Table 2.

Pharmacological effects of the natural antioxidants in iron chelation activity.

Bioactive Compound	Doses	In Vitro/ In Vivo/ Clinical Study	Model	Bioactive Effect	References
EGCG and GSE		in vitro	cell culture of Caco-2 cells MEL cell culture mouse erythroleukemia (MEL) cell line	↓transepithelial heme iron transpor ↑ apical heme iron uptake (GSE) ↓ the cellular assimilation of heme (EGCG)	[83]
EGCG and GSE		in vitro	human Caco-2 (HTB-37TM) cell line murine erythroleukemia (MEL) cell line	↓heme iron absorption by reducing the basolateral iron export in Caco-2 cells	[108]
Curcumin	0.5% and 2.0%	in vivo	FVB mice treated with curcumin for 12 weeks	↓ in the H and L subunits of the iron storage protein ferritin ↑ transferrin receptor 1 ↑ activated iron-regulatory proteins (IRPs) ↓ in levels of ferritin in the liver	[88]
Curcumin	0.2%, 0.5%, and 2.0%	in vivo	C3H/HeNCrlmice AIN93M basal diet modified to contain various amounts of iron and curcumin: 5, 12, 50, or 1000 mg iron/kg diet plus curcumin at 0% (control), 0.2%, 0.5%, and 2.0% (wt/wt) for 26 weeks	↓ HTC, Hb, serum iron, and transferrin saturation ↓ iron levels in the bone marrow and spleen -appearance of hypochromic RBCs ↑ transferrin receptor 1 (TfR1) ↑ iron-responsive element-binding protein (IRP) ↓ ferritin ↓ hepcidin	[89]
Silybin		in vitro		-iron chelating role -high affinity for ferric ion -binds Fe(III) even at acidic pH	[105]
Silybin	140 mg silybin (Legalon Forte)	clinical study	patients with hereditary haemochromatosis	↓ postprandial iron absorption	[106]
Quercetin	100 mg/kg body weight	in vivo in vitro	ethanol-induced iron overload and liver damage in mice mouse primary hepatocytes	-attenuated the hepatic iron deposition in mice exposed to ethanol or excess iron -prevented ethanol induced hepatic iron overload by regulating hepcidin expression via the BMP6/SMAD4 signaling pathway	[109]
Myrecitin		in vitro	HepG2 an HEK293 cells	↓ HAMP mRNA levels ↓SMAD1/5/8 phosphorylation	[103]
Myrecitin	40-mg/kg myricetin daily for 1 or 5 days 10-mg/kg myricetin for 5 days, after which the mice were injected with LPS (5 mg/kg, ip) 0.2% (w/w) myricetin for up to 30 days	in vivo	C57BL/6 mice	↓ hepatic hepcidin expression ↓ splenic iron levels ↑ serum iron levels ↑ red blood cell counts ↑ Hb	[103]
Black soybean seed coat anthocyanins extract (BSSCE)	200 mg/mL BSSCE 2% BSSCE	in vitro in vivo	AIN-76A diet containing 2% BSSCE feeded to 8-week-old male C57BL/6 mice for 0, 1, 7, 15 or 30d	↓ hepcidin expression ↓ splenic Fe concentrations ↑ serum Fe concentrations ↑ in erythrocyte counts, Hb concentrations, HTC values	[110]
Citrus flavonoids-rich extracts from bergamot and orange juices		in vitro	iron overloaded human lung epithelial cells basal epithelial cell line A549, derived from human lung carcinoma	↓ ROS ↓ lipid peroxidation ↑mitochondrial function ↑ iron chelation -prevented DNA-oxidative damage in iron-exposed cells ↑ catalase activity	[111]
Baicalein (Scutellaria baicalensis)		in vitro		-induced iron chelation -inhibition of iron-mediated Fenton reaction via a combination of chelation and radical scavenging mechanism	[112]
Genistein		in vivo in vitro	-zebrafish embryo (Danio rerio) -the human hepatocarcinoma cell line, HepG2	↑ hepcidin expression and promoter activity in zebrafish and human hepatocytes in a STAT3- dependent and SMAD4-dependent manner	[113]
Vitamin C	50 and 100 mg/mL	in vivo	hepcidin-producing HepG2 cell line	-inhibition of hepcidin expression	[114]
Tucum-Do-Cerrado (Bactris setosa Mart.)	AIN-93G diet with 150 g of tucum-do-cerrado fruit (pulp and peel)/kg diet iron-supplemented rodent diet (350 mg of iron/kg diet) and 150 g of tucum-do-cerrado fruit/kg diet	in vivo	Wistar rats	↓ spleen lipid and protein oxidation; mRNA levels of hepatic Hamp and ferritin ↑ serum antioxidant capacity ↑ hepatic mRNA levels of BMP6, Hmox1, Nqo1, and Nrf2 -abrogated the liver Hamp iron-induced upregulation -prevented intestinal iron accumulation; hepatic lipid peroxidation; splenic protein damage ↑ of CAT, GR, and GSH-Px activity	[115]
