Clinical Research on Antioxidant-Based Modalities in 2020
Authors: ROS Editorial Office 
Published: February 2021

This Education & Resources web page lists major clinical studies on antioxidant-based modalities or related entities in disease intervention and health promotion, which were published in highly influential journals during 2020. It should be noted that this is not intended to be a complete list, but is rather to focus on rigorously designed and well conducted high-profile randomized controlled trials (RCTs) whose findings were reported in medical or bioscience journals of the highest impact. For more comprehensive information on antioxidant-based clinical trials, the reader may refer to the ClinicalTrials.gov (https://clinicaltrials.gov), the largest clinical trials database, run by the US National Library of Medicine, that holds registrations from over 368,000 trials from 219 countries.
2020 LIST IN REVERSE CHRONOLOGICAL ORDER
Feofanova et al. A Genome-wide association study discovers 46 loci of the human metabolome in the Hispanic Community Health Study/Study of Latinos. Am J Hum Genet 2020 Nov 5; 107(5):849-863. doi: https://dx.doi.org/10.1016/j.ajhg.2020.09.003.
Key finding: High levels of vitamin E metabolites were associated with lower odds of coronary heart disease.
Note: Vitamin E and derivatives are antioxidants, but also possess other biological activities, such as inhibition of protein kinase C-mediated signaling.
Horsfall et al. Genetically raised serum bilirubin levels and lung cancer: a cohort study and Mendelian randomisation using UK Biobank. Thorax 2020 Nov; 75(11):955-964. doi: https://dx.doi.org/10.1136/thoraxjnl-2020-214756.
Key finding: High serum bilirubin was associated with decreased lung cancer incidence.
Note: Bilirubin is a potent antioxidant. According to Dr Davey Smith,  Mendelian randomization is a method of using measured variation in genes of known function to examine the causal effect of a modifiable exposure on disease in observational studies (from the US CDC website: https://cdc.gov). A positive finding in a Mendelian randomization study provides strong evidence for a causal relationship.
Morris et al. Impact of arginine therapy on mitochondrial function in children with sickle cell disease during vaso-occlusive pain. Blood 2020 Sep 17;136(12):1402-1406. doi: https://dx.doi.org/10.1182/blood.2019003672.
Key finding: Arginine therapy increased mitochondrial activity and reduced oxidative stress in children with sickle cell disease with vaso-occlusive pain episodes.
Note: Arginine is the substrate for nitric oxide synthetase and possesses antioxidative activities. Nitric oxide acts also as an antioxidant in biological systems.
Yubero-Serrano et al. Mediterranean diet and endothelial function in patients with coronary heart disease: an analysis of the CORDIOPREV randomized controlled trial. PLoS Med 2020 Sep 9; 17(9):e1003282. doi: https://dx.doi.org/10.1371/journal.pmed.1003282.
Key finding: Mediterranean diet intake led to improved endothelial function and lower ROS production.
Note: Mediterranean diet is rich in antioxidants and anti-inflammatory compounds and possesses many health benefits, especially cardiovascular protection. However, the exact contribution of the antioxidant components to the health benefits of Mediterranean diet remains to be established.
Cienfuegos et al. Effects of 4- and 6-h time-restricted feeding on weight and cardiometabolic health: a randomized controlled trial in adults with obesity. Cell Metab 2020 Sep 1; 32(3):366-378.e3. doi: https://dx.doi.org/10.1016/j.cmet.2020.06.018.
Key finding: Time-restricted feeding reduced body weight, insulin resistance, and oxidative stress.
Nathan et al. A randomized, double-blind, placebo-controlled study of pulsed, inhaled nitric oxide in subjects at risk of pulmonary hypertension associated with pulmonary fibrosis. Chest 2020 Aug; 158(2):637-645. doi: https://dx.doi.org/10.1016/j.chest.2020.02.016.
Key finding: Inhaled nitric oxide led to clinical improvement in the patients with pulmonary fibrosis.
Note: Nitric oxide at physiological levels acts an antioxidative and cytoprotective molecule.
McEvoy et al. Vitamin C to pregnant smokers persistently improves infant airway function to 12 months of age: a randomised trial. Eur Respir J 2020 Jul 2; 1902208. doi: https://dx.doi.org/10.1183/13993003.02208-2019.
Key finding: Vitamin C supplementation (0.5 g per day) to pregnant smokers improved infant airway function.
Note: Vitamin C is a multitasking compound; it is an antioxidant, but also possesses many other biological functions.
Chang et al. Combined treatment with hydrocortisone, vitamin c, and thiamine for sepsis and septic shock: a randomized controlled trial. Chest 2020 Jul; 158(1):174-182. doi: https://dx.doi.org/10.1016/j.chest.2020.02.065.
Key finding: Null
Note: Vitamin C is a multitasking compound; it is an antioxidant, but also possesses many other biological functions.
Iglesias et al. Outcomes of metabolic resuscitation using ascorbic acid, thiamine, and glucocorticoids in the early treatment of sepsis: the ORANGES trial. Chest 2020 Jul; 158(1):164-173. doi: https://dx.doi.org/10.1016/j.chest.2020.02.049.
Key finding: Combination of intravenous ascorbic acid, thiamine, and hydrocortisone significantly reduced the time to resolution of septic shock.
Note: Vitamin C is a multitasking compound; it is an antioxidant, but also possesses many other biological functions.
Streese et al. High-intensity interval training modulates retinal microvascular phenotype and DNA methylation of p66Shc gene: a randomized controlled trial (EXAMIN AGE). Eur Heart J 2020 Apr 14; 41(15):1514-1519. doi: https://dx.doi.org/10.1093/eurheartj/ehz196.
Key finding: High-intensity interval training improved microvascular dysfunction in patients at risk, likely related to reduced p66Shc, a redox enzyme implicated in mitochondrial ROS production.
Ambrosone et al. Dietary supplement use during chemotherapy and survival outcomes of patients with breast cancer enrolled in a cooperative group clinical trial (SWOG S0221). J Clin Oncol 2020 Mar 10; 38(8):804-814. doi: https://dx.doi.org/10.1200/JCO.19.01203.
Key finding: Antioxidant supplement (vitamins A, C, and E; carotenoids; coenzyme Q10) both before and during breast cancer chemotherapy was associated with an adverse outcome.
Note: Antioxidants have been shown to promote tumorigenesis and cancer metastasis in various experimental models in studies published in the most influential journals, including Nature and Cell.
Vallerga et al. Analysis of DNA methylation associates the cystine-glutamate antiporter SLC7A11 with risk of Parkinson's disease. Nat Commun 2020 Mar 6;11(1):1238. doi: https://dx.doi.org/10.1038/s41467-020-15065-7.
Key finding: Down-regulation of the SLC7A11 gene was associated with Parkinson’s disease.
Note: SLC7A11 codes for a cysteine-glutamate antiporter that regulates regulating cellular levels of the reduced form of glutathione (GSH).
Choi et al. Causal associations between serum bilirubin levels and decreased stroke risk: a two-sample Mendelian randomization study. Arterioscler Thromb Vasc Biol 2020 Feb; 40(2):437-445. doi: https://dx.doi.org/10.1161/ATVBAHA.119.313055.
Key finding: The study supported a causal relationship between high serum levels of bilirubin and decreased stroke risk in Korean population.
Note: Bilirubin is a potent antioxidant. Mendelian randomization study provides evidence for a causal relationship.