Mitochondria are cellular substructures that function as energy powerhouses for almost all eukaryotic cells, including those of humans [1]. The number of mitochondria in a cell can vary widely [2]. Red blood cells, for example, have none, whereas liver cells can contain up to two thousand [2]. Mitochondria are integral to our survival due to the variety of roles they play in our biochemistry, the most important of which is the production of adenosine triphosphate (ATP) by aerobic respiration [1]. This process involves oxidative phosphorylation, which utilizes oxygen to release the energy contained in the foods we eat. The energy is initially stored in ATP, which subsequently releases this energy to power the body’s metabolic reactions. During this process, ATP is broken down into adenosine diphosphate (ADP) and inorganic phosphate (P_i).

Since mitochondria are essential to our very existence, it is unsurprising that the effects of mitochondrial diseases can be severe, and sometimes lethal, spanning a wide-ranging spectrum of physiological and biochemical symptoms [1,3,4] (see Table 1 for examples). Mitochondrial diseases in humans can arise from a myriad of mutations in mitochondrial and nuclear (cellular) DNA [4]. Collectively, mitochondrial diseases are reported to affect 1 in every 5,000 adults, making them quite prevalent in comparison to other hereditary metabolic disorders [4].

Table 1. Some well-known clinically defined primary mitochondrial diseases and their respective symptoms.

Mitochondrial diseases are characterized by both a diminished capacity to produce ATP as well as an elevated production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) [3]. Commonly known as free radicals, ROS and RNS are naturally produced during oxidative phosphorylation and serve an essential role as signalling molecules in the normal functioning of a cell [4]. However, a dysregulated increase in the level of these free radicals, as seen in mitochondrial diseases, can result in oxidative damage by overwhelming the cellular antioxidant defence mechanism, of which glutathione is the principal component [4]. The consequent depletion of glutathione [3] impedes the efficient quenching of free radicals, leading to redox imbalance and oxidative stress [4]. This, in turn, can compromise the structural and functional integrity of the cell’s nucleic acids, proteins and lipids [4]. As a result, the activity of the electron transport chain (ETC) is hindered, decreasing ATP production during oxidative phosphorylation [8]. Since the cellular synthesis of glutathione is ATP-dependent, decreased ETC activity also undermines glutathione synthesis, further exacerbating oxidative stress in a vicious cycle [8]. Hence, mitochondrial diseases present as a two-front attack on cellular glutathione levels; the excess free radicals deplete glutathione reserves, and the decreased ATP production slows glutathione replenishment, ultimately resulting in chronic glutathione deficiency [8].

The appreciably high incidence of mitochondrial diseases highlights a growing need to devise effective therapeutic strategies. With the current absence of technologies to rectify the actual mutations that underlie mitochondrial diseases, medical science can only address the resulting oxidative stress as a potential therapeutic option. Therefore, therapy primarily focuses on providing patients with supportive care to manage their symptoms using dietary supplements [9]. Commonly prescribed or recommended dietary supplements include coenzyme Q₁₀ and vitamin B, C, E and K [9,10]. Unfortunately, no concrete evidence of their efficacy exists to support their beneficial use in addressing the symptoms of mitochondrial diseases [9, 10].

Given the strong association between glutathione depletion and the progression of mitochondrial diseases, dietary supplements with the potential to increase intracellular glutathione reserves have been the subject of much research in recent years [11]. One of the prime candidates has been N-acetylcysteine (NAC), which is the gold standard antidote for acute acetaminophen (paracetamol) overdose. In this particular case, cysteine is severely depleted, and NAC helps to restore cellular glutathione levels to homeostasis by providing a source of cysteine. However, no clinical trials have been reported that provide any evidence of its effectiveness for raising the chronically low homeostatic level of glutathione that occurs in primary mitochondrial diseases [1, 11]. Additionally, in the context of lowered ATP production, which is a hallmark of mitochondrial diseases, it is important to note that NAC, essentially only being a form of cysteine, will require 2 ATP molecules to be converted to glutathione. This is because cysteine is at the very beginning of the two-step cellular synthesis of glutathione (see Figure 1). For a detailed explanation, read our article on NAC https://www.glutathionereporter.com/n-acetylcysteine-nac-cannot-increase-cellular-glutathione-levels/.

Figure 1. The two sequential ATP-dependent reactions by which glutathione is synthesized inside cells, with the enzyme catalyzing the reaction and the number of ATP molecules required for the reaction to occur, displayed above and below the arrows respectively.

Unlike NAC, dietary supplementation with gamma-glutamylcysteine (GGC), the immediate precursor to glutathione, can elevate intracellular glutathione levels above homeostasis [12]. This increased glutathione pool may help contend with the increased flow of free radicals from dysfunctional mitochondria. Moreover, the conversion of GGC to glutathione only requires 1 molecule of ATP as it is the product of the first step in glutathione synthesis, as shown in Figure 1. This low energy feature of GGC may be particularly useful for overcoming the ATP inadequacy that occurs in mitochondrial diseases. Finally, GGC may be capable of acting as an antioxidant in its own right by removing key ROS such as hydrogen peroxide and superoxide anions independently of glutathione [13]. This may be advantageous in severe cases of mitochondrial diseases where there could be insufficient ATP available to synthesize glutathione from GGC.

In summation, GGC’s potential to elevate intracellular glutathione levels above homeostasis in an energy-efficient manner, makes it a promising candidate as a potential therapeutic for mitochondrial diseases.

