An overview of potential cardioprotective benefits of xanthophylls in atherosclerosis: an evidence-based review

Yuting Su; Feng Chen; Jiehua Chen; Mingfu Wang

doi:10.26599/FSHW.2022.9250147

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An overview of potential cardioprotective benefits of xanthophylls in atherosclerosis: an evidence-based review

Yuting Su^{^a^,^b^,^c}, Feng Chen^{^a^,^b}, Jiehua Chen^{^a^,^b}(), Mingfu Wang^{^a^,^b^,^d}()

Shenzhen Key Laboratory of Marine Microbiome Engineering, Institute for Advanced Study, Shenzhen University, Shenzhen 518060, China

Institution for Innovative Development of Food Industry, Shenzhen University, Shenzhen 518060, China

College of Civil and Transportation Engineering, Shenzhen University, Shenzhen 518060, China

Shenzhen Key Laboratory of Food Nutrition and Health, Shenzhen University, Shenzhen 518060, China

Peer review under responsibility of Tsinghua University Press.

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Abstract

Atherosclerosis, as the most prevalent form of cardiovascular disease, is characterized by oxidized lowdensity lipoprotein (ox-LDL) accumulation in the vascular wall, increased inflammation of the large arteries, dysfunction of the endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), which may eventually lead to the formation of plaques. Xanthophylls, one of the main groups of carotenoids, have been proposed as preventive agents or adjunct therapies to prevent and slow the progression of atherosclerosis due to their cardioprotective properties. However, the underlying preventive mechanism of action of xanthophylls on the pathogenesis of atherosclerosis remains unclear, and clinical evidence of the effect of xanthophylls on atherosclerosis have not yet been summarized and critically reviewed. In this regard, we conducted a comprehensive literature search in four scientific databases (PubMed, Google Scholar, ScienceDirect and Web of Science) and carefully analyzed the existing evidence to provide meaningful insights on the association between xanthophylls and atherosclerosis from various aspects. Based on the evidence from in vitro and in vivo studies, we explored several potential mechanisms, including antioxidant effect, anti-inflammatory effect, regulation of lipid metabolism, and modulation of ECs and VSMCs dysfunction, and we found that a clear picture of regulatory pathways of xanthophylls on atherosclerosis prevention and treatment is still lacking. In addition, epidemiological studies suggested the possible relationship among high dietary intake of xanthophylls, high plasma/serum xanthophylls and a reduced risk of atherosclerosis. Direct evidence from interventional studies investigating the effect of xanthophylls on atherosclerosis is very sparse, whilst indirect clinical evidence was only limited to astaxanthin and lutein. Therefore, well-designed long-term randomized controlled trials (RCTs) are highly recommended for future studies to investigate the effective dose of different xanthophylls on atherosclerosis prevention and their possible ancillary effect in conjunction with drug therapies on different stages of atherosclerosis.

Keywords

Atherosclerosis Xanthophylls Antioxidant Anti-inflammation Lipid metabolism

References

[1]

A. Gisterå, D.F.J. Ketelhuth, S.G. Malin, et al., Animal models of atherosclerosis-supportive notes and tricks of the trade, Circ. Res. 130 (2022) 1869-1887. https://doi.org/10.1161/CIRCRESAHA.122.320263.

