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Editorial

The Interplay between Antioxidants and the Immune System: A Promising Field, Still Looking for Answers

1
Department of Translational and Precision Medicine—Sapienza University of Rome, 00161 Rome, Italy
2
Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
*
Author to whom correspondence should be addressed.
Nutrients 2020, 12(6), 1550; https://doi.org/10.3390/nu12061550
Submission received: 12 May 2020 / Accepted: 20 May 2020 / Published: 26 May 2020
Modulation of the immune response has long been proposed as a therapeutic target in several widespread diseases, including cancer, autoimmune disorders, cardiovascular diseases, and also during the dysregulated response phase towards a systemic infection [1,2]. Potential benefits of immunomodulation depend on the interplay between immune cells and the disease progression, as observed in atherosclerosis [3,4], heart failure [5] and different types of neoplasms, although with different levels of evidence. Immunosuppression is also an established cornerstone for the treatment of autoimmune disorders, including systemic lupus erythematosus, rheumatoid arthritis, and other connective tissue diseases. However, most of the drugs targeting the immune system carry several side effects, one of the most important being the increased risk of infection, a logical consequence of the reduced activity of the immune system.
In the unstoppable search for the “silver bullet”, which aims to maximize the efficacy and minimize side effects, Malaguarnera provides a thorough review of the effects of Resveratrol [6], focusing on the mechanisms behind the complex interplay between these molecules and the immune cells. The antioxidant effects of Resveratrol have been known for decades [7], and its use has been investigated in different clinical contexts. Resveratrol is found in red wine and has been speculated to be the primary factor responsible for the so-called "French Paradox", although with no conclusive evidence. [8] As elegantly summarized by Malaguarnera, Resveratrol may express its action through a complex interplay with Sirtuins [6]; however, the clinical application has been limited by its low oral bioavailability, which reduces its effectiveness [9]. A potential role as an immunomodulating agent has been theorized in recent decades, although, to date, extensive and definitive data on its clinical efficacy have been lacking.
Research on the complex interplay between oxidative stress, the immune system, and agents targeting both pathways is gathering growing interest among the scientific community. Several other agents have been studied, such as steroids, Vitamin C, and Vitamin D, especially in the field of cardiovascular and infectious diseases [10,11,12,13]. The intensive care setting has been one of the most investigated scenarios in the search for immunomodulating agents, with Vitamin C failing to show a significant effect on improving outcomes in sepsis [12,13]. Steroids are the most common immunosuppressive agents used to improve symptoms in auto-immune disorders, in which the immune response is increased by the production of inflammatory cytokines and auto-antibodies. The immunomodulatory effect of steroids has been postulated, and their use in the setting of intensive care has been widely studied, with conflicting results [14,15]. Currently, steroids find application in refractory septic shock therapy [16].
Resveratrol may represent, in this context, an alternative approach. Several experiments in animal models have shown potential efficacy in the prevention and treatment of different diseases [17,18]. Interest in this molecule has increased due to its natural presence in many different foods, including peanuts, red grapes, and red wine [19,20]. However, its relatively low oral bioavailability, along with pharmacokinetics issues and the quality of the commercially-available supplements, have somewhat limited the application in clinical practice [9,21]. Translation of the results obtained in animal models has also been slowed by the heterogeneity in dosage protocols among human studies, and the optimal dose for clinical application is far from being clarified [22].
These issues are shared by many other nutraceuticals and antioxidants [23,24,25]. To date, the lack of standardized formulation and dose regimens, as well as low numbers of high-quality studies in humans, limit the evidence available on the clinical use of these substances, the commercialization of which is often not under the control of international regulatory agencies.
