Coumarins as Modulators of the Keap1/Nrf2/ARE Signaling Pathway

Table 1

Effect of coumarins on Nrf2 in animal models of different diseases.

Coumarin	Disease/model	Animal	Effects	Reference(s)
IMP	Nrf2 knockout	Mice	IMP induced hepatic antioxidant activities via the Nrf2/ARE mechanism.; IMP induced hepatic GST and/or NQO1 activities.	[75]
	Allergic responses mediated by mast cells	Mice	IMP attenuated allergic responses.; IMP inhibited mast cell degranulation, MAPK, NF-κB, and inflammatory mediators’ expression.; IMP activated PI3K/Akt and Nrf2/HO-1 pathways.	[77]
Visnagin	Cerulein-induced acute pancreatitis	Mice	Visnagin upregulated Nrf2 and attenuated oxidative stress.; Visnagin mitigated pancreatic inflammation and NF-κB p65 nuclear translocation.	[86]
Urolithin B	LPS-induced systemic inflammation	Mice	Urolithin B reduced intracellular ROS production and NADPH oxidase expression.; Urolithin B upregulated AMPK phosphorylation and Nrf2/ARE signaling and HO-1 expression.	[92]
Urolithin A	Colitis	Mice	Urolithin A enhanced gut barrier function and inhibited inflammation through Nrf2-dependent pathways.	[104]
	High cholesterol diet-fed rats	Rats	Urolithin A upregulated aortic scavenger receptor-class B type I expression and Nrf2 and inhibited ERK1/2 phosphorylation levels.	[264]
Scopoletin	MG-induced hyperglycemia and insulin resistance	Rats	Scopoletin increased insulin sensitivity, decreased AGEs, and activated Nrf2 by Ser40 phosphorylation.	[121]
Daphnetin	Cisplatin-induced nephrotoxicity	Mice	Daphnetin inhibited ROS generation, lipid peroxidation, NF-κB activation, and proinflammatory cytokines.; Daphnetin upregulated Nrf2 and HO-1 expression.	[132]
	CCl4-induced hepatotoxicity	Rats	Daphnetin improved liver function, inhibited histological alterations and lipid peroxidation, and increased Nrf2 and HO-1 gene expression.	[138]
	7,12-Dimethylbenz[a]anthracene-induced mammary carcinogenesis	Rats	Daphnetin inhibited lipid peroxidation, enhanced GSH and antioxidant enzymes, decreased NF-κB expression, and activated Nrf2 pathway.	[265]
Esculin	LPS/D-galactosamine-induced liver injury	Mice	Esculin suppressed lipid peroxidation, MPO, TNF-α, IL-1β, and NF-κB and increased the expression of Nrf2 and HO-1.	[146]
Esculetin	Cerebral I/R	Mice	Esculetin ameliorated mitochondrial oxidative stress, fragmentation, and stress and increased SOD and Nrf2 expression.	[165]
UMB	Hepatic injury in diabetic db/db mice	Mice	UMB ameliorated liver function, serum lipids, and lipid peroxidation and suppressed NF-κB and TLR-4.; UMB activated Nrf2 signaling pathway.	[180]
	Cyclophosphamide-induced hepatotoxicity	Rats	UMB ameliorated liver function and inhibited histological alterations, lipid peroxidation, and inflammation.; UMB upregulated Nrf2, HO-1, PPARγ, and antioxidants and suppressed iNOS and NF-κB.	[44]
	CCl4-induced hepatotoxicity	Rats	UMB improved liver function, inhibited histological alterations and lipid peroxidation, and increased Nrf2 and HO-1 gene expression.	[138]
	MTX-induced nephrotoxicity	Rats	UMB inhibited inflammatory response via downregulation of both NF-κB and p38 MAPK genes.; UMB downregulated Keap1 and upregulated Nrf2.	[174]
Fraxetin	Malaria infection	Mice	Fraxetin suppressed lipid peroxidation and boosted GSH and antioxidant enzymes via Nrf2-ARE activation.	[193]
Fraxin	CCl4-induced hepatotoxicity	Rats	Fraxin ameliorated liver function and lipid peroxidation and increased GSH and Nrf2-mediated antioxidant enzyme system.	[198]
Glycycoumarin	Acute alcoholic liver injury	Mice	Glycycoumarin prevented liver injury via induction of autophagy and activation of Nrf2 signaling.	[225]
Osthole	Alzheimer's disease model	Mice	Osthole restored the mitochondrial membrane potential, ameliorated apoptosis markers, and activated Nrf2 and its downstream antioxidant proteins.	[243]
	Transient global brain ischemia	Mice	Osthole improved the cognitive functions and upregulated Nrf2/HO-1 signaling pathway.	[246]
	Focal segmental glomerulosclerosis	Mice	Osthole suppressed NF-κB-mediated COX-2 expression, PGE2 production, apoptosis, and podocyte injury and activated Nrf2.	[247]
	IgA nephropathy	Mice	Osthole inhibited excessive ROS generation and NF-κB/NLRP3 signaling and increased Nrf2 nuclear translocation.	[248]
	LPS-induced acute lung injury	Mice	Osthole upregulated Nrf-2/thioredoxin 1 and prevented lung injury.	[249]
Hydrangenol	UVB-irradiated hairless mice	Mice	Hydrangenol downregulated MMP-1/-3, COX-2, IL-6, MAPKs, and STAT1 and upregulated Nrf2, HO-1, NQO1, GCLM, and GCLC.	[252]