Reference

1. Schapira, AHV 2006, ‘Mitochondrial Disease’, The Lancet, vol. 368, no. 9529, pp. 70-82. 
2. Jones, M, Fosbery, R, Gregory, J, Taylor, D 2014, Cambridge International AS and A Level Biology Coursebook, 4^th edn, Cambridge University Press, United Kingdom.
3. Atkuri, KR, Cowan, TM, Kwan, T, Ng, A, Herzenberg, LA, Herzenberg, LA, Enns, GM 2009, ‘Inherited disorders affecting mitochondrial function are associated with glutathione deficiency and hypocitrullinemia’, Proceedings of the National Academy of Sciences, vol. 106, no. 10, pp. 3941-3945.
4. Enns, GM, Moore, T, Le, A, Atkuri, K, Shah, MK, Cusmano-Ozog, K, Niemi, AK, Cowan, TM 2014, ‘Degree of Glutathione Deficiency and Redox Imbalance Depend on Subtype of Mitochondrial Disease and Clinical Status’, The Public Library of Science One, vol. 9, no. 6.
5. Baertling, F, Rodenburg, RJ, Schaper, J, Smeitink, JA, Koopman, WJH, Mayatepek, E, Morava, E, Distelmaier, F 2014, ‘A guide to diagnosis and treatment of Leigh syndrome’, Journal of Neurology, Neurosurgery & Psychiatry, vol. 85, no. 3, pp. 257-265.
6. Saneto, RP, Cohen, BH, Copeland, WC, Naviaux, RK 2013, ‘Alpers-Huttenlocher Syndrome’, Pediatric Neurology, vol. 48, no. 3, pp. 167-178.
7. El-Hattab, AW, Adesina, AM, Jones, J, Scaglia, F 2015, ‘MELAS syndrome: Clinical manifestations, pathogenesis, and treatment options’, Molecular genetics and metabolism, vol. 106, no. 1-2, pp. 4-12.
8. Hargreaves, IP, Sheena, Y, Land, JM, Heales, SJR 2005, ‘Glutathione deficiency in patients with mitochondrial disease: Implications for pathogenesis and treatment’, Journal of Inherited Metabolic Disease, vol. 28, no. 1, pp. 81-88.
9. Chinnery, PF, Turnbull, DM 2001, ‘Epidemiology and treatment of mitochondrial disorders’, American Journal of Medical Genetics, vol. 106, no. 1, pp. 94-101.
10. Gorman, GS, Chinnery, PF, DiMauro, S, Hirano, M, Koga, Y, McFarland, R, Suomalainen, A, Thorburn, DR, Zeviani, M, Turnbull, DM 2016, ‘Mitochondrial diseases’, Nature Reviews Disease Primers, vol. 2, no. 26080, pp. 1-22.
11. Enns, GM, Cowan, TM 2017, ‘Glutathione as a Redox Biomarker in Mitochondrial Disease – Implications for Therapy’, Journal of Clinical Medicine, vol. 6, no. 5, pp. 50.
12. Zarka, MH, Bridge, WJ 2017, ‘Oral administration of γ-glutamylcysteine increases intracellular glutathione levels above homeostasis in a randomised human trial pilot study’, Redox Biology, vol. 11, pp. 631-636.
13. Quintana-Cabrera, R, Fernandez-Fernandez, S, Bobo-Jimenez, V, Escobar, J, Sastre, J, Almeida, A, Bolaños, JP 2012, ‘γ-Glutamylcysteine detoxifies reactive oxygen species by acting as glutathione peroxidase-1 cofactor’, Nature Communications, vol. 3, no. 718, pp. 1-8.

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A biological antioxidant is defined as “any substance that, when present at low concentrations, significantly delays or prevents the oxidation of oxidizable substrates” [1]. Oxidizable substrates in the body, such as DNA and proteins, can incur damage by accepting electrons from unstable reactive oxygen species (ROS), which are generated by exogenous and endogenous means. Ultra-violet radiation (UVR) is a type of ionizing radiation that significantly increases ROS formation as its short wavelength and high frequency possesses enough energy to knock electrons out of oxygen molecules. This makes them highly unstable. Everyday UVR exposure often leads to sunburn, and long-term repeated exposure can additionally result in substantial skin and DNA damage that may lead to the development of melanoma and other skin cancers [2].

When the body’s antioxidant defence system becomes overwhelmed due to an influx of ROS, a cascade of oxidative damage can occur. If the DNA or membrane of a cell is irreversibly damaged, it will be marked for programmed cell death (apoptosis). This process releases inflammatory markers such as prostaglandins, which are responsible for inducing the symptoms of sunburn: Vasodilation, swelling and pain [3]. Oxidative damage can accumulate over time if UVR exposure is frequent, accelerating photoaging and consequently increasing the appearance of wrinkles, pigmentation and blotchiness.  The Skin Cancer Foundation states that photoaging is responsible for 90% of visible changes to the skin [4]. The symptoms of photoaging occur due to the oxidation of dermal collagen fibre bundles, which are proteins responsible for providing strength and elasticity to our skin [5]. Since the body produces less collagen as we age, the symptoms of photoaging will naturally accumulate over time. Long-term UVR exposure evidently hastens this process.

Depending on its wavelength, UVR is categorized intoUVA (315-400 nm), UVB (280-315 nm) and UVC (100-280 nm). Each type differs in their biological activity and ability to penetrate our skin. Of the UVR entering the atmosphere, 90% of UVA, 10% of UVB, and none of the UVC radiation reaches the Earth’s surface. For this reason, the only possible routes of UVC exposure are from man-made devices such as tanning beds and lasers. Radiation in the UVA spectrum is primarily responsible for ROS generation and sunburn, while UVB can directly damage DNA by inducing the formation of thymine-thymine cyclobutane dimers, which can lead to mutation, and potentially skin cancers if not repaired [6]. Considerable levels of OH• (hydroxyl radical) and H₂O₂ (hydrogen peroxide) are produced within 15 minutes of UVR exposure and continue for up to 60 minutes afterwards [2].

Glutathione (GSH) has been shown to play a protective role during UVR exposure via three mechanisms. The primary function of GSH is to neutralize the oxidation capacity of H₂O₂ by converting it to water (see Reaction 1 below). In this process, catalyzed by the enzyme glutathione peroxidase, reduced glutathione (GSH) is oxidized to (GSSG), which the cell then recycles back to the reduced form using the enzyme glutathione reductase (see Reaction 2 below).

Reaction 1. H₂O₂ + 2GSH     —->    2H₂O + GSSG

Reaction 2. GSSG + NADPH + H⁺   —->    2GSH + NADP⁺

Melanin is a skin pigment that acts as a photoprotector by absorbing UVR. The production of melanin in the epidermis (melanogenesis) is accelerated during UVR exposure, which concurrently generates ROS [7]. The second function of GSH is to downregulate UVR-induced melanogenesis, which consequently lowers the increased level of ROS production [7]. Lastly, GSH also supports the activity of DNA repair enzymes [8], lowering the incidence of mutations which are a precursor to skin cancer, as well as apoptosis which leads to sunburn [9].

