Sinomenine-Type Drugs to Treat Rheumatoid Arthritis

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This entry is adapted from the peer-reviewed paper 10.3390/molecules27248645

Sinomenine is the main component of the vine Sinomenium acutum. It was first isolated in the early 1920s and has since attracted special interest as a potential anti-rheumatoid arthritis (RA) agent, owing to its successful application in traditional Chinese medicine for the treatment of neuralgia and rheumatoid diseases.

sinomenine rheumatoid arthritis traditional Chinese medicine

1. Introduction

Rheumatoid arthritis (RA) is a chronic autoimmune and inflammatory disorder characterized by symmetrical pain and swelling of the hands, wrists, feet, and knees. It is associated with severely impaired movement, early death, and significant socioeconomic burden ^[1]. It arises more frequently in females than in males and is predominantly observed between the ages of 50 and 60 years, with a worldwide prevalence of approximately 5 per 1000 ^[2]. Non-steroidal anti-inflammatory drugs and disease-modifying anti-rheumatic drugs (DMARDs) are frequently used to treat RA by alleviating inflammation and pain, reducing joint damage, and preserving the structure and function of the joints. The most common conventional DMARDs include methotrexate (MTX), sulfasalazine, and hydroxychloroquine; however, their use is accompanied by adverse events related to their unique action mechanisms ^[2]^[3]. For example, MTX, the most frequently used DMARD in clinical practice, can cause stomach upset, mouth sores, and bone lesions. In contrast, sulfasalazine causes changes in blood count, photosensitivity, nausea or vomiting, skin rash, and headaches. Thus, the development of alternative therapies is crucial for the management and treatment of RA.

Complementary and alternative medicines (CAMs) have been widely used to treat RA for thousands of years and confer certain advantages relative to conventional therapies, such as mild toxicity and a lower risk of addiction ^[4]. CAMs are also a rich source of potential anti-RA agents. Sinomenium acutum, a Chinese herbal medicine, has been broadly used as a folk remedy to treat neuralgia and rheumatoid diseases (Figure 1) ^[5]. Sinomenine (Figure 1C), the main chemical component of this herbal medicine, was first isolated by Ishiwari in the 1920s ^[6]^[7] and has since attracted special interest as a potential anti-RA agent, owing to its successful application in traditional Chinese and Japanese medicine to treat inflammatory and rheumatic diseases. Numerous pharmacological and clinical studies have demonstrated that sinomenine possesses extensive therapeutic properties, such as anti-inflammatory, immunosuppressive, and analgesic effects ^[8]. Sinomenine hydrochloride has been developed in various formulations as an effective and relatively safe drug to treat RA in China ^[7]. The therapeutic efficacy and mild side-effect profile of sinomenine and combination therapies in RA patients have been demonstrated in multiple clinical trials, and the underlying mechanisms of action have been thoroughly investigated ^[9]^[10]. Furthermore, several sinomenine derivatives were synthesized to improve their anti-inflammatory, immunosuppressive, and analgesic effects ^[11].

Figure 1. Traditional use of S. acutum and clinical application of its main active component, sinomenine. (A) Plant S. acutum; (B) dry rattan stem of S. acutum, the picture is reproduced with permission; (C) structure of sinomenine.

