Table 1.
Apoptosis inducting activities of herbal medicine and its active components in fibroblast-like synoviocytes.
| Potential Pathways | Detail Mechanisms | Extracts/Monomers (dose/concentration) | Cells/Tissues | Related Genes/Proteins | Reference |
|---|---|---|---|---|---|
| Death receptors mediated apoptotic pathway | Up-regulating Fas and FasL; Down-regulating Bcl-2 | XFC (1.8 g/kg, p.o.) | Synovia tissues in rats | Fas, FasL, Bcl-2 | [40] |
| Up-regulating Fas | ERSM (0.4 mg/mL) | RA-FLS | Fas | [41] | |
| Up-regulating Caspase-8, Fas and FasL | FSBT (9.5–38 g/kg, p.o.) | Synovia tissues in rats | Caspase-8, Fas, FasL | [42] | |
| Up-regulating Caspase-8 and FLIP | Resveratrol (50–400 μM) | rFLS (CIA) | Caspase-8, FLIP | [44] | |
| Increasing Fas mRNA | Propyl gallate (64 μg/mL) | RA-FLS | Fas | [48,49] | |
| Up-regulating Caspase -3, -8, -9, and FasL | Daphnetin (40 μg/mL) | rFLS (CIA) | FasL, TNF, Bid, Bax, Bcl-2, Cyt-C, Caspase-3, -8, and -9 | [50,51] | |
| Mitochondrial apoptotic pathway | Up-regulating Bax and Caspase-3; Down-regulating Bcl-2 |
SWPD (15–25 mg/mL) | RA-FLS | Bcl-2, Bax, Caspase-3 | [53] |
| Down-regulating Bcl-2; Activating Caspase-3; Increasing Cyt-C release |
FSNC (0.33–1.32 g/kg) | rFLS (CIA) | Bcl-2, Caspase-3, Cyt-C | [54] | |
| Up-regulating Bax and Caspase-3; Down-regulating Bcl-2 |
DHJS medicated serum, (0.75, 1.5 and 3 g/kg) | rFLS (AIA) | Bax, Bcl-2, and Caspase-3 | [55] | |
| Up-regulating p53, Bax and Caspase-3; Downreglulating Bcl-2 |
SDP (5–15 mg/mL) | rFLS (AIA) | p53, Bax, Caspase-3, Bcl-2 | [56] | |
| Up-regulating p53, Bak, Cyt-C, Bax, Caspase-3, -9; Down-regulating Bcl-2 and Bcl-xL; Activating Caspase-3, -9 |
PHSE (25–100 μg/mL) | MH7A | p53, Bax, Bak, Bcl-2, Bcl-xL, Cyt-C, Caspase-3, -9 | [57] | |
| Inhibiting proinflammatory cytokines; Up-regulating Caspase-3, -9 and Bax; Down-regulating Bcl-2, |
GSZD (0.4–1.6 mg/mL) | MH7A, stimulated by TNF-α (20 ng/mL) | Caspase-3, -9, Bax, Bcl-2 | [16] | |
| Up-regulating Bax; Down-regulating Bcl-2; Decreasing MCMP (Δψm); Activating Caspase -3 |
Scopoletin (250–1000 μM) | rFLS (AIA), stimulated by LPS (5 μg/mL) | MCMP, Caspase-3, Bax, Bcl | [58] | |
| Up-regulating Caspase-3 and Bax; Down-regulating Bcl-2; Activating Caspase-3 |
DMHP (10–250 μM) | rFLS (AIA) | Caspase-3, Bax, Bcl-2 | [59] | |
| Increasing Caspase-3, -9, Bax and PARP; Decreasing Bcl-2, Bcl-xL and MCMP (Δψm) |
Berberine (5–75 μM) | RA-FLS | Caspase-3, -9, Bax, PARP, Bcl-2, Bcl-xL | [60] | |
| Up-regulating Bax and Caspase-3; Down-regulating Bcl-2 |
