TABLE 4.
Effects and mechanism of Salvia miltiorrhiza and its active ingredients on rheumatoid arthritis.
| Ingredient | In vivo/In vitro | Model | Administration | Dose/Time | Treatment effect | Mechanism | Diseases | References |
|---|---|---|---|---|---|---|---|---|
| Salvianolate | In vivo; In vitro | Prednisone-treated rheumatoid arthritis rats; TNF-α-induced MC3T3-E1 | Intraperitoneal injection | 20 mg/kg/d for 90 days; 1 μM for 72 h | Increase BMD and trabecular/cortical bone mass, suppress inflammation, and improve bone biomechanical properties compared to CIA control and PDN treatment; Increase Osterix, OPN and Runx2 in TNF-α-induced MC3T3-E1 | Regulate RANKL/RANK/OPG Signaling | RA | Gao et al. (2021) |
| Protocatechuic aldehyde | In vitro | Human monocytes | - | 10∼100 μM for 48 h/s | Inhibit IL-1α or PMA-induced IL-1β production without inhibiting total protein synthesis and without cytotoxicity | Inhibit PKC signaling pathway | RA | Watanabe et al. (1993) |
| Salvia miltiorrhiza injection | In vitro | RA FLSs | - | 0.4 mg/mL for 24 h | Promote the apoptosis and inhibit the proliferation of RA FLSs cultured in serum | - | RA | Liu et al. (2013) |
| Tanshinone ⅡA | In vitro | RA FLSs | - | 2.5∼80 μM for 24, 48, 72 h | Block the cell cycle in the G2/M phase, and regulate the protein expression of Bcl-2, Bax, and Apaf-1, the release of mitochondrial Cyt-c, and the activation of caspase-9 and caspase-3 | Through blockade of the cell cycle in the G2/M phase and a mitochondrial pathway | RA | Jie et al. (2014) |
| Tanshinone ⅡA | In vitro | RA FLSs | - | 1, 5,10, 20, 40 and 80 μM for 24, 48, 72 h | Reduce the activity and promote the apoptosis of RAFLS. Upregulate the expression of cleaved caspase-3/caspase-9 | Upregulate lncRNA GAS5 and inhibit PI3K/AKT signaling | RA | Li et al. (2018) |
| Salvia miltiorrhiza injection | In vitro | RA FLS | - | 0.195 and 0.39 mg/mL for 24 h | Promote the expression of apoptotic genes | - | RA | Liu et al. (2015) |
| Tanshinone ⅡA | In vivo | Adjuvant-induced arthritis mice | Intraperitoneal injection | 30 mg/kg/d for 40 days | Inhibit the expression of IL-6 and TNF-α and the release of neutrophils, and promote the apoptosis of neutrophils | - | RA | Zhang et al. (2017a) |
| Tanshinone ⅡA | In vivo; In vitro | Collagen-induced arthritis mice; RA FLSs | Oral gavage | 5 mg/kg/d for 27 days; 1, 3, and 10 μM for 24 h | Decrease the production of IL-1β, IL-6, MMP-1, and MMP-3 in TNF-α-treated RA-HFLSs, alleviate rheumatoid arthritis progression and prevent inflammation damage in joint tissues of collagen-induced arthritis mice | Block MAPK/NF-κB pathways | RA | Wang et al. (2019c) |
| Tanshinone ⅡA | In vivo; In vitro | Collagen-induced arthritis mice; RA FLSs | Intraperitoneal injection | 30 mg/kg/d for 29 days; 5, 10, and 20 μM for 24 h | Effectively suppress the increase in mRNA expression of some matrix metalloproteinases and pro-inflammatory factors induced by TNF-α in RA-FLSs, resulting in inflammatory reactivity inhibition and blocking the destruction of the knee joint | Regulate the MAPK, AKT/mTOR, HIF-1 and NF-κB pathways | RA | Du et al. (2020) |
| Cryptotanshinone | In vivo; In vitro | collagen-induced arthritis in rats; Raw 264.7 | oral | 6, 18 mg/kg/d for 16 days; 3, 10, and 30 mM for 5 h | Effectively improve inflammation and joint destruction in CIA rats, inhibit the production of RANKL-induced pro-inflammatory cytokines such as IL-1, TNF-α and IL-17 in bone marrow macrophages, decrease the activity of MMP-9, and inhibit osteoclast differentiation | Downregulate NF-κB pathway | RA | Wang et al. (2015) |
| Salvianolic acid B | In vivo | collagen-induced arthritis in rats | oral | 20 and 40 mg/kg/d for 28 days | Reduce oxidative stress and inflammation in central nervous system rats | Downregulate NF-κB pathway | RA | Xia et al. (2018) |
| Salvianolic acid B | In vitro | LPS-induced MH7A | - | 10 μM for 48 h | Improve the damage of MH7A cells by LPS, increase cell vitality, inhibit apoptosis, inhibit the expression of p53 and p21, and reduce the release of MCP-1, IL-6 and TNF-α | Upregulate miR-142-3p and regulate NF-κB and JNK pathways | RA | Meng et al. (2019) |
Note: RA, rheumatoid arthritis; TNF-α, tumor necrosis factor-α; CIA, Collagen Induced Arthritis; IL-1, Interleukin-1; IL-17, Interleukin-17; MMP-9, Matrix metallopeptidase 9; LPS, Lipopolysaccharide; PDN, Prednisone; RA FLSs, Rheumatoid arthritis fibroblastic synovial cells; BMD, bone mineral density; OPN, Osteopontin; PKC, protein kinase C; Bax, BCL2-Associated X; bcl-2, B-cell lymphoma-2; Apaf-1, Apoptotic Protease Activating Factor 1; Cyt-c, Cytochrome c; GAS5, Growth Arrest-specific Transcripts; NF-κB, Nuclear factor kappa-B; MAPK, mitogen-activated protein kinase; PI3K, Phosphatidylinositol-3-kinase; AKT, protein kinase B; IL-6, Interleukin-6; MMP-1, Matrix metallopeptidase 1; MMP-3, Matrix metallopeptidase 3; mTOR, mammalian target of rapamycin; HIF-1, Hypoxia inducible factor-1; MCP-1, Monocyte Chemoattractant Protein-1; JNK, c-Jun N-terminal kinase.