoptosis (Zhang Q. et al., 2019). Furthermore, FLS produce several enzymes connected with invasive activities of FLS, such as collagenases, aggrecanases, cathepsins, and RANKL (Tu et al., 2018). Expansion of FLS increases oxygen consumption in synovium and forms a hypoxic environment, contributing to synovium angiogenic processes and pannus formation. FLS also stimulate overproduction of MMPs including MMP1, MMP3 and MMP13, leading to degradation of the collagen-rich structures of extracellular matrix (Nygaard and Firestein, 2020). Consequently, FLS can be regarded as hopeful therapeutic target for the treatment of RA (Aletaha and Smolen, 2018).

Icariin, kaempferol, kaempferitrin, chlorogenic acid and apigenin enhanced apoptosis and restrained proliferation of RAFLS via regulating miR-223-3p/NLRP3 signaling pathway (Wu et al., 2020), cell cycle and mitochondrial pathway (Pu et al., 2021), MAPK pathway (Yoon et al., 2013), NF-κB pathways (Yoon et al., 2013; Lou et al., 2015; Wang and Zhao, 2019), JAK/STAT pathways (Lou et al., 2015) and PI3K/Akt/mTOR signaling pathway (Sun et al., 2012; Wang and Zhao, 2019). Quercetin elevated apoptosis and decreased the migration and invasion of FLS through mitochondrial pathway and p53 phosphorylation (Xiao et al., 2013), PI3K/Akt pathway (Pan et al., 2016) and miR-146a/GATA6 axis (Zhao et al., 2020). Kaempferol, hyperoside and luteolin had suppressive effects on either migration or proliferation of FLS by TNF signaling pathway (Ling et al., 2021), fibroblast growth factor receptor 3–ribosomal S6 kinase 2 signaling pathway (Lee et al., 2018), MAPK pathway (Hou et al., 2009; Fu. et al., 2020), NF-κB signaling pathway (Lou et al., 2015; Jin et al., 2016), PI3K/Akt pathways (Hou et al., 2009) and JAK/STAT signaling pathways (Lou et al., 2015). Magnoflorine inhibited migration, invasion, proliferation and induced apoptosis and cell cycle arrest of RAFLS via inhibiting the PI3K/Akt/NF-κB axis signaling pathway and activating the Keap1-Nrf2/HO-1 signaling pathway (Shen et al., 2022).

Antiangiogenic activities

Angiogenesis, the formation of new capillaries, is related to leukocyte ingress into the synovium, synovial hyperplasia and pannus formation (Wang Z et al., 2021). Angiogenesis can be induced by angiogenic mediators including various growth factors, cytokines, chemokines, cell adhesion molecules, etc (Bodolay et al., 2002). Vascular endothelial growth factor (VEGF), one of the most vital growth factors, has a mitogenic and an anti-apoptotic effect on endothelial cells and increases the vascular permeability and cell migration (Melincovici et al., 2018). VEGF is activated by hypoxia and hypoxia-inducible factors 1 (HIF-1) and HIF-2 and pro-inflammatory cytokines including TNF-α and IL-1 (Szekanecz and Koch, 2009).

Histological evaluation demonstrated that quercetin reduced pannus formation in CIA mice (Kawaguchi et al., 2019), the mechanism of which might be associated with inhibition of VEGFA, HIF-1α and capillaries density in synovial tissue of CIA mice (Chu. et al., 2021). The expression of VEGF, VEGFR1 and VEGFR2 in synovial tissues of CIA mice and vascular cell adhesion molecule (VCAM) in human umbilical vein endothelial cells (HUVECs) were significantly inhibited by apigenin (Li et al., 2019; Zhou et al., 2021). A recent study showed that luteolin suppressed the expression of VEGF and HIF-1α in CIA mice and HUVECs (Liu T et al., 2021; Zhou et al., 2021). In vivo and in vitro studies showed that β-sitosterol significantly inhibited the expression and phosphorylation of VEGFR2 (Qian et al., 2021).

Antioxidant activities

Effects on ROS production and mitochondria dysfunction

Generally, it has been reported that oxidative stress is an associated factors in the pathogenesis of RA (Phull et al., 2018). Oxidative stress arises when enhancement of ROS exceeds the normal physiological values (Smallwood et al., 2018). The excessive production of ROS contributes to inflammation, matrix degradation and chondrocytes apoptosis via MAPKs and NF-κB signaling pathway (Phull et al., 2018). Mitochondria are generally regarded as the source of ROS in animal cells and mitochondrial dysfunction is responsible for imbalance of antioxidant systems (Munro and Treberg, 2017).

In vivo studies showed that ROS production was inhibited with quercetin and kaempferol treatment (Santos et al., 2014; Saccol et al., 2020). Apigenin induced intracellular ROS production in MH7A cells, which was associated with activation of ERK1/2 and apoptosis (Shin et al., 2009). Quercetin improved impaired mitochondrial biogenesis and mitochondrial function in CIA mice via regulating the SIRT1/PGC-1α/NRF1/TFAM pathway (Shen et al., 2021). In vitro studies showed that icariin and quercetin treatment induced apoptosis through mitochondrial pathway (Xiao et al., 2013; Pu et al., 2021).

Effects of lipid peroxidation and myeloperoxidase activity

Previous studies have reported that RA patients have increased lipid peroxidation in the synovial fluid and blood serum (Mateen et al., 2016a). Malondialdehyde and thiobarbituric acid-reactive substance (TBARS) are widely used to measure lipid peroxidation (Ghani et al., 2017; Tsikas, 2017). 15-lipoxygenase, a lipid-peroxidizing enzyme, was largely expressed by macrophages, neutrophils and mast cells in RA synovium (Gheorghe et al., 2009).

Luteolin suppressed 15-lipoxygenase in RAW 264.7 macrophage cells (Lee and Kim, 2010). The augmentation in TBARS levels and 15-lipoxygenase were reversed with quercetin treatment (Lee and Kim, 2010; Saccol et al., 2020). Furthermore, other study reported that 12/15-lipoxygenase in lung and liver were inhibited with quercetin treatment in AIA mice (Gardi et al., 2015). Quercetin and kaempferol treatment reduced the myeloperoxidase activity in neutrophils (Santos et al., 2014).

Clinical trials

Although various compounds extracted from EH exert anti-RA effect, few compounds have been used in clinical. In a randomized controlled trial, compared to azathioprine plus placebo or lower doses of quercetin (500, 1000 mg/day), azathioprine plus quercetin (1500 mg/day) in patients with RA obviously downregulated IL-6, intercellular adhesion molecule-1, complement proteins and upregulated IL-10 (Al-Rekabi et al., 2015). Quercetin supplement (500 mg/day) for 8 weeks exerted the beneficial effects on pain, stiffness, disease activity, inflammatory factors and well-being in women with RA in a double-blind, randomized controlled trial (Javadi et al., 2017). However, another study reported that quercetin (500 mg/day) for women with RA after 8 weeks had no significant differences in total antioxidant capacity, oxidized low density lipoprotein, malondialdehyde and high sensitivity C-reactive protein compared to placebo groups (Javadi et al., 2014). The clinical trials of quercetin for the treatment of RA were shown in Table 4.

TABLE 4
www.frontiersin.org

TABLE 4. An overview on clinical trials evaluating effects of compounds involved in EH on RA.

Alternative strategies for the treatment of RA

Combination with approved drugs

According to European League Against Rheumatism (EULAR) recommendation, DMARDs should be started as soon as the diagnosis of RA (Smolen et al., 2020). Methotrexate (MTX), an efficacious DMARDs, is the first line for the treatment of RA. However, some adverse effects of MTX have limited their extensive clinical application, such as liver dysfunction, renal failure and nausea (Katturajan et al., 2021). In order to overcome the disadvantages and further improve the effective in treatment, it is necessary to explore combination therapy of compounds from EH and DMARDs for the treatment of RA.

Compared to the quercetin (30 mg/kg orally) or MTX (0.75 mg intraperitoneally twice a week) groups, the combination therapy significantly inhibited paw thickness and expression of proinflammatory cytokines including IL-1β, TNF-α, IL-6, and IL-17 in CIA mice (Haleagrahara et al., 2018). Moreover, quercetin reversed the transaminases levels of MTX groups including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (Costa et al., 2021). However, the other report showed that the concurrent therapy of quercetin (30 mg/kg orally) and MTX (0.5 mg/kg intraperitoneally) did not provide greater protection than a single agent (Haleagrahara et al., 2017).

Bioavailability improvement

EH has been commonly used in various traditional Chinese decoctions for the treatment of RA. Compared to other delivery routes, oral administration has clear advantages including lower pain and less risk of cross-infection (Das and Chaudhury, 2011). Consequently, oral administration was frequently chosen as the primary clinical administration approach. However, poor solubility, low permeability and inferior stability by oral administration result in restriction of their effectiveness (Zhao et al., 2019). For example, bioavailability of quercetin is pharmaceutically characterized as poor solubility, low bioavailability, poor permeability and instability (Cai et al., 2013). Furthermore, low concentration of those components by oral administration exerts curative effects in the joint cavities with systemic circulation. Given the above characteristics and disadvantages, new technologies have drawn increased attention to improve the bioavailability and effectiveness of the components. The new technologies of bioavailability improvement of EH were shown in Figure 4.

FIGURE 4
www.frontiersin.org

FIGURE 4. Limitations of flavonoids through oral administration in RA therapy and their delivery systems for a promising option.

Nanoencapsulation technology including liposomes, nanoemulsions, and nanocapsules appear to be a promising option to increase bioavailability of the compounds (Han et al., 2020). Treatment of 10 mg/kg quercetin carried by pectin/casein microcapsules reduced oxidative stress and had no hepatotoxicity and mitochondriotoxicity by oral administration in AIA rats (Souza et al., 2021). In vitro and in vivo studies reported that quercetin loaded in polycaprolactone microspheres increased the duration in joint cavity for more than 30 days (Natarajan et al., 2011). Quercetin loaded by nanoemulsion-based gel had no toxic effect on synoviocytes and improved drug permeation and attenuated paw edema over 24 h in AIA rats (Gokhale et al., 2019). Complexes of quantum dots and quercetin significantly inhibited inflammation and oxidative stress and improved cartilage regeneration in AIA rats (Jeyadevi et al., 2013). Compared with luteolin treatment, combination of polyethylene glycol-mesoporous silica nano-carriers and luteolin was more effective and had longer existence time in AIA rats (Pang et al., 2021).

