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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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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Additionally, both type 1 and 2 diabetes are associated with low glutathione. [1-9] The resulting oxidative stress and depletion of the cellular antioxidant defense system contributes to the progress of coronary artery disease. This plays a major role in the development of diabetes and its ongoing complications.

Glutathione in its role as a free radical scavenger has been shown to drastically reduce the occurrence and duration of oxidative stress. Enhancing cellular glutathione is therefore of paramount importance in managing diabetes and reducing negative medical outcomes.

References

1. Whillier, S., P.W. Kuchel, and J.E. Raftos, Oxidative Stress in Type II Diabetes Mellitus and the Role of the Endogenous Antioxidant Glutathione, in Role of the Adipocyte in Development of Type 2 Diabetes, C. Croniger, Editor. 2011.
2. Robertson, R.P., et al., Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes, 2003. 52(3): p. 581-7.
3. Ballatori, N., et al., Glutathione dysregulation and the etiology and progression of human diseases. Biological Chemistry, 2009. 390(3): p. 191-214.
4. Sekhar, R.V., et al., Glutathione Synthesis Is Diminished in Patients With Uncontrolled Diabetes and Restored by Dietary Supplementation With Cysteine and Glycine. Diabetes Care, 2011. 34(1): p. 162-167.
5. Sheikh-Ali, M., J.M. Chehade, and A.D. Mooradian, The Antioxidant Paradox in Diabetes Mellitus. American Journal of Therapeutics, 2011. 18(3): p. 266-278 10.1097/MJT.0b013e3181b7badf.
6. van der Crabben, S.N., et al., Erythrocyte glutathione concentration and production during hyperinsulinemia, hyperglycemia, and endotoxemia in healthy humans. Metabolism, 2011. 60(1): p. 99-106.
7. Furfaro, A.L., et al., Impaired synthesis contributes to diabetes-induced decrease in liver glutathione. International Journal of Molecular Medicine, 2012. 29(5): p. 899-905.
8. Pastore, A., et al., All glutathione forms are depleted in blood of obese and type 1 diabetic children. Pediatric Diabetes, 2012. 13(3): p. 272-277.
9. Darmaun, D., et al., Poorly controlled type 1 diabetes is associated with altered glutathione homeostasis in adolescents: apparent resistance to N-acetylcysteine supplementation. Pediatr Diabetes, 2008. 9(6): p. 577-82.

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Before 2014, trialling the use of Glutathione (GSH) as a supplement was uncommon. Clinicians then were well aware of its limited use.  However, several companies started manufacturing and marketing Glutathione (GSH) as a supplement shortly after that, even though there was very little evidence at best to show that it had potential to increase cellular Glutathione (GSH). Nonetheless, this led to researchers testing Glutathione’s (GSH’s) potential, and today, the U.S. Clinical Trial Register has a long list of over 30 completed trials, none of which have published any positive results.

One type of delivery system that keeps appearing in the literature is liposomal Glutathione (GSH). This is simply Glutathione (GSH) encapsulated in a lipid (fatty) membrane. This approach is also doomed to fail for the same reason mentioned above, but one wonders if it is just clever marketing. This strategy can only work for some specific hydrophilic drugs that are not taken up easily by cells. The liposome is a “hack”, if you like, that helps the drug get transported across the cell membrane. But only because the concentration of the drug is higher outside the cell than inside, and thus the diffusion is thermodynamically favourable. Yet even with the potential benefits of liposomal drug delivery, there are very few successful examples on the market. Glutathione (GSH) is certainly not one of them.

References

1. Wu, G., et al., Glutathione metabolism and its implications for health. Journal of Nutrition, 2004. 134(3): p. 489-92.

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Diabetes has become one of the most prominent chronic diseases in many of the world’s populations. Whilst type 1 is genetic in origin, type 2 is primarily a lifestyle disease. Diabetes and the associated hyperglycaemia (high blood glucose) is related to an increase in the production of free radicals by a process called glycation. In essence, it is a process whereby the elevated blood glucose binds to proteins, in turn creating free radicals. The free radicals produced by glycation can be up to 50 times higher than normal and are implicated in ageing and tissue damage.[1]

Additionally, both type 1 and 2 diabetes are associated with low glutathione. [1-9] The resulting oxidative stress and depletion of the cellular antioxidant defense system contributes to the progress of coronary artery disease. This plays a major role in the development of diabetes and its ongoing complications.

Glutathione in its role as a free radical scavenger has been shown to drastically reduce the occurrence and duration of oxidative stress. Enhancing cellular glutathione is therefore of paramount importance in managing diabetes and reducing negative medical outcomes.