GSH is only able to protect cells against UVR if there is a sufficient concentration within the cells to address the onslaught of UVR induced ROS.  This can be an issue, as UVA exposure has been shown to deplete GSH in the dermis and epidermis skin tissue [10]. Studies have shown that a diminished GSH pool stimulates apoptosis and leads to increased UVR sensitization and sunburn [11,12]. Research suggests that during UVR exposure, GSH in affected cells is progressively depleted due to inhibition of cysteine transport as well as decreased activity of the enzyme gamma-glutamate cysteine ligase (GCL) [13]. The product of GCL is gamma-glutamylcysteine (GGC), which is an essential precursor to GSH. Taking GGC supplements bypasses the need for GCL to be working at its maximal rate, allowing GSH to be continually produced and hence withstand depletion inside cells.

The risk of cellular oxidative stress can be lowered by limiting exposure to UVR and/or by strategies that increase the cellular GSH pool to provide a buffer against the UVR-induced acute increase in ROS production [10]. During long or acute periods of UVR exposure, the antioxidant defense system will eventually become overwhelmed, as the rate of GSH synthesis is outcompeted by the accumulation of ROS. Supplemental GGC has been shown to increase the intracellular GSH pool [14] and, if consumed before UVR exposure, there is great potential for the skin to further withstand oxidative stress through a heightened GSH antioxidant buffer. Supplements should always be used in conjunction with additional measures such as sunscreen and protective clothing to achieve a decreased risk of sunburn, photoaging and skin cancer.

References

1. Halliwell, B. and Gutteridge, J.M.C. (1999). Free radicals in biology and medicine. Journal of Free Radicals in Biology & Medicine, 1(4), 331–332, DOI: 10.1016/0748-5514(85)90140-0
2. Chen, L., Hu, J.Y. and Wang, S.Q. (2012). The role of antioxidants in photoprotection: A critical review. Journal of the American Academy of Dermatology, 67(5), 1013–1024, DOI: 10.1016/j.jaad.2012.02.009
3. Guerra, K.C., Urban, K. and Crane, J.S. (2021). Sunburn. StatPearls Publishing. PMID: 30521258.
4. Grabel, A. (2019). Photoaging: What You Need to Know About the Other Kind of Aging – The Skin Cancer Foundation. [online] The Skin Cancer Foundation. Available at: https://www.skincancer.org/blog/photoaging-what-you-need-to-know/.
5. Edwards, C., Pearse, A., Marks, R., Nishimori, Y., Matsumoto, K. and Kawai, M. (2001). Degenerative Alterations of Dermal Collagen Fiber Bundles in Photodamaged Human Skin and UV-Irradiated Hairless Mouse Skin: Possible Effect on Decreasing Skin Mechanical Properties and Appearance of Wrinkles. Journal of Investigative Dermatology, 117(6), pp.1458–1463, DOI: 10.1038/jid.2001.2
6. Adamiec, M. and Skonieczna, M. (2019). UV radiation in HCT 116 cells influences intracellular H2O2 and glutathione levels, antioxidant expression, and protein glutathionylation. Acta Biochimica Polonica, 66(4), 605-610, DOI: 10.18388/abp.2019_2892
7. Nagapan, T.S., Lim, W.N., Basri, D.F. and Ghazali, A.R. (2019). Oral supplementation of L-glutathione prevents ultraviolet B-induced melanogenesis and oxidative stress in BALB/c mice. Experimental Animals, 68(4), 541–548, DOI: 10.1538/expanim.19-0017
8. Schenk, H., Klein, M., Erdbrugger, W., Droge, W. and Schulze-Osthoff, K. (1994). Distinct effects of thioredoxin and antioxidants on the activation of transcription factors NF-kappa B and AP-1. Proceedings of the National Academy of Sciences, 91(5), 1672–1676, DOI: 10.1073/pnas.91.5.1672
9. Godic, A., Poljšak, B., Adamic, M. and Dahmane, R. (2014). The Role of Antioxidants in Skin Cancer Prevention and Treatment. Oxidative Medicine and Cellular Longevity, 2014, 1–6, DOI: 10.1155/2014/860479
10. Connor, M.J. and Wheeler, L.A. (1987). Depletion of cutaneous glutathione by ultraviolet radiation. Photochemistry and Photobiology, 46(2), 239–245, DOI: 10.1111/j.1751-1097.1987.tb04762.x
11. Friesen, C., Kiess, Y. and Debatin, K-M. (2004). A critical role of glutathione in determining apoptosis sensitivity and resistance in leukemia cells. Cell Death & Differentiation, 11(S1), S73–S85, DOI: 10.1038/sj.cdd.4401431
12. Tyrrell, R.M. and Pidoux, M. (1988). Correlation between endogenous glutathione content and sensitivity of cultured human skin cells to radiation at defined wavelengths in the solar ultraviolet range. Photochemistry and Photobiology, 47(3), 405–412, DOI: 10.1111/j.1751-1097.1988.tb02744.x
13. Zhu, M. and Bowden, G.T. (2007). Molecular Mechanism(s) for UV-B Irradiation-Induced Glutathione Depletion in Cultured Human Keratinocytes. Photochemistry and Photobiology, 80(2), 191–196, DOI: 10.1111/j.1751-1097.2004.tb00070.x
14. Bridge, W.J. and Zarka, M.H. (2017). Oral administration of γ-glutamylcysteine increases intracellular glutathione levels above homeostasis in a randomised human trial pilot study. Redox Biology, 11, 631–636, DOI: 10.1016/j.redox.2017.01.014

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Osteoporosis is a debilitating skeletal condition characterized by low bone density, causing bone fragility and increased risk of bone fractures ^[1]. The body constantly renews bone tissue by absorbing old tissue and regenerating new tissue. As we get older, these two processes become unbalanced, resulting in increased bone resorption and decreased bone formation ^[2]. This is a contributing factor for the gradual loss in bone density and strength as we age. Other factors impacting bone health may include cellular changes, genetic damage due to complex age-related changes as well as nutritional deficiencies of calcium and vitamin D. Oxidative stress can also negatively affect bone health ^[2].

