Table 1.
Potential Mechanism of QUE in Pre-Clinical Studies
| Therapeutic Effect | Experimental Model | Dosage Information | Molecular Mechanism | Signaling Pathway | |
|---|---|---|---|---|---|
| Anti-inflammatory effect | Effect on clinical parameters and inflammatory cytokines | Zymosan-induced arthritis mice | 0, 10, 30, 100 mg/kg s.c. 30 min before zymosan injection21 | Reduced mechanical hyperalgesia, joint edema, and recruitment of total leukocytes, neutrophil, mononuclear cells in joint, decreased TNF-α, IL-1β, prepro-ET-1, COX-221 | NF-κB21 |
| CIA model | 150 mg·kg−1·0.5 mL−1 three times a week orally administrated for 17 or 28 days;23 0, 50, 100mg/kg/d orally administrated for 5 weeks;24 150mg/kg daily orally administrated for 14 days22 or 21 days;25 30mg/kg daily orally administrated for 49 days26 | Mitigated paw edema, inflammatory cells infiltration, synovium hyperplasia, cartilage and bone erosion, decreased TNF-α, IL-1β, IL-6, PGE2, and NLRP3 inflammasome (NLRP3, Caspase-1 and IL-1β)22–26 | SIRT1/PGC-1α/NRF1/TFAM and HMGB1/TLR4/p38/ERK1/2/NF-κB p6524 | ||
| AA model | 150 mg/rat (30 mg every 2 days, orally administrated for 10 days) or 25, 50 mg/rat (5 or 10 mg every 2 days, intra-cutaneous injection following the appearance of first arthritic symptoms);27 25 mg/kg/d orally administrated for 14 days;31 0, 5, 25 50 mg/kg/d orally administrated for 45 days;29 30mg/kg/d injected intra-peritoneally 31 days;30 100mg/kg injected intra-peritoneally three times a week for 3 weeks;28 0, 50, 100, 150 mg/kg/d orally administrated for 28 days;32 150mg/kg/d orally administrated for 28 days33 | Reduced arthritis scores, paw thickness and inflammatory infiltration, increase paw thermal latency.27–32 Increased IL-4 and IL-10, decreased TNF-α, NO, IFN-γ, IL-6, IL-1β, MCP-1, MPO,27–30,32,33 decreased 12/15-LOX in liver and lung.33 Decreased ADA enzyme activity and gene expression in sera and joints28 | GSK-3β, NF-κB and ERK30,32,33 | ||
| Human RAFLS | 50 nmol/L;37 0, 20, 100, 200μM38 |
Decreased IL-1β stimulated COX-2 and PGE2,38 decreased TNF-α-induced IL-1β, IL-6, IL-8 and MCP-136,37 | MAPKs (ERK, p-38, JNK)38 and NF-κB,36,38 lncRNA XIST/miR-485/PSMB8 axis37 | ||
| Inhibition of oxidative stress | Zymosan-induced arthritis mice | 0, 10, 30, 100 mg/kg s.c. 30 min before zymosan injection21 | Increased GSH, decreased gp91 phox21 | Nrf2/HO-121 | |
| CIA model | 150mg/kg daily orally administrated for 14 days22 | Increased HO-1 in synovium and FLS, failed to downregulate inflammatory cytokines and mediators (TNF-α, IL-1β, IL-6, PGE2, iNOS and COX-2) in HO-1 siRNA transfection CIA-FLS22 | - | ||
| AA model | 30mg/kg/d injected intra-peritoneally 31 days;30 0, 5, 25, 50 mg/kg/d orally administrated for 45 days;42 150mg/kg/d orally administrated for 28 days33 | Decreased neutrophil infiltration, activation, and invasion, increased neutrophil apoptosis, decreased NETs formation by inhibiting autophagy.30 Reduced ROS level and increased catalase activity in serum.42 Further increased HO-1 expression in joint, and restored HO-1 to control level in lung33 | NF-κB and ERK33 | ||
