Table 1.
Pharmacological characteristic of the key active phytochemicals in SHM against OA.
| Phytochemicals | Herbs | Molecular targets against OA | Effect on TLR-4 | Other pharmacological activities | Pharmacokinetics | OB | DL | Toxicity |
|---|---|---|---|---|---|---|---|---|
| β-Sitosterol | Minister: RAS, RPA, MH, and RGM; assistant: VH and RD; guide: RC | Phosphorylation of NF-κB and the other components of the NF-κB pathway (↓) [29] | Protein expression (↓) [30] | SOD, CAT, and MDA (↓); GSH-PX, GSH, and Nrf2 (↑) [31]a | / | 36.91 | 0.75 | No toxicity [32] |
| Oleanolic acid | Minister: RPA, RGM, and CPL; assistant: VH; guide: RC and RG | SIRT3 (↑) and NF-κB (↓) [33]; MMP-3 (↓); MMP-13, PGE2, IL-6, and caspase 9 (↓), PPARg and SOD2 (↑) [34]; RANKL-induced osteoclastogenesis (↓) [35] | Protein expression (↓) [36] | NF-κB, iNOS, TNF-α, IL-1β, and IL-6 (↓); MDA (↓); SOD, GSH-px, and Nrf2 (↑) [37]a | C max: 12.12 ± 6.84 ng/mL; Tmax: 5.2 ± 2.9 h; t1/2: 8.73 ± 6.11 h; AUC0−t: 114.34 ± 74.87 ng/h/mL; CL/F: 555.3 ± 347.7 L/h; Vd/F: 3371.1 ± 1990.1 L (dose: 20 mg, oral, human) [38] | 29.02 | 0.76 | No influence on C57BL/6 mice at the concentrations below 90 mg/kg [39] |
| Licochalcone A | Guide: RG | Phosphorylation of NF-κB p65 and IκBα (↓), iNOS and COX-2 (↓); Wnt/β-catenin signaling (↓); Nrf2 and HO-1 (↑); [35, 36] RANKL-induced osteoclastogenesis (↓) [40] | Protein expression (↓) [41] | SIRT1/AMPK (↑) [42], NF-κB, AP-1, and, JNK (↓) [36]; Nrf2 signaling (↑); [41, 43]a CYP3A4, CYP2C9, CYP1A2, CYP2C8, CYP2E1, CYP2D6, and P-gp (↓); BCRP and MRP2 (↑). [41–43] | / | 40.79 | 0.29 | No influence on HFF cell viability at the concentrations below 9 μg/mL (MTT cell viability assays) [44] |
| Quercetin | Minister: CPL and MH; guide: RC and RG | M2 polarization of synovial macrophages (↑) [45]; SIRT1/AMPK (↑); SOD and TIMP-1 (↑), MMP-13 (↓) [46]; TLR-4 and NF-κB (↓) [47]; RANKL-induced osteoclastogenesis (↓) [48] | Protein expression (↓) [49] | Akt/NF-κB signaling (↓); PI3K signaling, TLR4/MyD88/PI3K, JAK-STAT, NF-κB, p38 MAPK (↓); Nrf2 signaling, and AP-1 (↑) [50]b; CYP2E1,CYP3A4,CYP2C19,MRP2,BCRP,P-gp, CYP1A2, and CYP2C8(↓); ABCA1, CYP1A1, and CYP2A6(↑) [51] | C max: 15.4 ng/ml; Tmax: 3 h; t1/2: 3.47 h; AUC0−t: 62.5 ng/h/mL; CL/F: 35300 L/h (dose: 500 mg, oral, human) [52] | 46.43 | 0.28 | >1500 mg/day with nephrotoxiciy [53] |
| Isorhamnetin | Assistant: VH | ROS production, RANKL-induced osteoclastogenesis, and MAPK/NF-κB/AKT signaling (↓) [54]; NF-κB and p65 (↓) [54] | Inhibiting the bond of LPS with TLR4 [55] | MAPK, NF-κB signaling (↓), PXR (↑); Nrf2 signaling (↑) [56]b | C max: 75.2 ± 6.9 ng/mL; Tmax: 7.2 ± 2.3 h; t1/2, t1/2α: 8.7 ± 4.7 h; t1/2β: 11.2 ± 2.0 h; t1/2ka: 8.3 ± 3.5 h; AUC0−t: 1623.4 ± 464.4 ng/h/mL; CL/F: 0.107 ± 0.061 L/h/kg; Vd/F: 1.72 ± 1.06 L/kg; V1/F: 1.55 ± 0.48 L/kg (dose:1.00 mg/kg, oral, rats) [57] | 49.60 | 0.31 | No toxicity [58] |
| Kaempferol | Minister: RPA; guide: RG | NF-κB (↓) [59]; MAPK-associated ERK and P38 signaling (↓) [60] | Protein expression (↓) [61] | TLR4/MyD88/NF-κB P65 signaling (↓); SOD, GPx, GCLC, and Nrf2 signaling (↑); UGT1A1, CYP3A4, P-gp, and CYP2E1 (↓) [62, 63] | t 1/2: 4.05 ± 0.4048 min; AUC0−t: 992 ± 107 ng/h/mL; CL: 4.06 ± 0.432 L/h/kg; Vd: 0.396 ± 0.0624 L/kg (dose: 4 mg/kg, iv, rats) [64] | 41.88 | 0.24 | No data from in vivo studies evidencing these effects [65] |