TAHP (50, 250 μM) | rFLS (AIA) | Bcl-2, Bax, Caspase-3 | [61] | |
| Up-regulating Bax and Cyt-C; Down-regulating Bcl-2; Activating Caspase -3 |
AGPD (10–30 μM) | RA-FLS | Bax, Bcl-2, Caspase-3, Cyt-C | [62] | |
| Increasing Caspase-3 activity; Up-regulating Bax and p53; Down-regulating Bcl-2 |
Gallic acid (0.1, 1 μM) | RA-FLS | Caspase-3,Bax, p53, Bcl-2 | [63] | |
| Increasing Caspase-3, -9, PARP, Fas and Bax; Decreasing Bcl-2 and MCMP (Δψm) |
Celastrol (1, 2, 5 μM) | RA-FLS | Caspase-3, -9, PARP, Fas, Bax, Bcl-2 | [64] | |
| Increasing Caspase-3, -9, Cyto C; Decreasing Bcl-2 |
Quercetin (100–300 μM) | RA-FLS | Caspase-3, -9, Cyto C, Bcl-2 | [65] | |
| Up-regulating Bax; Down-regulating Bcl-2; Activating Caspase -3 and PARP Increasing Cyt-C release; Decreasing MCMP (Δψm) |
Bufalin (10–40 nM) | RA-FLS, stimulated by IL-1β (1 ng/mL) | MCMP, Bax, Bcl-2, PARP, Caspase-3, Cyt-C | [66] | |
| Up-regulating Bax, cytosolic Cyto C, Apaf-1, Caspase-3, -9; Down-regulating Bcl-2 |
Tanshinone IIA (2.5–20 μM) | RA-FLS | Bax, Cyto C, Apaf-1, Caspase-3, -9, Bcl-2 | [67] | |
| Up-regulating Caspase-3,-8, -9, Bax, Bid and Cyt-C; Down-regulating Bcl-2 |
Daphnetin (40 μg/mL) | rFLS (CIA) | FasL, TNF, Cyt-C, Bid, Bax, Bcl-2, Caspase-3, -8, -9 | [68] | |
| Decreasing MCMP (Δψm); Increasing Cyt-C release; Up-regulating Caspase-3 -9 and PARP |
Oridonin (5–40 μM) | RA-FLS, stimulated by IL-1β (1 μg/mL) | MCMP, Caspase-3,-9, PARP, Cyt- C | [69] | |
| Down-regulating MCMP (Δψm) | Resveratrol (50–400 μM) | rFLS (AIA), stimulated by H2O2 (5 μM) | MCMP | [70,71] | |
| Up-regulating Bax and Caspase-3; Down-regulating Bcl-2 |
Pristimerin (0.75–3 μM) | rFLS (AIA) | Bax, Caspase-3, Bcl-2 | [73] | |
| Down-regulating Bcl-2/Bax | Liquirtin (0.345–34.5 μM) | RA-FLS | Bcl-2, Bax | [74] | |
| Increasing ROS; Up-regulating Bad, Caspase-3, PARP; Down-regulating Bcl-2 |
Cryptotanshinone (5 μM) | MH7A cells and RA-FLS cells | Bcl-2, Bad, Caspase-3, PARP | [75] | |
| NF-κB mediated apoptotic pathway | Down-regulating Bcl-2, MyD88 and TRAF-6 | Sinomenine (0.5–3.2 mM) | RA-FLS | MyD88, TRAF-6, Bcl-2 | [81,82,83] |
| Up-regulating Bax and IκBα; Down-regulating Bcl-2, p-IKK and p-IκBα | Scopoletin (250–1000 μM) | rFLS (AIA), stimulated by LPS (5 μg/mL) | Bax, IκBα, Bcl-2, p-IKK, p-IκBα | [57] | |
| Inhibiting phosphorylation of NF-κB and IκBα; Activating Caspase-3, -7 |
Curcumin (12.5–80 μM) | RA-FLS, MH7A, stimulated by IL-1β (10 ng/mL) | NF-κB, IKBα, Caspase-3, -7 | [84,85] | |
| Inhibiting phosphorylation of IKK and IκBα; Down-regulating NF-κB p65 |