Safety assessment of EH

EH is an ancient traditional Chinese herbal for 2000 years and has been frequently used to treat various disease. However, it was reported that EH could cause drug-induced liver injury. Wang et al. found that water extract and alcohol extract of Epimedium brevicornu Maxim (20, 40, 80 g/kg) for 8 weeks reduced body weight of mice. Furthermore, the organ coefficient, blood indicators, serum biochemical indicators had a certain degree of change (P<0.05), indicating that EH at 140 times the maximum human dose have certain toxic effects on mice for 8 weeks (Wang. et al., 2018). In vivo study showed that Epimedium koreanum Nakai had liver toxicity which was enhanced by increased dosage and prolonged time (Zhang. et al., 2018). Therefore, although EH is relatively safe for clinical use, it is still necessary to be cautious and do not take large doses or take it for a long time.

Previous research has reported that quercetin at dietary intake levels did not exert harmful effects on human health (Harwood et al., 2007). Recent study also showed that no zebrafish died or had abnormal morphology under 200 μM icariin (Zhong et al., 2019).

In vivo studies reported that hyperoside (65 and 500 mg/kg) had chronic hepatotoxicity and nephrotoxicity in beagle dogs, but the destruction was reversed and returned to normal after withdrawal (Ai. et al., 2015). High concentrations (36 μg/ml) of ikarisoside A induced liver injury in HL-7702 and HepG2 Cells via enhancing oxidative stress and inducing apoptosis (Zhang L. et al., 2019).

Conclusion and future perspectives

RA is a chronic autoimmune disease and causes of RA are unclear. In TCM theory, the patients with RA are affected by “Wind”, “Cold”, “Damp” and “Kidney deficiency”. EH can strengthen bones and muscle, dispel wind chill and tonify the kidney, so it has been widely used in prescriptions of TCM for the treatment of RA. Remarkable curative effects in clinic draw increased attention and pharmacological research to investigate material foundation and pharmacological mechanism.

In this review, 293 components were searched from EH in different database and 15 compounds were filtered for the treatment of RA. Then, therapeutic effect, pharmacological mechanism, bioavailability and toxicity of the components were overall summarized and analyzed. This paper summarized the mechanism of the compounds in the treatment of RA through studies in vivo and in vitro. Studies showed that the components from EH have extensive pharmacological activities including anti-inflammatory, immunoregulatory, antioxidant, antiangiogenic, anti-FLS and osteoprotective effects.

By summarizing, it is no wonder that icariin is prime component and one of chemical markers for quality control of EH, which have bright particularly attention to the health-promoting effects. Icariin has anti-RA effects via anti-inflammatory, immunoregulatory, osteoprotective and antioxidant activities. A schematic view of anti-RA effects of icariin was shown in Figure 5. However, most of data were acquired from laboratory tests in several animal and cellular models. Clinical trials are required to carried out to explore the possible therapeutic effects of icariin for the management of RA.

FIGURE 5
www.frontiersin.org

FIGURE 5. A schematic view of anti-RA effects of icariin (↑ = up-regulation; ↓ = down-regulation; red arrow = icariin) (images cited from Servier Medical Art images at www.servier.com).

A large number of components from EH were searched and the results indicate that EH may have the multicomponent and multifunctional traits in the treatment of RA. The mechanism of compounds from EH for the treatment of RA was shown in Table 5. However, there are few published studies exploring the anti-RA effects of other compounds isolated from EH. In this review, anti-RA effects of the compounds in other species were inferred to EH. Therefore, it is necessary to investigate the anti-RA effects of other compounds from EH in the future.

TABLE 5
www.frontiersin.org

TABLE 5. The mechanism of compounds from EH for the treatment of RA.

Author contributions

L-BZ and YY contributed equally to this work and they collated documents and wrote the manuscript; JH, P-PW, and J-PW polished the language; XC, T-YL, Y-XG, JL, and Z-RY helped to organize the literatures; Q-WT and YX contributed significantly to design and revision of the manuscript.

Funding

The work was supported by National Key R&D Program of China (NO. 2018YFC1705502), National High Level Hospital Clinical Research Funding (NO.2022-NHLHCRF-LX-02-02), Beijing Chinese Medicine Science and Technology Development Fund Project (Youth Planning Project QN-2020-32), Elite Medical Professionals project of China-Japan Friendship Hospital (No. ZRJY2021-TD06).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

Ahmed, A. H., and Abd Elkarim, A. S. (2021). Bioactive compounds with significant anti- rheumatoid arthritis effect isolated for the first time from leaves of bougainvillea spectabilis. Curr. Pharm. Biotechnol. 22 (15), 2048–2053. doi:10.2174/1389201021666201229111825

PubMed Abstract | CrossRef Full Text | Google Scholar

Ai, G., Wang, D., Huang, Z., and Zhang, H. (2015). Long-term toxicity of hyperoside in Beagle dogs. Chin. J. New Drugs 24 (14), 1641–1647.

Google Scholar

Al-Rekabi, M. D., Ali, S. H., Al-Basaisi, H., Hashim, F., Hussein, A. H., and Abbas, H. K. (2015). Immunomodulatory effects of quercetin in patient with active rheumatoid arthritis. Br. J. Med. Health Res. 2 (6), 23–34. doi:10.3390/ijms19051453

CrossRef Full Text | Google Scholar

Alamgeer, S. T., Hasan, U. H., Uttra, A. M., Qasim, S., Ikram, J., Saleem, M., et al. (2020). Phytochemicals targeting matrix metalloproteinases regulating tissue degradation in inflammation and rheumatoid arthritis. Phytomedicine 66, 153134. doi:10.1016/j.phymed.2019.153134

PubMed Abstract | CrossRef Full Text | Google Scholar

Aletaha, D., and Smolen, J. S. (2018). Diagnosis and management of rheumatoid arthritis: A review. JAMA 320 (13), 1360–1372. doi:10.1001/jama.2018.13103

PubMed Abstract | CrossRef Full Text | Google Scholar

Armas-Gonzalez, E., Dominguez-Luis, M. J., Diaz-Martin, A., Arce-Franco, M., Castro-Hernandez, J., Danelon, G., et al. (2018). Role of CXCL13 and CCL20 in the recruitment of B cells to inflammatory foci in chronic arthritis. Arthritis Res. Ther. 20 (1), 114. doi:10.1186/s13075-018-1611-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Aureal, M., Machuca-Gayet, I., and Coury, F. (2020). Rheumatoid arthritis in the view of osteoimmunology. Biomolecules 11 (1), 48. doi:10.3390/biom11010048

PubMed Abstract | CrossRef Full Text | Google Scholar

Bodolay, E., Koch, A. E., Kim, J., Szegedi, G., and Szekanecz, Z. (2002). Angiogenesis and chemokines in rheumatoid arthritis and other systemic inflammatory rheumatic diseases. J. Cell. Mol. Med. 6 (3), 357–376. doi:10.1111/j.1582-4934.2002.tb00514.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Boyle, W. J., Simonet, W. S., and Lacey, D. L. (2003). Osteoclast differentiation and activation. Nature 423 (6937), 337–342. doi:10.1038/nature01658

PubMed Abstract | CrossRef Full Text | Google Scholar

Brennan, F. M., and McInnes, I. B. (2008). Evidence that cytokines play a role in rheumatoid arthritis. J. Clin. Invest. 118 (11), 3537–3545. doi:10.1172/JCI36389

PubMed Abstract | CrossRef Full Text | Google Scholar

Burmester, G. R., and Pope, J. E. (2017). Novel treatment strategies in rheumatoid arthritis. Lancet 389 (10086), 2338–2348. doi:10.1016/s0140-6736(17)31491-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Bustamante, M. F., Garcia-Carbonell, R., Whisenant, K. D., and Guma, M. (2017). Fibroblast-like synoviocyte metabolism in the pathogenesis of rheumatoid arthritis. Arthritis Res. Ther. 19 (1), 110. doi:10.1186/s13075-017-1303-3

PubMed Abstract | CrossRef Full Text | Google Scholar

Cai, X., Fang, Z., Dou, J., Yu, A., and Zhai, G. (2013). Bioavailability of quercetin: Problems and promises. Curr. Med. Chem. 20 (20), 2572–2582. doi:10.2174/09298673113209990120

PubMed Abstract | CrossRef Full Text | Google Scholar

Canavan, M., Marzaioli, V., McGarry, T., Bhargava, V., Nagpal, S., Veale, D. J., et al. (2020). Rheumatoid arthritis synovial microenvironment induces metabolic and functional adaptations in dendritic cells. Clin. Exp. Immunol. 202 (2), 226–238. doi:10.1111/cei.13479

PubMed Abstract | CrossRef Full Text | Google Scholar

Carmona-Rivera, C., Carlucci, P. M., Moore, E., Lingampalli, N., Uchtenhagen, H., James, E., et al. (2017). Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis. Sci. Immunol. 2 (10), eaag3358. doi:10.1126/sciimmunol.aag3358

PubMed Abstract | CrossRef Full Text | Google Scholar

Cecchi, I., Arias de la Rosa, I., Menegatti, E., Roccatello, D., Collantes-Estevez, E., Lopez-Pedrera, C., et al. (2018). Neutrophils: Novel key players in Rheumatoid Arthritis. Current and future therapeutic targets. Autoimmun. Rev. 17 (11), 1138–1149. doi:10.1016/j.autrev.2018.06.006

PubMed Abstract | CrossRef Full Text | Google Scholar

Chakraborty, D., Gupta, K., and Biswas, S. (2021). A mechanistic insight of phytoestrogens used for Rheumatoid arthritis: An evidence-based review. Biomed. Pharmacother. 133, 111039. doi:10.1016/j.biopha.2020.111039

PubMed Abstract | CrossRef Full Text | Google Scholar

Chauhan, P. S., Satti, N. K., Sharma, P., Sharma, V. K., Suri, K. A., and Bani, S. (2012). Differential effects of chlorogenic acid on various immunological parameters relevant to rheumatoid arthritis. Phytother. Res. 26 (8), 1156–1165. doi:10.1002/ptr.3684

PubMed Abstract | CrossRef Full Text | Google Scholar

Chen, L., Yan, X., Shi, G., and Zhao, C. (2021). Clinical observation on Wangbi Tablet treating on early rheumatoid arthritis with syndrome of liver and kidney deficiency and syndrome of wind-dampness blocking collaterals. China J. Traditional Chin. Med. Pharm. 36 (04), 2400–2403.

Google Scholar

Chen, M., Wu, J., Luo, Q., Mo, S., Lyu, Y., Wei, Y., et al. (2016). The anticancer properties of Herba epimedii and its main bioactive componentsicariin and icariside II. Nutrients 8 (9), 563. doi:10.3390/nu8090563

PubMed Abstract | CrossRef Full Text | Google Scholar

Cheng, L., Huo, X., Yang, L., Zhang, Y., and Zhou, K. (2022). Determination of 11 effective components in Epimedium from different primordium by UPLC. J. Tianjin Univ. Traditional Chin. Med. 41 (02), 237–242.

