The Use of Nutraceuticals to Counteract Atherosclerosis: The Role of the Notch Pathway

Table 2

List of nutraceuticals acting through Notch signaling modulation.

Nutraceutical	Disease	Major findings	Role of Notch	References
Epigallocatechin-3-gallate (EGCG)	Cardiovascular	EGCG inhibits macrophage accumulation and inflammation response in the skin wounds of STZ-induced diabetes mellitus	EGCG reduces expression of Notch-1 and 2 in wound tissues of diabetic mice	[299]
		In RAW 264.7, EGCG limits LPS-mediated release of proinflammatory IL-1β	EGCG reduces expression of Notch-1 and 2 and of Notch target gene HES1. EGCG binds Notch-1 and limits its activity
		In HUVECs, EGCG induces expression of iNOS and eNOS and inhibits oxLDL-mediated apoptosis	EGCG restores the expression of Jagged-1 and of target proteins (MATH1, HES1, and HES5)	[276]
			Jagged-1 is the key effector of EGCG-protective effect against oxLDL-induced endothelial dysfunction
		EGCG attenuates the HFD-induced accumulation of atherosclerotic plaque in ApoE-deficient mice	EGCG protects ApoE-KO mice from atherosclerosis through the Jagged-1/Notch-1 pathway
	Cancer	EGCG inhibits the self-renewal capacity of head and neck squamous carcinoma (HNSC) cancer stem cells (CSCs) by suppressing their sphere forming capacity and attenuates the expression of stem cell markers. EGCG augments cisplatin-mediated chemosensitivity	EGCG decreases HNSC CSC traits by inhibiting the Notch-1 pathway	[225]
Norisoboldine	Cardiovascular	Norisoboldine suppresses VEGF-induced HUVEC migration	Norisoboldine induces VEGF-mediated migration through activation of Notch-1	[301]
Docosahexaenoic acid (DHA)	Cardiovascular	DHA significantly decreases VSMC migration/proliferation induced by IL-1β as well as fibrinolytic/MMP activity	DHA increases Notch-3 expression and HES1 transcription and enhances γ-secretase complex activity	[300]
Diosgenin	Cardiovascular	Diosgenin reduces the HFD-induced atherogenesis in rat aorta	Diosgenin prevents nuclear translocation of NICD in aorta and in differentiated macrophage cells	[302]
Berberine (BBR)	Cardiovascular	BBR significantly improves cardiac function recovery and decreases myocardial apoptosis, infarct size, serum creatine kinase, and lactate dehydrogenase levels in rats following myocardial IRI	Both in vitro and in vivo, BBR upregulates NICD translocation and HES1 expression	[304]
		In H9C2, BBR attenuates simulated IRI-induced myocardial apoptosis	In vitro, antiapoptotic effect of BBR is blocked by Notch-1 or HES1 siRNA
Polydatin	Cardiovascular	Following myocardial IRI, polydatin preserves cardiac function, ameliorates myocardial oxidative/nitrative stress damage, and reduces myocardial infarct size in STZ-induced diabetic rats	Polydatin exerts cardioprotection against diabetic myocardial IRI by activating myocardial Notch-1/HES1 signaling. DAPT blunts the beneficial effects of polydatin	[305]
2,3,5,4-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG)	Cardiovascular	TSG significantly improves cardiac function and suppresses IRI-induced myocardial apoptosis	Both in vitro and in vivo, TSG upregulates NICD and HES1 expression	[306]
		In H9C2, TSG pretreatment dose-dependently decreases simulated IRI-induced apoptosis	In vitro, antiapoptotic effect of TSG is blocked by DAPT
Honokiol	Cancer	Honokiol inhibits the growth of melanospheres formed by CSC	In vitro, Honokiol downregulates Notch-2, HES1, and cyclin D1 expression	[285]
Withaferin-A	Cancer	In three colon cancer cell lines, Withaferin-A mediates c-Jun-NH(2)-kinase-mediated apoptosis	Withaferin-A inhibits Notch-1 signaling	[286]
Tricin and p-coumaric acid	Cancer	Tricin and p-coumaric acid inhibits the growth of CSCs and VEGF and HIF1α expression	Tricin and p-coumaric acid inhibits Dll-1 and Notch-1 expression	[287]
Curcumin	Cancer	Curcumin inhibits hepatocellular cancer cell (HCC) proliferation	Curcumin decreases NICD expression in HCC	[289]
		Curcumin treatment results in a 40% decrease in tumor growth in a nude mouse xenograft model
		Curcumin inhibits proliferation and colony formation in esophageal cancer cell lines and upregulates expression of let-7a miRNA	Curcumin reduces Notch-1 activation and expression of Jagged-1 and HES1	[288]
			Curcumin reduces expression of Notch-1-specific microRNAs (miR-21 and miR-34a) and upregulates tumor suppressor let-7a miRNA
		Curcumin decreases markers associated with CSCs in Burkitt lymphoma and acute myeloid leukemia cells	Curcumin reduces expression of Notch-1 and cyclin D1	[93]
Resveratrol	Cancer	Resveratrol increases apoptosis and suppresses proliferation in MOLT-4 acute lymphoblastic leukemia cells	Resveratrol reduces NICD levels in a dose-dependent manner and inhibits the expression of HES1	[293]
	Cardiovascular	Resveratrol inhibits phenotypic switching of neointimal VSMCs after balloon injury in rats	Resveratrol decreases Notch-1, Jagged-1, Hey1, and Hey2 mRNA in balloon-injured arteries at 7 days	[303]
All-trans retinoic acid (ATRA)	Cancer	ATRA exerts a strong antimigratory action in the HER2-positive SKBR3 cell line	ATRA inhibits Notch-1 pathway	[295]
Oroxylin A	Cancer	Oroxylin A inhibits the hypoxia-induced invasion and migration of ERα-positive breast cancer cells	Oroxylin A inhibits NICD translocation into the nucleus	[296]
Alpinetin	Cancer	Alpinetin suppresses the proliferation and invasiveness of glioma stem cells (GSCs) and induces their apoptosis	Alpinetin reduces Notch-1 activity. Notch reactivation, by using recombinant Jagged-1, rescues the effect of alpinetin on GSCs	[297]
Cowanin	Cancer	Cowanin shows potent cytotoxicity against human leukemic HPB-ALL cells	Cowanin degrades nicastrin, a component of γ-secretase, thus hampering Notch-1 activation	[298]