Type of xanthophylls	Type of study	Characteristics of subjects	Intervention Strategy	Main Effects	References
Notes: CCA-IMT, intima-media thickness of the common carotid artery; CRP, C-reactive protein; FMD, flow-mediated vasodilation; FMD, flow-mediated vasodilation; HDL, high density lipoprotein; IMT, intima-media thickness; LDL, low density lipoprotein; sICAM-1, soluble intercellular adhesion molecule-1; VCAM, vascular cell adhesion molecule-1.
Lutein	Cohort study	Women (n=269; aged 45-60 y), men (n=304; aged 40-60 y) with no history of heart attack, angina, revascularization, or stroke	Assessment of the association between serum lutein with risk factors for atherosclerosis for 18 months	IMT progression declined with increasing plasma lutein	[73]
Lutein, zeaxanthin, β-cryptoxanthin	Cohort study	Middle-aged women (n=220) and men (n=257) free of symptomatic cardiovascular disease at baseline	Common carotid arteries, lipid level determination, and risk factor assessment were monitored for 18-months	IMT was significantly inversely related to plasma level of lutein, β-cryptoxanthin and zeaxanthin	[74]
Lutein + zeaxanthin, β-cryptoxanthin	Cohort study	Patients with stable angina (SA, n=134) and patients with acute coronary syndrome (n=59)	Carotenoids and IL-6 in plasma were monitored for 3 months	Only lutein + zeaxanthin was inversely correlated with IL-6 in SA patients in baseline and follow-up	[92]
Lutein + zeaxanthin, β-cryptoxanthin	Cross-sectional study	2947 participants (934 men and 2013 women) aged 50-57 years in China Guangzhou (2008-2013)	Examine the association between the level of carotenoids in diets and serum and IMT	Higher carotenoids levels in diet and serum were associated with lower carotid IMT value	[67]
Lutein + zeaxanthin, β-cryptoxanthin	Cross-sectional study	1312 men and 1544 women without coronary heart disease or cancer from NHANES 2003-2006	Dietary data collected from 24h dietary recalls and blood cholesterol, CRP and tHcy measurement.	Significantly inverse associations between lutein + zeaxanthin intake with LDL cholesterol. Dietary lutein + zeaxanthin had positive association with HDL cholesterol.	[68]
lutein, zeaxanthin, β-cryptoxanthin	Cross-sectional study	1212 elderly men (61-80 years) in Eastern Finland grouped by quartile of CCA-IMT (2005-2008)	Early signs of carotid atherosclerosis and plasma level of carotenoids	Plasma level of β-cryptoxanthin decrease linearly with increasing CCA-IMT	[75]
Lutein, zeaxanthin	Cross-sectional study	379 participants (178 men and 201 women) aged (42±14) years in Zeist (29 June to 16 September 1998)	Examine the relationships between serum carotenoids and markers of endothelial function and inflammation	Serum lutein was inversely related to sICAM-1, Zeaxanthin was inversely related to FMD	[79]
Lutein, β-cryptoxanthin,	Case-control study	280 incident cases of acute myocardial infraction and 560 matched controls from a cohort of 63257 Chinese men and women aged 45-74 years in Singapore (1993-1998)	Evaluating the association between the level of plasma β-cryptoxanthin and lutein and incidence of acute myocardial infraction	High plasma levels of β-cryptoxanthin and lutein were associated with lower risk of acute myocardial infraction	[71]
Lutein, zeaxanthin	Case-control study	Early atherosclerosis patients without clinical cardiovascular events (n=40) and healthy controls aged 45–68 years (n=40)	Evaluation of the association between serum carotenoids, early atherosclerosis, and serum cytokines.	Serum lutein was inversely associated with IL-6, positively associated IFN-γ; Serum zeaxanthin showed negative association with VCAM-1 and apoE; Serum lutein and zeaxanthin were associated with reduced risk of atherosclerosis.	[72]
β-cryptoxanthin, lutein + zeaxanthin	Case-control study	Asymptomatic subjects and field center-matched case-control (231 vs. 231) pairs form Atherosclerosis risk in Communities study cohort (1986-1989).	Detecting the association between the level of carotenoids in diets and serum and IMT	Serum β-cryptoxanthin, lutein + zeaxanthin level had a modest inverse association with early carotid artery IMT	[76]
Lutein, zeaxanthin	Case-control study	125 subjects with early atherosclerosis (IMT > 750 nm, mean age, (55.5±5.4) y), 107 controls aged 45-68 y	Assessment of the association between serum carotenoids with carotid IMT and arterial stiffness	Only serum lutein had significantly inversed association with carotid IMT	[77]

