Oral Glucoraphanin and Curcumin Supplements Modulate Key Cytoprotective Enzymes in the Skin of Healthy Human Subjects: A Randomized Trial
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design
2.2. Patient Population
2.3. Randomization
2.4. Dose Procurement and Validation
2.5. UV Treatment
2.6. Clinical Assessment
2.6.1. Specimen Collection
- Blood and Urine. Following the 7th dose of either GR, CUR, or both, the subjects collected and supplied their entire production of urine excreted during the preceding 24 h for evaluation of SF metabolites. They were instructed to collect for the first 8 h, and the subsequent 16 h, in separate containers. Blood was drawn from the participants on day 7 of both the non-intervention and intervention phases and processed for peripheral blood mononuclear cells (PBMC) isolation [12]. Briefly, 8 mL of whole blood was drawn from the participants into Vacutainer CPT tubes (Becton, Dickinson and Company, Franklin Lakes, NJ, USA) at room temperature, centrifuged, and PBMCs were washed twice with phosphate-buffered saline. PBMC pellets were stored at −80 °C for RNA extraction.
- Biopsies. Two 6-mm skin punch biopsies were taken approximately 24 h after UV irradiation (one from a UV-irradiated area, and the other one from a vicinal non-irradiated area), on day 8 of both phases. Individual biopsies were immediately placed in cryotubes, snap-frozen in liquid nitrogen, and stored at −80 °C. Immediately prior to RNA extraction, each frozen biopsy was cut into halves. One half was reserved for dithiocarbamates (DTC) measurement, and the other for RNA extraction. Additional biopsies were taken after 3 days of UV irradiation (Day 10 of each phase) and embedded for H&E staining and subsequent measurement of dyskeratotic keratinocytes.
2.6.2. Laboratory Studies
- Total RNA Extraction and Quantitative Real-Time PCR. Frozen skin biopsies were pulverized in liquid nitrogen and homogenized in 0.6 mL of Buffer RLT (from RNeasy mini kit, QIAGEN, Valencia, CA, USA), and then were transferred to QIAshredder (QIAGEN, Valencia, CA, USA). After centrifugation at 14,000 rpm for 2 min, the homogenized lysates were used for RNA extraction using an RNeasy mini kit. Total cellular RNA was also extracted from frozen PBMC using QIAshredder and RNeasy mini kit [12]. Synthesis of cDNA and quantitative real-time PCR was performed as described [12]. Primer sequences for gene amplification are provided in Supplementary Table S1.
- Biomarkers. To evaluate the effect of GR and CUR on cytoprotective mechanisms, we measured mRNA levels of markers of the Keap1/Nrf2-linked cytoprotective phase 2 response, the inflammatory response, and matrix metalloproteinase activity, following 7 days of oral supplement intake. Measurements were made both in blood and in skin samples harvested from the same subjects. All comparisons were made to baseline samples taken from the same individuals just prior to ingestion of the first supplement doses. Gene targets and their functions are provided in Supplementary Table S2.
- Preparation of Biopsies for DTC Measurement. Frozen biopsies were pulverized into powder under liquid N2. The powder was weighed and about 30 mg was resuspended in ice-cold buffer (100 mM potassium phosphate, pH 7.4; 100 mM KCl; 0.1 mM EDTA), homogenized in an ice bath, and subjected to centrifugation at 4 °C (15,000× g for 10 min) [23].
- Cyclocondensation. This assay measures DTC, which is the sum of SF and its conjugation products, and it has a limit of detection of 5 pmol. Cyclocondensation was performed on both urine and pulverized biopsied skin according to published methods [36] and was used to confirm compliance and assess bioavailability with treatment assignments.
- Urine: Total DTC excretion in each urine sample (three per subject) and urine creatinine concentrations were determined, as an indicator of compliance.
- Blood: Measurement (HPLC) of CUR and its major conjugates, curcumin glucuronide, and curcumin sulfate, in plasma samples, was attempted, but as expected did not yield useful data.
- Skin: An a priori decision was made not to process biopsies from the “curcumin, only” treatment arm. However, due to a −80 °C freezer loss associated with lab closure, we were able only to process 6 of the 12 samples in the treatment arms that had received GR (the GR and GR + CUR arms), as 6 of the tissue samples remaining after biopsies had been split for RNA extraction were lost.
