Impact of hesperidin in 100% orange juice on chronic disease biomarkers: A narrative systematic review and gap analysis

Figures & data

Table 1. Search terms associated with each disease condition.

Condition/disorder/disease	Search term
Bone conditions	“bone health”; “bone conditions”; “osteoporosis”; “bone biomarkers—bone turnover, bone microarchitecture”;
Cancer	“cancer”; “tumor”; “metastasis”; “carcinogenesis”; “cancer biomarkers—tumor growth, tumor suppression, white blood cell”;
Cardiovascular disease	“cardiovascular disease”; “hypertension/blood pressure”; “heart attack”; “stroke”; “cardiac biomarkers—cardiac troponin, creatine kinase, C-reactive protein, low density lipoprotein, lipoprotein A, serum creatinine, tumor necrosis factor α”;
Inflammation	“inflammatory disease”; “arthritis”; “inflammatory bowel disease”; “celiac disease”; “hepatitis”; “inflammatory biomarkers—C-reactive protein, IFN-γR, IL-1β, IL-4, IL-10, IL-12, TNF-α”;
Neurological Conditions	“neurological conditions”; “Alzheimer’s disease”; “ALS”; “Cognitive Decline”; “Dementia”; “Multiple Sclerosis”; “Parkinson’s”; “neurological biomarkers—C-reactive protein, IFN-γR, IL-1β, IL-4, IL-10, IL-12, TNF-α”;
Metabolic Disorders	“type 2 diabetes”; “pre-diabetes”; “metabolic syndrome”; “metabolic biomarkers—hemoglobin A1C, advanced glycation end products, glycated albumin, C-reactive protein, IL-6”

Table 2. Data extraction of studies included in narrative systematic review (n = 20).