Type of xanthophylls	Possible mechanisms	Cell models	Treatment	Main Effect	References
Notes: ↑ Significantly increased; ↓ significantly decreased; AMPK, AMP-activated protein kinase; CREB, cAMP-response element-binding protein; CXCL-10, C-X-C motif chemokine ligand 10; FAK, phosphorylation of focal adhesion kinase; HAECs, human aortic endothelial cells; Hcy, homocysteine; HUVECs, human umbilical vein endothelial cells; ICAM-1, intercellular adhesion molecule 1; IL-1β, interleukin 1β; IL-6, interleukin 6; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemotactic protein-1; M-CSF, macrophage colony-stimulating factor; NADPH, nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor kappa B; NQO1, NAD(P)H:quinone dehydrogenase 1; Nrf2, nuclear factor erythroid 2-related factor 2; PBMCs, peripheral blood mononuclear cells; PKC, protein kinase C; PDGF, platelet-derived growth factor; PGC-1α, peroxisome proliferator-activated receptor-gamm a coactivator-1 alpha; PINK, phosphatase and tensin homolog-induced putative kinase 1; TNF-α, tumor necrosis factor-α; VCAM-1, vascular cell adhesion molecule 1; VEGF-VEGFR2, vascular endothelial growth factor-vascular endothelial growth factor receptor 2; VICs, valve interstitial cells; VSMCs, vascular smooth muscle cells.
Astaxanthin	Antioxidation; Regulate endothelial dysfunction	Hcy-induced endothelial dysfunction in HUVECs	Astaxanthin (5 μmol/L)	Antioxidation ↓ ROS generation Regulate endothelial dysfunction ↑ HUVECs migration & tube formation ↑ FAK ↑ VEGF-VEGFR2-FAK signaling axis	[144]
Astaxanthin	Antioxidation; Regulate VSMCs dysfunction	Hcy-induced cardiotoxicity in H9c2 rat cardiomyocytes	Astaxanthin (4 μmol/L)	Antioxidation ↓ intracellular ROS Regulate endothelial dysfunction ↓ apoptosis, active-caspase-3,7,9 ↑ mitochondrial dysfunction via regulating Bcl-2 family expression	[97]
Astaxanthin	Antioxidation; Regulate endothelial dysfunction	tert-butyl hydroperoxide-induced intracellular oxidative stress in HUVECs	Astaxanthin (5 μmol/L)	↓ HUVECs intracellular ROS	[98]
Astaxanthin	Antioxidation; Regulate VSMCs dysfunction	Angiotensin (Ang) II-injured rat aortic VSMCs	Astaxanthin (20 μmol/L)	Antioxidation ↓ cellular and mitochondrial ROS ↑ NADPH oxidase, SOD Regulate VSMCs dysfunction ↑ mitochondrial biosynthesis, mitophagy recovery ↑ PINK, parkin, mitochondrial transcription factor A, PGC-1α ↓ VSMCs proliferation & migration ↓ MAPK & Akt signal pathway	[103]
Astaxanthin	Lipid metabolism regulation	Ox-LDL loaded THP-1 macrophages	Astaxanthin (0, 0.5, 5, 50 μmol/L)	↑ cholesterol efflux from macrophages via upregulating three specific circRNAs	[127]
