The Multifunctional Effects of Nobiletin and Its Metabolites In Vivo and In Vitro

Table 1

The biological effects of NOB on different cell types/animals.

Cell types/animals	Biological functions	Ref
3T3-L1 preadipocytes	Differentiation↑, IBMX↑, insulin↑, STAT 5↑, PPARγ2↓, p-CREB↓	[36]
	Intracellular triglyceride↓, adiponectin↑, MCP-1↓, resistin↓	[7]
	Lipid accumulation↓, GPDH↓, PPARγ↓, C/EBPα↓, AMPK↑	[38]
3T3-F442A adipocytes	Glucose uptake↑, PI3K/Akt1/2↑, PKA/CREB signaling↑	[35]
3XTg-AD mice model	Soluble Aβ production↓	[13]
A2780/T cells	ABCB1 transporter efflux↓, Akt/ERK/Nrf2↓	[89]
AGS cells	MMP-2↓, MMP-9↓, c-Raf↓, Ras↓, Rac-1↓, RhoA↓, Cdc42↓, PI3K/Akt signaling↓, FAK activation↓, NF-κB signaling↓	[5]
BV2 microglia cells	IL-1β↓, TNFα↓, IL-6↓, NO↓	[47]
C6 glioma cells	cellular proliferation↓, Ras activity↓, MEK/ERK signaling↓	[25]
CUMS-induced rats	BDNF↑, TrkB↑, synapsin I↑	[28]
Diet-induced obese mice	Energy expenditure↑, locomotor activity↑, metabolic disorders↓, circadian rhythms↑	[52]
DU-145 cells	cMyc↓, p50↓	[58]
Freshly isolated hepatocytes	SCD1 mRNA expression↓, hyperlipidemia↓, adiposity↓	[37]
H1299 cells	NOTCH-1↓, Jagged 1/2↓, Hey-1↓, Hes-1↓	[66]
H1299, A549 cells	EMT↓, p-Src↓, p-paxillin↓, p-FAK↓, MMP-2↓, MMP-9↓, slug↓, snail↓, ZEB1↓, twist↓	[67]
HepG2 cells	ApoB secretion (IC50 = 29 μM)↓, cholesterol synthesis (IC50 = 68 μM)↓, triglyceride synthesis (IC50 = 73 μM)↓	[39]
	Dyslipidemia↓, insulin resistance↓, atherogenesis↓, apoB100↓, MAPK↑, LDLR↑, MTP↓, DGAT1/2↓, Pgc1α↑, Cpt1α↑, β-oxidation↑	[51]
Hepatocytes	NO (IC50 = 50 μM)↓	[1]
HFD-induced obese mice	Plasma triglyceride↓, body weight gain↓, WAT weight↓, PPARα↑, PPARγ↑, fatty acid synthase↑, sterol regulatory element-binding protein-1c↑, stearoyl-CoA desaturase-1↑, adiponectin↑, carnitine palmitoyltransferase 1↑, uncoupling protein-2↑, monocyte chemoattractant protein-1↓, TNFα↓, GLUT4↑, p-Akt↑, IκBα degradation↓	[34]
HL-60 cell line	ERK↓, caspase-3↑, caspase-9↑, caspase-8↑, MAPK↑	[56]
HOS and U2OS cells	ERK/JNK↓, MMP-2↓, MMP-9↓, CREB↓, SP-1↓, NF-κB↓	[71]
HT22 cells	p-p38↓, p-JNK↓, Bax↓, caspase-3↓, Bcl-2↑, cognitive impairment↓, apoptosis↓	[22]
HuH-7, SK-N-SH, 3Y1	Trib3 ↓, Ddit3↓, Asns↓, E2f8↓, Ccna2↓, Ccne2↓, Txnip↓	[87]
Human intestinal mast cells	CCL3↓, CCL4↓, CXCL8↓, IL-1β↓, TNFα↓	[42]
Human ovarian cancer cells	HIF-1α↓, Akt↓, NF-κB↓, VEGF↓	[64]
Human fetal membranes and myometrium	IL-1β↓, TNFα↓, IL-8↓, IL-6↓, MMP-9↓, COX-2↓, pro-MMP-9↓, PGE2↓	[65]
Human dermal fibroblasts	MMP-9↓, p-p38 MAPK↓	[92]
