Autoimmune diseases are a worldwide health problem with growing rates of morbidity, and are characterized by breakdown and dysregulation of the immune system. Although their etiology and pathogenesis remain unclear, the application of dietary supplements is gradually increasing in patients with autoimmune diseases, mainly due to their positive effects, relatively safety, and low cost. Quercetin is a natural flavonoid that is widely present in fruits, herbs, and vegetables. It has been shown to have a wide range of beneficial effects and biological activities, including anti-inflammation, anti-oxidation, and neuroprotection. In several recent studies quercetin has reportedly attenuated rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and systemic lupus erythematosus in humans or animal models. This review summarizes the evidence for the pharmacological application of quercetin for autoimmune diseases, which supports the view that quercetin may be useful for their prevention and treatment.

The morbidity and mortality of autoimmune diseases (Ads) have been increasing worldwide, and the identification of novel therapeutic strategies for prevention and treatment is urgently needed. Sirtuin 1 (SIRT1), a member of the class III family of nicotinamide adenine dinucleotide (NAD⁺)-dependent histone deacetylases, has been reported to participate in the progression of several diseases. SIRT1 also regulates inflammation, oxidative stress, mitochondrial function, immune responses, cellular differentiation, proliferation and metabolism, and its altered functions are likely involved in Ads. Several inhibitors and activators have been shown to affect the development of Ads. SIRT1 may represent a novel therapeutic target in these diseases, and small molecules or natural products that modulate the functions of SIRT1 are potential therapeutic agents. In the present review, we summarize current studies of the biological functions of SIRT1 and its role in the pathogenesis and treatment of Ads.

Background: Wutou Decoction (WTD), as a classic prescription, has been generally used to treat rheumatoid arthritis (RA) for two thousand years in China. However, the potential protective effects of WTD on rheumatoid arthritis and its possible mechanism have rarely been reported.Purpose: The aim of this study was to explore the possible mechanism of WTD against RA and a promising alternative candidate for RA therapy.Methods: A model of collagen-induced arthritis (CIA) was constructed in rats to assess the therapeutic effects of WTD. Histopathological staining, immunofluorescence, and western blotting of synovial sections were conducted to detect the antiangiogenic effects of WTD. Then, cell viability assays, flow cytometry, scratch healing assays, and invasion assays were conducted to explore the effects of WTD on MH7A human fibroblast-like synoviocyte (FLS) cell proliferation, apoptosis, migration, and invasion in vitro. The ability of WTD to induce blood vessel formation after MH7A cell and human umbilical vein endothelial cell line (HUVEC) coculture with WTD intervention was detected by a tube formation assay. The mechanisms of WTD were screened by network pharmacology and confirmed by in vivo and in vitro experiments.Results: WTD ameliorated the symptoms and synovial pannus hyperplasia of CIA rats. Treatment with WTD inhibited MH7A cell proliferation, migration, and invasion and promoted MH7A apoptosis. WTD could inhibit MH7A cell expression of proangiogenic factors, including VEGF and ANGI, to induce HUVEC tube formation. Furthermore, the PI3K-AKT-mTOR-HIF-1α pathway was enriched as a potential target of WTD for the treatment of RA through network pharmacology enrichment analysis. Finally, it was confirmed in vitro and in vivo that WTD inhibits angiogenesis in RA by interrupting the PI3K-AKT-mTOR-HIF-1α pathway.Conclusion: WTD can inhibit synovial hyperplasia and angiogenesis, presumably by inhibiting the migration and invasion of MH7A cells and blocking the production of proangiogenic effectors in MH7A cells. The possible underlying mechanism by which WTD ameliorates angiogenesis in RA is the PI3K-AKT-mTOR-HIF-1α pathway.

Accumulated reactive oxygen species (ROS) directly contribute to biomacromolecule damage and influence various inflammatory responses. Reactive oxygen species act as mediator between innate and adaptive immune cells, thereby influencing the antigen-presenting process that results in T cell activation. Evidence from patients with chronic granulomatous disease and mouse models support the function of ROS in preventing abnormal autoimmunity; for example, by supporting maintenance of macrophage efferocytosis and T helper 1/T helper 2 and T helper 17/ regulatory T cell balance. The failure of many anti-oxidation treatments indicates that ROS cannot be considered entirely harmful. Indeed, enhancement of ROS may sometimes be required. In a mouse model of rheumatoid arthritis (RA), absence of NOX2-derived ROS led to higher prevalence and more severe symptoms. In patients with RA, naïve CD4⁺T cells exhibit inhibited glycolysis and enhanced pentose phosphate pathway (PPP) activity, leading to ROS exhaustion. In this “reductive” state, CD4⁺T cell immune homeostasis is disrupted, triggering joint destruction, together with oxidative stress in the synovium.

Thousands of years of clinical practice in the treatment of joint-related diseases support the efficacy and safety of Wutou decoction (WTD). Nevertheless, the lack of pharmacological evidence and unclear mechanisms make it difficult for WTD to become a recognized complementary therapy for the treatment of rheumatoid arthritis (RA). This study aimed to investigate the effect of WTD against synovial inflammation in RA and whether this effect depends on the regulation of macrophage polarization. Sprague-Dawley rats were used to establish the collagen-induced arthritis (CIA) model. WTD with low and high doses was administered for 45 days. RAW264.7 cells were stimulated by lipopolysaccharide (LPS) or interleukin (IL)-4 to polarize M1 and M2 macrophages, which were pre-treated with WTD extract for 4 h. The anti-arthritic and anti-inflammatory effects of WTD were studied using arthritis score, histopathological staining, immunostaining, and enzyme-linked immunosorbent assay (ELISA). The polarization state of RAW264.7 cells and related pro/anti-inflammatory cytokines was detected by ELISA, reverse transcription quantitative polymerase chain reaction and western blotting. Western blotting and immunofluorescence were used to investigate the effect of WTD on nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and peroxisome proliferator-activated receptors γ (PPARγ) activation both in vivo and in vitro. WTD significantly reduced the arthritis score and the pathological damage of the knee joint and decreased the expression of tumor necrosis factor alpha (TNF-α), IL-6 in serum, TNF-α, IL-1β, monocyte chemoattractant protein-1 (MCP-1), and matrix metalloproteinase-3 (MMP3) in the knee synovium. WTD inhibited M1 type polarization and promoted M2 type polarization, both in vitro and in vivo, and reduced the expression of pro-inflammatory cytokines while increasing the expression of anti-inflammatory cytokines. Experiments showed that WTD inhibited the phosphorylation of NF-κB and downstream p38 in the synovium of CIA rats and LPS-induced M1 type polarized RAW264.7 cells. In addition, PPARγ expression in the synovium of CIA rats was mainly located in the cytoplasm, and WTD treatment increased the nuclear translocation of PPARγ, which was further verified in RAW264.7 cells. NF-κB and PPARγ regulating M1 and M2 macrophage polarization and subsequent secretion of pro-inflammatory and anti-inflammatory cytokines are the underlying mechanisms of WTD that ameliorate RA synovial inflammation.