Fucoxanthin	Antioxidation; Regulate endothelial dysfunction	Ox-LDL loaded HUVECs	Fucoxanthin (50 μmol/L)	Antioxidation ↓ intracellular ROS Regulate endothelial dysfunction ↑ mitochondrial function ↑ phosphorylation of AMPK & Akt/CREB/PGC-1α signaling ↓ PKC/NADPH oxidase signaling pathway	[99]
Fucoxanthin	Antioxidation; Regulate endothelial dysfunction; Anti-inflammation	Ox-LDL loaded HUVECs	Fucoxanthin (5, 10, 25, 50 μmol/L)	Antioxidation ↓ ROS, HO-1, NQO-1 ↑ Nrf2 signaling pathway Anti-inflammation ↓ IL6, MCP-1, IL1β, TNF-α ↓ NF-κB activation	[100]
Fucoxanthin	Antioxidation; Regulate VICs dysfunction	H₂O₂-injured rat VICs	Fucoxanthin (0.5, 1 mg/mL)	Antioxidation ↓ intracellular ROS ↓ pAkt/Akt protein expression ratio Regulate VICs dysfunction ↓ apoptosis-related proteins: c-PARP, caspase 3, Bcl2 & Bax expression	[105]
Lutein	Antioxidation; Regulate VSMCs dysfunction	PDGF stimulated-VSMCs	Lutein (5, 10 μM)	Antioxidation ↓ intracellular ROS generation Regulate VSMCs dysfunction ↓ ERK1/2 & p38 MAPK activation ↓ PDGF-induced VSMCs migration ↓ oxidation of protein tyrosine phosphatase.	[104]
Lutein	Anti-inflammation	LPS-induced PBMCs from stable angina patients	Lutein (1, 5, 25 μM)	↓ IL6 and IL1β and TNF expression	[92]
Lutein & β-cryptoxanthin	Anti-inflammation	Fructose-stimulated HUVECs cocultured with U937 monocytes	1) lutein (0.1, 0.5 and 1μmol/L)	Both in lutein and β-cryptoxanthin trials: ↓ chemokines: MCP-1, M-CSF, CXCL-10 ↓ inflammatory cytokines: TNF-α, IL-1β ↓ adhesion molecules expression: ICAM-1, VCAM-1, E-selection, dose dependently. ↓ monocyte adhesion to HUVECs	[120]
Lutein & β-cryptoxanthin	Anti-inflammation	Fructose-stimulated HUVECs cocultured with U937 monocytes	2) β-cryptoxanthin (0.1, 0.5 and 1μmol/L)		[120]
Lutein	Regulate endothelial dysfunction	IL-1β stimulated HAECs	Lutein (0.9 μM)	↓ adhesion molecules: VCAM-1, E-selectin and ICAM-1 expression. ↓ HAECs adhesion to monocytes	[145]
Lutein	Regulate ECs and VSMSs dysfunction	LPS-stimulated monocytes cocultured with artery wall cells (ECs and SMCs from human aortas)	1) lutein (10~100 nmol/L)	↓ LDL-induced migration of monocytes in a dose-dependent manner ↓ chemotaxis on cocultures in type 1 trial (lutein pre-incubation with cocultures)	[73]
Lutein	Regulate ECs and VSMSs dysfunction		2) LDL mixed with lutein (10~100 nmol/L)		[73]
β-cryptoxanthin	Lipid metabolism regulation	THP-1 Macrophages	β-cryptoxanthin (5, 10 μmol/L)	↑ STRA6 receptor expression in THP-1 macrophages ↑ cholesterol efflux via increase mitochondrial sterol 27-hydroxylase (CYP27A1) production	[128]

