Table 4.
Anti-inflammatory activity of lignans ex vivo and in vivo.
| Lignan | Source | Model | Target | Dose, Road | Ref. |
|---|---|---|---|---|---|
| Arylnaphthalene structure group | |||||
| Sevanol | Thymus armeniacus | CFA-induced thermal hyperalgesia | ↑withdrawal latency of inflamed hind paw | 1–10 mg/kg of mice, i.v. | [119] |
| Synthetic | CFA-induced paw edema | ↓paw edema | 0.1–1 mg/kg of mice, i.m., i.n., p.o. | [120,121] | |
| Aryltetralin structure group | |||||
| Podophyllotoxin | Synthetic (G-003M) | TGR-exposed model | ↑survival, ↓NO, ↓IL-6, ↓TNF-α, ↓TGF-β1 | 5 mg/kg of mice, i.m. | [122] |
| Synthetic, conjugated with PAA dendrimer | HCC-induced model | ↓IL-6, ↓NF-κB, ↓α-SMA, ↓TGF-β | 10, 20 mg/kg of mice, p.o. | [123] | |
| Sauchinone | Saururus chinensis | OVA-induced asthma model | ↓neutrophil, lymphocyte, eosinophil infiltration in BALF, ↓IL-5, ↓IL-13, ↓Th2 cell development | 10, 100 mg/kg of mice, i.p. | [126] |
| Dibenzocyclooctadiene structure group | |||||
| Gomisin A | Schisandra chinensis Baill. | CCl4-induced hepatotoxicity | ↓TNF-α, ↓IL-1β, ↓iNOS, ↓NF-κB, ↓p-IκB | 50–100 mg/kg of rat, i.p. | [127] |
| Gomisin N | Schisandra chinensis Baill. | ethanol-induced liver injury | ↓ NF-κB p65, ↑ IκB, ↓ TNF-α, ↓ IL-6, ↓ MCP-1 | 5–20 mg/kg of mice, p.o. | [38] |
| Schisandrin A | Schisandra chinensis (Turcz.) Baill. | LPS-treated model | ↓NO level | 100–200 mg/kg of mice, i.p. | [173] |
| carrageenan-induced paw edema | ↓paw edema volume | ||||
| xylene-induced ear edema | ↓ear edema degree | 25–50 mg/kg of mice, p.o. | [174] | ||
| carrageenan-induced paw edema |
↓paw edema volume ↓TNF-α, ↓IL-1β, ↓MPO, ↓p-p65NF-κB, ↓p-IκB, ↓TLR4 |
25–50 mg/kg of mice, p.o. | |||
| Schisandrin B | Synthetic | Con A-induced lymphocytes | ↓IL-2, ↓IL-4, ↓IL-6, ↓IFN-γ | 80 mg/kg of mice, i.p. | [46] |
| myocardial infarction model | ↓in left ventricular end-systolic and end-diastolic diameter, ↓heart weight/body weight ratio, ↓infarct size, ↓NF-κB, ↓TGF-β1, ↓TNF-α | 80 mg/kg of mice, i.g. | [179] | ||
| Aβ-infused model | ↓ COX-2, ↓ iNOS, ↓ TNF-α, ↓ IL-1β, ↓ IL-6 | 25–50 mg/kg of rat, i.g. | [132] | ||
| I/R injury model | ↓ IL-1β, ↓ TNF-α, ↓ p-p38MAPK, ↓ p-ERK1/2, ↓ NF-κB p65 | 80 mg/kg of rat, p.o. | [134] | ||
| TSCI model | ↓ NF-κB p65, ↓ TNF-α | 50 mg/kg of rat, p.o. | [133] | ||
| IL-1β-induced rat chondrocytes | ↓IL-6, ↓iNOS, ↓MMP3, ↓MMP13, ↓NF-κB, ↓MAPK | 50 μM, i.a. | [180] | ||
