Effects of Different Combinations of Phytochemical-Rich Fruits and Vegetables on Chronic Disease Risk Markers and Gene Expression Changes: Insights from the MiBLEND Study, a Randomized Trial
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design
2.2. Dietary Interventions
2.3. Participants
2.4. Test Days
2.5. DNA Damage Markers
2.5.1. DNA Strand Breaks
2.5.2. Oxidized Purines
2.6. Oxidative Stress in Blood and Plasma
2.6.1. Antioxidant Capacity
2.6.2. Superoxide Scavenging
2.7. Retinal Microvasculature
2.7.1. Vessel Calibre (CRAE, CRVE, and AVR)
2.7.2. Vessel Branching and Tortuosity
2.8. Phytochemicals in Plasma and Urine
2.8.1. Total Polyphenols
2.8.2. Carotenoids
2.8.3. Vitamin C
2.9. Gene Expression Analysis
2.9.1. RNA Isolation
2.9.2. Library Prep and Sequencing
2.9.3. DATA Pre-Processing
2.9.4. Differentially Expressed Genes (DEG) and Pathway Analysis
contr.matrix <- makeContrasts( D0vsD1 = subsetPostTestD1 − subsetBaselineD1, D0vsD2 = subsetPostTestD2 − subsetBaselineD2, D0vsD3 = subsetPostTestD3 − subsetBaselineD3, D0vsD4 = subsetPostTestD4 − subsetBaselineD4, D0vsD5 = subsetPostTestD5 − subsetBaselineD5, D0vsD6 = subsetPostTestD6 − subsetBaselineD6, D0vsD7 = subsetPostTestD7 − subsetBaselineD7, AllDIs = (subsetPostTestD1 + subsetPostTestD2 + subsetPostTestD3 + subsetPostTestD4 + subsetPostTestD5 + subsetPostTestD6 + subsetPostTestD7)/7 − (subsetBaselineD1 + subsetBaselineD2 + subsetBaselineD3 + subsetBaselineD4 + subsetBaselineD5 + subsetBaselineD6 + subsetBaselineD7)/7, levels = colnames(design)) |
2.9.5. Gene Set Enrichment Analysis (GSEA)
2.10. Sample Size Calculation and Randomization
2.11. Statistical Analysis
3. Results
3.1. Participants
3.2. DNA Damage Markers
3.2.1. DNA Strand Breaks
Baseline | Post-Test 1 | Post-Test 2 | Blend 1 | Blend 2 | Blend 3 | Blend 4 | Blend 5 | Blend 6 | Blend 7 | ||
---|---|---|---|---|---|---|---|---|---|---|---|
Participant Characteristics | N | 146 | 126 | 117 | 38 | 37 | 40 | 9 | 40 | 39 | 40 |
% Female | 73% | 74% | 72% | 68% | 79% | 60% | 40% | 78% | 75% | 88% | |
Age (yr) | 27 ± 10 | 27 ± 10 | 27 ± 9 | 27 ± 9 | 26 ± 9 | 27 ± 11 | 34 ± 13 | 27 ± 10 | 25 ± 7 | 28 ± 9 | |
BMI (kg/m2) | 22.7 ± 2.2 | 22.6 ± 2.2 | 22.7 ± 2.2 | 22.6 ± 2.2 | 22.1 ± 2.5 | 22.1 ± 2.0 | 23.3 ± 2.6 | 22.5 ± 2.1 | 22.9 ± 2.4 | 22.6 ± 2.2 | |
DNA Damage | % Tail DNA | 12.85 ± 1.15 | 9.49 ± 0.99 ** | 10.28 ± 1.11 * | 9.04 ± 1.67 * | 10.22 ± 1.72 | 8.86 ± 1.64 * | 10.24 ± 3.66 | 11.68 ± 1.64 | 9.57 ± 1.75 | 9.66 ± 1.73 |
Tail Moment | 0.37 ± 0.04 | 0.28 ± 0.04 | 0.28 ± 0.04 | 0.24 ± 0.07 | 0.26 ± 0.07 | 0.25 ± 0.06 | 0.29 ± 0.15 | 0.34 ± 0.06 | 0.34 ± 0.07 | 0.26 ± 0.07 | |
8-OH-dG (ng/mmol creatinine) | 36.59 ± 4.04 | 38.13 ± 3.59 | |||||||||