Celastrol (0.25–2 μM) | RA-FLS | IKK, IκBα, NF-κBp65 | [86] | |
| Inhibiting phosphorylation of NF-κBp65 and IKKβ, IκB and MSK1; Down-regulating XIAP and Cyclin D1; Up-regulating GADD45a |
XAN (8.7–34.7 μM) | RA-FLS | NF-κBp65, IKKβ, IκB, MSK1, XIAP, Cyclin D1, GADD45a | [87,88] | |
| Down-regulating NF-κB p65, IKKα and IKKβ | JJD medicated serum | RA-FLS | NF-κBp65, IKKα, IKKβ | [89,90] | |
| Decreasing NF-κB p65, phospho-NF-κB p65 and acetyl-NF-κB p65, as well as pro-inflammatory cytokines | Baicalin (10, 20, 30 μM) | RA-FLS | NF-κB p65 | [91] | |
| Inhibiting phosphorylation of NF-κBp65 | PLM (5–20 μM) | RA-FLS, stimulated by TNF-α (10 ng/mL) | NF-κBp65 | [92] | |
| Down-regulating p-NF-κBp65 and p-IκB | Kaempferitrin (5–20 μM) | MH7A | NF-κBp65, p-NF-κBp65, IκB, p-IκB, | [93] | |
| Increasing ROS, cleaved Caspase-9, Cleaved PARP; Decreasing NF-κB p65 | Hypericin (0.25–4 μM) | MH7A | Caspase-9, PARP, NF-κB p65 | [94] | |
| Down-regulating XIAP; Up-regulating Caspase 3; Inhibit phosphorylation of NF-κBp65, IκB and IKK |
α-Mangostin (6–14 μg/mL) | RA-FLS, stimulated by TNF-α (10 ng/mL) | XIAP, Caspase 3, p65, IκB, IKK | [95] | |
| MAPK mediated apoptotic pathway | Up-regulating JNK, p38; Down-regulating ERK; Increasing DNA fragmentation |
Diosgenin (40 μM) | RA-FLS, stimulated by IL-1β (1 ng/mL) | JNK, ERK, p38 | [107] |
| Up-regulating JNK, p38α; Down-regulating ERK; Activating Caspase -3, -8, -9 |
Hecogenin and Tigogenin (10, 40 μM) | RA-FLS | JNK, ERK, p38α, Caspase-3,-8,-9 | [108] | |
| Up-regulating JNK, p38α; Down-regulating ERK1/2; Activating Caspase -3, - 7 and PARP-1 |
Apigenin (25–100 μM) | MH7A | JNK, ERK, p38, Caspase-3, - 7, PARP-1 | [109] | |
| Inhibiting Ras-MAPK signaling | Triptolide (0.28–200 nM) | RA-FLS, stimulated by TNF-α (10 ng/mL) | Ras, p38, ERK, JNK | [100,112] | |
| Up-regulating Bax, ERK, P38 and p21; Down-regulating Bcl-2, JNK | XAN (10, 30 μg/mL) | MH7A, stimulated by TNF-α (10 ng/mL) | Bax, ERK, p38, Bcl-2, JNK | [110] | |
| Down-regulating JNK and p-JNK | Brucine (0.125–2 mg/mL) | RA-FLS, stimulated by TNF-α (10 ng/mL) | JNK, p-JNK | [113] | |
| Up-regulating p38; Activating Caspase-3, -9 | β-Elemene (10–200 μg/mL) | RA-FLS | p38, Caspase- 3, - 9 | [114] | |
| ERS mediated apoptotic pathway | Up-regulating CHOP, GRP94 and GRP78; Activating PARP |
Hempseed oil (2.5%) | MH7A | CHOP, PARP | [119] |
| Up-regulating ATF4, CHOP and XBPI; Activating Caspase-3, -7 and PARP; Increasing phosphorylation of eIF2α, IRE1α and BiP |
