Table 3.

Phytochemicals exhibiting biphasic concentration/dose-responses.

Compound *	Model	Concentration	Effect	Mechanism	Refs
Arctigenin	K-562	~27, 54 μM	↑Mcl-1mRNA		[85]
		~107 μM	↓Mcl-1mRNA
Berberine	B16-F10,	1.25–5.00 μM	↑proliferation	↑MAPK/ERK1/2 ↑PI3K/AKT	[70]
	MDA-MB-231,	10–80 μM	↓proliferation
	MDA-MB-468,
	MCF-7, LS-174
	PC-12	0.1–1.0 μM	↑viability	↑PI3K/AKT/Bcl-2	[71]
		2–64 μM	↓viability
Caffeic acid	male F344 rats	0.14%	↓proliferation	↓epithelial cells, S-phase cells	[90]
		0.40, 1.64%	↑proliferation	↑epithelial cells, ↓S-phase cells in forestomach
(+) Catechin, rutin	Salmonella typhimurium/2-AAF	0.01–0.60 mM	↓mutagenicity		[35]
		1.2, 0.8 mM	↑mutagenicity
Cynarin	FSF-1,	1–50 µM	↑viability	↑HO-1 activity	[89]
		75–500 µM	↓viability
	hTERT-MSC	1–00 µM	↑viability	↑HO-1 activity	[89]
		75–500 µM	↓viability
EGCG	Caenorhabditis elegans	50–300 µM	↑lifespan	↑ROS; ↑AMPK/SIRT1/FOXO	[87]
		800–1000µM	↓lifespan
Falcarinol, Falcarindiol Isolated from carrot roots	primary myotube culture/H2O2	1.6–25.0 μM	↑ROS production	↑GPx, ↓Hsp70, HO-1	[72]
		50, 100 μM	↓ROS production	↓GPx, ↑Hsp70, HO-1
Falcarindiol isolated from carrot roots	primary	0.61–9.80 nM	↑viability		[72]
	myotube culture	2.5–5.0 μM	↓viability
	pBMEC	~0.04–0.20 μM	↑proliferation		[73]
		~4–41 μM	↓proliferation
	CaCo-2	1–10 μM	↑proliferation	↓caspase-3, DNA breakage	[74]
			↓apoptosis
		>20 μM	↓proliferation	↑caspase-3, DNA breakage
			↑apoptosis
Glyceollin I isolated from soybean	Saccharomyces cerevisiae	10–100 nM	↑CLS		[82]
		>1 μM	↓CLS
Luteolin	MCF-7	1–10 μM	↑viability		[77]
		30–1000 μM	↓viability
	HepG2	<35 μM	↑LC3-II		[78]
		~105 μM	↓LC3-II
	Salmonella typhimurium/2-AAF	0.006 mM	↑mutagenicity		[35]
		1.2 mM	↓mutagenicity
Nanteine isolated from Ocotea macrophilla	synaptosomal membranes	50 μM, 0.3 mM	↑K+ -p-NPPase activity		[84]
		>0.75 mM	↓K+ -p-NPPase activity
Naringenin	Drosophila melanogaster	200, 400 μM	↑lifespan	↑pupae formation	[75]
		600, 800 μM	↓lifespan	↓pupae formation
Naphazarin	Caenorhabditis elegans	50–500 μM	↑lifespan	↑skn-1	[86]
		1000 µM	↓lifespan
Panaxatriol saponins isolated from Panax notoginseng	PC-12	0.03–1.00 mg/ml	↑proliferation		[88]
		4 mg/ml	↓proliferation
	PC-12 /6-OHDA	0.03–2.00 mg/ml	↑viability	↑PI3K/AKT/mTOR ↑AMPK/SIRT1/FOXO3
		4 mg/ml	↓viability
Plumbagin	Caenorhabditis elegans	1–45 μM	↑lifespan	↑skn-1	[86]
		100 μM	↓lifespan
Rosmarinic acid	Caenorhabditis elegans	100–300 µM	↑lifespan	↑hsp	[34]
		600 µM	↓lifespan
Rutin	Drosophila melanogaster	200, 400 μM	↑lifespan	↑longevity associated genes	[76]
		600, 800 μM	↓lifespan
Salvianolic acid B	BMSCs	~4–111 μM	↑metabolic activity, ALP activity		[81]
		~223 μM	↓metabolic activity, ALP activity
Sulforaphane	T24, HepG2, Caco-2	1–5 μM	↑proliferation	↑RAS, RAF, MEK, ERK, PI3K, AKT and Nf-kB, FOXO Nrf2 pathways	[63]
		10–40 μM	↓proliferation
	T24	2.50, 3.75 μM	↑migration
		5–40 μM	↓migration
	HUVEC, PVC	2.5–5.0 μM	↑angiogenesis	↑tube formation
		10, 20 μM	↓angiogenesis	↓tube formation
Isolated from Brassica oleracea	MSCs	0.25, 1.00 μM	↑proliferation		[66]
		20 μM	↓proliferation
		<5 μM	↓apoptotic cells
		20 μM	↑apoptotic cells
		0.25, 1.00 μM	↓senescence cells
		5, 20 μM	↑senescence cells
		0.25 μM	↓ROS production
		20 μM	↑ROS production
Commercial source	MCF-7, HHL-5, HepG2, lymphoblastoid cells	<5 μM	↑proliferation		[67,68,69]
		>5 μM	↓proliferation
	lymphoblastoid cells	0.5–5.0 μM	↑GSH		[69]
		10 μM	↓GSH
Umbelliprenin isolated from Ferula szowitsiana	Jurkat T-CLL	10, 25 μM	↑apoptosis		[83]
		50, 100 μM	↓apoptosis
Z-ligustilide isolated from Ligusticum chuanxiong	PC-12/ OGD	1–25 μM	↑viability, ↓apoptosis	↑HO-1 and Nrf2 translocation	[79]
		50 μM	↓viability, ↑apoptosis
	Spodoptera litura larvae	0.1–0.5 mg/g diet	↑GST, AChE, CYP, CES activities	↑GSTS1, CYP4S9, CYP4M14	[80]
		1, 5 mg/g diet	↓GST, AChE, CYP activity	↓GSTS1, CYP4S9, CYP4M14