Between the promising findings of pre-clinical studies and the problems arising in clinical practice, only well-designed and rigorous clinical studies can provide definitive answers on the efficacy and safety of these compounds. While in vitro evidence suggests potential room in many clinical settings, including immune function [26], it is conceivable that the identification of more specific clinical scenarios will help in determining the true extent of the expected benefit of these drugs, including Resveratrol. The immune response represents a fascinating but complex target; to date, ongoing trials on Resveratrol are mainly focused on cardiovascular and metabolic diseases [27,28,29]. Neoplasia represents another setting in which Resveratrol was tested, with different results according to cancer types [30]. Looking at the interplay with the immune system may provide a new perspective to evaluate different clinical responses to antioxidants, but only thorough and well-conducted mechanistic studies will elucidate whether the supposed effects of these compounds—including Resveratrol—may translate into clinical results.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Khalil, D.N.; Smith, E.L.; Brentjens, R.J.; Wolchok, J.D. The future of cancer treatment: Immunomodulation, CARs and combination immunotherapy. Nat. Rev. Clin. Oncol. 2016, 13, 273–290. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Link, A.; Ayadhi, T.; Bohm, M.; Nickenig, G. Rapid immunomodulation by rosuvastatin in patients with acute coronary syndrome. Eur. Hear. J. 2006, 27, 2945–2955. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Ridker, P.M.; Everett, B.M.; Thuren, T.; MacFadyen, J.G.; Chang, W.H.; Ballantyne, C.; Fonseca, F.; Nicolau, J.; Koenig, W.; Anker, S.D.; et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N. Engl. J. Med. 2017, 377, 1119–1131. [Google Scholar] [CrossRef] [PubMed]
  4. Nilsson, J. Immunomodulation of Atherosclerosis. Implications for Vaccine Development. Arter. Thromb. Vasc. Boil. 2005, 25, 18–28. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Fildes, J.; Shaw, S.M.; Yonan, N.; Williams, S.G. The Immune System and Chronic Heart Failure. J. Am. Coll. Cardiol. 2009, 53, 1013–1020. [Google Scholar] [CrossRef] [PubMed]
  6. Malaguarnera, M. Influence of Resveratrol on the Immune Response. Nutrients 2019, 11, 946. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Frankel, E.; Waterhouse, A.L.; Kinsella, J. Inhibition of human LDL oxidation by resveratrol. Lancet 1993, 341, 1103–1104. [Google Scholar] [CrossRef]
  8. Catalgol, B.; Batirel, S.; Taga, Y.; Ozer, N.K. Resveratrol: French Paradox Revisited. Front. Pharmacol. 2012, 3. [Google Scholar] [CrossRef] [Green Version]
  9. Rossi, D.; Guerrini, A.; Bruni, R.; Brognara, E.; Borgatti, M.; Gambari, R.; Maietti, S.; Sacchetti, G. Trans-Resveratrol in Nutraceuticals: Issues in Retail Quality and Effectiveness. Molecules 2012, 17, 12393–12405. [Google Scholar] [CrossRef] [Green Version]
  10. Judd, S.E.; Tangpricha, V. Vitamin D deficiency and risk for cardiovascular disease. Am. J. Med Sci. 2009, 338, 40–44. [Google Scholar] [CrossRef] [Green Version]
  11. Cangemi, R.; Falcone, M.; Taliani, G.; Calvieri, C.; Tiseo, G.; Romiti, G.F.; Bertazzoni, G.; Farcomeni, A.; Violi, F.; Battaglia, S.; et al. Corticosteroid Use and Incident Myocardial Infarction in Adults Hospitalized for Community-acquired Pneumonia. Ann. Am. Thorac. Soc. 2019, 16, 91–98. [Google Scholar] [CrossRef] [PubMed]
  12. Fujii, T.; Luethi, N.; Young, P.J.; Frei, D.R.; Eastwood, G.M.; French, C.J.; Deane, A.M.; Shehabi, Y.; Hajjar, L.A.; Oliveira, G.; et al. Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock. JAMA 2020, 323, 423. [Google Scholar] [CrossRef] [PubMed]
  13. Fowler, A.; Truwit, J.D.; Hite, R.D.; Morris, P.E.; Dewilde, C.; Priday, A.; Fisher, B.; Thacker, L.R.; Natarajan, R.; Brophy, D.F.; et al. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The Citris-Ali Randomized Clinical Trial. JAMA 2019, 322, 1261–1270. [Google Scholar] [CrossRef] [PubMed]
  14. Annane, D.; Renault, A.; Brun-Buisson, C.; Mégarbane, B.; Quenot, J.-P.; Siami, S.; Cariou, A.; Forceville, X.; Schwebel, C.; Martin, C.; et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N. Engl. J. Med. 2018, 378, 809–818. [Google Scholar] [CrossRef] [PubMed]