Oxidative stress occurs due to excessive reactive oxygen species (ROS) paired with inadequate levels of antioxidants, in particular glutathione ^[3]. The level of ROS in the body increases with age and as a result of negative lifestyle factors such as smoking ^[4] and obesity ^[5]. This progressively weakens the maintenance of functional tissues ^[6] and further negatively impacts the balance of bone formation and bone resorption ^[7-8].

The body has a finely tuned antioxidant system which neutralizes ROS. This includes the group of antioxidant vitamins such as C & E, but in particular glutathione, which is the most powerful antioxidant in its own right. Glutathione also recycles Vitamins C & E and is therefore the cornerstone of our complex antioxidant response ^[9].

The importance of glutathione is well recognized in the medical community ^[9]. We also know that the body’s production of glutathione slows down as we age and is negatively affected by stress, toxins and illness ^[10]. Even strenuous exercise can temporarily reduce cellular glutathione below optimal. Strategies to enhance glutathione have been explored, but they have been met with very limited success. Supplements such as n-acetylcysteine (NAC), herbal remedies or even glutathione itself do not have the ability to increase glutathione within our cells and, although popular, fail to achieve their objective. For a supplement to be effective, it also needs to be able to increase cellular glutathione above homeostasis, or the natural set point determined by the enzymatic production of glutathione in our cells. This set point progressively becomes lower as we age resulting in suboptimal glutathione production.

Another contributing factor to bone health is Vitamin D, a deficiency of which has long been associated with weak bone formation. Rickets is a disease of the bone directly caused by low levels of Vitamin D as well as dietary calcium. A deficiency in Vitamin D also hinders the absorption of calcium and promotes the release of calcium from the bones, which can lead to the development of osteoporosis. This can significantly weaken bone strength and flexibility, leading to a reduced ability to withstand stress ^[11]. Recent studies have shown a strong correlation between glutathione depletion and the bioavailability of both vitamin D and dietary calcium ^[12-13]. Vitamin D supplements are therefore not successful unless glutathione status is at optimal levels ^[12]. Additionally, it has been shown that decreased glutathione, and the consequent increase in ROS levels, results in a decline of calcium absorption, hindering the effective mineralization of the skeleton ^[13].

Hence, it would be beneficial to have increased glutathione levels in order to ensure optimal Vitamin D absorption and minimal oxidative stress. Supplementation with gamma-glutamylcysteine has shown to increase cellular glutathione levels above homeostasis ^[14] and therefore proves to have potential value as a preventative therapy for osteoporosis by reducing oxidative stress and optimizing Vitamin D and calcium absorption.

References

1. Sozen, T.; Ozisik, L.; Calik Basaran, N. An Overview And Management Of Osteoporosis. European Journal of Rheumatology 2017, 4 (1), 46-56.
2. Corrado, A.; Cici, D.; Rotondo, C.; Maruotti, N.; Cantatore, F. Molecular Basis Of Bone Aging. International Journal of Molecular Sciences 2020, 21 (10), 3679.
3. Zhou X, Wang Z, Ni Y, Yu Y, Wang G, Chen L. Suppression effect of N-acetylcysteine on bone loss in ovariectomized mice. Am J Transl Res. 2020;12(3):731-742.
4. Kamceva, G.; Arsova-Sarafinovska, Z.; Ruskovska, T.; Zdravkovska, M.; Kamceva-Panova, L.; Stikova, E. Cigarette Smoking And Oxidative Stress In Patients With Coronary Artery Disease. Open Access Macedonian Journal of Medical Sciences 2016, 4 (4), 636-640.
5. Matsuda, M.; Shimomura, I. Increased Oxidative Stress In Obesity: Implications For Metabolic Syndrome, Diabetes, Hypertension, Dyslipidemia, Atherosclerosis, And Cancer. Obesity Research & Clinical Practice 2013, 7 (5), e330-e341.
6. Cui, H.; Kong, Y.; Zhang, H. Oxidative Stress, Mitochondrial Dysfunction, And Aging. Journal of Signal Transduction 2012, 2012, 1-13.
7. Almeida M, Han L, Martin-Millan M, Plotkin LI, Stewart SA, Roberson PK, Kousteni S, O’Brien CA, Bellido T, Parfitt AM, Weinstein RS, Jilka RL, Manolagas SC. Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids. J Biol Chem. 2007;282:27285–27297.
8. Domazetovic V, Marcucci G, Iantomasi T, Brandi ML, Vincenzini MT. Oxidative stress in bone remodeling: role of antioxidants. Clin Cases Miner Bone Metab. 2017;14:209–216. 
9. Pizzorno, J. Glutathione!. Integrative Medicine: A Clinician’s Journal 2014, 1 (13), 8-12.
10. Mosoni, L.; Breuillé, D.; Buffière, C.; Obled, C.; Mirand, P. Age-Related Changes In Glutathione Availability And Skeletal Muscle Carbonyl Content In Healthy Rats. Experimental Gerontology 2004, 39 (2), 203-210.
11. Laird, E.; Ward, M.; McSorley, E.; Strain, J.; Wallace, J. Vitamin D And Bone Health; Potential Mechanisms. Nutrients 2010, 2 (7), 693-724.
12. Jain, S.K., R. Parsanathan, A.E. Achari, P. Kanikarla-Marie, and J.A. Bocchini, Jr., Glutathione Stimulates Vitamin D Regulatory and Glucose-Metabolism Genes, Lowers Oxidative Stress and Inflammation, and Increases 25-Hydroxy-Vitamin D Levels in Blood: A Novel Approach to Treat 25-Hydroxyvitamin D Deficiency. Antioxid Redox Signal, 2018. 29(17): p. 1792-1807
13. Moine, L., M. Rivoira, G. Díaz de Barboza, A. Pérez, and N. Tolosa de Talamoni, Glutathione depleting drugs, antioxidants and intestinal calcium absorption. World J Gastroenterol, 2018. 24(44): p. 4979-4988.
14. Zarka, M.H. and W.J. Bridge, Oral administration of γ-glutamylcysteine increases intracellular glutathione levels above homeostasis in a randomized human trial pilot study. Redox Biology, 2017. 11: p. 631-636.

