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. 2019 May 2;2019:5470470. doi: 10.1155/2019/5470470

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]