Oxidative Stress Markers | TEAC | 1154 ± 9 | 1186 ± 9 *** | 1190 ± 9 *** | 1187 ± 12 *** | 1198 ± 12 *** | 1191 ± 11 *** | 1209 ± 21 * | 1185 ± 12 ** | 1195 ± 12 *** | 1165 ± 12 |
Superoxide Height (AU) | 3380 ± 171 | 3636 ± 197 | 3285 ± 157 | 3454 ± 254 | 3170 ± 259 | 3277 ± 244 | 3279 ± 446 | 3666 ± 250 | 3154 ± 257 | 3476 ± 251 | |
Superoxide AUC (×105 AU) | 12.04 ± 0.63 | 13.31 ± 0.79 | 11.98 ± 0.65 | 12.93 ± 1.03 | 12.13 ± 1.05 | 11.59 ± 1.00 | 12.27 ± 1.82 | 13.23 ± 1.02 | 11.31 ± 1.05 | 12.87 ± 1.03 | |
Retinal Microvasculature | CRAE (µm) | 121.08 ± 3.62 | 123.88 ± 3.76 *** | 124.75 ± 3.79 *** | 123.08 ± 3.87 * | 123.78 ± 3.86 * | 123.39 ± 3.87 * | 125.96 ± 4.35 * | 124.69 ± 3.86 *** | 124.30 ± 3.86 ** | 123.77 ± 3.86 * |
CRVE (µm) | 177.36 ± 5.28 | 175.52 ± 5.16 * | 177.51 ± 5.14 | 174.45 ± 5.25 * | 175.81 ± 5.26 | 175.81 ± 5.24 | 177.99 ± 5.75 | 175.99 ± 5.26 | 177.77 ± 5.26 | 176.53 ± 5.27 | |
AVR | 0.67 ± 0.01 | 0.70 ± 0.01 *** | 0.70 ± 0.01 *** | 0.70 ± 0.01 *** | 0.69 ± 0.01 *** | 0.69 ± 0.01 *** | 0.70 ± 0.01 * | 0.70 ± 0.01 *** | 0.69 ± 0.01 *** | 0.70 ± 0.01 *** | |
Branching | 60.54 ± 1.47 | 59.54 ± 1.48 | 61.23 ± 1.50 | 61.77 ± 1.87 | 59.65 ± 1.90 | 59.69 ± 1.87 | 58.40 ± 3.12 | 60.12 ± 1.87 | 61.03 ± 1.88 | 59.60 ± 1.91 | |
Tortuosity | 0.897 ± 0.001 | 0.897 ± 0.001 | 0.897 ± 0.001 | 0.896 ± 0.002 | 0.897 ± 0.002 | 0.898 ± 0.002 | 0.897 ± 0.004 | 0.896 ± 0.002 | 0.897 ± 0.002 | 0.897 ± 0.002 | |
Phytochemicals in Plasma & Urine | Total polyphenols | 254 ± 2 | 253 ± 2 | 253 ± 2 | 253 ± 3 | 252 ± 3 | 253 ± 3 | 248 ± 6 | 255 ± 3 | 252 ± 3 | 253 ± 3 |
Lutein (nM) | 277.6 ± 12.6 | 311.8 ± 12.9 *** | 301.2 ± 13.3 * | 292.6 ± 17.7 | 317.7 ± 18.2 * | 322.6 ± 17.4 ** | 294.8 ± 31.6 | 293.6 ± 17.8 | 272.6 ± 17.9 | 341.4 ± 17.6 *** | |
Lycopene (nM) | 444.5 ± 20.1 | 471.1 ± 21.5 | 458.6 ± 19.9 | 433.7 ± 28.9 | 461.9 ± 29.7 | 475.5 ± 28.3 | 473.3 ± 52.08 | 452.1 ± 29.1 | 480.7 ± 29.1 | 472.0 ± 28.7 | |
Alpha-carotene (nM) | 128.4 ± 11.8 | 150.2 ± 11.1 * | 151.9 ± 9.3 * | 105.1 ± 12.3 | 106.3 ± 12.5 | 212.3 ± 12.0 *** | 128.3 ± 20.6 | 112.7 ± 12.4 | 179.7 ± 12.4 *** | 176.3 ± 12.2 *** | |
Beta-carotene (nM) | 636.8 ± 44.5 | 737.9 ± 45.9 *** | 759.4 ± 42.3 *** | 572.0 ± 52.8 | 568.2 ± 53.8 | 955.4 ± 51.9 *** | 598.4 ± 84.6 | 621.9 ± 53.2 | 853.6 ± 53.1 *** | 911.8 ± 52.6 *** | |
Vitamin C (mg/mmol creatinine) | 0.66 ± 0.05 | 0.73 ± 0.04 | 0.74 ± 0.06 | 0.63 ± 0.07 | 0.69 ± 0.07 | 0.85 ± 0.07 * | 0.89 ± 0.15 | 0.70 ± 0.07 | 0.81 ± 0.07 * | 0.61 ± 0.07 | |
Gene expression | Significant DEGs | all post-tests vs. baseline = 846 | 1 | 2 | 2 | 18 | 0 | 9 | 4 | ||
Significant pathways after GSEA | all post-tests vs. baseline = 281 | 281 | 76 | 244 | 199 | 291 | 301 | 5 |