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Not long after COVID-19 became synonymous with the collapse of tourism, businesses and overburdened health systems, reports of people surfaced who suffered from a condition that became known as Long Covid. In essence, Long Covid is a lingering illness in people who have contracted COVID-19 and then presumably recovered because the virus was no longer detectable. Regardless of how severe the initial onset of COVID-19 manifested itself, a significant proportion of patients report debilitating symptoms long after the virus has been eliminated from their body ^[1].

An Irish study found that over 50% of patients with COVID-19 reported persistent fatigue more than 10 weeks after initial symptoms ^[2]. Likewise, researchers in Italy confirmed troublesome symptoms sixty days after initial onset ^[3]. The US Centers for Disease Control and Prevention similarly concluded ongoing symptoms such as fatigue and cough. They found this to be more prevalent in older people or those suffering from chronic diseases.

But is this a hallmark of SARS-CoV-2 and entirely unexpected? The short answer is no, because there is a range of viruses that cause post-infectious fatigue syndrome. Similar conditions have been reported for Ross River virus, Ebola virus, Dengue Fever virus and SARS coronavirus ^[1], just to name a few. Although the progression of disease and the organ damage they cause is quite different, chronic fatigue is a lingering condition they all share. Interestingly, the symptoms of post-infectious chronic fatigue are remarkably similar to those experienced by people who have Myalgic Encephalomyelitis, commonly known as Chronic Fatigue Syndrome . In fact, Dr Anthony Fauci, the Director of the National Institute for Allergy and Infectious Diseases, reported that patients who had COVID-19 often develop a post-viral syndrome that is remarkably like Chronic Fatigue Syndrome ^[4]. It is too early to tell how long this condition will last post-COVID-19.

The indirect cost of Chronic Fatigue Syndrome is staggering, up to 836 000 and 2.5 million individuals are affected in the United States alone before COVID-19 struck ^[5]. It remains to be seen how many additional cases will be added as a result of this pandemic.

So, what causes post-infectious chronic fatigue? We know that viruses such as SARS-CoV-2 can damage the heart, lungs or kidneys, and the impaired function of these organs would be sufficient to produce chronic fatigue.  Also, patients who have been on ventilators can suffer from post-traumatic stress disorder. Others may develop depression due to their reduced quality of life post-infection. It is highly likely that these psychiatric disorders also lead to chronic fatigue. However, many patients do not present with either physiological symptoms, such as organ damage, or psychiatric conditions and still suffer from post-infectious chronic fatigue ^[1].

To study this further, we can look at earlier research conducted on sufferers of Chronic Fatigue Syndrome. Even back in 1999, it was suspected that Chronic Fatigue Syndrome may have its roots in oxidative stress ^[6]. That lead to the conclusion that acute glutathione depletion may be involved. Some studies have revealed that glutathione is chronically depleted in some sufferers ^[7].

The role of glutathione in preventing oxidative stress is well understood. As an antioxidant, it performs many vital functions inside the cell. In the case of chronic fatigue, there appears to be a tug of war for this critical molecule. The immune system places great demands on glutathione when challenged, as is the case in Chronic Fatigue Syndrome. This can lead to competition for glutathione precursors since the muscular system also relies on glutathione for aerobic muscular contraction ^[8]. As the immune system takes priority in survival, insufficient glutathione may express itself as fatigue since skeletal muscles cannot sustain normal aerobic metabolism.

Time will tell how post-infectious chronic fatigue will progress in COVID-19 patients. It is hoped that further research will identify specific causes that lead to effective treatments. This may ultimately also relieve the symptoms of Chronic Fatigue Syndrome. Glutathione will most likely play a significant role in these studies, and an effective way to supplement cellular glutathione will be needed. Supplementation with gamma-glutamylcysteine has been demonstrated in a human clinical trial to increase cellular glutathione levels regardless of its initial (basal) concentration. And, most importantly, this increase occurred rapidly (within hours) ^[9]. With other supplements, a slight increase in glutathione (GSH) could only be observed after many months of daily supplementation. The recent commercial availability of gamma-glutamylcysteine means that researchers are now able to successfully test the effectiveness of increasing cellular glutathione (GSH) in treating the symptoms of Long Covid and Chronic Fatigue Syndrome.

References

1. Komaroff, A.L. and L. Bateman, Will COVID-19 Lead to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome? Frontiers in Medicine, 2021. 7(1132)
   https://www.frontiersin.org/article/10.3389/fmed.2020.606824
2. Townsend, L., A.H. Dyer, K. Jones, J. Dunne, A. Mooney, F. Gaffney, L. O’Connor, D. Leavy, K. O’Brien, J. Dowds, J.A. Sugrue, D. Hopkins, I. Martin-Loeches, C. Ni Cheallaigh, P. Nadarajan, A.M. McLaughlin, N.M. Bourke, C. Bergin, C. O’Farrelly, C. Bannan, and N. Conlon, Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection. PLoS One, 2020. 15(11): p. e0240784.
   https://doi.org/10.1371/journal.pone.0240784
3. Carfì, A., R. Bernabei, and F. Landi, Persistent Symptoms in Patients After Acute COVID-19. Jama, 2020. 324(6): p. 603-605. 10.1001/jama.2020.12603.
4. Topol, E. and A. Verghese, Fauci to Medscape:‘We’re All In It Together and We’re Gonna Get Through It’. 2020, Medscape.
5. Clayton, E.W., Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An IOM Report on Redefining an Illness. JAMA, 2015. 313(11): p. 1101-1102.
   https://doi.org/10.1001/jama.2015.1346
6. Bounous, G. and J. Molson, Competition for glutathione precursors between the immune system and the skeletal muscle: pathogenesis of chronic fatigue syndrome. Med Hypotheses, 1999. 53(4): p. 347-9. 10.1054/mehy.1998.0780
7. Shungu, D.C., N. Weiduschat, J.W. Murrough, X. Mao, S. Pillemer, J.P. Dyke, M.S. Medow, B.H. Natelson, J.M. Stewart, and S.J. Mathew, Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR Biomed, 2012. 25(9): p. 1073-87. 10.1002/nbm.2772
8. JAMMES, Y., J.G. STEINBERG, O. MAMBRINI, F. BRÉGEON, and S. DELLIAUX, Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise. Journal of Internal Medicine, 2005. 257(3): p. 299-310.
   https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2796.2005.01452.x
9. Zarka, M.H. and W.J. Bridge, Oral administration of γ-glutamylcysteine increases intracellular glutathione levels above homeostasis in a randomised human trial pilot study. Redox Biology, 2017. 11: p. 631-636.
   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5284489/pdf/main.pdf