DK-59 (10 μM) | MH7A | ATF4, CHOP, XBPI, Caspase-3, -7, PARP, eIF2α, IRE1α, BiP | [120] | |
| Up-regulating ATF4 and CHOP; Activating Caspase -7 and PARP; Increasing phosphorylation of eIF2α |
EJTE (37.5 μg/mL) | MH7A, stimulated by TNF-α (10 ng/mL) | ATF4, CHOP, Caspase- 7, PARP, IeIF2α | [121] | |
| Up-regulating Bax and CHOP; Down-regulating Bcl-2 |
Resveratrol (50–400 μM) | rFLS (AIA), stimulated by H2O2 (5 μM) | CHOP, Bcl-2 | [122] | |
| PI3K/AKT mediated apoptotic pathway | Up-regulating Bax; Down-regulating Bcl-2; Inhibiting phosphorylation of PI3K and Akt |
DTYD (100, 200 μg/mL) | RA-FLS | Bax, Bcl-2, PI3K, Akt | [128] |
| Up-regulating Bax; Down-regulating Bcl-2, PI3K and Akt |
SWXB medicated serum (4.32, 8.64, 17.28 g/kg) | RA-FLS | Bax, Bcl-2, PI3K, Akt | [129] | |
| Inhibiting phosphorylation of PI3K and Akt | TSDNR (100 μg/L) | rFLS, stimulated by IL-1β (10 μg/L) | PI3K, Akt | [127] | |
| Down-regulating HIF-α, p-PI3K, p-Akt, Bax, Bcl-2 in synovial tissue of CIA rats | HGTZFC (0.315 g/kg) | Synovial tissue of CIA rats | HIF-α, p-PI3K, p-Akt, Bcl-2, Bax | [130] | |
| Up-regulating Bax; Down-regulating Bcl-2; Inhibiting phosphorylation of Akt |
Genistein (50–200 μM) | rFLS (CIA) | Bax, Bcl-2, Akt | [131] | |
| Up-regulating lncRNA GAS5; Up-regulating cleaved Caspase-3, -9; Inhibiting PI3K/Akt signaling |
Tanshinone IIA (40 µM) | RA-FLS | lncRNA GAS5, Caspase-3, -9, PI3K, Akt | [132] | |
| Decreasing Akt and miR-633 | Anacardic acid (5, 30 and 60 µM) | RA-FLS, stimulated by TNF-α (10 ng/mL) | Akt | [133] | |
| Inhibiting the phosphorylation of Akt; Increasing p21 |
Juglone (30 µM) | RA-FLS | Akt, p21 | [134] | |
| Up-regulating cleaved Caspase-3, Bax; Down-regulating PI3K, Akt, mTOR |
Diosgenin (10, 20, 40 μg/mL) | RA-FLS | Caspase-3, Bax, PI3K, Akt, mTOR | [135] | |
| Up-regulating Bax; Down-regulating Bcl-2, PI3K and Akt |
Pectolinarin (10, 20 µM) | RA-FLS | Bax, Bcl-2, PI3K, Akt | [136] | |
| Other | Down-regulating Jak2 and STAT3; Inhibiting Jak2/STAT3 signaling |
TAHP (50, 250 μM) | rFLS (AIA) | Jak2, STAT3, p-STAT3 | [60] |
| Up-regulating Bax, LC3A, ATR, Chk-1 and ATR; Down-regulating Bcl-2, FasR and Cyclin-B1; Increasing phosphorylation of Cdc-2, -25; Activating Caspase-3, -9 and PARP; Increasing DNA damage G2/M phase of stagnation |
Celastrol (1–5 µM) | RA-FLS | Bax, LC3A, ATR, Chk-1, γ-H2AX, Bcl-2, FasR, Cyclin-b1, Cdc-25, Cdc-2, Caspase-3, -9, PARP | [138] | |
| Inducing pro-apoptosis effects on the RA-FLS | Wogonin (111, 0–200 μM) | RA-FLS | [143] | ||