2. Direct Targets of Sinomenine for Treating RA

To explore the drug targets of sinomenine, Guo et al. used network pharmacology to search for potential targets and signaling pathways through which sinomenine treats RA ^[12]. Consequently, 16 potential targets, including HSP90AA1, MAP3K3, F13A1, CTNNB1, HDAC6, ERBB2, and KIT, were identified in the sinomenine and RA intersection target networks and were subsequently validated via enrichment analysis. Although further experimental validation is required, their reliability in targeting RA has been reported. For example, HSP90AA1 is involved in arachidonic acid metabolism pathways, a major mediator of many inflammatory diseases, and is thus considered an “RA-specific” gene ^[13]. MAP3K3, another well-studied RA identification gene, is also involved in the immune response ^[14]. The human coagulation factor XIII A subunit gene F13A1 plays an essential role in early innate immune responses by modulating inflammation ^[15], whereas CTNNB1 plays a critical role in inhibiting the proliferation and inflammatory response of fibroblast-like synoviocytes (FLSs) in RA pathogenesis ^[16]. Moreover, according to enrichment analysis results, these targets could ameliorate RA by inhibiting synovial hyperplasia, angiogenesis, and cartilage destruction ^[12]. Recently, Chen et al. used an activity-based protein profiling approach to elucidate the direct anti-inflammatory effect of sinomenine on the murine macrophage RAW 264.7 ^[17]. First, a clickable probe was synthesized and confirmed to retain an anti-inflammatory function similar to that of sinomenine. Subsequently, in-gel fluorescence analysis revealed that probe-induced labeling was highly influenced by pretreatment of the cell lysate with sinomenine, indicating that the probe-labeled proteins were sinomenine targets. Using this probe, 2755 proteins were identified, of which 92 were considered potential sinomenine targets. Bioinformatic analysis revealed that the anti-inflammatory effects of sinomenine follow a poly-pharmacological mode of action. The top 20 potential protein targets were selected to illustrate their effects on inflammation. Knockdown of certain genes, such as Ripk 3, Ptges3, Prdx4, and Dbnl, decreased inflammatory cytokine levels, including interleukin (IL)-1β and IL-6, as well as tumor necrosis factor (TNF)-α in lipopolysaccharide (LPS)-stimulated cells. ADH5, Ddx27, Dld, Myh11, Snx5, Syne3, and Utp18 knockdown resulted in significant inflammation following the induction with LPS, suggesting their roles in attenuation of inflammation ^[17].

The above results indicate that sinomenine could be a multitarget anti-RA drug. Additionally, Chen et al. revealed that a selective reduction in the carbon–carbon double bond of α,β-unsaturated ketones significantly reduced the ability of sinomenine to inhibit inflammatory cytokine expression, indicating that the α,β-unsaturated ketone group is the key active group and may covalently bind to the target proteins ^[17]. Further investigation should be conducted to elucidate the sites and mechanisms of binding of sinomenine to these target proteins and how they correlate with RA regulation.

3. Immunosuppressive and Anti-Inflammatory Effects of Sinomenine

Inflammation is an immune-related protective response that follows several events, such as infections, exposure to toxins, and post-ischemic changes ^[18]. As an anti-RA drug, the immunosuppressive and anti-inflammatory properties of sinomenine have been previously documented ^[10]; sinomenine suppresses lymphocyte activity by inducing apoptosis, inhibiting proliferation, and regulating the Th1/Th2 imbalance ^[19]^[20]^[21] (Figure 2). In particular, sinomenine-induced apoptosis in CD4+ primary lymphocytes is mediated through the caspase 3-dependent pathway rather than the B-cell lymphoma-2 protein family ^[21]. Furthermore, the potential suppressive effects of sinomenine on dendritic cells (DCs) and monocytes/macrophages have been documented; sinomenine was reported to moderate DC differentiation, maturation, and functionality and improve antigen uptake by LPS-stimulated DC ^[22] (Figure 2). Zhao et al. reported that sinomenine could decrease the antigen-presenting activity of DCs by suppressing the NF-κB pathway by decreasing I-κBα phosphorylation rather than attenuating RelB and p38SAPK expression ^[23]. He et al. reported that sinomenine induced RAW264.7 apoptosis by activating the extracellular signal-regulated protein kinase (ERK), which was accompanied by increased p27 and Bax expression in the apoptotic macrophages ^[24]. Furthermore, Ou et al. reported that sinomenine markedly inhibited activated human monocytic THP-1 cell migration and invasion in a dose-dependent pattern ^[25]. A possible mechanism for this phenomenon is through reduced expression of matrix metalloproteinases 2 and 9, which highly correlates with attenuated CD147 activity.

Figure 2. Molecular mechanisms of sinomenine for treatment of RA. Sinomenine exhibits its therapeutic effects on RA by modulating several key immune responses and inflammatory pathways, attenuating inflammation, alleviating pain, and inhibiting bone and joint destruction.

Novel insights into the molecular mechanisms underlying the immunomodulatory and anti-inflammatory functions of sinomenine have recently been reported. In 2015, Tong et al. reported that sinomenine modulated Th17 and regulatory T-cell frequency in intestinal lymph nodes and yielded tissue-selective lymphocyte trafficking from the gut to the joint, thereby suppressing collagen-induced arthritis (CIA) ^[26] (Figure 2). In 2016, they also reported that sinomenine was an aryl hydrocarbon receptor (AhR) agonist that can induce AhR target gene expression, promote the dissociation of the AhR/Hsp90 complex and the nuclear translocation of AhR, induce XRE reporter activity, and facilitate AhR/XRE binding. In a CIA mouse model, the antiarthritic effect of sinomenine was largely diminished by the AhR antagonist resveratrol ^[27].