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GGC was recently used in a study by a group of scientists at the University of New South Wales on cell lines from individuals with cystic fibrosis in a series of revealing in vitro studies [1].  The efficacy of GGC against oxidative stress induced by Pseudomonas aeruginosa, which is a common and chronic pathogen infecting lungs of cystic fibrosis patients was evaluated. When assessed as both a prophylactic and as a treatment GGC effectively attenuated some forms of oxidative stress, while significantly increasing total intracellular glutathione levels, metabolic viability and improving epithelial cell barrier integrity.

Together, these findings indicate that GGC has therapeutic potential for treatment and prevention of oxidative stress-related damage to airways in cystic fibrosis.

For more information see:- https://encyclopedia.pub/4014

Reference

1.            Hewson, C.K.C., A.; Wong, S.L.; Pandzic, E.; Zhong, L.; Fernando, B.S.M.; Awatade, N.T.; Hart-Smith, G.; Whan, R.M.; Thomas, S.R.; Jaffe, A.; Bridge, W.J.; Waters, S.A., Novel Antioxidant Therapy with the Immediate Precursor to Glutathione, γ-Glutamylcysteine (GGC), Ameliorates LPS-Induced Cellular Stress in In Vitro 3D-Differentiated Airway Model from Primary Cystic Fibrosis Human Bronchial Cells. Antoxidants, 2020. 9: p. 1204.  https://www.mdpi.com/2076-3921/9/12/1204/htm

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Author:- Ishika Jaitly

Cataract

A cataract [1-5] is an opacification of the lens and is the leading cause of blindness worldwide. The WHO estimates around 20 million people have bilateral blindness from cataracts. As longevity increases, the impact of cataracts on society is also expected to increase [6].

The three major risk factors in the development of cataracts are ageing, diabetes and exposure to sunlight [7,8], with ageing considered to be the most prominent [9]. While little can be done to modify the risk that advanced age poses, limiting exposure to sunlight is associated with a lower incidence of cataracts. Although not yet fully understood, the likely cause is the ionizing UV radiation spectrum of sunlight. This ionizing radiation promotes oxidative stress in the lens by producing damaging reactive oxygen species (ROS) [5]. Commonly known as free radicals, ROS are primarily quenched by the two principal components of the antioxidant defence system of the lens: Glutathione (GSH) and ascorbic acid [10]. Both are crucial in preventing the gradual loss of transparency of the lens [11], which is the classic symptom of cataracts.

During childhood, the lens possesses the highest levels of GSH of all tissues in the body [11]. However, with increasing age, GSH homeostasis becomes progressively dysfunctional in the centre of the lens [10]. Eventually, this results in chronically insufficient GSH levels to neutralize the ROS, leading to oxidative stress that damages lens proteins. The consequence is the formation of a cataract [10].

Another contributing factor to cataract formation is ascorbic acid, a powerful antioxidant that suffers from the same age-related decline as GSH [10]. Ascorbic acid serves to bolster the antioxidant defence and functional integrity of the lens [10,11]. Experimental evidence has demonstrated that a decrease in ascorbic acid levels is tied to GSH depletion [12]. Dehydroascorbate (DHA), an oxidant, is formed from ascorbic acid during the removal of ROS, yet the enzyme responsible for converting DHA back to ascorbic acid is dependent on GSH. Hence, a decline in GSH negatively affects this critical interconversion between ascorbic acid and DHA [8,10]. Diminishing ascorbic acid levels are inevitably accompanied by the toxic accumulation of DHA, leading to redox imbalance. The build-up of DHA favours the development of cataracts by exacerbating oxidative stress, eventually resulting in damaged lens proteins [8,9]. The fact that this redox imbalance occurs as a consequence of GSH depletion may explain why several clinical trials have provided no evidence of significant cataract prevention arising from the administration of high dosages of ascorbic acid [13]. Therefore, unless GSH levels in the lens are returned to optimal, supplementing with ascorbic acid is unlikely to offer any significant benefit.

Although cataract surgery is currently the primary treatment approach, it is very costly and often associated with complications. The reoccurrence of cataracts is, unfortunately, quite common.  It can reasonably be predicted that cataract formation may be inhibited by maintaining an optimal concentration of GSH in the lens. Supplementation with gamma-glutamylcysteine (GGC) could provide the answer as it has been shown to increase cellular GSH above homeostasis effectively [14].

Macular degeneration

Macular degeneration is an eye disease that causes permanent vision loss. It is triggered by damage to the retinal pigment epithelium (RPE) of the eye resulting in overall blurred vision as well as loss of vision in the centre of the eye. It is a major concern in the elderly and is prevalent in most developed countries. Often, genetic factors predispose individuals to this disease, but unhealthy lifestyle choices such as poor diet or smoking, can also contribute to its development [15]. Since the exact risk factors may be hard to establish, treatment can be challenging [15].

Oxidative stress in the RPE, induced by ROS such as hydrogen peroxide, is hypothesized to be an important driving force in the progression of this disease [16]. This is unsurprising as the RPE has a high level of metabolic activity, and therefore oxygen demand, making it a significant source of ROS [17].  Mitochondria, which are structures within the cells of the RPE that act as energy powerhouses, are particularly susceptible to ROS-induced damage [17]. This further exacerbates ROS production and the ensuing oxidative stress [17], while also leaving the cells of the RPE with insufficient energy to divide and carry out their normal functions.