Glutathione and infertility

Globally, infertility is a major health problem and can cause significant financial and psychological stress. In many cases, the cause of infertility cannot be established, but oxidative stress is believed to be a major contributor due to its influence on the reproductive lifespan of both men and women.

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. [10-13]

Glutathione and cardiovascular diseases

Cardiovascular disease (CDV) is the number 1 cause of death globally, taking an estimated 18 million lives each year. Whilst an increased risk of CDV is often genetic in origin, the effect of negative lifestyle choices such as excessive alcohol consumption, smoking and poor diet play a well documented role in the development of CVD.

Complications in the cardiovascular system arise from elevated levels of free radicals which cause tissue damage and interrupt cellular signalling mechanisms [14]. 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 [15].

Means to prevent this sustained damage caused by oxidative stress have been studies extensively and are of major therapeutic interest [16]. 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. [14-22]

Glutathione and kidney disease

Oxidative stress is considered a main player in kidney disease and associated mortality rates. This sustained production of free radicals is in part caused by the frequent and regular dialysis required to treat patients. Glutathione demand in these patients is therefore much higher in order to cope with the increased oxidative stress.

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.[23]  [24, 25]

References

1.            Whillier, S., P.W. Kuchel, and J.E. Raftos, Oxidative Stress in Type II Diabetes Mellitus and the Role of the Endogenous Antioxidant Glutathione, in Role of the Adipocyte in Development of Type 2 Diabetes, C. Croniger, Editor. 2011.

2.            Robertson, R.P., et al., Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes, 2003. 52(3): p. 581-7.

3.            Ballatori, N., et al., Glutathione dysregulation and the etiology and progression of human diseases. Biological Chemistry, 2009. 390(3): p. 191-214.

4.            Sekhar, R.V., et al., Glutathione Synthesis Is Diminished in Patients With Uncontrolled Diabetes and Restored by Dietary Supplementation With Cysteine and Glycine. Diabetes Care, 2011. 34(1): p. 162-167.

5.            Sheikh-Ali, M., J.M. Chehade, and A.D. Mooradian, The Antioxidant Paradox in Diabetes Mellitus. American Journal of Therapeutics, 2011. 18(3): p. 266-278 10.1097/MJT.0b013e3181b7badf.

6.            van der Crabben, S.N., et al., Erythrocyte glutathione concentration and production during hyperinsulinemia, hyperglycemia, and endotoxemia in healthy humans. Metabolism, 2011. 60(1): p. 99-106.

7.            Furfaro, A.L., et al., Impaired synthesis contributes to diabetes-induced decrease in liver glutathione. International Journal of Molecular Medicine, 2012. 29(5): p. 899-905.

8.            Pastore, A., et al., All glutathione forms are depleted in blood of obese and type 1 diabetic children. Pediatric Diabetes, 2012. 13(3): p. 272-277.

9.            Darmaun, D., et al., Poorly controlled type 1 diabetes is associated with altered glutathione homeostasis in adolescents: apparent resistance to N-acetylcysteine supplementation. Pediatr Diabetes, 2008. 9(6): p. 577-82.

10.          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.

11.          Adeoye, O., et al., Review on the role of glutathione on oxidative stress and infertility. JBRA Assist Reprod, 2018. 22(1): p. 61-66.

12.          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.

13.          Lanzafame, F.M., et al., Oxidative stress and medical antioxidant treatment in male infertility. Reproductive biomedicine online, 2009. 19(5): p. 638-659.

14.          Bajic, V.P., et al., Glutathione “Redox Homeostasis” and Its Relation to Cardiovascular Disease. Oxid Med Cell Longev, 2019. 2019: p. 5028181.

15.          Goszcz, K., et al., Antioxidants in Cardiovascular Therapy: Panacea or False Hope? Front Cardiovasc Med, 2015. 2: p. 29.

16.          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.

17.          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.

18.          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.

19.          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.

20.          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.

21.          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.

22.          Mills, B.J., et al., Blood glutathione and cysteine changes in cardiovascular disease. Journal of Laboratory & Clinical Medicine, 2000. 135(5): p. 396-401.

23.          Alhamdani, M.S., Impairment of glutathione biosynthetic pathway in uraemia and dialysis. Nephrol Dial Transplant, 2005. 20(1): p. 124-8.

24.          Santangelo, F., et al., Restoring glutathione as a therapeutic strategy in chronic kidney disease. Nephrology Dialysis Transplantation, 2004. 19(8): p. 1951-5.

25.          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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