| Regulation of behavior of FLS | Human RAFLS | 0, 10, 20, 30 μM;49 0, 10, 50, 100, 150, 200, 300 μM;44 0, 100, 200, 300 μM,45 0, 20, 100, 200μM38 | Increased apoptosis and decreased IL-1β-induced proliferation.38 Increased apoptosis via upregulating lncRNA MALAT1.44 Upregulated caspase-3, caspase-9, Bax, downregulated Bcl-2,44,45 caused a loss in mitochondrial membrane potential, and enhanced the subsequent release of cytochrome c from mitochondria.45 Inhibited migration and invasion49 | MAPKs (ERK, p38, JNK), NF-κB38 and PI3K/AKT,44 p53 activation,45 miRNA-146a/GATA6 axis.49 | |
| Immune-regulatory effect | - | CIA model | 0, 50, 100mg/kg/d orally administrated for 5 weeks;24 150mg/kg daily orally administrated for 14 days22 or 21 days25 | Decreased IL-17A, IL-21, IL-23, increased IL-10, TGF-β, decreased CD4+IL-17A+T cell proportion, increased CD4+CD25+Foxp3+ T cells proportion; upregulated Foxp3 and downregulated RORγt of Th17 cells and Treg cells,22,24,25 decreased serum autoantibodies levels (anti-CII IgG, anti-CII IgG1 and anti-CII IgG2a)22,24 | PPARγ25 |
| AA model | 100mg/kg injected intra-peritoneally three times a week for 3 weeks;28 0, 5, 25 50 mg/kg/d orally administrated for 45 days29 | Decreased anti-CCP, RF.28 Reversed the increase of E-NTPDase activity and the decrease of E-ADA activity in lymphocytes, lowered the increased serum adenosine levels, decreased the elevated levels of IFN-γ and IL-429 | - | ||
| Human PBMC cultured with Th17-differentiation conditions | 0, 1, 5, 25 μM52 | Reduced IL17 production in the culture medium, suppressed the percentage of IL-17-expressing CD4+ T cells, but exhibited no effect to the percentage of CD25Foxp3-expressing CD4+ regulatory T cells52 | mTOR, ERK, IκB-α and AMPK52 | ||
| Mouse naïve CD4+ T cells | 0, 1, 3, 10 μM25 | Decreased CXCR3, inhibited CD4+ T cells polarized into Th17 cells, and decrease the proportion of CXCR3+IL-17A+ T cells and IFN-γ+IL-17A+CD4+ T cells25 | |||
| Bone-protective effect | - | Human RAFLS | 0, 1, 5, 25 μM;52 100μM38 | Suppressed IL-17 produced RANKL expression at mRNA and protein level, inhibited RANKL- and IL-17- produced TRAP positive osteoclasts formation, and decreased the expression of the osteoclast markers, including TRAP, cathepsin K, NF-ATc1, DC-STAMP, ATP6vOd2, and OC-STAMP, decreased TRAP positive osteoclasts formation and the osteoclast markers in culture system of monocytes with IL-17-prestimulated RAFLS, and in osteoclast precursors (pre-OC) with Th17 cells and M-CSF.52 Inhibit IL-1β stimulated MMP-1, MMP-3 at mRNA and protein level38 | mTOR, ERK, IκB-α, AMPK.52 MAPKs (ERK, p38, JNK) and NF-κB38 |
| Anti-extra-articular effect | Hepatoprotective Cytoprotective Genoprotective |
AA model | 0, 5, 25, 50 mg/kg/d orally administrated for 45 days42 | Decreased the increased serum AST except for ALT, ALP, decreased TBARS, DNA damage42 | - |
| Neuroprotective | AA model | 50 mg/kg/d orally administrated for 60 days58 | Reversed the density of the enteric neurons and the enteric glial cells (EGC) in the myenteric and submucosal plexuses, the expression of GFAP and GDNF expression, reduced intestinal inflammation58 | - | |