GSH is undoubtedly the most crucial component of the antioxidant defence of the eye. The chronic depletion of GSH, closely linked to ageing and diabetes, can precipitate cell death and impede cell division in the RPE via the mechanisms described above [18,19]. Increasing the pool of GSH in the RPE through supplementation with GGC [14], can potentially inhibit the progression of macular degeneration. Furthermore, GGC itself may be capable of directly acting as an antioxidant by supporting the activity of the enzyme GSH peroxidase [20], which is responsible for eliminating hydrogen peroxide in the RPE [21].

References

1. Giblin, F.J., Glutathione: a vital lens antioxidant. Journal of Ocular Pharmacology & Therapeutics, 2000. 16(2): p. 121-35.

2. Lou, M.F., Redox regulation in the lens. Progress in Retinal and Eye Research, 2003. 22(5): p. 657-682.

3. Beebe, D.C., and Y.-B. Shui, Progress in Preventing Age-Related Cataract, in Ocular Therapeutics, Y. Thomas, F.C. Abbot, and B.W. Martin, Editors. 2008, Academic Press: London. p. 143-165.

4. Shoham, A., M. Hadziahmetovic, J.L. Dunaief, M.B. Mydlarski, and H.M. Schipper, Oxidative stress in diseases of the human cornea. Free Radical Biology and Medicine, 2008. 45(8): p. 1047-1055.

5. Ho, M.-C., Y.-J. Peng, S.-J. Chen, and S.-H. Chiou, Senile cataracts and oxidative stress. Journal of Clinical Gerontology and Geriatrics, 2010. 1(1): p. 17-21.

6. Beebe, D.C., Y.-B. Shui, and N.M. Holekamp, Biochemical mechanisms of age-related cataract, in Ocular Disease, A.L. Leonard, et al., Editors. 2010, W.B. Saunders: Edinburgh. p. 231-237.

7. Lim, J.C., Arredondo, M.C., Braakhuis, A.J., and Donaldson, P.J., Vitamin C and the Lens: New Insights into Delaying the Onset of Cataract. Nutrients, 2020. 12(10): p. 3142.

8. Kisic, B., Miric, D., Zoric, L., Ilic, A., and Dragojevic, I., Antioxidant Capacity of Lenses with Age-Related Cataract. Oxidative Medicine and Cellular Longevity, 2012. 2012.

9. Truscott, R.J.W., Age-related nuclear cataract—oxidation is the key. Experimental Eye Research, 2005. 80(5): p. 709-725.

10. Lim, J.C., Grey, A.C., Zahraei, A., and Donaldson, P.J., Age‐dependent changes in glutathione metabolism pathways in the lens: New insights into therapeutic strategies to prevent cataract formation-A Review. Clinical and Experimental Ophthalmology, 2020. 48(8): p. 1031–1042.

11. Heruye, S.H., Nkenyi, L.N.M., Singh, N.U., Yalzadeh, D., Ngele, K.K., Njie-Mbye, Y., Ohia, S.E., and Opere, C.A., Current Trends in the Pharmacotherapy of Cataracts. Pharmaceuticals, 2020. 13(1): p. 15.

12. Meister, A., Glutathione-Ascorbic Acid Antioxidant System in Animals. Journal of Biological Chemistry, 1994. 269(13): p. 9397-9400.

13. Fernandez, M.M. and Afshari, N.A., Nutrition and the prevention of cataracts. Current Opinion in Ophthalmology, 2008. 19(1): p. 66-70.

14. Zarka, M.H. and Bridge, W.J., Oral administration of γ-glutamylcysteine increases intracellular glutathione levels above homeostasis in a randomised human trial pilot study. Redox Biology, 2017. 11: p. 631-636.

15. Lim, L.S., Mitchell, P., Seddon, J.M., Holz, F.G., Wong, T.Y., Age-related macular degeneration. The Lancet, 2012. 379(9827): p. 1728-1738.

16. Kularatne, R.N., C. Bulumulla, T. Catchpole, A. Takacs, A. Christie, M.C. Stefan, and K.G. Csaky, Protection of human retinal pigment epithelial cells from oxidative damage using cysteine prodrugs. Free Radical Biology and Medicine, 2020. 152: p. 386-394

17. Yang, M., So, K., Lam, W.C., and Lo, A.C.Y., Novel Programmed Cell Death as Therapeutic Targetsin Age-Related Macular Degeneration? International Journal of Molecular Sciences, 2020. 21(19): p. 7279.

18. Samiec, P.S., C. Drews-Botsch, E.W. Flagg, J.C. Kurtz, P. Sternberg, R.L. Reed, and D.P. Jones, Glutathione in Human Plasma: Decline in Association with Aging, Age-Related Macular Degeneration, and Diabetes. Free Radical Biology and Medicine, 1998. 24(5): p. 699-704.

19. Sun, Y., Zheng, Y., Wang, C., and Liu, Y., Glutathione depletion induces ferroptosis, autophagy, and premature cell senescence in retinal pigment epithelial cells. Cell Death & Disease, 2018. 9(7): p. 753.

20. Quintana-Cabrera, R., Fernandez-Fernandez, S., Bobo-Jimenez, V., Escobar, J., Sastre, J., Almeida, A., and Bolaños, J.P., γ-Glutamylcysteine detoxifies reactive oxygen species by acting as glutathione peroxidase-1 cofactor. Nature Communications, 2012. 3(718): p. 1-8.

21. Cohen, S.M., Olin, K.L., Feuer, W.J., Hjelmeland, L., Keen, C.L., and Morse, L.S., Low glutathione reductase and peroxidase activity in age-related macular degeneration. British Journal of Ophthalmology, 1994. 78(10): p. 791-794.

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A recent review on the role of glutathione in osteoarthritis has revealed a that depleted glutathione exacerbated oxidative stress as seen in chronic inflammatory disorders such as osteoarthritis [3]. In addition, some studies showed that the current treatments for increasing glutathione including supplementation with n-acetylcysteine were showing some minor improvements in symptoms. 

With its ability to be efficiently transported into cells and rapidly increase cellular glutathione, orally administered gamma-glutamylcysteine is expected to show an even greater effect by reducing cartilage degradation and inflammation markers as well as significant improvements in pain and functional outcomes.   