* If the source of the compound was not specified it was obtained commercially; ↑ = increase, ↓ = decrease; 2-AAF—2-Acetylaminofluorene; 6-OHDA—6-hydroxydopamine; AChE—acetylcholinesterase; AKT—protein kinase B; ALP—alkaline phosphatase; B16-F10—murine melanoma cell line; BMSCs—bone marrow-derived mesenchymal stem cells; CaCo-2—human colon cancer cell line; CES—carboxylesterase; CLS—chronologic life span; CYP—cytochrome P450; CYP4M14 (4S9)—cytochrome P450 4M14 (4S9); EGCG—epigallocatechin-3-gallate; FSF-1—human skin fibroblasts; GPx—glutathione peroxidase; GST—glutathione S-transferase; GSTS1—glutathione S transferase S1; HHL-5—human normal liver cell line; HO-1—heme oxygense 1; Hsp70—heat shock protein; HepG2—human liver cancer cell line; HUVEC—human umbilical vein endothelial cells; Jurkat T-CLL—Jurkat T-cell lymphocyte leukemia cells; K562—immortalized cell line derived from human leukemia; K+ -p-NPPase activity—K+ -p- nitrophenylphosphatase; LC3— microtubule-associated protein 1A/1B-light chain 3; LS-174—human colon cancer cell line; MDA-MB-231, MDA-MB-468, MCF-7MCF-7—human breast carcinoma cell lines; MSCs—mesenchymal stem cell line; OGD—oxygen-glucose deprivation; pBMEC—primary bovine mammary epithelial cells; PC-3—human prostatic carcinoma cell line; PC-12—phaeochromocytoma cell line; PI3K—phosphatidylinositol 3-kinase; PVC—pericytes; skn-1—cap’n’collar transcription factor; T24—bladder cancer cell line; hTERT-MSC—human normal telomerase-immortalized mesenchymal stem cells.