Table 3.

Mechanism and function of esculetin in treatment of inflammation.

Pharmacological Mechanism	Inhibition/Activation/ Downregulation/Upregulation	Model Used	Dosage	Application	Reference
	Downregulate inflammatory cytokines and chemokines (TNF-α, IL-1β, IL-6, CCL2 and iNOS) Inhibit NF-κB, STAT1 and STAT3 expression in macrophage Attenuate IKKα/β, IKBα phosphorylation and p65 levels in LPS-stimulated macrophage Inhibit translocation of p65 from cytoplasm to nucleus in LPS-stimulated macrophage Downregulate phosphorylation of ERK1/2, JNK and p38 levels in macrophage Suppress STAT1 and STAT3 activation in LPS-induced macrophage and sepsis mice	E. coli-induced mice sepsis mice and LPS-stimulated macrophage of lung injury (RAW 264.7 cells)	20, 40 and 60 mg/kg	In vitro and in vivo	[67]
	Decrease iNOS and COX-2 level Inhibition of NO and PGE2 production Inhibit TNF-α, IL-1β expression Inhibit LPS-mediated nuclear translocation of NF-κBp65 by suppressing IKβ-α degradation Inhibit ROS generation	LPS-induced inflammation in RAW 264.7 cells	12 µg/mL	In vitro	[68]
	Reverse LTA-induced IkB degradation Reverse NF-κBp65 phosphorylation Increase Nrf2 activity and scavenge DPPH radicals Inhibit NF-κBp65 translocation to nucleus	RAW 264.7 cells	20 µM	In vitro	[69]
	Reduce IL-1β, IL-6, TNF-α in serum and hippocampus Downregulate iNOS and COX-2 in hippocampus Inhibit LPS-induced pIKK-α, pIKK-β, pIKB-α and p-NF-kB65 activation Upregulate p-TrKB protein expression in hippocampus due to activation of BDNF/TrKB signaling pathway, thus exhibit neuroprotective activity	LPS-induced neuro-inflammation in mice and hippocampus protein extract	20, 40 mg/kg	In vivo	[72]
	Increase endocytic activity and augmented NO and iNOS levels in LPS-treated macrophage	LPS-induced inflammation in RAW 264.7 cells and BALB/c mice	80 and 120 µM	In vitro and in vivo	[73]
	Reduce MMP-1 in cartilage Reduce NO and PGE2 in synovial fluid	Knee OA model of rabbit	100 and 200 mg/kg	In vivo	[74]
	Decrease NO, TNF-α and MCP-1 expression Inhibit PPARϒ and CCAAT/enhancer binding protein-α in adipocyte Inhibit iNOS level in macrophage Increase silencing of heme oxygenase	Adipose tissue inflammation model (RAW264.7 cells and 3T3-L1 adipocyte cells)	100 µM	In vitro	[75]
	Inhibit pro-inflammatory cytokines (IL-2, IL-1β, TNF-α, INF-ϒ) in colon Inhibit ROS generation Inhibit MPO and ALP Decrease GSH depletion	TNBS-induced colitis in male Wistar rats and RAW 264.7 cells	5 mg/kg, 100 µM	In vitro and in vivo	[77]
	Increase GSH and serotonin (5-HT) level in brain tissue Decrease TBARS, TNF-α, IL-1β levels in brain tissue	Reserpine-induced fibromyalgia in female Swiss albino mice	100 mg/kg	In vivo	[78]
	Suppress histamine-induced expressions and secretion of IL-6, IL-8, MUC5AC by inhibiting NF-kB signaling pathway Suppress histamine-induced p-p65 expression and p-IKBα degradation	Allergic rhinitis model (Human nasal epithelial cells)	10, 20 and 40 µmol/L	In vivo	[79]
Anti-inflammatory	Reduction in ear swelling Decrease DFE/DNCB-induced scratching Decrease epidermal and dermal thickness Decrease accumulation of mast cells Decrease TNF-α, INF-ϒ, IL-4, IL-13, IL-31, IL-17A-induced phosphorylation of STAT1 and NF-κB (p65) translocation by degrading IKBα	DNCB/DFE—induced atopic skin inflammation model (Female BALB/c mice and Human HaCaT keratinocytes cells)	2, 10, 50 mg/kg and 10 µM	In vitro and in vivo	[80]
	Decrease attenuation of LPS-induced phosphorylation of ERK1/2 and NF-κB expression Protect cells from LPS-induced apoptosis and necrosis Decrease LPS-induced TRAIL, IL-1β, TNFR expression Inhibit LPS-induced MnSOD and GPx Downregulate IL-6, IL-12, VEGF expressions	LPS-induced inflammation in Human retinal pigment epithelial cells (ARPE-19 cells)	5 µM	In vitro	[81]
	Decrease MPO, IL-6, TNF-α, IL-1β expression Inhibit neutrophils infiltration Inhibit LPS-induced RhoA/Rho kinase pathway Block NF-κB activation	LPS-induced acute lung injury (lung epithelial A549 cells and BALB/c mice)	20, 40 mg/kg and 0.1, 1 and 10 µM	In vitro and in vivo	[82]
	Decrease MPO, COX-2, iNOS levels Activate HIF-1in HCT116 cells and increase HIF-1α protein expression Increase secretion of VEGF in HCT116 cells Inhibit HIF-prolyl hydroxylase-2 Enzyme	TNBC-induced colitis (Human colon carcinoma HCT116 cells and Sprague Dawley colitic rats)	100 and 200 µM	In vitro and in vivo	[83]
	Ameliorate skin lesion of psoriatic mice Inhibit CD3+ and CD8+ T-cell infiltration in psoriatic mice skin Decrease Ki67 and K10 mRNA expression Lower effector CD8+ T-cells in lymph nodes and spleen Inhibit NF-κB signaling by suppressing phosphor-IKKα and phosphor-p65 expression Increase CD4+ FOXp3+ Treg frequency in lymph node and spleen Downregulate IL-6, TNF-α, IFN-ϒ, IL-17A, IL-22, IL-23	Imiquimod-induced psoriasis in BALB/c mice	50 and 100 mg/kg	In vivo	[84]