| STZ-induced diabetes | ↑ IκBα, ↓ VCAM-1, ↓ TNF-α | 20 mg/kg of mice, p.o. | [135] | ||
| Ang II-induced vascular injury model | ↓α-SMA, ↓p-Smad2/3, ↑VE-cadherin | 20 mg/kg of mice, p.o. | [176] | ||
| DSS induced colitis | ↓TNF-α, ↓IL-6, ↓IL-18, ↓IL-1β, ↓NLRP3, ↑p-AMPK | 10 mg/kg of mice, i.p. | [177] | ||
| Schisantherin A | Synthetic | MCAO/R-induced brain injury model | ↓IL-1β, ↓IL-6, ↓p-IκBα, ↓NF-κB, ↓p-ERK, ↓p-JNK, ↓p-p38, ↓TLR4, ↓C5aR1 | 5–10 mg/kg of rat, i.g. | [142] |
| LPS-induced acute kidney injury |
↓accumulation neutrophils and T-lymphocytes, ↓NF-κB, ↓TNF-α, ↓Rantes |
40 mg/kg of mice, i.p. | [55] | ||
| Dibenzylbutane structure group | |||||
| Meso-dihydroguaiaretic acid | Machilusphilippinensis Merr. | LPS-induced ARDS model | ↓MPO, ↓4-HNE, ↓elastase accumulation | 30 mg/kg of mice, i.p. | [58] |
| Nordihydroguaiaretic acid | Synthetic | TPA-treated model | ↓LPO level, ↓XOD, ↓MPO | 15–25 μM, shaved area of dorsal skin | [64] |
| spinal cord injury | ↓MPO, ↓TNF-α, ↓IL-1β | 30 mg/kg of rat, i.p. | [211] | ||
| leptin-deficient (ob/ob) mice |
↑PPARα, ↑p-AMPK ↑fatty acid oxidation pathway |
0.83 g/kg, 2.5 g/kg, diet | [212] | ||
| CLP-induced sepsis | ↓lung edema, ↓lactate, ↓blood urea nitrogen, ↓histologic lung injury | 20 mg/kg of rat, i.p. | [213] | ||
| Secoisolariciresinol diglucoside | Synthetic | CLP-induced sepsis | ↓p-IκBα, ↓NF-κΒ | 100 mg/kg of mice, i.p. | [76] |
| BaP-injured model | ↓MPO, ↓NO level, ↓TNF-α, ↓IL-6, ↓IL-1β, ↓NF-κB | 100 mg/kg of mice, i.g. | [149] | ||
| Dibenzylbutyrolactone structure group | |||||
| Arctigenin | Forsythia fructus | OVA-induced asthma model | ↓ PDE | 10–100 μM | [186] |
| 48/80-induced RPMCs | ↓ histamine release | 10 μM | |||
| IgE-rich mouse serum-induced PCA skin model | ↓ amount of Evans blue leakage | 15–45 mg/kg of rat, p.o. | |||
| anti-rat rabbit serum antibody-induced RCA skin model | ↓ skin edema | ||||
| SRBC-induced Arthus reaction model | ↓footpad thickness, ↓hemolysis tier, ↓hemagglutinin titer, ↓plaque-forming cells | 15–45 mg/kg of mice, p.o. | |||
| SRBC-induced DTH model | ↓ footpad thickness, ↓ rosette-forming cells | ||||
| DNFB/PC-induced contact dermatitis | ↓ ear edema | 0.1–1 mg/ear of mice | |||
| Arctium lappa Linn. | LPS-/PGN-stimulated peritoneal macrophages | ↓IL-6, ↓TNF-α, ↓IL-1β, ↑IL-10, ↑CD204, ↓p-PI3K, ↓p-Akt, ↓p-p65, ↓p-IKKβ | 10–20 μM | [216] | |
| LPS-/PGN-induced model | ↓TNF-α, ↓IL-1β | 5 mg/kg of mice, i.p. | |||