Author (year)	Location/Population	Design/Duration	Diet	Intervention Components	Amount/Frequency	Evaluation measures
Alharbi et al. (2016)	UK Healthy Adults (n = 24)	RCT^a (Crossover) Double-Blind 2 days/2 weeks	Low polyphenol diet; Evening at home meal prior to each test-day: low-fat standardized chicken and rice	Intervention: 240-ml FR^b drink Control: Placebo	Amount: 240 ml Frequency: Once (5 min) Hesperidin: 220.5 mg/d	Cognitive Tests: Function; Subjective Mood: PANAS^c
Buscemi et al. (2012)	Italy Non-diabetic with increased CVD risk (n = 19) Healthy, non-obese (n = 12)	RCT (crossover) Single-Blind 3 weeks	Eat the same diet 3 d preceding basal measurements and during the last 3 d of periods 1 and 2.	Intervention: 500 mL red OJ^d Control: 500 mL placebo	Amount: 500 mL Frequency: 250 ml twice/d for 1 week Hesperidin: 159.5 mg/d	Inflammatory biomarkers: CRP^e, IL-6^f, TNF-α^g; NO^h plasma concentration; Plasma PC groups
Constans et al. (2015)	France Men with cardiovascular risk factors (n = 25)	RCT (Cross-over) 13 weeks	French National Program for Nutrition and Health (4 weeks before the study)	Intervention: 200 mL of blond OJ Control: Control beverage (mimicking OJ, including vitamin C but no phyto-micronutrients)	Amount: 600 mL Frequency: 3x daily for 4 weeks Hesperidin: 212 mg/d	Lipid panel: TC^i, LDL^j, HDL^k, ApoA-I^l Antioxidant activity: ORAC^m; FRAP^n; CAT^o; plasma ascorbic acid and homocysteine concentrations Endothelial function biomarkers: Plasma concentrations of sVCAM-1^p
Pascual-Teresa et al. (2007)	Spain Healthy adults (n = 14)	Controlled study 2 weeks	Usual dietary habits and physical activity level	Intervention 1: Dose response test − 400 g of minimally processed oranges Intervention 2: Multiple-dose-response − 200 g of orange in the morning, for 2 consecutive weeks	Amount: Intervention 1: 400 g (200 ml) Intervention 2: 200 g (100 ml) Frequency: Intervention 1: Once Intervention 2: Each morning for 2 consecutive weeks Hesperidin: Intervention 1: 198 mg/d Intervention 2: 49 mg/d	FRAP
Dourado and Cesar (2015)	Norway Healthy Normal weight adults (n = 21) Healthy Overweight adults (n = 25)	Controlled trial 8 weeks	Usual dietary habits and physical activity level	Intervention: 750 mL of OJ Control: N/A	Amount: 750 ml Frequency: At least two intakes/d for 8 weeks Hesperidin: 77.5 mg/d	Lipid panel: TC, LDL, HDL, TG^q Oxidative stress biomarker: Lipid peroxidation Plasma vitamin C and folate concentration Plasma insulin concentration Inflammatory biomarkers: CRP, cytokines (IL-4^r and TNF-α)
Escudero-López et al. (2018)	Spain Healthy Adults Intervention (n = 15) Healthy Adults Control (n = 15)	RCT 5 weeks	Limit beer or wine intake to a maximum of six servings per week and to avoid any intake of spirits over the study period.	Intervention: 500 mL- orange beverage (OB) Control: Did not consume OB during a 2-week period	Amount: 500 mL Frequency: Per day for 2 weeks Hesperidin: 0.0025 mg/d	Lipid Panel: TC, LDL, HDL, TG Oxidative stress biomarker: TBARS^s Plasma insulin concentration Antioxidant activity and endothelial function biomarkers: CAT; ORAC; FRAP; Plasma concentrations of sVCAM-1; Uric acid
Franke et al. (2005)	USA Healthy Adults (n = 13)	Controlled Trial 3 weeks	Usual dietary habits and physical activity level	Intervention: Daily 256 mg vitamin C, 229 mg hesperidin, 6 mg carotenoids, 0.16 mg folate in 236 mL of OJ Control: N/A	Amount: 236 ml Frequency: Daily for 3 weeks Hesperidin: 229 mg/d	Lipid Panel: TC, HDL, LDL, TG, HDL-LDL ratio Oxidative stress biomarker: TBARS Plasma vitamin C, folate, homocysteine and phenolic concentrations