Microsomal prostaglandin E 2 synthase 1 (mPGES-1) catalyzes the terminal step of prostaglandin E2 (PGE2) biosynthesis and has been associated with various types of human diseases, including RA. Thus, mPGES-1 is considered a potential anti-RA drug target ^[28]. Zhou et al. reported that sinomenine reduced PGE2 levels via selective suppression of mPGES-1 expression without affecting the formation of prostacyclin and thromboxane ^[29]. In the edema rat model and CIA DBA mouse model, mPGES-1 protein expression was downregulated following sinomenine treatment in inflamed paw tissues, suggesting that sinomenine can selectively inhibit mPGES-1. In a follow-up study, the exact mechanism was investigated ^[30]; the DNA demethylating agent 5-AzaC was reported to reverse the inhibition of sinomenine on mPGES-1. Sinomenine selectively increased methylation levels at the specific GCG sites in the mPGES-1 gene promoter, and 5-azacytidine pretreatment suppressed this effect.

In 2018, Liu et al. measured several clinical indices, inflammatory cytokine secretion, and the disease activity score (DAS28) in RA patients treated with sinomenine to explore its anti-inflammatory mechanism in a clinical setting ^[31]. The results demonstrated that sinomenine can regulate eotaxin-2, GM-CSF, IL-1α, IL-1β, IL-6, IL-10, IL-12 p40, KC (CXCL1), MCP-1, M-CSF, RANTES, and TNF-α secretion and reduce RA activity and the DAS28 score. Moreover, the CD14+CD16+ blood monocyte count was decreased. The anti-RA effect of sinomenine was reported to be mediated by gut-sourced vasoactive intestinal polypeptide (VIP), which is generated through α7nAChR activation ^[32]. Orally administered sinomenine improved systemic inflammatory conditions in CIA rats in a manner similar to the administration of nicotinic receptor antagonists, including α7nAChR antagonists but not muscarinic receptor antagonists. In addition, elevated VIP levels in the small intestine and serum of rats negatively correlated with joint destruction. The anti-RA effect of oral sinomenine can be summarized in the following order: (1) stimulation of α7nAChR; (2) activation the PI3K/Akt/mTOR pathway; and (3) generation of the anti-inflammatory neuropeptide VIP in the small intestine, which enters systemic circulation to regulate the inflammatory response pathway. The role of α7nAChR in the inflammation reflex and the potential mechanism of sinomenine in the modulation of α7nAChR have recently been elucidated ^[33]. In RAW264.7 cells treated with α7nAChR shRNA and stimulated with LPS, multiple classical M1 markers, such as IL-6, iNOS, and TNF-α, were downregulated, whereas M2 markers, such as Arg-1, Fizz1, and IL-10, were upregulated. Sinomenine suppressed Egr-1 and p-ERK1/2 expression in the LPS-induced RAW264.7 cells, and α7nAChR expression was inhibited by U0126, which in turn reduced the expression of Egr-1 and p-ERK1/2. This supports the notion that sinomenine downregulates α7nAChR through the α7nAChR/ERK/Egr-1 feedback pathway, which subsequently inhibits the polarization of the M1-type macrophage and resolves inflammation.

Macrophage migration is known as a fundamental process in immune responses, whereby monocytes leave the blood and differentiate into macrophages within the inflammation site of tissues ^[34]. Gao et al. recently reported that sinomenine can reduce the population of RAW264.7 cells migrating toward inflammatory paws and block the migration of bone-marrow-derived macrophages. The absence of macrophage migration after the depletion of circulating and peripheral macrophages reduced the inflammatory response severity. Research has revealed that sinomenine can inhibit macrophage migration by activating the Src/FAK/P130Cas axis ^[35].

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Cuili Zhang

Shujie Zhang

Jingjing Liao

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Haining Lyu

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1. Introduction

2. Direct Targets of Sinomenine for Treating RA

3. Immunosuppressive and Anti-Inflammatory Effects of Sinomenine

References