- Measurement of Dyskeratotic Keratinocytes. Embedded 6 mm biopsies taken on Day 10 were sectioned and standard hematoxylin and eosin (H&E) were performed. Epidermal thickness (taken from the top of granular layer to the basal layer) was measured using an Olympus BX41 microscope and a number of dyskeratotic keratinocytes (DK) was scored per epidermal area (EPI) to create an index DK/EPI.
2.7. Data Analysis and Statistics
2.7.1. Clinical Assessment
2.7.2. Biomarker Evaluation
3. Results
3.1. Study Subjects and Compliance
3.2. Outcomes
3.2.1. UV-Induced Erythema
3.2.2. Biomarker Modulation
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AGE | advanced glycation endproduct(s) |
AhR | aryl hydrocarbon receptor |
AP1 | activation protein-1 |
COX | cyclooxygenase |
CUR | curcumin |
DK | dyskeratotic keratinocytes |
DTC | dithiocarbamate(s) |
EPI | epidermal area |
GR | glucoraphanin |
IL | interleukin |
Keap1 | Kelch-like ECH-associated protein 1 |
LTB4 | leukotriene B4 |
LTC4 | leukotriene C4 |
M.E.D. | minimum erythematous dose |
MMP | matrix metalloproteinase(s) |
NF-кB | nuclear factor kappa B |
Nrf2 | nuclear factor-erythroid 2 p45-related factor 2 |
PBMC | peripheral blood mononuclear cells |
PGE2 | prostaglandin E synthase 2 |
SF | sulforaphane |
TNFα | tumor necrosis factor alpha |
UV | ultraviolet |
VEGF | vascular endothelial growth factor |
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GR (N = 6) | CUR (N = 6) | GR + CUR (N = 6) | |
---|---|---|---|
Age, years AVG (SD) | 47 (17.1) | 33.2 (13.6) | 36.5 (18.7) |
Sex, females, N (%) | 1 (16.7) | 4 (66.7) | 4 (66.7) |
Attrition, N (%) | 0 | 0 | 0 |
Adverse events, N (%) | 1 (16.7) * | 0 | 0 |
Gene or Functional Grouping | N | Mean | StdErr | t | Pr (T < t) | Pr (T > t) |
---|---|---|---|---|---|---|
| ||||||
NQO1 | 18 | 3.361 | 0.360 | 6.404 | 1.000 | 0.000 |
xCT | 18 | 1.086 | 0.168 | 0.512 | 0.692 | 0.308 |
HO-1 | 18 | 0.784 | 0.102 | −2.123 | 0.024 | 0.976 |
IL-6 | 18 | 1.309 | 0.273 | 1.132 | 0.863 | 0.137 |
IL-1β | 18 | 0.728 | 0.127 | −2.138 | 0.024 | 0.976 |
TNF-α | 18 | 0.777 | 0.091 | −2.445 | 0.013 | 0.987 |
IL-17 | 18 | 0.759 | 0.139 | −1.737 | 0.050 | 0.950 |
STING | 18 | 0.943 | 0.112 | −0.509 | 0.309 | 0.691 |
CYR61 | 18 | 0.831 | 0.120 | −1.416 | 0.087 | 0.913 |
MMP2 | 18 | 0.964 | 0.253 | −0.143 | 0.444 | 0.556 |
MMP9 | 18 | 1.182 | 0.144 | 1.266 | 0.889 | 0.111 |
MMP3 | 18 | 0.960 | 0.190 | −0.211 | 0.418 | 0.582 |
Cytoprotective/antioxidant | 54 | 1.725 | 0.205 | 3.545 | 1.000 | 0.000 |
Inflammatory | 108 | 0.891 | 0.065 | −1.680 | 0.048 | 0.952 |
Matrix metalloprotein | 54 | 1.035 | 0.114 | 0.307 | 0.620 | 0.380 |
| ||||||
NQO1 | 15 | 1.447 | 0.192 | 2.330 | 0.982 | 0.018 |
xCT | 15 | 0.779 | 0.096 | −2.269 | 0.020 | 0.980 |
HO-1 | 15 | 0.875 | 0.100 | −1.249 | 0.116 | 0.884 |
IL-6 | 15 | 22.765 | 5.068 | 4.294 | 1.000 | 0.000 |