| TNBS-induced colitic model | ↓IL-6, ↓TNF-α, ↓IL-1β, ↓MPO, ↑IL-10, ↓p-PI3K, ↓p-Akt, ↓p-p65 | 30–60 mg/kg of mice, p.o. | |||
| acetic acid-induced chronic ulcer model | ↓ TNF-α, ↓ IL-6, ↑ IL-10, ↓ CRP | 0.05–0.45 mg/kg of rat, p.o. | [151] | ||
| LPS-induced acute inflammation model | ↓CD86, ↓IL-6, ↓IL-12, ↓TNF-α, ↓IL-1β, ↑IL-10, ↑G-MDSCs, ↓M-MDSCs, ↓IRF8, ↑miR-127-5p, ↓M1 macrophage polarization, ↑Arg-1, ↑iNOS | 50 mg/kg of mice, i.p. | [187] | ||
| Synthetic | JEV-infected model | ↓ iNOS, ↓ TNF-α, ↓ IFN-γ, ↓ MCP-1, ↓ IL-6, ↓ p-p38 MAPK, ↓ p-c-Jun ↓ p-ERK-1/2, ↑ p-Akt | 10 mg/kg of mice, i.p. | [152] | |
| LPS-injured model | ↓ nitrate/nitrite ratio, ↓ iNOS, ↓ TNF-α, ↓ IL-6, ↓ MIP-2, ↓ p-ERK1/2, ↓ p-JNK, ↓ p-p38 | 50 mg/kg of mice, i.p. | [153] | ||
| EAE model | ↓IFN-γ, ↓T-bet, ↓IL-17, ↓ROR-γt, ↓Th1, ↓Th17 | 5–10 mg/kg of mice, i.p. | [217] | ||
| ConA-induced acute hepatitis | ↑IL-4, ↓F4/80, ↓CD49b, ↓CD4 T cells | 5–10 mg/kg of mice, i.p. | [188] | ||
| AMI model | ↓ iNOS, ↓ COX-2, ↓ IL-1β, ↓ IL-6, ↓ p-ERK1/2 | 100–200 μmol/kg of rat | [155] | ||
| BLM-induced skin fibrosis model | ↓ TGF-β1, ↓ IL-1β, ↓ IL-4, ↓ IL-6, ↓ TNF-α, ↓ MCP-1 | 3 mg/kg of mice, i.p. | [156] | ||
| DMM model | ↓cartilage erosion, ↓hypocellularity, ↓proteoglycan loss | 30 mg/kg of mice, p.o. | [189] | ||
| imiquimod-induced murine psoriasis model | ↑p-CREB, ↑cAMP, ↑IL-10, ↓TNF-α, IFN-γ, ↓COX-2, ↓iNOS, ↓IL-2, ↓IL-6, ↓IL-12, ↓IL-17, ↓IL-22, ↓IL-23, ↓IL-27 | 5% cream | [190] | ||
| silicosis model | ↓TGF-β, ↓TLR-4 | 30–60 mg/kg of rat, i.g. | [88] | ||
| cadmium-intoxicated model | ↓NF-κB p65, ↓TNF-α, ↓IL-1β | 80 mg/kg of rat, i.g. | [157] | ||
| Hinokinin | Synthetic | high-fat diet/STZ-induced type 2 diabetic | ↓TLR 4, ↓MYD88, ↓NF-κB p65, ↑IKBα, ↓TNF-α, ↓IL-1β, ↓p38, ↓ERK 1/2, ↓JNK, ↓MEK | 20–40 mg/kg of mice, p.o. | [158] |
| Matairesinol | Synthetic | IRBP/CFA-induced EAU model | ↓T17 cells, ↓IL-17A, ↓IL-17F, ↓IL-21, ↓GM-CSF, ↓IRF-4, ↓Hif1, ↓Batf, ↓ROR-γt, ↓TNF-α | 1 mg/kg of mice, i.p. | [192] |
| CLP-induced sepsis | ↓TNF-α, ↓IL-1β, ↓IL-6, ↓IFN-γ, ↓IL- 8, ↓MCP1, ↓MAPK, ↓JNK, ↓NF-κB | 5–20 mg/kg of rat, p.o. | [93] | ||
| Nortrachelogenin | Synthetic | carrageenan-induced paw edema | ↓paw edema volume | 100 mg/kg of mice, i.p. | [194] |
| Furanoid structure group | |||||
| Nectandrin B | Guaiacum officinale L. | IL-1β-treated rat hepatocytes | ↓ NO level | IC50 43.4 μM | [218] |
