Table 2.
Outline of the forementioned anti-inflammatory compounds, their molecular mechanisms, and dose exhibition effects.
| Type | Compound | Mechanism | Model | Dose Exhibiting Effects | Reference |
|---|---|---|---|---|---|
| Polyunsaturated Fatty Acids | |||||
| ω-3 LC-PUFA | Docosahexaenoic acid (DHA) | Reduction of intracellular ROS levels Decreased expressions of IL-6, IFN-γ, MCP-1, TNF-α, IL-1β and IL-10 |
PMA-stimulated monocyte cell line THP-1 | 300 µM | [90] |
| Reduction in phosphorylation and activation of TAK1 and NF-κB Decreased TNF-α production Activation of GP120, thus blocking IKK-β/NF-κB pathway by retaining TAB1 through β-arrestin-2 |
TNF-α-stimulated rHypoE-7 cell line from the embryonic rat hypothalamus | 100 µM | [91] | ||
| ω-3 LC-PUFA | Docosatrienoic acid (DTA) | Reduction of intracellular ROS levels Decreased expressions of IL-6, IFN-γ, MCP-1, TNF-α, IL-1β and IL-10 |
PMA-stimulated monocyte cell line THP-1 | 300 µM | [90] |
| ω-6 LC-PUFA | Docosadienoic acid (DDA) | Reduction of intracellular ROS levels Decreased expressions of IL-6, IFN-γ, MCP-1, TNF-α, IL-1β and IL-10 |
PMA-stimulated monocyte cell line THP-1 | 300 µM | [90] |
| Simple Phenolic Compounds | |||||
| Hydrobenzoic acid | Urolithin A | Downregulation of COX-2 and iNOS expression and decreased PGE2 an NO generation Inhibition of TNF-α and IL-6 production Prevention of IκB-α phosphorylation and p65 translocation into the nucleus Decreased PI3K and Akt phosphorylation, thus amelioration of PI3K/Akt/NF-κB pathway activation |
Primary human osteoarthritis chondrocytes | 30 µM | [92] |
| Inhibition of Akt and JNK phosphorylation Suppression of NF-κB and AP-1 activation Inhibition of NADPH oxidase (NOX) and reduction of intracellular accumulation of ROS Reduction in TNF-α and IL-6 production |
LPS-activated RAW264.7 macrophages ICR-mouse resident peritoneal macrophages |
10–20–40 µM | [93] | ||
| Inhibition of phosphorylation of MAPK pathway members (ERK1/2, JNK, p38) Suppression of COX-2, iNOS and MMPsInhibition of p65 phosphorylation and NF-κB pathway activation |
IL-1β stimulated primary chondrocytes from Sprague Dawley rats | 15 µM | [94] | ||
| Hydrobenzoic acid | Gallic acid | Inhibition of xanthine oxidase Inhibition of COX-2 Inhibition of TNF-α, IL-6 |
LPS-stimulated THP-1 cells | 10 µM | [95] |
| Hydroxycinnamic acid | p-Coumaric acid | Suppression of COX-2, iNOS, TNF-α and IL-1β expression Inhibition of IκB-α phosphorylation and nuclear translocation of p65, preventing activation of NF-κB pathway Inhibition of phosphorylation of ERK1/2 and JNK |
LPS-activated RAW264.7 macrophages | 50–100 µg/mL | [96] |
| Hydroxycinnamic acid | Ferulic acid | Inhibition of xanthine oxidase Inhibition of COX-2 Inhibition of TNF-α, IL-6 |
LPS-stimulated THP-1 | 10 µM | [95] |
| Inhibition of NF-κB translocation into the nucleus Inhibition of IKK/TAK1 activation Inhibition of Nrf2 pathway by impairing the reduction of cysteine residues in Keap1 Reduced MnSOD and TLR4 protein levels |
LPS-activated RAW264.7 macrophages | 100 µM | [97] | ||
| Hydroxycinnamic acid | Caffeic acid | Inhibition of xanthine oxidase Inhibition of COX-2 Inhibition of TNF-α, IL-6 |
LPS-stimulated THP-1 | 10 µM | [95] |
| Hydroxicinnamic acid | Curcumin | Inhibition of the synthesis of proinflammatory mediators IL-1β, IL-6, and iNOS and NO production Increased production of anti-inflammatory cytokines IL-6, IL-10, and Arg-1 Microglial polarization to M2 phenotype (decreased iNOS and increased CD206 immunoreactivity) Increased TREM2 expression and inhibition of TLR4 expression and p65 NF-κB phosphorylation |