Type of xanthophylls	Possible mechanisms	Animal models	Treatment	Main Effect	References
Notes: ↑ Significantly increased; ↓ significantly decreased; ↔ no statistically significant difference; ABCA1/G1, ATP-binding cassette transport A1 and G1; ACAT, cholesterol acyltransferase; ACC, acetyl-CoA carboxylase; ACOX1, acyl-CoA oxidase 1; API, atherogenic plasma index; aPTT, activated partial thromboplastin time; CME, coronary microembolization; CPT1A, carnitine palmitoyltransferase 1A; CRP, C-reactive protein; GSH, glutathione; GSH-Px, glutathione-peroxidase; HCD, high cholesterol diet; Hcy, homocysteine; HFD, High-fat diet; HMGR, 3-hydroxy-3-methylglutaryl CoA reductase; LVH, left ventricular hypertrophy index; MDA, malondialdehyde; MnSOD, manganese superoxide dismutase; NF-κB, nuclear factor kappa B; NHDL-C, non-high density lipoprotein cholesterol; NOX, NADPH oxidase; NPSH, nonprotein thiol group; Nrf2, nuclear factor erythroid 2-related factor 2; PCNA, proliferating cell nuclear antigen; PCSK, protein convertase subtilisin/kexin type 9; PGF1α, prostaglandin F1α; PPARα, peroxisome proliferator-activated receptor α; RCT, reverse cholesterol transport; SHRs, spontaneously hypertensive rats; SIRT1, sirtuin 1; SR-BI, scavenger receptor class B type I; SREBP-2, sterol regulatory element binding protein 2; TXB2, thromboxane B2; VSMCs, vascular smooth muscle cells.
Astaxanthin	Antioxidation; Regulate endothelial dysfunction	HFD-induced hyperlipidemic rats	Gavage with astaxanthin (5, 10, 30 mg/kg/d) for 4 weeks	Antioxidation: ↓ MDA content ↑ activity of SOD, NO level (10, 30 mg/kg/d) Regulate endothelial dysfunction: ↓ Blood coagulation (aPTT) ↓ platelet aggregation (TXB2/6-keto-PGF1α) ↑Fibrinolytic activity (PAI-a)	[108]
Astaxanthin	Antioxidation; Lipid metabolism regulation	HCD-fed SD rats	Gavage with astaxanthin (50 mg/kg/d) for 45 days	Antioxidation: ↓ Thiobarbituric acid reactive substances (lipid peroxidation) Lipid metabolism regulation: ↓ total cholesterol, LDL-C, very LDL-C & triglycerides ↑ HDL-C	[109]
Astaxanthin	Antioxidation	1% cholesterol diet-induced atherosclerotic lesion in Rabbits	Diet supplemented with 50, 100, 500 mg astaxanthin for 60 days	↓ lipid peroxidation ↑ nonprotein thiol group (NPSH) ↓ catalase activity (in 100 and 500 mg group) ↔ hypercholesterolemia or atherosclerotic lesion prevention	[107]
Astaxanthin	Antioxidation Anti-inflammation	HFD-induced cardiac damage & fibrosis rats	HFD+ astaxanthin (200 mg/kg/orally) for 14 weeks	Antioxidant: ↓ ROS ↑ GSH, catalase, MnSOD ↑ SIRT1, Nrf2 activity Anti-inflammation\ ↓ TNF-α, IL-6 ↓ NF-κB p65	[110]
Astaxanthin	Antioxidation; Regulate VSMCs dysfunction	SHRs	Intragastric injection of 200 mg/kg/d of astaxanthin for 11 weeks	Antioxidant ↓ ROS, H₂O₂ level ↑ SOD2 Improving VSMCs dysfunction ↓ blood pressure, ↓ aortic wall thickness and fibrosis, ↓ proliferation indicators: PCNA & ki67	[103]
Astaxanthin	Regulate endothelial dysfunction	SHRs	Astaxanthin-enriched diet (75 or 200 mg/kg bw/d) for 8 weeks	↓ systolic blood pressure, LVH & cardiovascular remodeling ↑ endothelial function on resistance arteries	[146]
Astaxanthin	Regulate endothelial dysfunction	SHRs	(1) SHR fed with egg yolk diet (20g/d/rat) supplemented with various doses of astaxanthin (0.00, 0.02, 0.008, 0.002 mg/g/d) for 15 weeks	↓ Carbamoylcholine-induced contraction of the thoracic aorta segments ↓ arterial blood pressure before hypertension development (trial 1)	[147]
Astaxanthin	Regulate endothelial dysfunction	SHRs	(2) SHR fed with standard diet supplemented with astaxanthin 0.02 mg/g/d for 5 weeks		[147]
Astaxanthin	Antioxidation; Regulate endothelial dysfunction	CME SD rat model	Oral administration of astaxanthin (40 mg/kg/d) for 2 weeks prior to CME modeling operation	Antioxidation: ↑ GSH-Px, CAT, SOD1, SOD2 ↑ Nrf2/HO-1 signaling Regulate endothelial dysfunction ↓ cardiomyocyte apoptosis ↑ Bcl-2/Bax expression ratio	[148]