Google Scholar

Cheng, Y., Wang, N., Wang, X., Zhang, D., Huang, W., and Yao, X. (2006). Chemical constituents of Epimedium koraiensis. J. China Pharm. Univ. 23 (10), 644–647+657.

Google Scholar

Chi, A., Shen, Z., Zhu, W., Sun, Y., Kang, Y., and Guo, F. (2017). Characterization of a protein-bound polysaccharide from Herba Epimedii and its metabolic mechanism in chronic fatigue syndrome. J. Ethnopharmacol. 203, 241–251. doi:10.1016/j.jep.2017.03.041

PubMed Abstract | CrossRef Full Text | Google Scholar

Chi, L., Gao, W., Shu, X., and Lu, X. (2014). A natural flavonoid glucoside, icariin, regulates Th17 and alleviates rheumatoid arthritis in a murine model. Mediat. Inflamm. 2014, 1–10. doi:10.1155/2014/392062

PubMed Abstract | CrossRef Full Text | Google Scholar

Cho, J. H., Jung, J. Y., Lee, B. J., Lee, K., Park, J. W., and Bu, Y. (2017). Epimedii Herba: A promising herbal medicine for neuroplasticity. Phytother. Res. 31 (6), 838–848. doi:10.1002/ptr.5807

PubMed Abstract | CrossRef Full Text | Google Scholar

Choi, E. J., Bae, S. C., Yu, R., Youn, J., and Sung, M. K. (2009). Dietary vitamin E and quercetin modulate inflammatory responses of collagen-induced arthritis in mice. J. Med. Food 12 (4), 770–775. doi:10.1089/jmf.2008.1246

PubMed Abstract | CrossRef Full Text | Google Scholar

Choi, E. M., and Lee, Y. S. (2010). Luteolin suppresses IL-1β-induced cytokines and MMPs production via p38 MAPK, JNK, NF-kappaB and AP-1 activation in human synovial sarcoma cell line, SW982. Food Chem. Toxicol. 48 (10), 2607–2611. doi:10.1016/j.fct.2010.06.029

PubMed Abstract | CrossRef Full Text | Google Scholar

Choi, H. J., Park, Y. R., Nepal, M., Choi, B. Y., Cho, N. P., Choi, S. H., et al. (2010). Inhibition of osteoclastogenic differentiation by Ikarisoside A in RAW 264.7 cells via JNK and NF-κB signaling pathways. Eur. J. Pharmacol. 636 (1-3), 28–35. doi:10.1016/j.ejphar.2010.03.023

PubMed Abstract | CrossRef Full Text | Google Scholar

Chu, X., Chai, J., Guo, S., Wang, Y., and Chen, C. (2021). Effect of quercetin on synovial angiogenesis in rats with collagen-induced arthritis. J. Shanxi Med. Univ. 52 (03), 301–309. doi:10.13753/j.issn.1007-6611.2021.03.010

CrossRef Full Text | Google Scholar

Costa, A. C. F., de Sousa, L. M., Dos Santos Alves, J. M., Goes, P., Pereira, K. M. A., Alves, A., et al. (2021). Anti-inflammatory and hepatoprotective effects of quercetin in an experimental model of rheumatoid arthritis. Inflammation 44 (5), 2033–2043. doi:10.1007/s10753-021-01479-y

PubMed Abstract | CrossRef Full Text | Google Scholar

Cui, X., Deng, L., and Huang, S. (2010). Studies on chemical constituents in chloroform extraction of Epimedium sagittatum. Chin. J. Exp. Traditional Med. Formulae 16 (13), 101–103. doi:10.13422/j.cnki.syfjx.2010.13.032

CrossRef Full Text | Google Scholar

Cush, J. J. (2021). Rheumatoid arthritis: Early diagnosis and treatment. Med. Clin. North Am. 105 (2), 355–365. doi:10.1016/j.mcna.2020.10.006

PubMed Abstract | CrossRef Full Text | Google Scholar

Das, S., and Chaudhury, A. (2011). Recent advances in lipid nanoparticle formulations with solid matrix for oral drug delivery. AAPS PharmSciTech 12 (1), 62–76. doi:10.1208/s12249-010-9563-0

PubMed Abstract | CrossRef Full Text | Google Scholar

Du, X., Zou, X., Cai, T., and Ruan, F. (2019). Effect of xianling spleen combined with tripterygium wilfordii in the treatment of rheumatoid arthritis. Zhejiang J. Traditional Chin. Med. 54 (12), 884–886. doi:10.13633/j.cnki.zjtcm.2019.12.014

CrossRef Full Text | Google Scholar

Fang, Q., Zhou, C., and Nandakumar, K. S. (2020). Molecular and cellular pathways contributing to joint damage in rheumatoid arthritis. Mediat. Inflamm. 2020, 1–20. doi:10.1155/2020/3830212

PubMed Abstract | CrossRef Full Text | Google Scholar

Feldmann, M., Brennan, F. M., and Maini, R. N. (1996). Rheumatoid arthritis. Cell 85 (3), 307–310. doi:10.1016/s0092-8674(00)81109-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Fresneda Alarcon, M., McLaren, Z., and Wright, H. L. (2021). Neutrophils in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus: Same foe different M.O. Front. Immunol. 12, 649693. doi:10.3389/fimmu.2021.649693

PubMed Abstract | CrossRef Full Text | Google Scholar

Fu, Q., Jin, X., Gao, Y., Wang, J., and Yan, P. (2020). Effect of hyperoside on synoviocytes of rheumatoid arthritis and its mechanism. J. Jinzhou Med. Univ. 41 (03), 7–12. doi:10.13847/j.cnki.lnmu.2020.03.002

CrossRef Full Text | Google Scholar

Fu, X., Lyu, X., Liu, H., Zhong, D., Xu, Z., He, F., et al. (2019). Chlorogenic acid inhibits BAFF expression in collagen-induced arthritis and human synoviocyte MH7A cells by modulating the activation of the NF-κB signaling pathway. J. Immunol. Res. 2019, 1–10. doi:10.1155/2019/8042097

PubMed Abstract | CrossRef Full Text | Google Scholar

Gardi, C., Bauerova, K., Stringa, B., Kuncirova, V., Slovak, L., Ponist, S., et al. (2015). Quercetin reduced inflammation and increased antioxidant defense in rat adjuvant arthritis. Arch. Biochem. Biophys. 583, 150–157. doi:10.1016/j.abb.2015.08.008

PubMed Abstract | CrossRef Full Text | Google Scholar

Ghani, M. A., Barril, C., Bedgood, D. R., and Prenzler, P. D. (2017). Measurement of antioxidant activity with the thiobarbituric acid reactive substances assay. Food Chem. x. 230, 195–207. doi:10.1016/j.foodchem.2017.02.127

PubMed Abstract | CrossRef Full Text | Google Scholar

Gheorghe, K. R., Korotkova, M., Catrina, A. I., Backman, L., af Klint, E., Claesson, H. E., et al. (2009). Expression of 5-lipoxygenase and 15-lipoxygenase in rheumatoid arthritis synovium and effects of intraarticular glucocorticoids. Arthritis Res. Ther. 11 (3), R83. doi:10.1186/ar2717

PubMed Abstract | CrossRef Full Text | Google Scholar

Gokhale, J. P., Mahajan, H. S., and Surana, S. J. (2019). Quercetin loaded nanoemulsion-based gel for rheumatoid arthritis: In vivo and in vitro studies. Biomed. Pharmacother. 112, 108622. doi:10.1016/j.biopha.2019.108622

PubMed Abstract | CrossRef Full Text | Google Scholar

Guazelli, C. F. S., Staurengo-Ferrari, L., Zarpelon, A. C., Pinho-Ribeiro, F. A., Ruiz-Miyazawa, K. W., Vicentini, F., et al. (2018). Quercetin attenuates zymosan-induced arthritis in mice. Biomed. Pharmacother. 102, 175–184. doi:10.1016/j.biopha.2018.03.057

PubMed Abstract | CrossRef Full Text | Google Scholar

Haleagrahara, N., Hodgson, K., Miranda-Hernandez, S., Hughes, S., Kulur, A. B., and Ketheesan, N. (2018). Flavonoid quercetin-methotrexate combination inhibits inflammatory mediators and matrix metalloproteinase expression, providing protection to joints in collagen-induced arthritis. Inflammopharmacology 26 (5), 1219–1232. doi:10.1007/s10787-018-0464-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Haleagrahara, N., Miranda-Hernandez, S., Alim, M. A., Hayes, L., Bird, G., and Ketheesan, N. (2017). Therapeutic effect of quercetin in collagen-induced arthritis. Biomed. Pharmacother. 90, 38–46. doi:10.1016/j.biopha.2017.03.026

PubMed Abstract | CrossRef Full Text | Google Scholar

Han, D., Chen, Q., and Chen, H. (2020). Food-derived nanoscopic drug delivery systems for treatment of rheumatoid arthritis. Molecules 25 (15), 3506. doi:10.3390/molecules25153506

PubMed Abstract | CrossRef Full Text | Google Scholar

Han, Y. (2022). Comparative study on the content of main flavonoids in Epimedium. Guangming J. Chin. Med. 37 (06), 991–993.

