Metabolic reprogramming by Nitric Oxide. Oxidant Therapies

Majid Ali, M.D.

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For over 35 years, this writer, a surgeon-turned-pathologist- turned-integrationist believed that, in matters of health, aging, and disease reversal, oxygen matters have clear primacy over those of antioxidants. With this background, he read with keen interest the paper by Zhou et al. published in the journal Nature in January 2019 (ref. 1). This article sheds important additional and revealing light on what I consider to be the single most important question for everyone interested in personal health and healing: What has primacy over the other: inexpensive oxygen therapies (oxidant therapeutics) or expensive antioxidants (antioxidant therapeutics)?


Author’s Essay e-Published in Nature


The author is most grateful to the editors of the journal Nature for allowing me to freely and fully participate in the reader-discussion sections of the seminal papers published by the Journal. Below, I include the full text of my comments concerning the Zhou paper. Nature e-publishes communications concerning such papers at the end of the respective papers. These communications are available without cost to the Journal subscribers, including libraries of nearly all U.S. universities as well as many public libraries. Most librarians, I happily add, graciously comply with citizens’ requests for downloads.

Zhou and his colleagues report that nitric oxide (NO) protects the kidneys by reprogramming metabolism and its levels are regulated by a two-component system in mice (Nature. 2019;565:96-100),  ref. 1). Specifically, they observed that renal injury caused by ischaemia-reperfusion events was worse in mice genetically engineered to lack eNOS, the endothelial NO-synthesizing enzyme, than in wild-type mice.

With a lifetime of a few seconds, NO is highly reactive and diffuses freely across membranes, so becoming an ideal transient paracrine and autocrine signaling molecule. NO signaling is readily deactivated when it is converted to nitrates and nitrites by oxygen and water. In a companion commentary on the Zhou report, Lowenstein explains that nitric oxide attaches to the molecule S-coenzyme A (S-C)A) to form S-nitroso-coenzymeA (SNO-CoA) which, in turn, delivers NO to the enzyme pyruvate kinase M2 (PKM2), modifying PKM2 and thereby inhibiting glycolysis – a process that consumes glucose (ref.2). As a consequence glucose is pushed to an alternate metabolic pathway, the pentose phosphate pathway, which generates NADPH, a cofactor used by antioxidants.

Inhaled NO as a vasodilator and redox-active agent has been used to treat pulmonary hypertension and related diseases with inconsistent clinical results (3,4). Beyond sound clinical trials, commercial products containing putative “nitric oxide boosters,” such as beetroot extracts, pine bark (for pycnogenol), quercitin, arginine, and L-citrulline) are heavily promoted for their putative muscle-building and circulatory benefits.
In 2015, Nature published an article entitled “Science myths that will not die (ref. 5).”The Journal cited two papers in support of its dismissal of the beneficial role of antioxidants: one showed that mice genetically engineered to overproduce free radicals lived just as long as normal mice (ref. 6); and the other revealed that mice engineered to overproduce antioxidants didn’t live any longer than normal (ref. 7). In his comments on this subject, this writer pointed out that he liberally prescribes redox-active agents (oxidants and antioxidants) for his patients with chronic immune-inflammatory disorders for three overarching goals: (a) restoring compromised oxygen signaling; (b) normalizing accentuated insulin signaling which commonly exists in such disorders; and (c) restoring gut microbiome in states of altered gut ecology (ref. 8). These subjects were discussed previously in the 10th, 11th, and 12th volumes of The Principles and Practice of Integrative Medicine (ref. 9-11).
Zhou et al. show that nitric oxide inhibits glycolysis in the setting of renal ischaemia (re.1). Lowenstein points out that nitric acid is also known to promote glycolysis under other conditions (ref.2). Integration of signaling, metabolic, redox-reactive bioenergetics, and clinical benefits of NO (albeit limited so far) raise important and intriguing clinical questions for integrationists, who liberally prescribe predominantly pro-oxidant treatments, such as: (a) hydrogen peroxide foot soaks, baths, and infusions; (b) hyperbaric oxygen; and (3) ozone infusions (ref. 9-11). Beyond such direct oxidative therapeutics, clinical benefits of other therapies that focus on self-regulation with meditative breathing and indigenous measures for bowel and detox largely accrue from improved tissue oxygenation and its pro-oxidant effects. It is noteworthy in this context that several well-conducted large trials of robust nutritional therapies have failed to show clear therapeutic benefits of antioxidant regimens. Notably among them are Canadian Critical Care Trials Groups (ref.12), the REDOX Study (Reducing Death Due to Oxidative Stress the SIGNET study) Scottish Intensive Care Glutamine or Selenium Evaluating trial, the OMEGA study, and the MetaPlus trial (ref.13-15).