Murine BV2 microglial cell line | 5–10 µM | [98] |
| Polyphenols | |||||
| Stilbene | Resveratrol | Inhibition of NF-κB and AP-1 activation Downregulation of ICAM-1, VCAM-1, E-selectin expression Downregulation of MCP-1, M-CSF expression |
Human umbilical vein endothelial cells (HUVEC) | 10–25 µM | [99] |
| Inhibition of IL-1β-induced VEGF, COX-2, MMP-3, MMP-9 gene expressionPrevention of IκB-α degradation (by inhibiting proteasome function) and NF-κB activation | Isolated primary human articular chondrocytes | 100 µM | [100] | ||
| Inhibition of ROS (O2−, H2O2) production Inhibition of arachidonic acid release, COX-2 induction and PGE2 synthesis |
CD-1-mouse resident peritoneal macrophages stimulated by LPS or PMA | 30 µM | [101] | ||
| Flavonol | Kaempferol | Suppression of COX-2 and iNOS expression Inhibition of PGE2 production |
LPS-activated RAW264.7 macrophages | 15–25 µM | [102] |
| Inhibition of NF-κB and AP-1 activation Downregulation of ICAM-1, VCAM-1, E-selectin expression Inhibition of MCP-1 synthesis and secretion |
Human umbilical vein endothelial cells (HUVEC) | 10–25 µM | [99] | ||
| Inhibition of PGE2 production | LPS-stimulated human mononuclear cells | 10–100 µM | [103] | ||
| Flavonol | Myricetin | Reduction in NF-κB and AP-1 activation Downregulation of ICAM-1, VCAM-1, E-selectin expression Inhibition of MCP-1 synthesis and secretion |
Human umbilical vein endothelial cells (HUVEC) | 10–25 µM | [99] |
| Flavonol | Quercetin | Inhibition of NO production and iNOS protein expression Stabilization of IκB-α and IκB-β preventing NF-κB activation Inhibition of activation of MAPK (Erk1/2, p38, JNK/SAPK) Inhibition of phosphorylation and activation of JAK/STAT |
LPS-activated RAW264.7 macrophages | 50 µM | [104] |
| Inhibition of NF-κB and AP-1 activation Downregulation of ICAM-1, VCAM-1, E-selectin expression Downregulation of MCP-1, M-CSF expression |
Human umbilical vein endothelial cells (HUVEC) | 10–25 µM | [99] | ||
| Inhibition of iNOS expression and NO production Attenuation of IκB-α phosphorylation and NF-κB activation Inhibition of DNA binding activity of AP-1 and STAT1 Induction of heme oxygenase-1 (HO-1) expression, possibly through Src family members |
Murine BV2 microglial cell line | 3–10–30 µM | [105] | ||
| Flavanol | Epigallocatechin 3-gallate/epigallocatechin gallate (EGCG) | Suppression of TNF-α, IL-1β, and IL-6 expression | Human dermal fibroblasts | 50 µM | [106] |
| Downregulation of COX-2 and iNOS expression | LPS-activated RAW264.7 macrophages | 20–40 µM | [107] | ||
| Flavanol | (-)-epicatechins | Inhibition of the production of NO, PGE2, TNF-α, IL-6 | LPS-activated RAW264.7 macrophages | 5–25–50 µM | [108] |
| Flavanol | Catechin | Inhibition of gene expression of pro-inflammatory cytokines (IL-1α, IL-1β, IL-6, IL-12p35) and enzymes (COX-2, iNOS) Up-regulation of anti-inflammatory cytokines (IL-4, IL10) Inhibition of the activation of NF-κB, AMPK, FOXO3a and SIRT1 |
TNF-α induced 3T3-L1 adipocytes | 10–25–50–100 μg/mL | [109] |
| Flavone | Apigenin | Suppression of COX-2 and iNOS expression Inhibition of PGE2 and NO production Inhibition of IKK activity preventing NF-κB activation |
LPS-activated RAW264.7 macrophages | 5–15–25 µM | [102] |
| Flavone | Luteolin | Suppression of TNF-α, IL-6, iNOS, COX-2 gene expression Decreased Akt and IKK phosphorylation Blockade of NF-κB and AP-1 activation Inhibition of ROS generation |
LPS-activated RAW264.7 macrophages | 5–10–25 µM | [110] |