Google Scholar

Haque, M. A., Jantan, I., Harikrishnan, H., and Abdul Wahab, S. M. (2018). Magnoflorine enhances LPS-activated pro-inflammatory responses via MyD88-dependent pathways in U937 macrophages. Planta Med. 84 (17), 1255–1264. doi:10.1055/a-0637-9936

PubMed Abstract | CrossRef Full Text | Google Scholar

Harwood, M., Danielewska-Nikiel, B., Borzelleca, J. F., Flamm, G. W., Williams, G. M., and Lines, T. C. (2007). A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food Chem. Toxicol. 45 (11), 2179–2205. doi:10.1016/j.fct.2007.05.015

PubMed Abstract | CrossRef Full Text | Google Scholar

Hou, Y., Wu, J., Huang, Q., and Guo, L. (2009). Luteolin inhibits proliferation and affects the function of stimulated rat synovial fibroblasts. Cell Biol. Int. 33 (2), 135–147. doi:10.1016/j.cellbi.2008.10.005

PubMed Abstract | CrossRef Full Text | Google Scholar

Hu, Y., Li, H., Ji, G., Shen, X., Wei, X., Fu, L., et al. (2021). Chemical constituents with HDAC inhibitory effects from Epimedium sagittatum. Nat. Prod. Res. Dev. 33 (10), 1681–1690. doi:10.16333/j.1001-6880.2021.10.007

CrossRef Full Text | Google Scholar

Hwang, J. K., Noh, E. M., Moon, S. J., Kim, J. M., Kwon, K. B., Park, B. H., et al. (2013). Emodin suppresses inflammatory responses and joint destruction in collagen-induced arthritic mice. Rheumatol. Oxf. 52 (9), 1583–1591. doi:10.1093/rheumatology/ket178

PubMed Abstract | CrossRef Full Text | Google Scholar

Itoh, Y. (2017). Metalloproteinases in rheumatoid arthritis: Potential therapeutic targets to improve current therapies. Prog. Mol. Biol. Transl. Sci. 148, 327–338. doi:10.1016/bs.pmbts.2017.03.002

PubMed Abstract | CrossRef Full Text | Google Scholar

Javadi, F., Ahmadzadeh, A., Eghtesadi, S., Aryaeian, N., Zabihiyeganeh, M., Rahimi Foroushani, A., et al. (2017). The effect of quercetin on inflammatory factors and clinical symptoms in women with rheumatoid arthritis: A double-blind, randomized controlled trial. J. Am. Coll. Nutr. 36 (1), 9–15. doi:10.1080/07315724.2016.1140093

PubMed Abstract | CrossRef Full Text | Google Scholar

Javadi, F., Eghtesadi, S., Ahmadzadeh, A., Aryaeian, N., Zabihiyeganeh, M., Foroushani, A. R., et al. (2014). The effect of quercetin on plasma oxidative status, C-reactive protein and blood pressure in women with rheumatoid arthritis. Int. J. Prev. Med. 5 (3), 293–301.

PubMed Abstract | Google Scholar

Jeyadevi, R., Sivasudha, T., Rameshkumar, A., Ananth, D. A., Aseervatham, G. S., Kumaresan, K., et al. (2013). Enhancement of anti arthritic effect of quercetin using thioglycolic acid-capped cadmium telluride quantum dots as nanocarrier in adjuvant induced arthritic Wistar rats. Colloids Surfaces B Biointerfaces 112, 255–263. doi:10.1016/j.colsurfb.2013.07.065

PubMed Abstract | CrossRef Full Text | Google Scholar

Ji, M., Wang, C., Yang, T., Meng, X., Wang, X., and Li, M. (2021). Integrated phytochemical analysis based on UPLC-MS/MS and network pharmacology approaches to explore the effect of odontites vulgaris moench on rheumatoid arthritis. Front. Pharmacol. 12, 707687. doi:10.3389/fphar.2021.707687

PubMed Abstract | CrossRef Full Text | Google Scholar

Jia, Q., Wang, T., Wang, X., Xu, H., Liu, Y., Wang, Y., et al. (2019a). Astragalin suppresses inflammatory responses and bone destruction in mice with collagen-induced arthritis and in human fibroblast-like synoviocytes. Front. Pharmacol. 10, 94. doi:10.3389/fphar.2019.00094

PubMed Abstract | CrossRef Full Text | Google Scholar

Jia, Q., Wang, Y., Liang, Q., and Shi, Q. (2019b). Effect of quercetin on the expression of inflammatory factors and matrix metalloproteinases in fibroblast-like synoviocytes of human rheumatoid arthritis. Chin. J. Osteoporos. 25 (06), 738–741.

Google Scholar

Jiang, Q., Yang, G., Liu, Q., Wang, S., and Cui, D. (2021). Function and role of regulatory T cells in rheumatoid arthritis. Front. Immunol. 12, 626193. doi:10.3389/fimmu.2021.626193

PubMed Abstract | CrossRef Full Text | Google Scholar

Jin, C. H., So, Y., Nam, B., Han, S. N., and Kim, J. B. (2017). Isoegomaketone alleviates the development of collagen antibody-induced arthritis in male balb/c mice. Molecules 22 (7), 1209. doi:10.3390/molecules22071209

PubMed Abstract | CrossRef Full Text | Google Scholar

Jin, Q., Lee, C., Lee, J. W., Yeon, E. T., Lee, D., Han, S. B., et al. (2014). 2-Phenoxychromones and prenylflavonoids from Epimedium koreanum and their inhibitory effects on LPS-induced nitric oxide and interleukin-1β production. J. Nat. Prod. (Gorakhpur). 77 (7), 1724–1728. doi:10.1021/np400831p

PubMed Abstract | CrossRef Full Text | Google Scholar

Jin, S., Chen, H., Li, Y., Zhong, H., Sun, W., Wang, J., et al. (2018). Maresin 1 improves the Treg/Th17 imbalance in rheumatoid arthritis through miR-21. Ann. Rheum. Dis. 77 (11), 1644–1652. doi:10.1136/annrheumdis-2018-213511

PubMed Abstract | CrossRef Full Text | Google Scholar

Jin, X., Gao, W., Feng, X., Sui, H., and Fu, Q. (2021). Therapeutic effect of hyperoside on mice with collagen-induced arthritis. J. Pract. Med. 37 (17), 2199–2203. doi:10.3969/j.issn.1006⁃5725.2021.17.006

CrossRef Full Text | Google Scholar

Jin, X. N., Yan, E. Z., Wang, H. M., Sui, H. J., Liu, Z., Gao, W., et al. (2016). Hyperoside exerts anti-inflammatory and anti-arthritic effects in LPS-stimulated human fibroblast-like synoviocytes in vitro and in mice with collagen-induced arthritis. Acta Pharmacol. Sin. 37 (5), 674–686. doi:10.1038/aps.2016.7

PubMed Abstract | CrossRef Full Text | Google Scholar

Katturajan, R., S, V., Rasool, M., and Evan Prince, S. (2021). Molecular toxicity of methotrexate in rheumatoid arthritis treatment: A novel perspective and therapeutic implications. Toxicology 461, 152909. doi:10.1016/j.tox.2021.152909

PubMed Abstract | CrossRef Full Text | Google Scholar

Kawaguchi, K., Kaneko, M., Miyake, R., Takimoto, H., and Kumazawa, Y. (2019). Potent inhibitory effects of quercetin on inflammatory responses of collagen-induced arthritis in mice. Endocr. Metab. Immune Disord. Drug Targets 19 (3), 308–315. doi:10.2174/1871530319666190206225034

PubMed Abstract | CrossRef Full Text | Google Scholar

Kennedy, A., Fearon, U., Veale, D. J., and Godson, C. (2011). Macrophages in synovial inflammation. Front. Immunol. 2, 52. doi:10.3389/fimmu.2011.00052

PubMed Abstract | CrossRef Full Text | Google Scholar

Kim, H. R., Kim, B. M., Won, J. Y., Lee, K. A., Ko, H. M., Kang, Y. S., et al. (2019). Quercetin, a plant polyphenol, has potential for the prevention of bone destruction in rheumatoid arthritis. J. Med. Food 22 (2), 152–161. doi:10.1089/jmf.2018.4259

PubMed Abstract | CrossRef Full Text | Google Scholar

Kim, J.-Y., and Shim, S. H. (2019). Epimedium koreanum extract and its flavonoids reduced atherosclerotic risk via suppressing modification of human HDL. Nutrients 11 (5), 1110. doi:10.3390/nu11051110

PubMed Abstract | CrossRef Full Text | Google Scholar

Kim, J. Y., Park, S. J., Yun, K. J., Cho, Y. W., Park, H. J., and Lee, K. T. (2008). Isoliquiritigenin isolated from the roots of Glycyrrhiza uralensis inhibits LPS-induced iNOS and COX-2 expression via the attenuation of NF-κB in RAW 264.7 macrophages. Eur. J. Pharmacol. 584 (1), 175–184. doi:10.1016/j.ejphar.2008.01.032

PubMed Abstract | CrossRef Full Text | Google Scholar

Kitaura, H., Marahleh, A., Ohori, F., Noguchi, T., Shen, W. R., Qi, J., et al. (2020). Osteocyte-related cytokines regulate osteoclast formation and bone resorption. Int. J. Mol. Sci. 21 (14), 5169. doi:10.3390/ijms21145169

PubMed Abstract | CrossRef Full Text | Google Scholar

Lee, C. J., Moon, S. J., Jeong, J. H., Lee, S., Lee, M. H., Yoo, S. M., et al. (2018). Kaempferol targeting on the fibroblast growth factor receptor 3-ribosomal S6 kinase 2 signaling axis prevents the development of rheumatoid arthritis. Cell Death Dis. 9 (3), 401. doi:10.1038/s41419-018-0433-0

PubMed Abstract | CrossRef Full Text | Google Scholar

Lee, J. H., Kim, B., Jin, W. J., Kim, H. H., Ha, H., and Lee, Z. H. (2017). Pathogenic roles of CXCL10 signaling through CXCR3 and TLR4 in macrophages and T cells: Relevance for arthritis. Arthritis Res. Ther. 19 (1), 163. doi:10.1186/s13075-017-1353-6

PubMed Abstract | CrossRef Full Text | Google Scholar

Lee, J. H., and Kim, G. H. (2010). Evaluation of antioxidant and inhibitory activities for different subclasses flavonoids on enzymes for rheumatoid arthritis. J. Food Sci. 75 (7), H212–H217. doi:10.1111/j.1750-3841.2010.01755.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Lei, J., Zhang, Z., He, M., and Li, H. (2020). Effect of icariin on NLRP3 inflammatory corpuscle signaling pathway in mice with rheumatoid arthritis. Mod. J. Integr. Traditional Chin. West. Med. 29 (29), 3206–3211.