| Taxiresinol | Taxus baccata Linn. | carrageenan-induced paw edema | ↓paw edema volume | 100 mg/kg of mice, p.o. | [219] |
| Furofuranoid structure group | |||||
| Acanthoside B | Salicornia europaea Linn. | Amnesic AD-like model | ↓iNOS, ↓COX-2, ↓TNF-α, ↓IL-1β, ↓IL-6, ↑IL-10 | 10, 20 mg/kg of mice, p.o. | [220] |
| (+)-Diayangambin | Piper fimbriulatum | carrageenan-induced paw edema | ↓paw volume, ↓prostaglandin E2 | 40 mg/kg of mice, p.o. | [197] |
| Fargesin | Magnolia sp. | DSS-induced colitis | ↓inflammatory infiltration, ↓MPO, ↓TNF-α, ↓NO, ↑IκBα, ↓NF-κB | 50 mg/kg of mice, p.o. | [199] |
| Synthetic | ApoE−/− model | ↓macrophage infiltration, ↑M2 phenotype polarization, ↓TNF-α, ↓IL-1β, ↓IL-6, ↓MCP-1, ↑IL-10 | 50 mg/kg of mice, p.o. | [221] | |
| Isoeucommin A | Eucommia ulmoides Oliv. | STZ-induced diabetic nephropathy | ↓immune infiltration, ↓TNF-α, ↓IL-1β, ↓IL-6 | 2.5–10 mg/kg of rat, i.v. | [104] |
| Koreanaside A | Forsythia koreana | DSS-induced acute colitis |
↓iNOS, ↓COX-2, ↓IL-6, ↓TNF-α ↓p-c-Fos, ↓p-p65, ↓p-STAT1, ↓p-STAT3 |
5–20 mg/kg of mice, i.p. | [200] |
| Phillygenin | Forsythia koreana | carrageenan-induced paw edema | ↓paw volume | 12.5–100 mg/kg of mice, i.p. | [201] |
| Forsythia fructus | CCl4-induced liver fibrosis | ↓LPS, ↓MIP-1, ↓TNF-α, ↓IL-1β, ↓IL-6, ↓immune infiltration | 20, 40 mg/kg of mice, i.g. | [222] | |
| Pinoresinol diglucoside | Synthetic | Aβ-infused model | ↓TLR4, ↓NF-κB p65, ↓TNF-α, ↓IL-1β | 5–10 mg/kg of mice, i.g. | [160] |
| MCAO model | ↓TNF-α, ↓IL-1β, ↓IL-6, ↓p-IKKβ, ↓p-IkBα, ↑cNF-κB p65, ↓p-p65 | 5–10 mg/kg of mice, i.v. | [161] | ||
| Sesamin | Sesamum indicum Linn. | fMLF-induced inflammation in a murine air-pouch model | ↓leukocyte infiltration | 12 mg/kg of mice, i.p. | [203] |
| PCA model | ↓PCA reaction | 50–200 mg/kg of rat, p.o. | [204] | ||
| LPS-treated model | ↓TNF-α, ↓MCP-1, ↓IL-1β | 10 mg/kg of rat, p.o. | [168] | ||
| LPS-treated model | ↓NF-κB, ↓TLR4, ↓Cox2, ↓TNF-α, ↓IL-6 | 100 mg/kg of mice, p.o. | [169] | ||
| DSS-induced colitis model | ↓IL-6, ↓IL-1β, ↓TNF-α | 50–100 mg/kg of mice, i.g. | [113] | ||
| cisplatin-injured model | ↓TNF-α, ↓IL-1β, ↓TGF-β1, ↓MPO | 5 mg/kg of rat, p.o. | [170] | ||
| Synthetic | CCl4-induced hepatotoxicity model | ↓TNF-α | 60–120 mg/kg of mice, p.o. | [164] | |
| carrageenan-induced lung inflammation | ↑A20, ↑TAX1BP1, ↓IL-6, ↓IL-8, ↓IL-1β, ↓TNF-α, ↓MIP-2, ↓MPO, ↓β-glucuronidase, ↓p-p65, ↓TRAF6 | 50–100 mg/kg of rat, p.o. | [205] | ||