| Isoflavone | Genistein | Suppression of COX-2 and iNOS expression Inhibition of PGE2 production | LPS-activated RAW264.7 macrophages | 15–25 µM | [102] |
| Suppression of protein expression of iNOS, COX-2, TNF-α, IL-1β, IL-6 Prevention of MAPKs and NF-κB pathways activation Up-regulation of G protein-coupled estrogen receptor (GPER) gene expression |
Murine BV2 microglial cell line Primary microglia cell culture |
10 µM | [111] | ||
| Anthocyanins (Flavonoid) | Anthocyanins-rich extract from berries | Reduction in TNF-α secretion Inhibition of NF-κB translocation into the nucleus Reduction of cellular ROS levels Downregulation of IL-1β and NADPH oxidases 1 (NOX-1) expression |
LPS-activated RAW264.7 macrophages | 20 µg/mL | [112] |
| Anthocyanins (Flavonoid) | Anthocyanins-rich extract | Inhibition of COX-2 and iNOS expression, and inhibition of PGE2 and NO production Inhibition of TNF-α and IL-1β expression Prevention of IκB-α degradation and NF-κB translocation Inhibition of Akt and MAPKs (ERK, JNK, p38) phosphorylation |
Murine BV2 microglial cell line | 50–100 µg/mL | [113] |
| Anthocyanins (Flavonoid) | Delphinidin | Inhibition of COX-2 expression Inhibition of phosphorylation of c-Jun, thus inhibiting AP-1 Inhibition of NF-κB activation by blocking IκB-α degradation and p65 translocation Inhibition of the three MAPK signalling pathways (JNK, ERK, p38) |
LPS-activated RAW264.7 macrophages | 50–75–100 µM | [114] |
| Other compunds | Gingerol | Decreased PGE2 and NO secretion Decreased COX-2, iNOS, TNF-α, IL-1β, IL-6 expression Inhibition of NF-κB activation by suppressing phosphorylation of IκBα and p65 |
LPS-activated RAW264.7 macrophages | 50–100–200–300 μg/mL | [115] |
| Decreased of ROS production (in PMNs) Inhibition of NO production (in macrophages) Inhibition of PGE2 production (in macrophages) |
Human polymorphonuclear neutrophils (PMN) LPS-activated RAW264.7 macrophages |
6 µM | [116] | ||
| Other compunds | Oleocanthal | Inhibition of iNOS expression and NO production Suppression of MIP-1α, IL-6, IL-1β, TNF-α,and GM-CSF expression |
Murine macrophages J774 Murine chondrocytes ATDC5 |
15–50 µM | [117] |
| Terpenes and Terpenoids | |||||
| Terpenoid (carotenoid) | Lycopene | Downregulation of TNF-α, IL-1β, IL-6, iNOS, and COX-2 expression Inhibition of PGE2 and NO production Decreased JNK, ERK and NF-κB protein expression |
LPS-stimulated SW 480 human colorectal cancer cells | 20–30 µM | [118] |
| Terpenoid (carotenoid) | β-carotene | Suppression of expression of COX-2, iNOS and TNF-α and IL-1β pro-forms PGE2, NO and ROS production Inhibition of IκB-α degradation and NF-κB activation |
LPS-activated RAW264.7 macrophages BALB/c mice peritoneal macrophages stimulated by LPS |
50 µM | [119] |
| Diterpene | Carnosol and carnosic acid | Inhibition of LOX and mPGES-1 (microsomal PGE2 synthase-1) enzymes and formation of arachidonic acid-derived eicosanoids | Activated human primary monocytes and neutrophils | 3–30 µM | [120] |
| Reduction in NO and PGE2 production Inhibition of COX-2 activity Downregulation of iNOS, IL-1α, IL-6 or CXCL10/IP-10 genes expression (in macrophages) Downregulation of CCL5/RANTES and CXCL10/IP-10 gene expression (in SW1353 cells) Downregulation of interleukine (IL-1α, IL-1β, IL-6) and chemokine genes expression (CXCL8/IL-8, CCL20/MIP-3α, CCL5/RANTES) Inhibition of NF-κB (p65) translocation into the nucleus |
LPS-stimulated RAW264.7 macrophages IL-1β activated chondrosarcoma SW1353 cells IL-1β activated primary human articular chondrocytes |
12.5 µM | [121] | ||