L-Arginine-induced AP	Plasma amylase↓, pancreatic myeloperoxidase↓, plasma proinflammatory factors↓, reactive oxygen species production↓, cell apoptosis↓, pancreatic necrosis↓, p-p38MAPK↓, p-AKT↓	[45]
MDA-MB-231 cells	MMP-9 (IC50 = 24 μM)↓, CXCR4 (IC50 = 32 μM)↓, MAPKs↓, NF-κB↓	[61]
MDA-MB-468 cells	ERK1/2↓, cyclin D1↓, p21↑, Bcl-xL↓, Akt↓, mTOR↓	[63]
MPP^+-triggered rat PD	Microglia activation↓, dopaminergic neuron degeneration↓	[23]
MPTP-triggered mice PD	Dopamine release↑, Ca^2+/CaMKII autophosphorylation↑, DARPP-32↑, TH↑, cognitive and motor functions↑	[24]
NK leukemia cell	Granzyme B↑, p38 MAPK↑, cytolytic activity of KHYG-1 cells↑	[57]
NPC-BM, HONE-1 cells	MMP-2↓, NF-κB↓, AP-1↓, TIMP-2↑	[69]
Normal human melanocytes	Tyrosinase↓, TRP1↓, PMEL↓, MITF↓, p-CREB↓, p-MEK/p-ERK1/2↓, p-Raf-1↓	[91]
OVCAR-3, A2780/CP70 cells	Cell Viability↓, proliferation↓, VEGF↓	[62]
OVX mice	Bone resorption↓, osteoclast formation↓, NF-κB↓, COX-2↓, PGE2↓	[70]
P53-mutated SNU-16 human gastric cancer cells	Proliferation↓, caspase-3↑, caspase-9↑, Bax/Bcl-2 ratio↑, PARP degradation↑, apoptosis↑	[43]
PC12 cells	Aβ self-induced aggregation↓	[14]
	NR1↑, NR2A↑, NR2B↑, c-FOS↑, learning impairment↓, CRE-dependent transcription↑, PKA/ERK/MEK/CREB↑	[17]
PC-3 cells	Viability↓, VEGF↓, NF-κB↓, AKT/HIF-1α↓	[58]
PDGF-BB treated VSMCs	Proliferation↓, migration↓, ROS↓, p-ERK1/2↓, NF-κB p65 nuclear translocation↓	[53]
Postischemic	HO-1↑, Nrf2↑, GSH↑, SOD1↑, MMP-9↓, MDA↓, NF-κB↓, neurological deficits↓, brain edema↓	[11]
Rats	Hexokinase↑, succinate dehydrogenase↑, mitochondrial metabolism↑	[30]
Rat I/R injury	Infarct volume↓, brain edema↓, cell death↓	[20]
	CREB↑, Akt↑, BDNF↑, Bcl-2↑, neurological deficits↓, brain edema↓, BBB permeability↓	[21]
Rat primary astrocytes	iNOS↓, NO production↓, NF-κB↓, p38-MAPK phosphorylation↓	[6]
RAW 264.7 cells	NO (IC50 = 27 μM)↓	[46]
	Bone resorption↓, osteoclast formation↓, osteoclastogenesis↓	[8]
RBL-2H3 cells	IL-4↓, TNFα↓, AP-1↓, NF-κB↓, p38↓, PKC↓	[86]
SAMP8 mice model	Aging cognitive impairment↓, tau phosphorylation↓, oxidative stress↓	[12]
SK-N-SH cells	NEP↑	[15]
	TXNIP↓	[27]
SMMC-7721 cells	Proliferation↓, Bcl-2↓, COX-2↓, Bax↑, caspase-3↑	[48]
STZ-induced C57BL mice	TGFβ1↓, fibronectin↓, CTGF↓, collagen 1α↓, p22↓, p67↓, p91↓, p38 MAPK/JNK↓, NF-κB↓	[50]
STZ-induced rats	Oxidative stress↓, hemodynamic parameters↓, vascular reactivity↓, MMP-2↓, MMP-9↓, collagen↓	[10]
TNBS-triggered colitis	COX-2↓, iNOS↓, Akt-NF-κB-MLCK signaling↓	[41]
U87, Hs683 glioma cells	Cell viability↓, cyclin D1↓, E2 promoter-binding factor 1↓, CDK2↓, CDK4↓, p-PKB↓, p-p38 MAPK↓, p-ERK↓, p-JNK↓	[26]