Google Scholar

Li, F., Du, B. W., Lu, D. F., Wu, W. X., Wongkrajang, K., Wang, L., et al. (2017). Flavonoid glycosides isolated from Epimedium brevicornum and their estrogen biosynthesis-promoting effects. Sci. Rep. 7 (1), 7760. doi:10.1038/s41598-017-08203-7

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, H., Chen, H. Y., Liu, W. X., Jia, X. X., Zhang, J. G., Ma, C. L., et al. (2017). Prostaglandin E2 restrains human Treg cell differentiation via E prostanoid receptor 2-protein kinase A signaling. Immunol. Lett. 191, 63–72. doi:10.1016/j.imlet.2017.09.009

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, H., and Wan, A. (2013). Apoptosis of rheumatoid arthritis fibroblast-like synoviocytes: Possible roles of nitric oxide and the thioredoxin 1. Mediat. Inflamm. 2013, 1–8. doi:10.1155/2013/953462

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, L., Peng, L., Miao, J., Qiu, Y., Zhou, Y., Gao, X., et al. (2011). Icariin induces the expression of toll-like receptor 9 in ana-1 murine macrophages. Phytother. Res. 25 (11), 1732–1735. doi:10.1002/ptr.3514

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, W., Pan, J.-Q., Lü, M.-J., Zhang, R.-Y., and Xiao, P.-G. (1995a). A 9, 10-dihydrophenanthrene derivate from Epimedium koreanum. Phytochemistry 39 (1), 231–233. doi:10.1016/0031-9422(94)00926-k

CrossRef Full Text | Google Scholar

Li, W., Xiao, P., and Zhang, R. (1994). Chemical constituents of Epimedium koreanum Nakai. Nat. Prod. Res. 03, 4–8. doi:10.16333/j.1001-6880.1994.03.002

CrossRef Full Text | Google Scholar

Li, W., Zhang, R., and Xiao, P. (1995b). Study on chemical constituents of Epimedium koraiensis. Chin. Tradit. Herb. Drugs 09, 453–455+503.

Google Scholar

Li, X., Han, Y., Zhou, Q., Jie, H., He, Y., Han, J., et al. (2016). Apigenin, a potent suppressor of dendritic cell maturation and migration, protects against collagen-induced arthritis. J. Cell. Mol. Med. 20 (1), 170–180. doi:10.1111/jcmm.12717

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, Y., Yang, B., Bai, J. Y., Xia, S., Mao, M., Li, X., et al. (2019). The roles of synovial hyperplasia, angiogenesis and osteoclastogenesis in the protective effect of apigenin on collagen-induced arthritis. Int. Immunopharmacol. 73, 362–369. doi:10.1016/j.intimp.2019.05.024

PubMed Abstract | CrossRef Full Text | Google Scholar

Liang, Q., Duan, Y., and Qin, C. (2019). Effect of tonifying liver and kidney decoction combined with rutine therapy on serum inflammatory factors and quality of Life for RA patients. J. Sichuan Traditional Chin. Med. 37 (07), 143–146.

Google Scholar

Lin, F., Luo, X., Tsun, A., Li, Z., Li, D., and Li, B. (2015). Kaempferol enhances the suppressive function of Treg cells by inhibiting FOXP3 phosphorylation. Int. Immunopharmacol. 28 (2), 859–865. doi:10.1016/j.intimp.2015.03.044

PubMed Abstract | CrossRef Full Text | Google Scholar

Lin, L., Gu, X., Chen, L., Zhang, T., Wang, C., Wang, Z., et al. (2021). Study on the alleviation of Fengshi Gutong capsule on rheumatoid arthritis through integrating network pharmacology and experimental exploration. J. Ethnopharmacol. 280, 114471. doi:10.1016/j.jep.2021.114471

PubMed Abstract | CrossRef Full Text | Google Scholar

Lin, Y. J., Anzaghe, M., and Schulke, S. (2020). Update on the pathomechanism, diagnosis, and treatment options for rheumatoid arthritis. Cells 9 (4), 880. doi:10.3390/cells9040880

PubMed Abstract | CrossRef Full Text | Google Scholar

Ling, Y., Xu, H., Ren, N., Cheng, C., Zeng, P., Lu, D., et al. (2021). Prediction and verification of the major ingredients and molecular targets of Tripterygii Radix against rheumatoid arthritis. Front. Pharmacol. 12, 639382. doi:10.3389/fphar.2021.639382

PubMed Abstract | CrossRef Full Text | Google Scholar

Liu, J., and Li, F. (2018). Kidney-tonifying arthralgia-eliminating decoction combined with western medicine in treating 60 Cases of rheumatoid arthritis, West. J. Traditional Chin. Med. 31 (06), 93–95.

Google Scholar

Liu, R., Hao, D., Xu, W., Li, J., Li, X., Shen, D., et al. (2019). β-Sitosterol modulates macrophage polarization and attenuates rheumatoid inflammation in mice. Pharm. Biol. 57 (1), 161–168. doi:10.1080/13880209.2019.1577461

PubMed Abstract | CrossRef Full Text | Google Scholar

Liu, S., Zhu, L., Zhang, J., Yu, J., Cheng, X., and Peng, B. (2016). Anti-osteoclastogenic activity of isoliquiritigenin via inhibition of NF-κB-dependent autophagic pathway. Biochem. Pharmacol. 106, 82–93. doi:10.1016/j.bcp.2016.03.002

PubMed Abstract | CrossRef Full Text | Google Scholar

Liu, T., Zhao, M., Zhang, Y., Qiu, Z., Zhang, Y., Zhao, C., et al. (2021). Pharmacokinetic-pharmacodynamic modeling analysis and anti-inflammatory effect of Wangbi capsule in the treatment of adjuvant-induced arthritis. Biomed. Chromatogr. 35 (7), e5101. doi:10.1002/bmc.5101

PubMed Abstract | CrossRef Full Text | Google Scholar

Liu, Y., Feng, W., He, D., and Wang, Q. (2013). Effect of icariin on bone destruction and serum RANKL/OPG levels in type II collagen-induced arthritis rats. Chin. J. Integr. Traditional West. Med. 33 (09), 1221–1225.

Google Scholar

Liu, Y., Lu, B., Wu, Y., Qi, Q., Liu, M., Yang, C., et al. (2021). Inhibitory effect of luteolin on activation of NLRP3 inflammatory corpuscle and protection of joint bone in rheumatoid arthritis rats. China J. Traditional Chin. Med. Pharm. 36 (01), 513–516.

Google Scholar

Lou, L., Liu, Y., Zhou, J., Wei, Y., Deng, J., Dong, B., et al. (2015). Chlorogenic acid and luteolin synergistically inhibit the proliferation of interleukin-1β-induced fibroblast-like synoviocytes through regulating the activation of NF-κB and JAK/STAT-signaling pathways. Immunopharmacol. Immunotoxicol. 37 (6), 499–507. doi:10.3109/08923973.2015.1095763

PubMed Abstract | CrossRef Full Text | Google Scholar

Luo, H., He, D., Feng, W., Zhu, W., Yu, J., and Qiu, M. (2019). 40 cases of rheumatoid arthritis with kidney deficiency and cold-dampness syndrome treatment with Yishen Qubi Tongluo decoction. J. JIANGXI Univ. TCM 31 (05), 35–38.

Google Scholar

Ma, H., He, X., Yang, Y., Li, M., Hao, D., and Jia, Z. (2011). The genus Epimedium: An ethnopharmacological and phytochemical review. J. Ethnopharmacol. 134 (3), 519–541. doi:10.1016/j.jep.2011.01.001

PubMed Abstract | CrossRef Full Text | Google Scholar

Ma, W., Yao, G., Jia, Q., Ouyang, H., Chang, Y., and he, J. (2019). Qualitative analysis on chemical constituents from Epimedium brevicornu by UPLC-Q-TOF-MS/MS. J. Chin. Med. Mater. 42 (07), 1554–1559. doi:10.13863/j.issn1001-4454.2019.07.020

CrossRef Full Text | Google Scholar

Mamani-Matsuda, M., Kauss, T., Al-Kharrat, A., Rambert, J., Fawaz, F., Thiolat, D., et al. (2006). Therapeutic and preventive properties of quercetin in experimental arthritis correlate with decreased macrophage inflammatory mediators. Biochem. Pharmacol. 72 (10), 1304–1310. doi:10.1016/j.bcp.2006.08.001

PubMed Abstract | CrossRef Full Text | Google Scholar

Marahleh, A., Kitaura, H., Ohori, F., Kishikawa, A., Ogawa, S., Shen, W. R., et al. (2019). TNF-Alpha directly enhances osteocyte RANKL expression and promotes osteoclast formation. Front. Immunol. 10, 2925. doi:10.3389/fimmu.2019.02925

PubMed Abstract | CrossRef Full Text | Google Scholar

Mateen, S., Moin, S., Khan, A. Q., Zafar, A., and Fatima, N. (2016a). Increased reactive oxygen species formation and oxidative stress in rheumatoid arthritis. PLoS One 11 (4), e0152925. doi:10.1371/journal.pone.0152925

PubMed Abstract | CrossRef Full Text | Google Scholar

Mateen, S., Zafar, A., Moin, S., Khan, A. Q., and Zubair, S. (2016b). Understanding the role of cytokines in the pathogenesis of rheumatoid arthritis. Clin. Chim. Acta 455, 161–171. doi:10.1016/j.cca.2016.02.010

PubMed Abstract | CrossRef Full Text | Google Scholar

McCracken, J. M., and Allen, L. A. (2014). Regulation of human neutrophil apoptosis and lifespan in health and disease. J. Cell Death 7, JCD.S11038–23. doi:10.4137/JCD.S11038

PubMed Abstract | CrossRef Full Text | Google Scholar

McInnes, I. B., Buckley, C. D., and Isaacs, J. D. (2016). Cytokines in rheumatoid arthritis - shaping the immunological landscape. Nat. Rev. Rheumatol. 12 (1), 63–68. doi:10.1038/nrrheum.2015.171

PubMed Abstract | CrossRef Full Text | Google Scholar

Meeuwisse, C. M., van der Linden, M. P., Rullmann, T. A., Allaart, C. F., Nelissen, R., Huizinga, T. W., et al. (2011). Identification of CXCL13 as a marker for rheumatoid arthritis outcome using an in silico model of the rheumatic joint. Arthritis Rheum. 63 (5), 1265–1273. doi:10.1002/art.30273

PubMed Abstract | CrossRef Full Text | Google Scholar

Melincovici, C. S., Boşca, A. B., Şuşman, S., Mărginean, M., Mihu, C., Istrate, M., et al. (2018). Vascular endothelial growth factor (VEGF) - key factor in normal and pathological angiogenesis. Rom. J. Morphol. Embryol. 59 (2), 455–467.