Ghanim et al. (2007)	USA Healthy Adults (n = 32)	Controlled Trial 1 day	Usual dietary habits and physical activity level	Intervention 1: 300-cal drink of glucose (75 g) Intervention 2: 300-cal drink of fructose (75 g) Intervention 3: 300-cal drink of OJ Control: Water sweetened with saccharin	Amount: 300-cal (654.5 ml) Frequency: Single dose, within 10 min Hesperidin: 3.70 mg/d	Plasma insulin concentration Oxidative stress biomarker: ROS^t generation Inflammatory biomarkers: CRP
Gonçalves et al. (2017)	Brazil Adults with chronic hepatitis C (n = 43) Intervention (n = 23) Control (n = 20)	RCT 8 weeks	Usual dietary habits and physical activity level	Intervention: 500 mls of OJ Control: No regular consumption of OJ	Amount: 500 ml Frequency: Two (250 mls) daily portions over eight consecutive weeks Hesperidin: 16.4 mg/d	Lipid Panels: TG, LDL, HDL, TC Oxidative stress biomarker: TBARS Plasma insulin concentration Inflammatory biomarkers: CRP
Hollands et al. (2018)	UK Men with a waist measurement >94 cm and women with >80 cm (n = 41)	RCT (crossover) 11 weeks	Excluded food sources high in total anthocyanin intake. Advised to drink the juice with a meal/food or through a straw.	Intervention: 500 ml blood OJ providing 50 mg anthocyanins Control: 500 ml blonde OJ without anthocyanins	Amount: 500 ml Frequency: Daily for 28 d Hesperidin: Intervention: 67 mg/d Control: 104 mg/d	Lipid Panel: TC, HDL, LDL, TG Inflammatory biomarkers: high-sensitivity CRP status; NO plasma concentration
Li et al. (2020)	UK Healthy men and premenopausal women (n = 15)	RCT (crossover) 5 weeks	Usual dietary habits and physical activity level	Intervention: 400 mL Blood OJ Control: 400 mL sugar matched control drink	Amount: 400 mL Frequency: 200 mL twice/d for 2 weeks Hesperidin: Intervention: 320.8 ± 10.8 mg/d Control: 25.2 ± 0.8 mg/d	Lipid Panel: TC, HDL, LDL, TG Blood Pressure: 3 consecutive measurements Inflammatory biomarkers: CRP
Kean et al. (2015)	UK Healthy Adults Intervention (n = 19) Healthy Adults control (n = 18)	RCT 20 weeks	Fast from alcohol for 48 h; Avoid polyphenol-rich foods for 24 h	Intervention: HF^u drink Control: LF^v drink	Amount: Intervention: 180 kcal/500-ml Control: 165 kcal/500-mL Frequency: 250 mL twice/d for 8 weeks Hesperidin: Intervention: 274.5 mg/d Control: 32 mg/d	Cognitive Tests: Global Cognitive Function; Subjective mood: PANAS Blood Pressure: 3 consecutive measurements
Kurowska et al. (2000)	Canada Adult Men (n = 16) and Adult Women (n = 9) with elevated plasma total and LDL-cholesterol and normal plasma TG concentrations	Crossover Trial 22 weeks	American Heart Association (AHA) Step I lipid-lowering diet; Avoid taking supplements during the study.	Intervention: 1, 2, or 3 cups (250 mL each) of OJ Control: N/A	Amount: 1, 2 or 3 cups (250 ml each) Frequency: Daily for 4 weeks Hesperidin: Dietary Period 1: 11.6 mg/d Dietary Period 2: 23.2 mg/d Dietary Period 3: 34.7 mg/d	Lipid panel: LDL, HDL, HDL-LDL ratio; TGs; Apo B and Apo A-1 Plasma Vitamin C, folate and homocysteine concentrations
Morand et al. (2011)	France Healthy Overweight men (n = 24)	RCT (Crossover) 18 weeks	Refrain from citrus-containing foods; Limit total intake of flavonoid rich beverages	Intervention 1: 500 mL OJ Intervention 2: 500 mL control drink plus hesperidin (CDH) Control: 500 mL control drink plus placebo (CDP)	Amount: 500 ml Frequency: 250 ml twice/d for 4 weeks Hesperidin: 292 mg/d	Lipid panel: TC, LDL, HDL, TG Blood pressure: 3 consecutive measurements Plasma ascorbic acid concentration Plasma insulin concentration Inflammatory and endothelial activation biomarkers: CRP, IL-6, sVCAM-1, NO plasma concentration; Uric acid