IL-1β | 15 | 2.262 | 0.401 | 3.146 | 0.997 | 0.004 |
TNF-α | 15 | 0.768 | 0.130 | −1.782 | 0.048 | 0.952 |
IL-17 | 15 | 0.573 | 0.075 | −5.688 | 0.000 | 1.000 |
STING | 15 | 0.953 | 0.088 | −0.531 | 0.302 | 0.698 |
CYR61 | 15 | 1.763 | 0.211 | 3.626 | 0.999 | 0.001 |
MMP2 | 15 | 0.545 | 0.100 | −4.557 | 0.000 | 1.000 |
MMP9 | 15 | 1.114 | 0.226 | 0.505 | 0.689 | 0.311 |
MMP3 | 15 | 8.871 | 2.655 | 2.964 | 0.995 | 0.005 |
Cytoprotective/antioxidant | 54 | 4.279 | 1.478 | 2.552 | 0.993 | 0.007 |
Inflammatory | 108 | 2.307 | 0.685 | 1.908 | 0.970 | 0.030 |
Matrix metalloprotein | 18 | 7.565 | 2.311 | 2.841 | 0.995 | 0.006 |
| ||||||
NQO1 | 18 | 1.678 | 0.220 | 3.085 | 0.997 | 0.003 |
xCT | 18 | 1.344 | 0.198 | 1.741 | 0.950 | 0.050 |
HO-1 | 18 | 1.122 | 0.134 | 0.905 | 0.811 | 0.189 |
IL-6 | 18 | 1.915 | 0.459 | 1.994 | 0.969 | 0.031 |
IL-1β | 18 | 1.370 | 0.278 | 1.331 | 0.900 | 0.101 |
TNF-α | 18 | 0.964 | 0.176 | −0.202 | 0.421 | 0.579 |
IL-17 | 18 | 1.149 | 0.190 | 0.787 | 0.779 | 0.221 |
STING | 18 | 1.022 | 0.114 | 0.195 | 0.576 | 0.4244 |
CYR61 | 18 | 1.077 | 0.153 | 0.504 | 0.690 | 0.310 |
MMP2 | 18 | 1.229 | 0.226 | 1.015 | 0.838 | 0.162 |
MMP9 | 18 | 1.409 | 0.193 | 2.121 | 0.976 | 0.025 |
MMP3 | 18 | 1.084 | 0.018 | 0.480 | 0.682 | 0.319 |
Cytoprotective/antioxidant | 54 | 1.382 | 0.111 | 3.443 | 0.999 | 0.001 |
Inflammatory | 108 | 1.250 | 0.107 | 2.344 | 0.990 | 0.010 |
Matrix metalloprotein | 54 | 1.241 | 0.114 | 2.107 | 0.980 | 0.020 |
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Chien, A.L.; Liu, H.; Rachidi, S.; Feig, J.L.; Wang, R.; Wade, K.L.; Stephenson, K.K.; Kecici, A.S.; Fahey, J.W.; Kang, S. Oral Glucoraphanin and Curcumin Supplements Modulate Key Cytoprotective Enzymes in the Skin of Healthy Human Subjects: A Randomized Trial. Metabolites 2025, 15, 360. https://doi.org/10.3390/metabo15060360
Chien AL, Liu H, Rachidi S, Feig JL, Wang R, Wade KL, Stephenson KK, Kecici AS, Fahey JW, Kang S. Oral Glucoraphanin and Curcumin Supplements Modulate Key Cytoprotective Enzymes in the Skin of Healthy Human Subjects: A Randomized Trial. Metabolites. 2025; 15(6):360. https://doi.org/10.3390/metabo15060360
Chicago/Turabian StyleChien, Anna L., Hua Liu, Saleh Rachidi, Jessica L. Feig, Ruizhi Wang, Kristina L. Wade, Katherine K. Stephenson, Aysegul Sevim Kecici, Jed W. Fahey, and Sewon Kang. 2025. "Oral Glucoraphanin and Curcumin Supplements Modulate Key Cytoprotective Enzymes in the Skin of Healthy Human Subjects: A Randomized Trial" Metabolites 15, no. 6: 360. https://doi.org/10.3390/metabo15060360
APA StyleChien, A. L., Liu, H., Rachidi, S., Feig, J. L., Wang, R., Wade, K. L., Stephenson, K. K., Kecici, A. S., Fahey, J. W., & Kang, S. (2025). Oral Glucoraphanin and Curcumin Supplements Modulate Key Cytoprotective Enzymes in the Skin of Healthy Human Subjects: A Randomized Trial. Metabolites, 15(6), 360. https://doi.org/10.3390/metabo15060360