Study Phase | Average Blend | ||||
---|---|---|---|---|---|
Nutrient Type | Baseline/Run-In Phase | Intervention Phase 1 | Washout Phase | Intervention Phase 2 | |
Calories (kcal) | 1708.9 ± 40 | 1817 ± 42 *** | 1693 ± 41 | 1829 ± 43 *** | 182 |
Carbohydrates (g) | 206 ± 7 | 244 ± 8 *** | 202 ± 7 | 239 ± 8 *** | 44 |
Proteins (g) | 78 ± 2 | 76 ± 3 | 76 ± 2 | 80 ± 2 | 3 |
Fats (g) | 66 ± 2 | 65 ± 2 | 65 ± 2 | 65 ± 3 | 1 |
Cholesterol (mg) | 145 ± 13 | 134 ± 14 | 144 ± 13 | 152 ± 14 | 0 |
Sodium (mg) | 865 ± 73 | 861 ± 76 | 815 ± 75 | 931 ± 77 | 41 |
Sugars (g) | 42 ± 2 | 66 ± 2 *** | 41 ± 2 | 62 ± 2 *** | 28 |
Fibers (g) | 13 ± 1 | 24 ± 1 *** | 13 ± 1 | 23 ± 1 *** | 11 |
3.2.2. Oxidized Purines
3.3. Oxidative Stress in Blood and Plasma
3.3.1. Antioxidant Capacity
3.3.2. Superoxide Scavenging
3.4. Retinal Microvasculature
3.4.1. Vessel Calibre (CRAE, CRVE, and AVR)
3.4.2. Vessel Branching and Tortuosity
3.5. Phytochemicals in Plasma and Urine
3.5.1. Total Polyphenols
3.5.2. Carotenoids
3.5.3. Vitamin C
3.6. Gene-Expression Analysis
3.6.1. RNA Isolations
3.6.2. Data Pre-Processing
3.6.3. DEG Analysis
3.6.4. GSEA
4. Discussion
4.1. Protection from Oxidative Stress and Damage
4.2. Changes in Retinal Microvasculature
4.3. Absorption and Excretion of Phytochemicals
4.4. Gene-Expression Changes and Pathway Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Blend | Composition | Over-Represented Phytochemicals | Fruits and Vegetables | Calories (kcal) | Carbohydrate (g) | Fat (g) | Protein (g) | Sodium (mg) | Sugars (g) | Fiber (g) |
---|---|---|---|---|---|---|---|---|---|---|
1 | 1 | Flavonoids (e.g., quercetin, catechins) | Apples (400 g), green tea (2 g in 100 mL water a) | 207 | 55 | 1 | 1 | 4 | 41 | 10 |
2 | 2 | Anthocyanins (subclass of flavonoids) | Blueberries (100 g), blue grapes (100 g), blackberries (100 g), raspberries (100 g) | 222 | 54 | 1 | 3 | 3 | 34 | 14 |
3 | 3 | Carotenoids | Tomato (133 g), carrots (133 g), red bell pepper (133 g) | 112 | 26 | 1 | 4 | 103 | 15 | 8 |
4 | 4 | Diallyl sulfide Glucosinulates | Broccoli (133 g), cauliflower (133 g), Brussels sprouts (133 g) | 136 | 27 | 1 | 11 | 117 | 8 | 11 |
5 | 1 + 2 | Flavonoids Anthocyanins | Apples (200 g), green tea (1 g in 50 mL water), blueberries (50 g),blue grapes (50 g), blackberries (50 g), raspberries (50 g) | 218 | 54 | 1 | 3 | 3 | 36 | 13 |
6 | 1 + 2 + 3 | Flavonoids Anthocyanins Carotenoids | Apples (133 g), green tea (0.66 g in 33 mL water), blueberries (33 g), blue grape (33 g), blackberries (33 g), raspberries (33 g), tomato (44 g), carrots (44 g), red bell pepper (44 g) | 178 | 44 | 1 | 3 | 41 | 28 | 11 |