Perche et al. (2014)	France Healthy Adults (n = 24)	RCT (Crossover) 18 weeks	Limited consumption of polyphenol-rich drinks like coffee, tea, wine and cocoa (less than 200 mL/day).	Intervention 1: Orange Juice Intervention 2: Isocaloric control drink with 292 mg of pure hesperidin Control: Control drink with a placebo (292 mg starch)	Amount: 500 ml Frequency: 2 equal intakes daily Hesperidin: Intervention 1: 292 mg/d Intervention 2: 292 mg/d	Cytokines production (IL-4) Oxidative stress biomarker: ROS generation
Rangel-Huerta et al. (2015)	Spain Overweight/Obese adults, 1 clinical sign of metabolic syndrome (n = 100) Intervention (n = 54) Control (n = 46)	RCT (Crossover) Double-Blind 31 weeks	Usual dietary habits Avoid heavy physical activity, alcohol use (24 h), and smoking (2 h) before visits.	Intervention: 1.5 g/L [OJ with a high polyphenol concentration (HPJ)] Control: 0.6 g/L [OJ with a normal polyphenol concentration (NPJ)]	Amount: 500 ml Frequency: 2 daily doses (250 ml/each) for 12 weeks Hesperidin: Intervention: 582.5 mg/d Control: 237 mg/d	Lipid metabolism: Total, HDL, LDL, TG, Apo-B, ApoA-1 Plasma insulin concentration Oxidative stress biomarker: Lipid peroxidation Antioxidant activity: CAT
Schar et al. (2015)	USA Healthy Adults with a 10-20% risk of CVD (n = 16)	RCT (Crossover) 1 day	Diet low in flavonoids (for 72 h); Refrain from strenuous exercise (for 48 h); Avoid alcohol, caffeine, and nitrate/nitrite-containing foods and beverages (for 24 h).	Intervention 1: OJ Intervention 2: Hesperidin supplement Control: Matched for sugar and vitamin C content	Amount: 767 ml Frequency: 1 dose Hesperidin: 320 mg/d	Blood pressure: 3 consecutive measurements Plasma vitamin C and total plasma phenolic concentrations
Simpson, Mendis, and Macdonald (2016)	UK Healthy, overweight adults (n = 36) Intervention (n = 18) Control (n = 18)	RCT Single-Blind 12 weeks	Usual dietary habits and physical activity level	Intervention: 250 ml OJ/day Control: Energy and sugars matched orange-flavored drink	Amount: 250 ml Frequency: Once a day for 12 weeks Hesperidin: 135.4 mg/d	Lipid panel: TG, TC, LDL, HDL, Apo-A1, Apo-B Plasma Fasting Insulin Sensitivity Inflammatory biomarkers: CRP, TNF-α, Uric acid
Snyder et al. (2011)	USA Healthy Adults (n = 16)	RCT (Crossover) 19 weeks	Discontinue antioxidant supplements; 12-hour fast, meal: 28 g (1 cup) of Kellogg's Corn Flakes and 118 mL (½ cup) of 2% milk	Intervention 1: Fresh squeezed OJ (positive control) Intervention 2: Placebo plus hesperidin, luteolin, and naringenin Intervention 3: Placebo plus hesperidin Control: Placebo—ascorbic acid and sugar equivalent to OJ (negative control)	Amount/Hesperidin: Intervention 1: 591 mL Intervention 2: Control + 210 mg hesperidin, 22.8 mg naringenin & 3.97 luteolin Intervention 3: Control + 210 mg hesperidin Control: AA (350 mg), fructose (12.76 g), glucose (11.17 g) and sucrose (23.81 g) dissolved in 591 mL water Frequency: One treatment per week Hesperidin: 210 mg/d	Oxidative stress biomarker: Lipoprotein oxidation Antioxidant capacity: ORAC Total plasma phenolic concentrations
Valls et al. (2021)	Spain Pre- or Stage-1 hypertensive individuals (n = 159)	RCT 12 weeks	Refrain from consuming citrus-containing foods and to limit their total intake of flavonoid-rich foods	Intervention 1: OJ Intervention 2: Hesperidin-enriched OJ Control: Control drink	Amount: 500 ml Frequency: Once/day for 12 weeks Hesperidin: Intervention 1: 345 mg/day Intervention 2: 600 mg/d	Blood pressure: 2 consecutive measurements Homocysteine concentration Inflammatory biomarkers: Uric acid