Astaxanthin	Antioxidation; Regulate endothelial dysfunction	Hcy-induced cardiotoxicity in a mouse model	Astaxanthin oral administration: 5 mg/kg/day for 4 weeks	Antioxidation ↓ oxidative damage Regulate endothelial dysfunction ↓ Hcy-induced cardiotoxicity and myocardial apoptosis ↑ angiogenesis	[97]
Astaxanthin	Lipid metabolism regulation	ApoE^-/- mice fed with HFD (15%)+HCD (0.2%)	HFD+HCD supplemented with astaxanthin (0.03%) for 4 weeks	↓ plasma total cholesterol & TG ↑ LDL receptor, HMGR and SREBP-2 expression ↑ fatty acid beta-oxidation in liver ↓ glutathione disulfide level	[130]
Astaxanthin	Lipid metabolism regulation	1) C57BL/6J mice 2) ApoE−/− mice	1) RCT mice fed with astaxanthin enriched diet (0.05%) for 12 weeks	Lipid metabolism regulation: ↑ ABCA1/G1 and SR-BI ↑ reverse cholesterol transport and excrete to feces ↓ plaque area of the aortic sinus and aortic cholesterol in ApoE−/− mice	[132]
Astaxanthin	Lipid metabolism regulation	1) C57BL/6J mice 2) ApoE−/− mice	2) ApoE−/− mice fed with astaxanthin enriched diet (0.05%, w/w) for 12 weeks		[132]
Astaxanthin	Lipid metabolism regulation	1) low-density lipoprotein receptor negative LDLR^-/- mice 2) ApoE^-/- mice	1) LDLR^-/- mice fed with 0.5% cholesterol diet plus 0.0%, 0.08%, 0.2%, 0.4% astaxanthin prodrug (CDX-085) for 4 weeks	↓ total cholesterol & aortic arch atherosclerosis level in 0.4% CDX-085 group in LDLR^-/- mice ↓ triglycerides in ApoE^-/- mice	[133]
Astaxanthin	Lipid metabolism regulation		2)ApoE^-/- mice fed with 0.5% cholesterol diet plus 0.0%, 0.08%, 0.4% CDX-085 for 12 weeks		[133]
Fucoxanthin	Antioxidation; Regulate endothelial dysfunction	Heart disease-diagnosed dogs	Fed with Fuco pets® (60 mg/kg fucoxanthin) for 0.5 to 2 years	Antioxidant ↓ oxidative stress Regulate endothelial dysfunction: ↑ compensatory cardiac hypertrophy & valve function	[105]
Fucoxanthin	Anti-inflammation; Lipid metabolism regulation	HFD-fed Wistar rats	HF diet + intragastic administration fucoxanthin (1mg/kg, bw/d) for 8 weeks	Lipid metabolism regulation: ↓ adipose tissue accumulation, blood pressure, cholesterol level in serum ↓ ACC gene expression Anti-inflammation ↑ anti-inflammatory markers: adiponectin ↓ pro-inflammatory cytokines: leptin, CRP and PAI-1, IL6 level in serum	[121]
Fucoxanthin	Lipid metabolism regulation	Diabetic/obese KK-A^y mice	Normal diet containing 0.2% fucoxanthin for 4 weeks	↑ HDL-cholesterol ↑ PCSK mRNA expression ↓ cholesterol uptake in liver ↓ LDLR and SR-B1	[134]
Fucoxanthin	Lipid metabolism regulation	HFD-fed C57BL/6N mice	HFD supplemented with 0.05% or 0.2% fucoxanthin for 6 weeks	↑ plasma HDL cholesterol ↑ fecal TG level ↓ adipocyte fatty acid synthesis ↓ cholesterol-regulating enzyme (HMGR, acyl coenzyme A: ACAT) activity	[135]
Lutein	Antioxidation Lipid metabolism regulation	HFD induced atherosclerosis in ApoE−/− mice.	HFD supplemented with lutein (25, 50, and 100 mg/kg bw) for 24 weeks	Antioxidation: ↑ SOD activity ↓ MDA level, NOX, aortic HO-1 & NOX subunits P47^phox and p22^phox; Lipid metabolism regulation: ↓ API and NHDL-C ↑ PPARα, CPT1A and ACOX1 in liver ↑ SR-BI expression	[106]
Lutein	Antioxidation; Anti-inflammation; Lipid metabolism regulation	HCD fed Guinea pigs	HCD supplemented with 0.1g/100g lutein for 12 weeks	Lipid metabolism regulation: ↓ aortic cholesterol Plasma lutein negatively correlated with (aortic) ox-LDL Antioxidation ↓ ox-LDL concentrations, MDA Anti-inflammation ↓ IFN-γ, TNF-α, IL-1β etc. inflammatory cytokines generation	[86]
Lutein	Regulate endothelial dysfunction	ApoE^-/- mice	1) normal diet supplement with lutein (0.2% bw) for 8 weeks 2) HFD+HCD supplement with lutein (0.2% bw) for 8 weeks.	↓ intima-media thickness in both 1) and 2) trials ↓ lesion size 44%, level of plasma lipid hydroperoxide and monocytes chemotactic activity only in normal diet trial 1) ↓lesion size 43% in HFD+HCD diet trial 2)	[73]