7 | 1 + 2 + 3 + 4 (most complex mixture) | Flavonoids Anthocyanins Carotenoids Diallyl sulfide Glucosinulates | Apples (100 g), green tea (0.5 g in 25 mL water), blueberries (25 g), blue grape (25 g), blackberries (25 g), raspberries (25 g), tomato (33 g), carrots (33 g), red bell pepper (33 g), broccoli (33 g), cauliflower (33 g), Brussels sprouts (33 g) | 176 | 39 | 1 | 5 | 62 | 23 | 11 |
Blend 1 | Blend 2 | Blend 3 | Blend 4 | Blend 5 | Blend 6 | Blend 7 | All Blends | |
---|---|---|---|---|---|---|---|---|
Down-regulated | 0 | 1 | 1 | 18 | 0 | 9 | 3 | 519 |
Not Significant | 10,576 | 10,575 | 10,575 | 10,559 | 10,577 | 10,568 | 10,573 | 9731 |
Up-regulated | 1 | 1 | 1 | 0 | 0 | 0 | 1 | 327 |
Pathway Category | Pathway Name | q Value | # of Entities | Total in Pathway |
---|---|---|---|---|
Cell Cycle | Deposition of new CENPA-containing nucleosomes at the centromere | 4.65 × 10−2 | 10 | 53 |
Nucleosome assembly | 4.65 × 10−2 | 10 | 53 | |
Chromatin Organization | HDACs deacetylate histones | 3.17 × 10−6 | 19 | 63 |
DNA Repair | Recognition and association of DNA glycosylase with site containing an affected purine | 1.94 × 10−2 | 10 | 38 |
Cleavage of the damaged purine | 2.20 × 10−2 | 10 | 44 | |
Depurination | 2.69 × 10−2 | 10 | 45 | |
Gene Expression (Transcription) | RNA Polymerase I Promoter Opening | 1.78 × 10−2 | 10 | 33 |
PRC2 methylates histones and DNA | 2.20 × 10−2 | 10 | 43 | |
RNA Polymerase I Promoter Escape | 3.18 × 10−2 | 12 | 60 | |
Signal Transduction | RHO GTPase cycle | 2.21 × 10−2 | 44 | 460 |
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DeBenedictis, J.N.; Murrell, C.; Hauser, D.; van Herwijnen, M.; Elen, B.; de Kok, T.M.; van Breda, S.G. Effects of Different Combinations of Phytochemical-Rich Fruits and Vegetables on Chronic Disease Risk Markers and Gene Expression Changes: Insights from the MiBLEND Study, a Randomized Trial. Antioxidants 2024, 13, 915. https://doi.org/10.3390/antiox13080915
DeBenedictis JN, Murrell C, Hauser D, van Herwijnen M, Elen B, de Kok TM, van Breda SG. Effects of Different Combinations of Phytochemical-Rich Fruits and Vegetables on Chronic Disease Risk Markers and Gene Expression Changes: Insights from the MiBLEND Study, a Randomized Trial. Antioxidants. 2024; 13(8):915. https://doi.org/10.3390/antiox13080915
Chicago/Turabian StyleDeBenedictis, Julia N., Courtney Murrell, Duncan Hauser, Marcel van Herwijnen, Bart Elen, Theo M. de Kok, and Simone G. van Breda. 2024. "Effects of Different Combinations of Phytochemical-Rich Fruits and Vegetables on Chronic Disease Risk Markers and Gene Expression Changes: Insights from the MiBLEND Study, a Randomized Trial" Antioxidants 13, no. 8: 915. https://doi.org/10.3390/antiox13080915