Notes. a = Randomized Control Trial; b = Flavonoid Rich; c = Positive and Negative Affect Scale; d = Orange Juice, e = C-reactive Protein, f = Interleukin 6, g = Tumor Necrosis Factor, h = Nitric oxide; i = Total Cholesterol; j = Low-density Lipoprotein; k = High-density Lipoprotein; l = Apolipoprotein A1, m = Oxygen Radical Absorbance Capacity; n = Ferric Reducing Antioxidant Power; o = catalase; p = Soluble Vascular Cell Adhesion Molecule; q = Triglyceride; r = Interleukin 4; s = Thiobarbituric Acid Reactive Substances; t = Reactive Oxygen Species; u = High-Flavanone; v = Low-Flavanone

Table 3. Data outcomes of studies included in narrative systematic review (n = 20).

Author (year)	Inflammation	Neurological	Cardiac	Insulin	Antioxidant/Phenolic	Oxidative Stress Biomarkers
Alharbi et al. (2016)	/	Cognitive Function Tests: No difference between control and intervention post-6 hours (p > 0.05) Subjective Mood: No difference between control and intervention post-6 hours (p > 0.05)	/	/	/	/
Buscemi et al. (2012)	CRP^a, IL-6^b, and TNF-α^c: Between groups, significant decrease in intervention post-14 days (p < 0.001) NO^d: No difference between control and intervention post-14 days (p = 0.087) PC^e: No difference between control and intervention post-14 days (p = 0.230)	/	/	/	/	/
Constans et al. (2015)	sVCAM^f: No difference between control and intervention post-4 weeks (p > 0.05)	/	HDL^g: No difference between control and intervention post-4 weeks (p > 0.05) LDL^h: No difference between control and intervention post-4 weeks (p > 0.05) Apo-AI^i: Between groups, significant increase in intervention post-4 weeks (p < 0.02) TC^j: No difference between control and intervention post-4 weeks (p > 0.05)	/	Homocysteine: No difference between control and intervention post-4 weeks (p > 0.05) Vitamin C: No difference between control and intervention post-4 weeks (p > 0.05) ORAC^k: Between groups, significant increase in intervention post-4 weeks (p < 0.05) FRAP^l: No difference between control and intervention post-4 weeks (p > 0.05) CAT^m: No difference between control and intervention post-4 weeks (p > 0.05)	/
Pascual-Teresa et al. (2007)	/	/	/	/	FRAP: No difference within control post-6.5 hours and intervention post-14 days (p > 0.05)	/
Dourado and Cesar (2015)	CRP: Significant decrease post-8 week intervention (p < 0.05) IL-4^n: No difference post-8 week intervention (p > 0.05) TNF-α: No difference post-8 week intervention (p > 0.05)	/	TG^o: No difference post-8 week intervention (p > 0.05) HDL: No difference post-8 week intervention (p > 0.05) LDL: Significant decrease post-8 week intervention (p < 0.05) TC: Significant decrease post- 8 week intervention (p < 0.05)	No difference post-8 week intervention (p > 0.05)	Vitamin C: Significant increase post-8 week intervention (p < 0.05) Folate: Significant increase post-8 week intervention (p < 0.05)	Peroxidation: Significant decrease post-8 week intervention (p < 0.05)
Escudero-López et al. (2018)	sVCAM: No difference within control or intervention (p > 0.05) Uric acid: Significant decrease post-intervention and washout (p < 0.05; p < 0.05), no difference in control (p > 0.05)	/	TG: No difference within control or intervention post-2 weeks (p > 0.05) HDL: No difference within control or intervention post-2 weeks (p > 0.05) LDL: No difference within control or intervention post-2 weeks (p > 0.05) Apo-AI: No difference within control or intervention post-2 weeks (p > 0.05) TC: No difference within control or intervention post-2 weeks (p > 0.05) Apo-B^q: No difference within control or intervention post-2 weeks (p > 0.05)	No difference within control or intervention post-2 weeks (p > 0.05)	ORAC: Significant increase post-intervention (p < 0.01), no difference in control (p > 0.05) FRAP: No difference within control or intervention post- 2 weeks (p > 0.05) CAT: Significant decrease post-intervention and washout (p < 0.05; p < 0.001), no difference in control (p > 0.05)	TBAR^p: Significant decrease post-intervention and washout (p < 0.05; p < 0.001), and in the control group post 2-weeks (p < 0.05)
Franke et al. (2005)	/	/	TG: Significant increase post-3 week intervention (p < 0.05) HDL: No difference post-3 week intervention (p > 0.05) LDL: No difference post-3 week intervention (p > 0.05) TC: No difference post intervention (p > 0.05) HDL: LDL Ratio: No difference post intervention (p > 0.05)	/	Homocysteine: Significant increase post-3 week intervention (p = 0.046) Vitamin C: Significant increase post intervention at 1 and 3-weeks (p < 0.001) Folate: Significant increase post intervention at 1 and 3-weeks (p = 0.018) Phenolic: Significant increase post-3 week intervention (p = 0.045)	TBAR: No difference post- 3 week intervention (p = 0.795)
Ghanim et al. (2007)	CRP: Between OJ^r intervention and control, significant decrease in intervention post-1 hour (p < 0.01)	/	/	OJ intervention and glucose intervention significantly increased compared to fructose intervention (p < 0.05)	/	ROS^s: No significant difference between OJ intervention, fructose intervention and control post-3 hours (p > 0.05)
Gonçalves et al. (2017)	CRP: Significant decrease post 8-week intervention (p < 0.05)	/	TG: No difference within control or intervention (p > 0.05) HDL: No difference within control or intervention (p > 0.05) LDL: Significant decrease post 8-week intervention (p < 0.05) TC: Significant decrease post-8 week intervention (p < 0.05)	No difference within control or intervention (p > 0.05)	Vitamin C: Significant increase post 8-week intervention (p < 0.05) Folate: Significant increase post 8-week intervention (p < 0.05)	TBAR: Significant decrease post 8-week intervention (p < 0.05)