Type of xanthophylls	Type of study	Characteristics of subjects	Intervention Strategy	Main Effects	References
Notes: ↑ Significantly increased; ↓ significantly decreased; ↔ no statistically significant difference; BAP, biological antioxidant potential; CRP, C-reactive protein; DBP, diastolic blood pressure; HDL, high density lipoprotein; HDL-C, high density lipoprotein-cholesterol; IMT, intima-media thickness; ISP, isoprostane; LDL, low density lipoprotein; LDL-C, low density lipoprotein-cholesterol; MCP-1, monocyte chemoattractant protein-1; MDA, malondialdehyde; PLOOH, phospholipid hydroperoxide; RCT, randomized controlled trial; SBP, systolic blood pressure; SOD, superoxide dismutase; TAC, total antioxidant capacity; TC, total cholesterol; TG, triglyceride.
Astaxanthin	RCT	Subjects with mild hyperlipidemia (n=61; aged 25-60 y; fasting serum triglyceride: 120-200mg/dl)	Placebo (n=15), astaxanthin, 6 mg/d (n=15), astaxanthin 12 mg/d (n=15), astaxanthin 18 mg/d (n=16) for 12 weeks	↓TG (12, 18 mg/d) serum HDL-C (6, 12 mg/d) ↔LDL-cholesterol	[81]
Astaxanthin	RCT	Overweight adults (n=27; 20-55 y; BMI > 25.0 kg/m²)	Placebo (n=13), astaxanthin, 20 mg/day (n=14) for 12 weeks	Lipid profile: ↓ LDL-C in the astaxanthin group ↓ApoB and ApoA1/ApoB ratio in the astaxanthin group ↔TC, TG, HDL-C Oxidative stress biomarkers: ↑ TAC ↓ MDA, ISP ↑ SOD in the astaxanthin group	[82]
Astaxanthin	RCT	Patients with type 2 diabetes (n=44; 46-62 y)	Placebo (n=22), astaxanthin, 8 mg/day (n=22) for 8 weeks	↓ VLDL-cholesterol, TG, SBP, visceral fat mass ↔HDL-cholesterol, LDL-cholesterol, TC	[83]
Astaxanthin	RCT	Healthy non-smoking men (n=40; 19-33 y)	Placebo (n=20), astaxanthin 8 mg/d (n=20) for 3 months	↓plasma 12-and 15-hydroxy fatty acids in the astaxanthin group ↔ TG, TC, HDL-C, LDL-C	[85]
Astaxanthin	RCT	Healthy aging subjects (n=30; 50-69 y)	Placebo (n=10), astaxanthin 6 mg/d (n=10), astaxanthin 12 mg/d (n=10) for 12 weeks	↓PLOOH in erythrocytes ↑erythrocyte antioxidant status	[87]
Astaxanthin	RCT	Healthy young women (n=42; 20-22 y)	Placebo (n=14), astaxanthin 2 mg/day (n=14), astaxanthin 8 mg/day (n=14) for 8 weeks	Inflammation: ↓plasma CRP (2mg/d) plasma IFN-γ, IL-6 (8 mg/d) ↔TNF, IL-2 (8 mg/d) Immune response: ↑ mitogen-induced lymphoproliferation, NK cells cytotoxic activity, total number of T and B cells (2, 8 mg/d)	[91]
Astaxanthin	Non-RCT	Healthy volunteers (n=24, aged (28.2±7.8)y)	Astaxanthin: control (n=6), 1.8 mg/d (n=5), 3.6 mg/d (n=5), 14.4 mg/d (n=3), 21.6 mg/d (n=5) for 14 days	↓LDL oxidation time in a dose dependent manner	[84]
Astaxanthin	Non-RCT	Smokers (n=39; ≥20 cigarettes per day)	Astaxanthin: 5, 20, 40 mg/day (n=13, each), for 3 weeks	Compared to baseline: ↓MDA & ISP; ↑ SOD & TAC	[89]
Astaxanthin	Single-arm pilot study	Healthy postmenopausal women with high oxidative stress levels (n=20, aged (55.7±4.8) y)	12 mg/day astaxanthin for 8 weeks	↓ blood pressure: SBP, DBP ↑ lower limb vascular resistance (vascular function) BAP	[90]
Lutein	RCT	Early atherosclerosis patients (n=65)	Placebo (n=31), Lutein 20 mg/d (n=34) for 3 months	Compared to the baseline in the lutein group: ↑plasma lutein ↓serum IL-6 ↓serum LDL-cholesterol, TG, apoE ↔HDL-cholesterol ↓MCP-1 Compared to the control group: ↑plasma lutein ↓MCP-1 Serum lutein was negatively associated with serum LDL-cholesterol in the lutein group	[80]
Lutein	RCT	Healthy subjects (n=117; aged 20-80 y, BMI between 18-30 kg/m²)	Placebo (n=39) Lutein 10mg/d (n=38) Lutein 20 mg/d (n=39) for 12 weeks	↑plasma lutein (10, 20 mg/d) ↓serum CRP in a dose dependent manner ↑TAC (10, 20 mg/d) ↓MDA (20 mg/d)	[88]