PubMed Abstract | Google Scholar

Minhas, R., Bansal, Y., and Bansal, G. (2020). Inducible nitric oxide synthase inhibitors: A comprehensive update. Med. Res. Rev. 40 (3), 823–855. doi:10.1002/med.21636

PubMed Abstract | CrossRef Full Text | Google Scholar

Miyabe, Y., Miyabe, C., Iwai, Y., and Luster, A. D. (2020). Targeting the chemokine system in rheumatoid arthritis and vasculitis. JMA J. 3 (3), 182–192. doi:10.31662/jmaj.2020-0019

PubMed Abstract | CrossRef Full Text | Google Scholar

Miyabe, Y., Miyabe, C., Murooka, T. T., Kim, E. Y., Newton, G. A., Kim, N. D., et al. (2017). Complement C5a receptor is the key initiator of neutrophil adhesion igniting immune complex-induced arthritis. Sci. Immunol. 2 (7), eaaj2195. doi:10.1126/sciimmunol.aaj2195

PubMed Abstract | CrossRef Full Text | Google Scholar

Moura, R. A., Cascao, R., Perpetuo, I., Canhao, H., Vieira-Sousa, E., Mourao, A. F., et al. (2011). Cytokine pattern in very early rheumatoid arthritis favours B-cell activation and survival. Rheumatol. Oxf. 50 (2), 278–282. doi:10.1093/rheumatology/keq338

PubMed Abstract | CrossRef Full Text | Google Scholar

Munro, D., and Treberg, J. R. (2017). A radical shift in perspective: Mitochondria as regulators of reactive oxygen species. J. Exp. Biol. 220, 1170–1180. doi:10.1242/jeb.132142

PubMed Abstract | CrossRef Full Text | Google Scholar

Natarajan, V., Krithica, N., Madhan, B., and Sehgal, P. K. (2011). Formulation and evaluation of quercetin polycaprolactone microspheres for the treatment of rheumatoid arthritis. J. Pharm. Sci. 100 (1), 195–205. doi:10.1002/jps.22266

PubMed Abstract | CrossRef Full Text | Google Scholar

Niu, R. (1989). Action of the drug Herba Epimedii on testosterone of the mouse plasma and its accessory sexual organ before and after processing. Zhongguo Zhong Yao Za Zhi 14 (9), 530574.

Google Scholar

Noack, M., and Miossec, P. (2014). Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun. Rev. 13 (6), 668–677. doi:10.1016/j.autrev.2013.12.004

PubMed Abstract | CrossRef Full Text | Google Scholar

Nygaard, G., and Firestein, G. S. (2020). Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes. Nat. Rev. Rheumatol. 16 (6), 316–333. doi:10.1038/s41584-020-0413-5

PubMed Abstract | CrossRef Full Text | Google Scholar

O'Neil, L. J., and Kaplan, M. J. (2019). Neutrophils in rheumatoid arthritis: Breaking immune tolerance and fueling disease. Trends Mol. Med. 25 (3), 215–227. doi:10.1016/j.molmed.2018.12.008

PubMed Abstract | CrossRef Full Text | Google Scholar

Okano, M., Sugata, Y., Fujiwara, T., Matsumoto, R., Nishibori, M., Shimizu, K., et al. (2006). E prostanoid 2 (EP2)/EP4-mediated suppression of antigen-specific human T-cell responses by prostaglandin E2. Immunology 118 (3), 343–352. doi:10.1111/j.1365-2567.2006.02376.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Pan, D., Li, N., Liu, Y., Xu, Q., Liu, Q., You, Y., et al. (2018). Kaempferol inhibits the migration and invasion of rheumatoid arthritis fibroblast-like synoviocytes by blocking activation of the MAPK pathway. Int. Immunopharmacol. 55, 174–182. doi:10.1016/j.intimp.2017.12.011

PubMed Abstract | CrossRef Full Text | Google Scholar

Pan, F., Zhu, L., Lv, H., and Pei, C. (2016). Quercetin promotes the apoptosis of fibroblast-like synoviocytes in rheumatoid arthritis by upregulating lncRNA MALAT1. Int. J. Mol. Med. 38 (5), 1507–1514. doi:10.3892/ijmm.2016.2755

PubMed Abstract | CrossRef Full Text | Google Scholar

Pandya, J. M., Lundell, A. C., Andersson, K., Nordstrom, I., Theander, E., and Rudin, A. (2017). Blood chemokine profile in untreated early rheumatoid arthritis: CXCL10 as a disease activity marker. Arthritis Res. Ther. 19 (1), 20. doi:10.1186/s13075-017-1224-1

PubMed Abstract | CrossRef Full Text | Google Scholar

Pang, J., Yang, F., Zhang, Z., Yang, W., Li, Y., and Xu, H. (2021). The role of luteolin nanocomposites in rheumatoid arthritis treatment. Mater. Express 11 (3), 303–309.

Google Scholar

Pang, X., Yin, S. S., Yu, H. Y., Zhang, Y., Wang, T., Hu, L. M., et al. (2018). Prenylated flavonoids and dihydrophenanthrenes from the leaves of Epimedium brevicornu and their cytotoxicity against HepG2 cells. Nat. Prod. Res. 32 (19), 2253–2259. doi:10.1080/14786419.2017.1405410

PubMed Abstract | CrossRef Full Text | Google Scholar

Park, J. Y., Pillinger, M. H., and Abramson, S. B. (2006). Prostaglandin E2 synthesis and secretion: The role of PGE2 synthases. Clin. Immunol. 119 (3), 229–240. doi:10.1016/j.clim.2006.01.016

PubMed Abstract | CrossRef Full Text | Google Scholar

Phull, A. R., Nasir, B., Haq, I. U., and Kim, S. J. (2018). Oxidative stress, consequences and ROS mediated cellular signaling in rheumatoid arthritis. Chem. Biol. Interact. 281, 121–136. doi:10.1016/j.cbi.2017.12.024

PubMed Abstract | CrossRef Full Text | Google Scholar

Pu, L., Meng, Q., Li, S., Liu, B., and Li, F. (2021). Icariin arrests cell cycle progression and induces cell apoptosis through the mitochondrial pathway in human fibroblast-like synoviocytes. Eur. J. Pharmacol. 912, 174585. doi:10.1016/j.ejphar.2021.174585

PubMed Abstract | CrossRef Full Text | Google Scholar

Qian, K., Zheng, X. X., Wang, C., Huang, W. G., Liu, X. B., Xu, S. D., et al. (2021). β-Sitosterol inhibits rheumatoid synovial angiogenesis through suppressing VEGF signaling pathway. Front. Pharmacol. 12, 816477. doi:10.3389/fphar.2021.816477

PubMed Abstract | CrossRef Full Text | Google Scholar

Qiao, H., Mei, J., Yuan, K., Zhang, K., Zhou, F., Tang, T., et al. (2022). Immune-regulating strategy against rheumatoid arthritis by inducing tolerogenic dendritic cells with modified zinc peroxide nanoparticles. J. Nanobiotechnology 20 (1), 323. doi:10.1186/s12951-022-01536-0

PubMed Abstract | CrossRef Full Text | Google Scholar

Ren, F. C., Jiang, X. J., Wen, S. Z., Wang, L. X., Li, X. M., and Wang, F. (2018). Prenylated 2-phenoxychromones and flavonoids from Epimedium brevicornum and revised structures of epimedonins A and B. J. Nat. Prod. (Gorakhpur). 81 (1), 16–21. doi:10.1021/acs.jnatprod.7b00514

PubMed Abstract | CrossRef Full Text | Google Scholar

Ross, E. A., Devitt, A., and Johnson, J. R. (2021). Macrophages: The good, the bad, and the gluttony. Front. Immunol. 12, 708186. doi:10.3389/fimmu.2021.708186

PubMed Abstract | CrossRef Full Text | Google Scholar

Saccol, R., da Silveira, K. L., Manzoni, A. G., Abdalla, F. H., de Oliveira, J. S., Dornelles, G. L., et al. (2020). Antioxidant, hepatoprotective, genoprotective, and cytoprotective effects of quercetin in a murine model of arthritis. J. Cell. Biochem. 121 (4), 2792–2801. doi:10.1002/jcb.29502

PubMed Abstract | CrossRef Full Text | Google Scholar

Santos, E. O., Kabeya, L. M., Figueiredo-Rinhel, A. S., Marchi, L. F., Andrade, M. F., Piatesi, F., et al. (2014). Flavonols modulate the effector functions of healthy individuals' immune complex-stimulated neutrophils: A therapeutic perspective for rheumatoid arthritis. Int. Immunopharmacol. 21 (1), 102–111. doi:10.1016/j.intimp.2014.04.014

PubMed Abstract | CrossRef Full Text | Google Scholar

Sheibanie, A. F., Khayrullina, T., Safadi, F. F., and Ganea, D. (2007). Prostaglandin E2 exacerbates collagen-induced arthritis in mice through the inflammatory interleukin-23/interleukin-17 axis. Arthritis Rheum. 56 (8), 2608–2619. doi:10.1002/art.22794

PubMed Abstract | CrossRef Full Text | Google Scholar

Shen, P., Lin, W., Ba, X., Huang, Y., Chen, Z., Han, L., et al. (2021). Quercetin-mediated SIRT1 activation attenuates collagen-induced mice arthritis. J. Ethnopharmacol. 279, 114213. doi:10.1016/j.jep.2021.114213

PubMed Abstract | CrossRef Full Text | Google Scholar

Shen, Y., Fan, X., Qu, Y., Tang, M., Huang, Y., Peng, Y., et al. (2022). Magnoflorine attenuates inflammatory responses in RA by regulating the PI3K/Akt/NF-κB and Keap1-Nrf2/HO-1 signalling pathways in vivo and in vitro. Phytomedicine 104, 154339. doi:10.1016/j.phymed.2022.154339

PubMed Abstract | CrossRef Full Text | Google Scholar

Shin, G. C., Kim, C., Lee, J. M., Cho, W. S., Lee, S. G., Jeong, M., et al. (2009). Apigenin-induced apoptosis is mediated by reactive oxygen species and activation of ERK1/2 in rheumatoid fibroblast-like synoviocytes. Chem. Biol. Interact. 182 (1), 29–36. doi:10.1016/j.cbi.2009.07.016

PubMed Abstract | CrossRef Full Text | Google Scholar

Shinozaki, M., Inoue, E., Nakajima, A., Hara, M., Tomatsu, T., Kamatani, N., et al. (2007). Elevation of serum matrix metalloproteinase-3 as a predictive marker for the long-term disability of rheumatoid arthritis patients in a prospective observational cohort IORRA. Mod. Rheumatol. 17 (5), 403–408. doi:10.1007/s10165-007-0608-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Shrivastava, A. K., and Pandey, A. (2013). Inflammation and rheumatoid arthritis. J. Physiol. Biochem. 69 (2), 335–347. doi:10.1007/s13105-012-0216-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Shu, B., and Cai, F. (2021). Clinical effect of Bushen Tongluo Recipe on rheumatoid arthritis of liver and kidney yin deficiency type and its influence on related cytokines. Beijing J. Traditional Chin. Med. 40 (02), 140–143. doi:10.16025/j.1674-1307.2021.02.009