References

1.            Daghestani, H.N. and V.B. Kraus, Inflammatory biomarkers in osteoarthritis. Osteoarthritis and cartilage, 2015. 23(11): p. 1890-1896. https://pubmed.ncbi.nlm.nih.gov/26521734

2.            Zhu, S., et al., Glutathione as a mediator of cartilage oxidative stress resistance and resilience during aging and osteoarthritis. Connective Tissue Research, 2020. 61(1): p. 34-47. https://doi.org/10.1080/03008207.2019.1665035

3.            Setti, T., et al., The protective role of glutathione in osteoarthritis. Journal of Clinical Orthopaedics and Trauma, 2020. https://www.journal-cot.com/article/S0976-5662(20)30440-9/fulltext

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Low levels of glutathione are a hallmark in kidney disease and this is thought to be caused by diminished levels of an enzyme called GCL which is the first step in the production of cellular glutathione. This enzyme is responsible for the production of gamma-glutamylcysteine, the direct precursor to glutathione. Since cysteine is removed from the blood in dialysis patients, supplementing with cysteine has a positive effect on glutathione levels, however it only addresses a small part of the problem. The diminished levels of GCL are of much greater concern. To address this problematic enzyme in dialysis patients, supplementation with gamma-glutamylcysteine has been shown to bypass GCL altogether by providing cells with the first building block of glutathione.  Not only does gamma-glutamylcysteine readily enter cells, once inside it is quickly and easily converted to glutathione.[1]  [2, 3]

References

1. Alhamdani, M.S., Impairment of glutathione biosynthetic pathway in uraemia and dialysis. Nephrol Dial Transplant, 2005. 20(1): p. 124-8.
2. Santangelo, F., et al., Restoring glutathione as a therapeutic strategy in chronic kidney disease. Nephrology Dialysis Transplantation, 2004. 19(8): p. 1951-5.
3. Ashworth, A. and S.T. Webb, Does the prophylactic administration of N-acetylcysteine prevent acute kidney injury following cardiac surgery? Interact CardioVasc Thorac Surg, 2010. 11(3): p. 303-308.

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Complications in the cardiovascular system arise from elevated levels of free radicals which cause tissue damage and interrupt cellular signalling mechanisms [1]. Apart from lifestyle choices, there is a wide range of medical conditions that, by their nature, produce excessive free radicals, including diabetes, hypertension, stroke, and obesity. Whilst small bouts of increased levels of free radicals is normal, indeed required for signalling purposes and immune responses, it is the oxidative stress caused by sustained and excessive free radical production that leads to deleterious health outcomes [2].

Means to prevent this sustained damage caused by oxidative stress have been studies extensively and are of major therapeutic interest [3]. Whilst there is an abundance of pharmacological means to control chronic diseases such as diabetes or hypertension, reducing excessive production of free radicals from all possible sources presents a major challenge.

As the principal intracellular antioxidant, Glutathione has been extensively researched. This interest stems from numerous studies into chronic diseases in which elevated levels of free radicals cause sustained oxidative stress. Glutathione acts directly by scavenging free radicals and several studies have reported that patients with heart disease have lower levels of glutathione. Furthermore, a reduction of glutathione levels was also reported in subjects with asymptomatic CVD, which suggest that measuring and supplementing glutathione levels may help detect and treat such cases early. [1-9]

References

1. Bajic, V.P., et al., Glutathione “Redox Homeostasis” and Its Relation to Cardiovascular Disease. Oxid Med Cell Longev, 2019. 2019: p. 5028181.
2. Goszcz, K., et al., Antioxidants in Cardiovascular Therapy: Panacea or False Hope? Front Cardiovasc Med, 2015. 2: p. 29.
3. Li, H.G., S. Horke, and U. Forstermann, Oxidative stress in vascular disease and its pharmacological prevention. Trends in Pharmacological Sciences, 2013. 34(6): p. 313-319.
4. van der Pol, A., et al., Treating oxidative stress in heart failure: past, present and future. Eur J Heart Fail, 2019. 21(4): p. 425-435.
5. Mistry, R.K. and A.C. Brewer, Redox-Dependent Regulation of Sulfur Metabolism in Biomolecules: Implications for Cardiovascular Health. Antioxid Redox Signal, 2019. 30(7): p. 972-991.
6. Kanaan, G.N. and M.E. Harper, Cellular redox dysfunction in the development of cardiovascular diseases. Biochim Biophys Acta Gen Subj, 2017. 1861(11 Pt A): p. 2822-2829.
7. Go, Y.-M. and D.P. Jones, Cysteine/cystine redox signaling in cardiovascular disease. Free Radical Biology and Medicine, 2011. 50(4): p. 495-509.
8. Houston, M.C., Nutraceuticals, Vitamins, Antioxidants, and Minerals in the Prevention and Treatment of Hypertension. Progress in cardiovascular diseases, 2005. 47(6): p. 396-449.
9. Mills, B.J., et al., Blood glutathione and cysteine changes in cardiovascular disease. Journal of Laboratory & Clinical Medicine, 2000. 135(5): p. 396-401.

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Treatments that focus on enhancing the cellular antioxidant defense mechanism therefore play an important role in combating infertility and complications during pregnancy. Glutathione has shown to be the most effective antioxidant in the body due to its ability to not only boost the antioxidant defense, but also recycle other key antioxidant such as Vitamin C. ^[1-4]

References

1. Agarwal, A. and L.H. Sekhon, The role of antioxidant therapy in the treatment of male infertility. Human Fertility, 2010. 13(4): p. 217-225.
2. Adeoye, O., et al., Review on the role of glutathione on oxidative stress and infertility. JBRA Assist Reprod, 2018. 22(1): p. 61-66.
3. Ross, C., et al., A systematic review of the effect of oral antioxidants on male infertility. Reproductive biomedicine online, 2010. 20(6): p. 711-723.
4. Lanzafame, F.M., et al., Oxidative stress and medical antioxidant treatment in male infertility. Reproductive biomedicine online, 2009. 19(5): p. 638-659.

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