| Morusin | Guide: RG | NF-κB signaling (↓) [66] | NONE | CYP3A4, CYP1A2, CYP2C9, CYP2E1, UGT1A6, UGT1A7, and UGT1A8 (↓) [67] | / | 11.52 | 0.76 | Unknown |
| Lupeol | Minister: MH; assistant: VH | RANKL, phosphorylation of MAPK, and NF-κB signaling (↓) [68] | Protein expression (↓) [69] | Phosphorylation of p38 MAPK, JNK, TLR4/MyD88/NF-κB P65 signaling, IRAK (↓), PI3K/Akt signaling, and caspase-3 activity; ROS (↓) and Nrf2 (↑) [70]b | C max: 8.071 ± 2.93 μg/mL; Tmax: 6.444 h; t1/2: 13.564 ± 2.912 h; AUC0−t: 71.387 ± 7.14 μg/h/mL; CL/F: 29.870 ± 4.596 L/h; Vd/F: 595.902 ± 210.773 L; (dose: 200 ng/kg, oral, CD-1 mice) [71] | 12.12 | 0.78 | No toxicity [72] |
| Pinocembrin | Guide: RG | NF-κB signaling (↓) [73] | Protein expression (↓) [74] | PI3K/Akt/NF-κB and MAPK signaling (↓), SIRT3 (↑); Erk1/2-Nrf2 (↑), SOD, MDA, and ROS (↓) [75]a | t 1/2 : 3.11 ± 1.21 h; AUC0−t: 518 ± 170 ng/h/mL; CL/F: 110 ± 31.4 L/h; Vd/F: 478 ± 213 L/kg (dose: 50 mg/kg, oral, SD rats) [76] | 64.72 | 0.18 | Unknown |
Herbs of SHM—CPL: Carica papaya L.; CR: Cibot Rhizome; FK: Frankincense; MH: Myrrha; RAB: Radix Achyranthis Bidentatae; RAS: Radix Angelicae Sinensis; RC: Radix Cyathulae; RD: Radix Dipsaci; RG: Radix Glycyrrhizae; RGM: Radix Gentianae Macrophyllae; RPA: Radix Paeoniae Alba; VH: Visci Herba; AP-1: activator protein-1; AMPK: AMP-activated protein kinase; ABCG2: ATP-binding cassette transporter G2 and also known as breast cancer resistance protein (BCRP); Akt: protein kinase B; AUC0-t: area under the concentration time curve from zero to time; COX: cyclooxygenase; CAT: catalase; CL: clearance; CL/F: apparent clearance; Cmax: the maximum plasma concentrations; DL: druglikeness; ERK: extracellular-regulated kinase; GSH: glutathione; GSH-Px: glutathione peroxidase; HO-1: hemeoxygenase-1; IL: interleukin; IRAK: interleukin-1 receptor-associated kinase; IκBα: nuclear factor of kappa light polypeptide gene enhancer in B-cell inhibitor, alpha; IRF5: interferon regulatory factor 5; JAK-STAT: Janus kinase/signal transduction and activator of transcription; JNK: Jun N-terminal kinase; MAPK: mitogen-activated protein kinase; MDA: malondialdehyde; MMP: matrix metalloproteinase; MRP2: multidrug resistance protein 2; MyD88: myeloid differentiation primary response gene 88; NF-κB: nuclear factor kappa B; Nrf2: nuclear factor- (erythroid derived 2-) like 2; OB: oral bioavailability; PI3K: phosphatidylinositol-3-kinase; PPAR: peroxisome proliferator-activated receptor; P-gp: P-glycoprotein 1; RANKL: receptor activator of the NF-κB ligand; ROS: reactive oxygen species; SIRT 3: sirtuin 3; SOD: superoxide dismutase; TLR4: Toll-like receptor 4; Tmax: time taken to reach the Cmax; t1/2: half-life; t1/2α: the distribution half-life; t1/2β: the elimination half-life; t1/2ka: the absorption half-life; TNF-α: tumor necrosis factor-α; UGT: UDP-glucuronosyltransferase; Vd: volume of distribution; Vd/F: apparent volume of distribution; V1/F: apparent volume of distribution to the central compartment. aHepatoprotection; bhepatoprotection and renoprotection.