CrossRef Full Text | Google Scholar

Smallwood, M. J., Nissim, A., Knight, A. R., Whiteman, M., Haigh, R., and Winyard, P. G. (2018). Oxidative stress in autoimmune rheumatic diseases. Free Radic. Biol. Med. 125, 3–14. doi:10.1016/j.freeradbiomed.2018.05.086

PubMed Abstract | CrossRef Full Text | Google Scholar

Smolen, J. S., Landewe, R. B. M., Bijlsma, J. W. J., Burmester, G. R., Dougados, M., Kerschbaumer, A., et al. (2020). EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann. Rheum. Dis. 79 (6), 685–699. doi:10.1136/annrheumdis-2019-216655

PubMed Abstract | CrossRef Full Text | Google Scholar

Souza, K. S., Moreira, L. S., Silva, B. T., Oliveira, B. P. M., Carvalho, A. S., Silva, P. S., et al. (2021). Low dose of quercetin-loaded pectin/casein microparticles reduces the oxidative stress in arthritic rats. Life Sci. 284, 119910. doi:10.1016/j.lfs.2021.119910

PubMed Abstract | CrossRef Full Text | Google Scholar

Srivastava, R. K., Dar, H. Y., and Mishra, P. K. (2018). Immunoporosis: Immunology of osteoporosis-role of T cells. Front. Immunol. 9, 657. doi:10.3389/fimmu.2018.00657

PubMed Abstract | CrossRef Full Text | Google Scholar

Su, X. D., Li, W., Ma, J. Y., and Kim, Y. H. (2018). Chemical constituents from Epimedium koreanum Nakai and their chemotaxonomic significance. Nat. Prod. Res. 32 (19), 2347–2351. doi:10.1080/14786419.2017.1405412

PubMed Abstract | CrossRef Full Text | Google Scholar

Sun, G., and Chen, X. (2021). Efficacy and safety of Kunxian capsule and Leigongteng Duogan tablets in the treatment of rheumatoid arthritis. China Prac. Med. 16 (33), 138–140. doi:10.14163/j.cnki.11-5547/r.2021.33.050

CrossRef Full Text | Google Scholar

Sun, M., Zhang, D., Ouyang, H., Chang, Y., and He, J. (2018). Simultaneous determination of 11 compounds in Epimedium of different places of origin by UPLC. Liaoning J. Traditional Chin. Med. 45 (10), 2146–2149. doi:10.13192/j.issn.1000-1719.2018.10.042

CrossRef Full Text | Google Scholar

Sun, Q. W., Jiang, S. M., Yang, K., Zheng, J. M., Zhang, L., and Xu, W. D. (2012). Apigenin enhances the cytotoxic effects of tumor necrosis factor-related apoptosis-inducing ligand in human rheumatoid arthritis fibroblast-like synoviocytes. Mol. Biol. Rep. 39 (5), 5529–5535. doi:10.1007/s11033-011-1356-3

PubMed Abstract | CrossRef Full Text | Google Scholar

Sun, Y. W., Bao, Y., Yu, H., Chen, Q. J., Lu, F., Zhai, S., et al. (2020). Anti-rheumatoid arthritis effects of flavonoids from Daphne genkwa. Int. Immunopharmacol. 83, 106384. doi:10.1016/j.intimp.2020.106384

PubMed Abstract | CrossRef Full Text | Google Scholar

Sung, M. S., Lee, E. G., Jeon, H. S., Chae, H. J., Park, S. J., Lee, Y. C., et al. (2012). Quercetin inhibits IL-1β-induced proliferation and production of MMPs, COX-2, and PGE2 by rheumatoid synovial fibroblast. Inflammation 35 (4), 1585–1594. doi:10.1007/s10753-012-9473-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Sze, S. C., Tong, Y., Ng, T. B., Cheng, C. L., and Cheung, H. P. (2010). Herba epimedii: Anti-oxidative properties and its medical implications. Molecules 15 (11), 7861–7870. doi:10.3390/molecules15117861

PubMed Abstract | CrossRef Full Text | Google Scholar

Szekanecz, Z., and Koch, A. E. (2009). Angiogenesis and its targeting in rheumatoid arthritis. Vasc. Pharmacol. 51 (1), 1–7. doi:10.1016/j.vph.2009.02.002

PubMed Abstract | CrossRef Full Text | Google Scholar

Tsikas, D. (2017). Assessment of lipid peroxidation by measuring malondialdehyde (MDA) and relatives in biological samples: Analytical and biological challenges. Anal. Biochem. 524, 13–30. doi:10.1016/j.ab.2016.10.021

PubMed Abstract | CrossRef Full Text | Google Scholar

Tu, J., Hong, W., Zhang, P., Wang, X., Korner, H., and Wei, W. (2018). Ontology and function of fibroblast-like and macrophage-like synoviocytes: How do they talk to each other and can they Be targeted for rheumatoid arthritis therapy? Front. Immunol. 9, 1467. doi:10.3389/fimmu.2018.01467

PubMed Abstract | CrossRef Full Text | Google Scholar

van der Woude, D., and van der Helm-van Mil, A. H. M. (2018). Update on the epidemiology, risk factors, and disease outcomes of rheumatoid arthritis. Best. Pract. Res. Clin. Rheumatol. 32 (2), 174–187. doi:10.1016/j.berh.2018.10.005

PubMed Abstract | CrossRef Full Text | Google Scholar

van Tuyl, L. H., Voskuyl, A. E., Boers, M., Geusens, P., Landewe, R. B., Dijkmans, B. A., et al. (2010). Baseline RANKL:OPG ratio and markers of bone and cartilage degradation predict annual radiological progression over 11 years in rheumatoid arthritis. Ann. Rheum. Dis. 69 (9), 1623–1628. doi:10.1136/ard.2009.121764

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, G. J., Tsai, T. H., and Lin, L. C. (2007). Prenylflavonol, acylated flavonol glycosides and related compounds from Epimedium sagittatum. Phytochemistry 68 (19), 2455–2464. doi:10.1016/j.phytochem.2007.05.035

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, G., Wang, T., and Dang, P. (2021). Clinical observation on 30 cases of rheumatoid arthritis treated with bushen quhan Zhiwang decoction combined with methotrexate. J. Basic Chin. Med. 27 (08), 1298–1300. doi:10.19945/j.cnki.issn.1006-3250.2021.08.027

CrossRef Full Text | Google Scholar

Wang, J., and Zhao, Q. (2019). Kaempferitrin inhibits proliferation, induces apoptosis, and ameliorates inflammation in human rheumatoid arthritis fibroblast-like synoviocytes. Phytotherapy Res. 33 (6), 1726–1735. doi:10.1002/ptr.6364

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, L., Li, Y., Guo, Y., Ma, R., Fu, M., Niu, J., et al. (2016). Herba epimedii: An ancient Chinese herbal medicine in the prevention and treatment of osteoporosis. Curr. Pharm. Des. 22 (3), 328–349. doi:10.2174/1381612822666151112145907

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, Q., Zhang, P., Yuan, X., Bi, Y., Zhou, K., and Zhang, Y. (2018). Long- term toxicity of different extracts of Epimedium Brevicornu Maxim in mice. Chin. J. Pharmacovigil. 15 (02), 65–69.

Google Scholar

Wang, Y., Chen, S., and Mei, J. (2019). Quercetin attenuates chondrocyte matrix degradation and apoptosis in rheumatoid arthritis rats by inhibiting NF-κB. Immunol. J. 35 (06), 485–491. doi:10.13431/j.cnki.immunol.j.20190075

CrossRef Full Text | Google Scholar

Wang, Y., Wu, H., and Deng, R. (2021). Angiogenesis as a potential treatment strategy for rheumatoid arthritis. Eur. J. Pharmacol. 910, 174500. doi:10.1016/j.ejphar.2021.174500

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, Z., Zhuo, F., Chu, P., Yang, X., and Zhao, G. (2019). Germacrone alleviates collagen-induced arthritis via regulating Th1/Th2 balance and NF-κB activation. Biochem. Biophys. Res. Commun. 518 (3), 560–564. doi:10.1016/j.bbrc.2019.08.084

PubMed Abstract | CrossRef Full Text | Google Scholar

Wehr, P., Purvis, H., Law, S. C., and Thomas, R. (2019). Dendritic cells, T cells and their interaction in rheumatoid arthritis. Clin. Exp. Immunol. 196 (1), 12–27. doi:10.1111/cei.13256

PubMed Abstract | CrossRef Full Text | Google Scholar

Wei, C. C., Ping, D. Q., You, F. T., Qiang, C. Y., and Tao, C. (2016). Icariin prevents cartilage and bone degradation in experimental models of arthritis. Mediat. Inflamm. 2016, 1–10. doi:10.1155/2016/9529630

PubMed Abstract | CrossRef Full Text | Google Scholar

Wu, F., Gao, J., Kang, J., Wang, X., Niu, Q., Liu, J., et al. (2021). B cells in rheumatoid ArthritisPathogenic mechanisms and treatment prospects. Front. Immunol. 12, 750753. doi:10.3389/fimmu.2021.750753

PubMed Abstract | CrossRef Full Text | Google Scholar

Wu, Z. M., Luo, J., Shi, X. D., Zhang, S. X., Zhu, X. B., and Guo, J. (2020). Icariin alleviates rheumatoid arthritis via regulating miR-223-3p/NLRP3 signalling axis. Autoimmunity 53 (8), 450–458. doi:10.1080/08916934.2020.1836488

PubMed Abstract | CrossRef Full Text | Google Scholar

Xiang, L., Tong, Y., Tian, X., Fang, R., and Wang, F. (2020). The effects of icariin on apoptosis of fibroblast-like synoviocytes and expression of sytokines in rheumatoid arthritis. Curr. Immunol. 40 (05), 360–365+423.

