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Oxidative stress and Glutathione

About 2 months ago, I presented certain supplements to boost your immune system in response to this global infectious disease crisis. Recently over the past month, more studies and case reports have supported a few of the key supplements I presented and I would like to share this information with you.

I've recently recommended liposomal glutathione, N-acetyl cysteine (or NAC), Vitamin D, Zinc, and Quercetin to several people that have been short of breath and suspected to have Covid-19 or SARS-Cov-2. The reason I made these recommendations is that oxidative stress on the cell and mitochondria play a key role in whether COVID-19 progresses to complications and a poor outcome. Glutathione is a key antioxidant. N-acetyl cysteine (or NAC), Vitamin D, and Zinc also play a role in decreasing complications and poor outcomes through other mechanisms.

First, let me explain what oxidative stress is. Oxidative stress can be a byproduct of energy production, an accumulation from environmental toxins (leading to damage), or the inability of the cell (or mitochondria) to properly self-regulate (among other things). Reactive oxygen species (ROS) are generated from many chemical reactions in the cell and mitochondria.  Superoxide (O2-) is an oxygen molecule with an extra electron and is an ROS and the key cause of oxidative stress (this was mentioned in last week’s lengthy discussion the mitochondrial deep dive). The reason superoxide is increased in a patient infected with COVID-19 is because of the following diagram. Angiotensin 2 that is produced in the cell normally can increase superoxide but is balanced by the fact it usually gets converted to angiotensin 1,7 by an enzyme called angiotensin converting enzyme 2 (ACE2). This enzyme is down regulated or inhibited by SARS-COV-2 so there is a higher amount of angiotensin 2 since it’s not being converted. To make matters worse, SARS-COV-2 also promotes the production and activity of polymorphonuclear neutrophils, which also lead to an increase in superoxide. The other downside is that angiotensin 1, 7 normally causes the reduction of superoxide and if it’s not being produced that also won't happen. Superoxide dismutase (we discussed extracellular superoxide dismutase elsewhere in the blog exercise decreases risk of viral respiratory complications and in the deep dive about the mitochondria) converts the superoxide to with oxygen or hydrogen peroxide. Hydrogen peroxide can be dangerous as it can break down to form a hydroxyl molecule (a free radical) that can cause damage. The body has 2 enzyme systems, one called catalase (also peroxiredoxins both requiring iron or Fe) to convert hydrogen peroxide (H2O2) to water and glutathione peroxidase (GSHPX) that also converts hydrogen peroxide to water H2O by oxidizing or adding an oxygen molecular to glutathione. Glutathione is made from glutamate, glycine and cysteine, which is the rate-limiting step (or the hardest of the three ingredients to come by). N-acetyl cysteine is a good source for the cysteine molecule, which will "recharge" the stores of glutathione. It is also a precursor to make glutathione directly.

There has been a recent study now that examined what if you just give glutathione directly instead of giving N acetyl cysteine (NAC) as a precursor for the body to make glutathione. The paper is entitled "Efficacy of Glutathione Therapy in Relieving Dyspnea Associated with Covid-19 Pneumonia: A Report of 2 cases by Richard I Horowitz, Phyllis R Freeman,  and James Bruzzese  published April 21, 2020. In the paper, it was cited "Infection with COVID-19 potentially can result in severe outcomes and death from “cytokine storm syndrome”, resulting in a novel coronavirus pneumonia (NCP) with severe dyspnea, acute respiratory distress syndrome (ARDS), fulminant myocarditis and multi-organ dysfunction with or without disseminated intravascular coagulation. It goes on to say, "We evaluated the effects of using high dose oral and/or IV glutathione in the treatment of 2 patients with dyspnea secondary to COVID-19 pneumonia. A trial of 2 g of PO or IV glutathione was used in both patients and improved their dyspnea within 1 h of use. Repeated use of both 2000 mg of PO and IV glutathione was effective in further relieving respiratory symptoms. They concluded: "Oral and IV glutathione, glutathione precursors (N-acetyl-cysteine) and alpha lipoic acid may represent a novel treatment approach for blocking NF-κB and addressing “cytokine storm syndrome” and respiratory distress in patients with COVID-19 pneumonia."

N-acetyl Cysteine (NAC) in other studies have shown a potent thrombolytic effect on arterial thrombi. Arterial thrombi have been thought to be the reason for hypoxemia with pulmonary arterial thrombosis. Von Willebrand factor causes the formation of disulfide bridges to forma a mesh like structure causing clotting to occur with many platelets in it.  N-acetyl Cysteine (NAC) and reduced Glutathione will break disulfide bonds and lyse these disulfide bonds thereby breaking up these clots. Recent autopsy reports have shown that patient's that died from COVID-19 had very small clots in the bronchioles of the lung. You may think of the lung in a shape of a tree with oxygen and Co2 coursing through instead of tree sap and water, spreading out with its branches and down to the level of the twigs and even smaller such has human bronchioles that can be 1/3 the diameter of human hair. If you can imagine tiny clots, plugging up different twigs and branches of the lung you can get an idea how these patient could have a lack of oxygen.

In another case report,  a Russian researcher Alexey V Polonikov at Kursk State Medical University published a paper entitled Endogenous deficiency of glutathione as the most likely cause of serious manifestations and death in patients with the novel coronavirus infection (COVID-19): a hypothesis based on literature data and own observations.  The abstract is as follows: Based on an exhaustive literature analysis and own observations, I proposed a hypothesis that glutathione deficiency is exactly the most plausible explanation for serious manifestation and death in COVID-19 infected patients. The major risk factors established for severe COVID-19 infection and relative glutathione deficiency found in COVID-19 infected patients with moderate-to-severe illness have converged me to two very important conclusions: (1) oxidative stress contributes to hyper-inflammation of the lung leading to adverse disease outcomes such as acute respiratory distress syndrome, multi-organ failure and death; (2) poor antioxidant defense due to endogenous glutathione deficiency as a result of decreased biosynthesis and/or increased depletion of GSH is the most probable cause of increased oxidative damage of the lung, regardless which of the factors aging, chronic disease comorbidity, smoking or some others were responsible for this deficit. The hypothesis provides novel insights into the etiology and mechanisms responsible for serious manifestations of COVID-19 infection and justifies promising opportunities for effective treatment and prevention of the illness through glutathione recovering with N-acetyl cysteine and reduced glutathione.

Therefore, from the discussion of the recent articles, we just went through and going back to our discussion from 2 months about immune boosting supplements, we can see that there is now more evidence to support the use of glutathione and N-acetyl cysteine.  Next week we’ll look at some papers supporting Vitamin D and Zinc.  I believe that these key supplements which help boost the immune system are among the best supplements we have at the current time to stay healthy in this global crisis.

If you would like to get the most absorbable form or bioavailable form of liposomal glutathione click here or call the office at (925) 736-9828.

Because of the questions and needs of several people, I went more in depth about these supplements and the supportive studies currently available. We have therefore postponed our discussion of the brain and mild cognitive decline this week.  I look forward to next week’s video and blog and hope to meet with you then.

For more information on food intolerances, mitochondria,  exercise to benefit respiratory and immune functions, sleep, supplements, foods, and stress reduction to help boost the immune system please see the blogs on

If you have comments, questions, or want to learn how functional medicine can help with improving your brain and immune function call our office or email Stay healthy and take care.

Jeffrey Mark, M.D. Helping clients with compassionate and comprehensive medical care for over 25 years with 4 board certifications in functional medicine, gastroenterology, internal medicine, and anti-aging/ regenerative medicine . IFMCP, ABIM Gastroenterology, NPAS Internal Medicine, ABAARM.

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