Hollands et al. (2018)	CRP: No difference between control and intervention post- 28 days (p > 0.05) NO: No difference between control and intervention post- 28 days (p > 0.05)	/	TG: No difference between control and intervention post- 28 days (p > 0.05) HDL: No difference between control and intervention post- 28 days (p > 0.05) LDL: No difference between control and intervention post- 28 days (p > 0.05) TC: No difference between control and intervention post- 28 days (p > 0.05) BP^t: No difference between control and intervention post- 28 days (p > 0.05)	/	/	/
Li et al. (2020)	CRP: No difference within control or intervention (p > 0.05)	/	TG: No difference within control or intervention (p > 0.05) HDL: No difference within control or intervention (p > 0.05) LDL: Significant decrease post 2-week intervention (p = 0.005) TC: No difference within control or intervention (p > 0.05) BP: No difference within control or intervention (p > 0.05)	/	/	/
Kean et al. (2015)	/	Cognitive Function: Between groups, significant increase in intervention post- 8 weeks (p < 0.05) Subjective Mood: No difference between control and intervention post- 8 weeks (p > 0.05)	BP: No difference between control and intervention post- 8 weeks (p > 0.05)	/	/	/
Kurowska et al. (2000)	/	/	TG: Significant increase within interventions (p < 0.05) HDL: Significant increase during third intervention (p < 0.05), unchanged in first two interventions LDL: No difference within interventions (p > 0.05) Apo-AI: No difference within interventions (p > 0.05) TC: No difference within interventions (p > 0.05) Apo-B^t: No difference within interventions (p > 0.05) HDL-LDL Ratio: Significant decrease during third intervention (p < 0.01), unchanged in first two interventions	/	Homocysteine: No difference within interventions (p > 0.05) Vitamin C: Significant increase during all interventions post- 4 weeks (p < 0.001) Folate: Significant increase during third intervention (p < 0.01), unchanged in first two interventions	/
Morand et al. (2011)	CRP: No difference between control and intervention post-4 weeks (p = 0.209) IL-6: No difference between control and intervention post-4 weeks (p = 0.586) NO: No difference between control and intervention post-4 weeks (p = 0.080) sVCAM: No difference between control and intervention post-4 weeks (p = 0.089) Uric acid: Between groups, significant decrease in intervention post-4 weeks (p = 0.017)	/	TG: No difference between control and intervention post-4 weeks (p = 0.642) HDL: No difference between control and intervention post-4 weeks (p = 0.388) LDL: No difference between control and intervention post-4 weeks (p = 0.091) TC: No difference between control and intervention post-4 weeks (p = 0.100) BP: Between groups, significant decrease of diastolic BP in intervention post-4 weeks (p = 0.023)	No difference between control and intervention post- 4 weeks (p = 0.642)	Vitamin C: Between groups, significant increase in intervention post-4 weeks (p = 0.0001) FRAP: No difference between control and intervention post-4 weeks (p = 0.905)	/
Perche et al. (2014)	IL-4: No difference between control and intervention post-4 weeks (p > 0.05)	/	/	/	/	ROS: No difference between control and intervention post-4 weeks (p > 0.05)
Rangel-Huerta et al. (2015)	/	/	TG: No difference between NPJ^u and HPJ^v groups post-2 weeks (p > 0.05) HDL: No difference between NPJ and HPJ groups post-12 weeks (p > 0.05) LDL: No difference between NPJ and HPJ groups post-12 weeks (p > 0.05) Apo-AI: No difference between NPJ and HPJ groups post-12 weeks (p > 0.05) TC: No difference between NPJ and HPJ groups post-12 weeks (p > 0.05) Apo-B: No difference between NPJ and HPJ groups post-12 weeks (p > 0.05) BP: No difference between NPJ and HPJ groups post-12 weeks (p > 0.05)	Between groups, significant decrease in NPJ group post-12 weeks (p = 0.007)	CAT: No difference between NPJ and HPJ groups post-12 weeks (p > 0.05)	Peroxidation: Between groups, significant decrease in NPJ group post-12 weeks (p = 0.003)
Schar et al. (2015)	/	/	BP: No difference between control and intervention post-5 hours (p > 0.05)	/	Vitamin C: No difference between control and intervention post-5 hours (p > 0.05) Phenolic: Between groups, significant increase in intervention post-5 hours (p < 0.0001)	/
Simpson, Mendis, and Macdonald (2016)	CRP: No difference between control and intervention post-12 weeks (p = 0.118) IL-6: No difference between control and intervention post-12 weeks (p = 0.987) TNF-α: No difference between control and intervention post-12 weeks (p = 0.959) Uric acid: No difference between control and intervention post-12 weeks (p = 0.303)	/	TG: No difference between control and intervention post-12 weeks (p > 0.05) HDL: No difference between control and intervention post-12 weeks (p > 0.05) LDL: No difference between control and intervention post-12 weeks (p > 0.05) TC: No difference between control and intervention post-12 weeks (p > 0.05) Apo-AI: No difference between control and intervention post-12 weeks (p > 0.05) Apo-B: No difference between control and intervention post-12 weeks (p > 0.05)	No difference between control and intervention post-12 weeks (p > 0.05)	/	/
Snyder et al. (2011)	/	/	/	/	ORAC: No difference between control and intervention post-3 hours (p > 0.05) Phenolic: No difference between control and intervention post-3 hours (p > 0.05)	LO^w: No difference between control and intervention post-3 hours (p > 0.05)
Valls et al. (2021)	Uric acid: Between groups, significant decrease in EOJ^x intervention post-12 weeks (p < 0.05)	/	BP: No difference between control and intervention on diastolic BP post- 12 weeks (p > 0.05). Between OJ intervention and control, systolic BP significantly decreased in intervention post-12 weeks and between EOJ intervention and control, systolic BP significantly decreased in intervention post- 2, 6, 10 and 12 weeks (p < 0.05)	/	Homocysteine: Between groups, significant decrease in OJ and EOJ interventions post-12 weeks (p < 0.05)	/