| fluoride-exposed model | ↓TNF-α | 0.5–1 g/kg of carp, diet | [165] | ||
| Syringaresinol | Rubia philippinensis | carrageenan-induced paw edema model | ↓paw edema volume | 50 mg/kg of mice, p.o. | [207] |
| CLP-induced sepsis | ↓TNF-α, ↓IL-6, ↓IL-18, ↓IL-1β | 50 mg/kg of mice, p.o. | [208] | ||
| STZ-induced type 1 diabetic model | ↓macrophage, monocyte, neutrophil infiltration in myocardium, ↓TNF-α, ↓IL-6, ↓IL-1β | 25 mg/kg of mice, p.o. | [116] | ||
| Albiziae cortex | LPS-treated model | ↓IL-6, ↓IL-1β, ↓TNF-α, ↓COX-2, ↓iNOS, ↓microglia activation | 60 mg/kg of mice, p.o. | [209] | |
4-HNE, 4-hydroxy-2-nonenal; AD, Alzheimer’s disease; Ang, angiotensin; ARDS, acute respiratory distress syndrome; BALF, brochoalveolar lavage fluid; Batf, basic leucine zipper transcriptional factor ATF-like; CFA, Complete Freund’s Adjuvant; CLP, cecal ligation and puncture; ConA, concanavalin A; CRP, C-reactive protein; DTH, delayed type hypersensitivity; DMM, destabilization of the medial meniscus; DNFB, 2,4-dinitro-1-fluorbenzene; DSS, dextran sulfate sodium; EAE, experimental autoimmune encephalomyelitis; EAU, experimental autoimmune uveitis; fMLF, N-Formyl-Met-Leu-Phe; G-003M, formulation of synthetic podophyllotoxin with rutin; GM-CSF, granulocyte-macrophage colony-stimulating factor; HCC, hepatocellular carcinoma; Hif1, hypoxia-inducible factor-1; i.a., intra-articular injection; i.g., intragastric administration; i.m., intramuscular injection; i.n., intranasal administration; i.p., intraperitoneal injection; i.v., intravenous injection; IRBP, inter photoreceptor binding protein; IRF-4/8, interferon regulatory factor 4/8; JEV, Japanese encephalitis virus; MCAO, middle cerebral artery occlusion model; MDSCs-G/M, myeloid-derived suppressor cells granulocytic/monocytic; MIP, macrophage inflammatory protein; OVA, ovalbumin; PAA, polyamidoamine; PC, picryl chloride; PCA, passive cutaneous anaphylaxis; PGN, peptidoglycan; p.o., oral administration; RCA, reversed cutaneous anaphylaxis; ROR-γt, retineic-acid-receptor-related orphan nuclear receptor gamma; SRBC, sheep red blood cell; STZ, streptozotocin; TGR, thoracic gamma radiation; Th2, T-helper 2; TLR4, Toll-like receptor 4; TNBS, 2,4,6-trinitrobenzene sulfonic acid; TPA, 12-O-tetradecanoylphorbol-13-acetate; XOD, xanthine oxidase. Downward-pointing red arrows reflect the downregulatory action, upward-pointing green arrows reflect the upregulatory action.