  15. Venkatesh, B.; Finfer, S.; Cohen, J.; Rajbhandari, R.; Arabi, Y.M.; Bellomo, R.; Billot, L.; Correa, M.; Glass, P.; Harward, M.; et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N. Engl. J. Med. 2018, 378, 797–808. [Google Scholar] [CrossRef] [PubMed]
  16. Rhodes, A.; Evans, L.; Alhazzani, W.; Levy, M.M.; Antonelli, M.; Ferrer, R.; Kumar, A.; Sevransky, J.E.; Sprung, C.L.; Nunnally, M.E.; et al. Surviving Sepsis Campaign. Crit. Care Med. 2017, 45, 486–552. [Google Scholar] [CrossRef] [PubMed]
  17. Zhou, J.; Yang, D.; Liu, K.; Hou, L.; Zhang, W. Systematic review, and meta-analysis of the protective effect of resveratrol on multiple organ injury induced by sepsis in animal models. Biomed. Rep. 2018, 10, 55–62. [Google Scholar] [CrossRef]
  18. Li, Y.; Feng, L.; Li, G.; An, J.; Zhang, S.; Li, J.; Liu, J.; Ren, J.; Yang, L.; Qi, Z. Resveratrol prevents ISO-induced myocardial remodeling associated with regulating polarization of macrophages through VEGF-B/AMPK/NF-kB pathway. Int. Immunopharmacol. 2020, 84, 106508. [Google Scholar] [CrossRef]
  19. Weiskirchen, S.; Weiskirchen, R. Resveratrol: How Much Wine Do You Have to Drink to Stay Healthy? Adv. Nutr. 2016, 7, 706–718. [Google Scholar] [CrossRef] [Green Version]
  20. Sales, J.M.; Resurreccion, A.V.A. Resveratrol in Peanuts. Crit. Rev. Food Sci. Nutr. 2013, 54, 734–770. [Google Scholar] [CrossRef]
  21. Smoliga, J.M.; Blanchard, O. Enhancing the Delivery of Resveratrol in Humans: If Low Bioavailability is the Problem, what is the Solution? Molecules 2014, 19, 17154–17172. [Google Scholar] [CrossRef] [PubMed]
  22. Smoliga, J.M.; Colombo, E.S.; Campen, M.J. A healthier approach to clinical trials evaluating resveratrol for primary prevention of age-related diseases in healthy populations. Aging 2013, 5, 495–506. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Padayatty, S.J.; Sun, H.; Wang, Y.; Riordan, H.D.; Hewitt, S.M.; Katz, A.; Wesley, R.A.; Levine, M. Vitamin C pharmacokinetics: Implications for oral and intravenous use. Ann. Intern. Med. 2004, 140, 533–537. [Google Scholar] [CrossRef] [PubMed]
  24. Paulsen, O.; Borgström, L.; Kagedal, B. Pharmacokinetics of N-acetylcysteine in man. Eur. J. Clin. Pharmacol. 1986, 31, 217–222. [Google Scholar] [CrossRef]
  25. Chen, Q.M.; Alpert, J. Nutraceuticals: Evidence of Benefit in Clinical Practice? Am. J. Med. 2016, 129, 897–898. [Google Scholar] [CrossRef] [Green Version]
  26. Falchetti, R.; Fuggetta, M.P.; Lanzilli, G.; Tricarico, M.; Ravagnan, G. Effects of resveratrol on human immune cell function. Life Sci. 2001, 70, 81–96. [Google Scholar] [CrossRef]
  27. Nicotinamide Riboside with and without Resveratrol to Improve Functioning in Peripheral Artery Disease Full Text View ClinicalTrials.gov. Available online: https://clinicaltrials.gov/ct2/show/NCT03743636?recrs=ab&cond=resveratrol&draw=2&rank=10 (accessed on 3 May 2020).
  28. Resveratrol and Cardiovascular Health in the Elderly. Available online: http://clinicaltrials.gov/show/NCT01842399 (accessed on 3 May 2020).
  29. Effect of Resveratrol and Vitamin C on Insulin Resistance among Postmenopausal Women Full Text View ClinicalTrials.gov. Available online: https://clinicaltrials.gov/ct2/show/NCT03090997?recrs=ab&cond=resveratrol&draw=2&rank=4 (accessed on 3 May 2020).
  30. Berman, A.Y.; Motechin, R.A.; Wiesenfeld, M.Y.; Holz, M.K. The therapeutic potential of resveratrol: A review of clinical trials. NPJ Precis. Oncol. 2017, 1, 35. [Google Scholar] [CrossRef] [Green Version]

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MDPI and ACS Style

Romiti, G.F.; Corica, B.; Raparelli, V.; Basili, S.; Cangemi, R. The Interplay between Antioxidants and the Immune System: A Promising Field, Still Looking for Answers. Nutrients 2020, 12, 1550. https://doi.org/10.3390/nu12061550

AMA Style

Romiti GF, Corica B, Raparelli V, Basili S, Cangemi R. The Interplay between Antioxidants and the Immune System: A Promising Field, Still Looking for Answers. Nutrients. 2020; 12(6):1550. https://doi.org/10.3390/nu12061550

Chicago/Turabian Style

Romiti, Giulio Francesco, Bernadette Corica, Valeria Raparelli, Stefania Basili, and Roberto Cangemi. 2020. "The Interplay between Antioxidants and the Immune System: A Promising Field, Still Looking for Answers" Nutrients 12, no. 6: 1550. https://doi.org/10.3390/nu12061550

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