Google Scholar

Xiao, P., Hao, Y., Zhu, X., and Wu, X. (2013). p53 contributes to quercetin-induced apoptosis in human rheumatoid arthritis fibroblast-like synoviocytes. Inflammation 36 (2), 272–278. doi:10.1007/s10753-012-9543-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Yamanaka, H., Matsuda, Y., Tanaka, M., Sendo, W., Nakajima, H., Taniguchi, A., et al. (2000). Serum matrix metalloproteinase 3 as a predictor of the degree of joint destruction during the six months after measurement, in patients with early rheumatoid arthritis. Arthritis Rheum. 43 (4), 852–858. doi:10.1002/1529-0131(200004)43:4<852::aid-anr16>3.0.co;2-7

PubMed Abstract | CrossRef Full Text | Google Scholar

Yanaba, K., Bouaziz, J. D., Haas, K. M., Poe, J. C., Fujimoto, M., and Tedder, T. F. (2008). A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses. Immunity 28 (5), 639–650. doi:10.1016/j.immuni.2008.03.017

PubMed Abstract | CrossRef Full Text | Google Scholar

Yang, X. H., Li, L., Xue, Y. B., Zhou, X. X., and Tang, J. H. (2020). Flavonoids from Epimedium pubescens: Extraction and mechanism, antioxidant capacity and effects on CAT and GSH-px of Drosophila melanogaster. PeerJ 8, e8361. doi:10.7717/peerj.8361

PubMed Abstract | CrossRef Full Text | Google Scholar

Yang, Y., Wu, Y., Li, W., Liu, X., Zheng, J., Zhang, W., et al. (2018a). Determination of geographical origin and icariin content of Herba Epimedii using near infrared spectroscopy and chemometrics. Spectrochimica Acta Part A Mol. Biomol. Spectrosc. 191, 233–240. doi:10.1016/j.saa.2017.10.019

PubMed Abstract | CrossRef Full Text | Google Scholar

Yang, Y., Zhang, X., Xu, M., Wu, X., Zhao, F., and Zhao, C. (2018b). Quercetin attenuates collagen-induced arthritis by restoration of Th17/Treg balance and activation of Heme Oxygenase 1-mediated anti-inflammatory effect. Int. Immunopharmacol. 54, 153–162. doi:10.1016/j.intimp.2017.11.013

PubMed Abstract | CrossRef Full Text | Google Scholar

Yoon, H. Y., Lee, E. G., Lee, H., Cho, I. J., Choi, Y. J., Sung, M. S., et al. (2013). Kaempferol inhibits IL-1β-induced proliferation of rheumatoid arthritis synovial fibroblasts and the production of COX-2, PGE2 and MMPs. Int. J. Mol. Med. 32 (4), 971–977. doi:10.3892/ijmm.2013.1468

PubMed Abstract | CrossRef Full Text | Google Scholar

You, W., Liang, Q., Zeng, G., Wu, H., Chen, J., Xiong, X., et al. (2009). Effects of apigenin on the proliferation and cytokine gene expression of murine T lymphocytes. Chin. Archives Traditional Chin. Med. 27 (06), 1194–1197. doi:10.13193/j.archtcm.2009.06.75.youwh.045

CrossRef Full Text | Google Scholar

Yuan, K., Zhu, Q., Lu, Q., Jiang, H., Zhu, M., Li, X., et al. (2020). Quercetin alleviates rheumatoid arthritis by inhibiting neutrophil inflammatory activities. J. Nutr. Biochem. 84, 108454. doi:10.1016/j.jnutbio.2020.108454

PubMed Abstract | CrossRef Full Text | Google Scholar

Yuan, M., He, Y., Dong, W., Yang, G., Cao, Y., and Wang, J. (2019). Study on treatment of synovial lesions in patients with active rheumatoid arthritis by bushen Jiedu Tongluo decoction combined with methotrexate. Zhejiang J. Traditional Chin. Med. 54 (08), 600–601. doi:10.13633/j.cnki.zjtcm.2019.08.035

CrossRef Full Text | Google Scholar

Zhang, D., Zhang, J., Fong, C., Yao, X., and Yang, M. (2012). Herba epimedii flavonoids suppress osteoclastic differentiation and bone resorption by inducing G2/M arrest and apoptosis. Biochimie 94 (12), 2514–2522. doi:10.1016/j.biochi.2012.06.033

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, G., Zhang, C., and Guo, Z. (2020a). Clinical observation on 50 cases of rheumatoid arthritis of phlegm-stasis-obstruction type treated by wanbi xinglei yin combined with leflunomide. Rheumatism Arthritis 9 (06), 24–26.

Google Scholar

Zhang, H., Wu, X., Wang, J., Wang, M., Wang, X., Shen, T., et al. (2020). Flavonoids from the leaves of Epimedium Koreanum Nakai and their potential cytotoxic activities. Nat. Prod. Res. 34 (9), 1256–1263. doi:10.1080/14786419.2018.1560283

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, H., Yan, L., Zhang, Q., and Wang, Z. (2013). Flavonoids from leaves of Epimedium pubescens. China J. Chin. Materia Medica 38 (12), 1942–1946.

Google Scholar

Zhang, J. F., Li, G., Chan, C. Y., Meng, C. L., Lin, M. C., Chen, Y. C., et al. (2010). Flavonoids of Herba Epimedii regulate osteogenesis of human mesenchymal stem cells through BMP and Wnt/β-catenin signaling pathway. Mol. Cell. Endocrinol. 314 (1), 70–74. doi:10.1016/j.mce.2009.08.012

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, J., Liu, W., Zhu, X., Zhou, M., and Zhu, X. (2015). The effect of acupuncture combined with apigenin treatment on Th1/Th2 cell subsets in mice with collagen-induced arthritis. Chin. J. Gerontology 35 (05), 1353–1355.

Google Scholar

Zhang, L. L., Xiao, H., Zhang, F., Wu, Y. J., Shu, J. L., Li, Y., et al. (2021). BAFF, involved in B cell activation through the NF-κB pathway, is related to disease activity and bone destruction in rheumatoid arthritis. Acta Pharmacol. Sin. 42 (10), 1665–1675. doi:10.1038/s41401-020-00582-4

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, L., Wang, T., Zhao, B. S., Zhang, J. X., Yang, S., Fan, C. L., et al. (2019). Effect of 2''-O-rhamnosyl icariside II, baohuoside I and baohuoside II in Herba epimedii on cytotoxicity indices in HL-7702 and HepG2 cells. Molecules 24 (7), 1263. doi:10.3390/molecules24071263

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, L., Zhang, J., Fan, Q., Su, Z., Chen, C., Peng, L., et al. (2018). Hepatoxicity of epimedii folium in rat model based on uniform design and regression analysis. Chin. J. Exp. Traditional Med. Formulae 24 (06), 189–197. doi:10.13422/j.cnki.syfjx.20180617

CrossRef Full Text | Google Scholar

Zhang, Q., Liu, J., Zhang, M., Wei, S., Li, R., Gao, Y., et al. (2019). Apoptosis induction of fibroblast-like synoviocytes is an important molecular-mechanism for herbal medicine along with its active components in treating rheumatoid arthritis. Biomolecules 9 (12), 795. doi:10.3390/biom9120795

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, S., Zhu, T., and Shi, J. (2020b). Clinical study on Fugui Gutong capsules for rheumatoid arthritis. J. NEW Chin. Med. 52 (12), 60–63. doi:10.13457/j.cnki.jncm.2020.12.018

CrossRef Full Text | Google Scholar

Zhao, J., Chen, B., Peng, X., Wang, C., Wang, K., Han, F., et al. (2020). Quercetin suppresses migration and invasion by targeting miR-146a/GATA6 axis in fibroblast-like synoviocytes of rheumatoid arthritis. Immunopharmacol. Immunotoxicol. 42 (3), 221–227. doi:10.1080/08923973.2020.1742732

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhao, J., Yang, J., and Xie, Y. (2019). Improvement strategies for the oral bioavailability of poorly water-soluble flavonoids: An overview. Int. J. Pharm. X. 570, 118642. doi:10.1016/j.ijpharm.2019.118642

PubMed Abstract | CrossRef Full Text | Google Scholar

Zheng, x., and Kong, L. (2002). Studies on chemical constituents of Epimedium koreanum. Chin. Traditional Herb. Drugs 11, 7–10.

Google Scholar

Zheng, X., Ye, R., Wang, H., Zhang, Y., Yan, Y., and Xu, Z. (2017). Curative effect of xianzhi fengsui tang for rheumatoid arthritis and its influence on the expression levels of osteoprotegerin in peripheral blood. J. NEW Chin. Med. 49 (12), 70–72. doi:10.13457/j.cnki.jncm.2017.12.024

CrossRef Full Text | Google Scholar

Zhong, R., Chen, Y., Ling, J., Xia, Z., Zhan, Y., Sun, E., et al. (2019). The toxicity and metabolism properties of Herba epimedii flavonoids on laval and adult zebrafish. Evidence-Based Complementary Altern. Med. 2019, 3745051–3745059. doi:10.1155/2019/3745051

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhou, D. C., Zheng, G., Jia, L. Y., He, X., Zhang, C. F., Wang, C. Z., et al. (2021). Comprehensive evaluation on anti-inflammatory and anti-angiogenic activities in vitro of fourteen flavonoids from Daphne Genkwa based on the combination of efficacy coefficient method and principal component analysis. J. Ethnopharmacol. 268, 113683. doi:10.1016/j.jep.2020.113683

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhu, L., Wei, H., Wu, Y., Yang, S., Xiao, L., Zhang, J., et al. (2012). Licorice isoliquiritigenin suppresses RANKL-induced osteoclastogenesis in vitro and prevents inflammatory bone loss in vivo. Int. J. Biochem. Cell Biol. 44 (7), 1139–1152. doi:10.1016/j.biocel.2012.04.003

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhu, M., Yuan, K., Lu, Q., Zhu, Q., Zhang, S., Li, X., et al. (2019). Emodin ameliorates rheumatoid arthritis by promoting neutrophil apoptosis and inhibiting neutrophil extracellular trap formation. Mol. Immunol. 112, 188–197. doi:10.1016/j.molimm.2019.05.010

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhu, X., Zeng, K., Qiu, Y., Yan, F., and Lin, C. (2013). Therapeutic effect of emodin on collagen-induced arthritis in mice. Inflammation 36 (6), 1253–1259. doi:10.1007/s10753-013-9663-6

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: Epimedii Herba, rheumatoid arthritis, pharmacology, bioavailability, toxicity

Citation: Zhang L-B, Yan Y, He J, Wang P-P, Chen X, Lan T-Y, Guo Y-X, Wang J-P, Luo J, Yan Z-R, Xu Y and Tao Q-W (2022) Epimedii Herba: An ancient Chinese herbal medicine in the prevention and treatment of rheumatoid arthritis. Front. Chem. 10:1023779. doi: 10.3389/fchem.2022.1023779

Received: 20 August 2022; Accepted: 02 November 2022;
Published: 17 November 2022.

Edited by:

Li Yang, Shanghai University of Traditional Chinese Medicine, China

Reviewed by:

Wei Long, Chinese Academy of Medical Sciences and Peking Union Medical College, China
Sreedhar Ranganath Pai, Manipal Academy of Higher Education, India

Copyright © 2022 Zhang, Yan, He, Wang, Chen, Lan, Guo, Wang, Luo, Yan, Xu and Tao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Yuan Xu, xuyuan2004020@163.com; Qing-Wen Tao, taoqg1@sina.com

These authors have contributed equally to this work and share first authorship

Download