| Up-regulating Bax and Caspase-3; Down-regulating Bcl-2; Inhibiting phosphorylation of JAK2, STAT-1, -3 |
Matrine (0.75 mg/mL) | rFLS (CIA) | Bax, Bcl-2, Caspase-3, JAK2, STAT1, -3 | [137] | |
| Down-regulating VEGF and MMP-3 | 10-HCPT (1, 10 μg/mL) | RA-FLS | VEGF and MMP-3 | [139] | |
| Activating Caspase-3, -7; Increasing G1 cell cycle |
Tamaractam; CFM; TFM (0.1, 1 µM) | RA-FLS | Caspase-3, -7 | [140] | |
| Inducing growth stagnation of synovial cells at G0/G1 stage | HCTD (6.25–100 µg/mL) | rFLS (CIA) | [141] | ||
| Up-regulating Bax and LC3A; Down-regulating Bcl-2, Atg5 and LC3B; Increasing ROS production and Ca2+ release |
Resveratrol (40–320 µM) | RA-FLS, stimulated by H2O2 (5 μM) | Bax, LC3A, Bcl-2, Atg5, LC3B | [142] | |
| Inducing pro-apoptosis effects on the RA-FLS | TGP (5–50 μg/mL) | RA-FLS | [144] | ||
| Inhibiting pro-inflammatory cytokines; Down-regulating Bcl-2, Jak2, STAT-3, -5; Inhibiting Jak2/STAT3 signaling |
GSZD (0.4–1.6 mg/mL) | MH7A, stimulated by TNF-α (20 ng/mL) | SOCS1, JAK2, STAT-3, -5 | [16] | |
| Inducing pro-apoptosis effects on the RA-FLS | CINA (1,10 μg/mL) | RA-FLS | [145] | ||
| Inducing pro-apoptosis effects on the RA-FLS | Paclitaxel (2,4,8 μM) | RA-FLS | [146] |
10-HCPT, 10-Hydroxycamptothecine; AGPD, Andrographolide; AIA, adjuvant-induced arthritis; CFM, cis-n-feruloyl-3-o-methylaids; CIA, collagen-induced arthritis; CINA, cinnamic aldehyde; DHJS medicated serum, Medicated serum of Duhuo Jisheng decoction; DMHP, 7,3′-Dimethoxy Hesperetin; DK-59, (E)-3-(3,5-dimethoxyphenyl)- 1-(1-hydroxynaphthalen-2-yl)prop-2-en-1-one; DTYD, Duanteng Yimu Decoction; EJTE, Eupatorium japonicum Thunb. Extracts; extracts from the roots of Salvia miltiorrhiza (ERSM), extracts from the roots of Salvia miltiorrhiza; FLIP, FLICE inhibitory protein; FSBT, Fengshi Bitong Prescription; FLS, fibroblast-like synoviocytes; FSNC, Fengshining Capsule; GSZD, Guizhi-Shaoyao-Zhimu decoction; HCTD, Huangqi Chongteng Drink; HGTZFC, Heiguteng-Zuifenghuoluo Capsule; JJD, Jinwu Jiangu Decoction; MCMP, Measurement of Mitochondrial Membrane Potentia; rFLS, FLS from rats; RA-FLS, FLS from RA patients; PHSE, Pterocarya Hupehensis Skan extracts; PLM, Piperlongumine; SDP, Polysaccharide from the Saposhnikovia divaricate; SWPD, Seaweed Polysaccharide; SWXB, Shuang-wu-xuan-bi granule; TAHP, 5,7,3’-triacetyl hesperetin; TFM, trans-n-feruloyl-3-O-methyla; TGP, total glucosides of paeonia; TSDNR, Total Saponin of Dioscoreae Nipponicae Rhizoma; XAN, 1,7-dihydroxy-, 4-dimethoxyxanthone; XFC, Xinfeng capsule.