Notes. (/) No results; a = C-reactive Protein; b = Interleukin 6; c = Tumor Necrosis Factor; d = Nitric Oxide; e = Plasma Protein Carbonyl; f = Soluble Vascular Cell Adhesion Molecule; g = High-density Lipoprotein; h = Low-density Lipoprotein; i = Apolipoprotein A1; j = Total Cholesterol; k = Oxygen Radical Absorbance Capacity; l = Ferric Reducing Antioxidant Power; m = Catalase; n = Interleukin 4; o = Triglyceride; p = Thiobarbituric Acid Reactive Substances; q = Apolipoprotein B, r = Orange Juice; s = Reactive Oxygen Species; t = Blood Pressure; u = Normal-Polyphenol-Concentration Orange Juice; v = High-Polyphenol-Concentration Orange Juice; w = Lipoprotein Oxidation; x = Hesperidin-Enriched Orange Juice

Alharbi, M. H., D. J. Lamport, G. F. Dodd, C. Saunders, L. Harkness, L. T. Butler, and J. P. E. Spencer. 2016. Flavonoid-rich orange juice is associated with acute improvements in cognitive function in healthy middle-aged males. European Journal of Nutrition 55 (6):2021–9. doi: 10.1007/s00394-015-1016-9.

 PubMed Web of Science ®Google Scholar

Buscemi, S., G. Rosafio, G. Arcoleo, A. Mattina, B. Canino, M. Montana, S. Verga, and G. Rini. 2012. Effects of red orange juice intake on endothelial function and inflammatory markers in adult subjects with increased cardiovascular risk. American Journal of Clinical Nutrition 95 (5):1089–95. doi: 10.3945/ajcn.111.031088.

 PubMed Web of Science ®Google Scholar

Constans, J., C. Bennetau-Pelissero, J. F. Martin, E. Rock, A. Mazur, A. Bedel, C. Morand, and A. M. Bérard. 2015. Marked antioxidant effect of orange juice intake and its phytomicronutrients in a preliminary randomized cross-over trial on mild hypercholesterolemic men. Clinical Nutrition 34 (6):1093–100. doi: 10.1016/j.clnu.2014.12.016.

 PubMed Web of Science ®Google Scholar

Pascual-Teresa, S. D., C. Sánchez-Moreno, F. Granado, B. Olmedilla, B. D. Ancos, and M. P. Cano. 2007. Short and mid-term bioavailability of flavanones from oranges in humans. Current Topics in Nutraceutical Research 5 (2-3):129–34.

 Web of Science ®Google Scholar

Dourado, G. K. Z. S., and T. B. Cesar. 2015. Investigation of cytokines, oxidative stress, metabolic, and inflammatory biomarkers after orange juice consumption by normal and overweight subjects. Food & Nutrition Research 59 (1):28147. doi: 10.3402/fnr.v59.28147.

 PubMed Web of Science ®Google Scholar

Escudero-López, B., Á. Ortega, I. Cerrillo, M.-R. Rodríguez-Griñolo, R. Muñoz-Hernández, H. C. Macher, F. Martín, D. Hornero-Méndez, P. Mena, D. Del Rio, et al. 2018. Consumption of orange fermented beverage improves antioxidant status and reduces peroxidation lipid and inflammatory markers in healthy humans. Journal of the Science of Food and Agriculture 98 (7):2777–86. doi: 10.1002/jsfa.8774.

 PubMed Web of Science ®Google Scholar

Franke, A. A., R. V. Cooney, S. M. Henning, and L. J. Custer. 2005. Bioavailability and antioxidant effects of orange juice components in humans. Journal of Agricultural and Food Chemistry 53 (13):5170–8. doi: 10.1021/jf050054y.

 PubMed Web of Science ®Google Scholar

Ghanim, H., P. Mohanty, R. Pathak, A. Chaudhuri, C. L. Sia, and P. Dandona. 2007. Orange juice or fructose intake does not induce oxidative and inflammatory response. Diabetes Care 30 (6):1406–11. doi: 10.2337/dc06-1458.

 PubMed Web of Science ®Google Scholar

Gonçalves, D., C. Lima, P. Ferreira, P. Costa, A. Costa, W. Figueiredo, and T. Cesar. 2017. Orange juice as dietary source of antioxidants for patients with hepatitis C under antiviral therapy. Food & Nutrition Research 61 (1):1296675. doi: 10.1080/16546628.2017.1296675.