Angelica sinensis polysaccharide (ASP)	ASP at 25, 50, and 100 mg kg−1	in vivo	BALB/c mice inoculated with H22 tumor cells	↓ hepcidin concentration in serum ↓ levels of serum IL-6 ↓ serum ferritin ↓ levels of serum Tf ↓ levels of serum TfR2 ↓ levels of serum TfR1 in the ASP 25 mg kg−1 treatment group	[116]
Hydro-alcoholic extract of Medicago sativa and Allium porrum	200 and 400 mg/kg body weight	in vivo	iron-overloaded rats	↓ serum ferritin ↓ serum iron level	[117]
Methanolic extract of Angel’s wings mushroom (Pleurotus porrigens)	200 and 400 mg/kg/24 h	in vivo	iron-overloaded mice NMRI mice	-chelation of excess iron ↓ in plasma Fe3+ content ↓ in the extent of necrotic hepatocytes, fibrous tissues, and pseudo-lobules	[118]
Methanol extract of Nerium indicum leaves	50, 100, and 200 mg/kg b.w.	in vivo	iron-overloaded mice	-antioxidant and iron-chelating properties ↓ iron overload induced toxicity -normalized the levels of ALAT, ASAT, ALP, and bilirubin ↑ levels of SOD, CAT, GST, and nonenzymatic-reduced glutathione ↓ levels of lipid peroxidation, protein carbonyl, hydroxyproline ↓ liver iron	[119]
Emblica officinalis fruit extract	50, 100, and 200 mg kg−1 body weight	in vivo	iron-overloaded Swiss albino mice	↓ liver iron ↓ serum ferritin ↓ ALAT, ASAT, ALP, and bilirubin ↓ in lipid peroxidation, protein oxidation, and collagen	[120]
Gallic acid (GA) and methyl gallate (MG) isolated from Spondias pinnata bark extract	2 and 4 mg/kg b.w. GA 2 and 4 mg/kg b.w. MG	in vitro in vivo	iron-overloaded Swiss albino mice	↓ ALAT, ASAT, ALP, and bilirubin ↓ ROS in liver and spleen homogenate ↓ ferritin-bound iron SOD, CAT, GST, GSH restioration	[121]
Aqueous and 70% methanol extracts of Clerodendrum colebrookianum leaves	50, 100 and 200 mg/kg body weight	in vitro in vivo	iron-overloaded Swiss albino mice	↓ liver iron ↓ serum ferritin ↓ ALAT, ASAT, ALP, and bilirubin SOD, CAT, GST, GSH restioration ↓ lipid peroxidation ↓ the protein carbonyl content	[122]
Methanol extract of Terminalia chebula Retz. fruit	50, 100, 200 mg/kg b.w.	in vitro in vivo	iron-overloaded Swiss albino mice	in vitro: iron chelation, and DNA protective effects in vivo: ↓ ALAT, ASAT, ALP, and bilirubin ↑ antioxidant acvtivity ↓ lipid peroxidation, protein carbonyl, hydroxyproline and liver iron ↓ iron overload-induced toxicity -potential activity for reductive release of ferritin iron	[123]
Baicalin and quercetin		in vitro in vivo	iron-dextran induced iron overload mice	in vitro study: released iron from ferritin In vivo: -inhibited iron overload induced lipid peroxidation and protein oxidation of liver ↓ hepatic iron and hepatic collagen content ↑ the serum non-heme iron level but not serum ferritin level ↑ the excretion of iron through feces	[124]
Mangiferin (M) and an aqueous leaf extract of Mangifera foetida L (EMF)	mangiferin 75 mg/kg EMF 2.930 g/kg	in vivo	iron-overloaded Sprague Dawley rats	↑ body weight ↓ plasma iron ↑ iron excretion via urine M and EMF antioxidant activity	[125]

EGCG (-), epigallocatechin-3-gallate; GSE, grape seed extract; MEL, mouse erythroleukemia; IRPs, iron-regulatory proteins; TfR1, transferrin receptor 1; IRP, iron-responsive element-binding protein; BSSCE, black soybean seed coat anthocyanins extract; VAD, vitamin A deficiency; IL-8, interleukin-8; ROS, reactive oxygen species; STAT3, signal transducer and activator of transcription 3; Tuc-AIN-93G added of tucum-do-cerrado; TucFe-AIN-93G with tucum-do-cerrado and iron-enriched; Hmox1, heme oxygenase 1; Nqo1, NADPH dehydrogenase quinone 1; Nrf2, factor nuclear factor-erythroid 2-related factor 2; GR, glutathione reductase; Tf, transferrin; TfR2, transferrin receptor 2; ALAT, alanine aminotransferase; ASAT, aspartate aminotransferase; ALP, alkaline phosphatase; GST, glutathione-S-transferase; GA, gallic acid; MG, methyl gallate; GSH, reduced glutathione; EMF, extract of Mangifera foetida L; HepG2, human hepatocellular carcinoma cells; HEK293, human embryonic kidney cells.