In closing the work of Zhou et al. sheds light on the antioxidant-pro-oxidant controversy in clinical medicine. Specifically, it provides additional support for this writer’s view that addressing issues of cellular oxygenation (with its potent pro-oxidant dynamics) need to be recognized as a higher clinical priority than administering ever-increasing doses of antioxidant, as is the common current practice among clinicians practicing integrative medicine.

  1. Zhou H-L, Zhang R, Ananad P, et al. Metabolic reprogramming by the S-nitroso-CoA reductase system protects against kidney injury. Nature. 2019;565:96-100.
    2. Lowenstein CJ, Metabolism reprogrammed by the nitric oxide signaling molecule. Nature. 2019;565:33-34.
    3. Griffith MJD, Evans TW. Inhaled Nitric Oxide Therapy in Adults. NEJM. 2005;353:2683-2695.
    4. Roberts JD, Finemen JR, Morin FC, et al. Inhaled Nitric Oxide and Persistent Pulmonary Hypertension of the Newborn. N Eng J Med 1997; 336:605-610.
    5. 4. Scudellari M. Science myths that will not die. Nature;2015:528:322-325.
    6. 5. Almeida A, Moncada S, Bolaños JP. The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C–Cdh1.. Nature 2004;6:45-51.
    7. 6. Doonan R, McElwee JJ, Matthiissens F, et al. Against the oxidative damage theory of aging: superoxide dismutases protect against oxidative stress but have little or no effect on life span in Caenorhabditis elegans. Genes Dev. 2008 Dec 1;22(23):3236-41.
    8. Ali M. Antioxidant use in clinical medicine. Comments e-published in Science myths that will not die. Nature;2015:528:322-325.
    9. 9. Ali M. Darwin, Oxygen Homeostasis, and Oxystatic Therapies. Volume X, 3 rd. Edi The Principles and Practice of Integrative Medicine (2009) New York. Institute of Integrative Medicine Press.
    10. Ali M. Darwin, Dysox, and Disease. Volume XI. 3rd. Edi. The Principles and Practice of Integrative Medicine 2000. 3rd. Edi. 2008. New York. (2009) Institute of Integrative Medicine Press.
    11. Ali M. Darwin, Dysox, and Integrative Protocols. Volume XII . The Principles and Practice of Integrative Medicine New York (2009). Institute of Integrative Medicine Press.
    12. Heyland D, Muscedere J, Wischmeyer PE, et al.Canadian Critical Care Trials Group. A randomized trial of glutathione and antioxidants in critically ill patients . N Eng J Med. 2013;368:1489-1497.
    13. Andrew PJ, Averell A, Noble DW, et al. Randomised trials of glutamine, selenium, or both to supplement parenteral nutrition for critically ill patients. BMJ 2011; 342: 1542.
    14. Rice T. Immunonutrition in Critical Illness. JAMA 2014;312:490-491.
    15. Van Zantan ARH, Sztark F, Kaisers UX, et al. High-protein Enteral Nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition and nosocomial infections in ICU. JAMA, 2014;312:515-523.






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