 PubMed Web of Science ®Google Scholar

Hollands, W. J., C. N. Armah, J. F. Doleman, N. Perez-Moral, M. S. Winterbone, and P. A. Kroon. 2018. 4-Week consumption of anthocyanin-rich blood orange juice does not affect LDL-cholesterol or other biomarkers of CVD risk and glycaemia compared with standard orange juice: A randomised controlled trial. British Journal of Nutrition 119 (4):415–21. doi: 10.1017/S0007114517003865.

 PubMed Web of Science ®Google Scholar

Li, L., G. K. Lyall, J. A. Martinez-Blazquez, F. Vallejo, F. A. Tomas-Barberan, K. M. Birch, and C. Boesch. 2020. Blood orange juice consumption increases flow-mediated dilation in adults with overweight and obesity: A randomized controlled trial. The Journal of Nutrition 150 (9):2287–94. doi: 10.1093/jn/nxaa158.

 PubMed Web of Science ®Google Scholar

Kean, R. J., D. J. Lamport, G. F. Dodd, J. E. Freeman, C. M. Williams, J. A. Ellis, L. T. Butler, and J. P. E. Spencer. 2015. Chronic consumption of flavanone-rich orange juice is associated with cognitive benefits: An 8-wk, randomized, double-blind, placebo-controlled trial in healthy older adults. American Journal of Clinical Nutrition 101 (3):506–14. doi: 10.3945/ajcn.114.088518.

 PubMed Web of Science ®Google Scholar

Kurowska, E. M., J. D. Spence, J. Jordan, S. Wetmore, D. J. Freeman, L. A. Piche, and P. Serratore. 2000. HDL-Cholesterol-raising effect of orange juice in subjects with hypercholesterolemia. The American Journal of Clinical Nutrition 72 (5):1095–100. doi: 10.1093/ajcn/72.5.1095.

 PubMed Web of Science ®Google Scholar

Morand, C., C. Dubray, D. Milenkovic, D. Lioger, J. F. Martin, A. Scalbert, and A. Mazur. 2011. Hesperidin contributes to the vascular protective effects of orange juice: A randomized crossover study in healthy volunteers. American Journal of Clinical Nutrition 93 (1):73–80. doi: 10.3945/ajcn.110.004945.

 PubMed Web of Science ®Google Scholar

Perche, O., J. Vergnaud-Gauduchon, C. Morand, C. Dubray, A. Mazur, and M. P. Vasson. 2014. Orange juice and its major polyphenol hesperidin consumption do not induce immunomodulation in healthy well-nourished humans. Clinical Nutrition 33 (1):130–5. doi: 10.1016/j.clnu.2013.03.012.

 PubMed Web of Science ®Google Scholar

Rangel-Huerta, O. D., C. M. Aguilera, M. V. Martin, M. J. Soto, M. C. Rico, F. Vallejo, F. Tomas-Barberan, A. J. Perez-de-la-Cruz, A. Gil, and M. D. Mesa. 2015. Normal or high polyphenol concentration in orange juice affects antioxidant activity, blood pressure, and body weight in obese or overweight adults. The Journal of Nutrition 145 (8):1808–16. doi: 10.3945/jn.115.213660.

 PubMed Web of Science ®Google Scholar

Schar, M. Y., P. J. Curtis, S. Hazim, L. M. Ostertag, C. D. Kay, J. F. Potter, and A. Cassidy. 2015. Orange juice-derived flavanone and phenolic metabolites do not acutely affect cardiovascular risk biomarkers: A randomized, placebo-controlled, crossover trial in men at moderate risk of cardiovascular disease. American Journal of Clinical Nutrition 101 (5):931–8. doi: 10.3945/ajcn.114.104364.

 PubMed Web of Science ®Google Scholar

Simpson, E. J., B. Mendis, and I. A. Macdonald. 2016. Orange juice consumption and its effect on blood lipid profile and indices of the metabolic syndrome: A randomised, controlled trial in an at-risk population. Food and Function 7 (4):1884–91. doi: 10.1039/c6fo00039h.

 PubMed Web of Science ®Google Scholar

Snyder, S. M., J. D. Reber, B. L. Freeman, K. Orgad, D. L. Eggett, and T. L. Parker. 2011. Controlling for sugar and ascorbic acid, a mixture of flavonoids matching navel oranges significantly increases human postprandial serum antioxidant capacity. Nutrition Research 31 (7):519–26. doi: 10.1016/j.nutres.2011.06.006.

 PubMed Web of Science ®Google Scholar