Healthcare e-Compendium
A joint initiative of DPSRU & DRSC
Healthcare e-Compendium
A joint initiative of DPSRU & DRSC
Author: Dr. Gaurav Maheshwari
MS, MRCS, DNB (Surgical Gastroenterology), Fellow in Liver Transplant & HPB Surgery (S. Korea), GI Surgery, Associate Director, Paras Hospital, Chandigarh
download ArticleAbstract
The novel coronavirus SARS-CoV-2 is continuously spreading across the globe and is affecting a wide range of population. It primarily affect the lungs and weaken the immune systems by immune-mediated processes. Glutathione, a tripeptide, anti‑oxidant, has low levels during the infection and this can affect immunity and different immune-mediated responses. During COVID-19 infection, it is very important to maintain the immunity along with counter the different immune-mediated responses. Glutathione plays an important role against oxidative damage of cells and also regulates various metabolic pathways which are essential to maintain the body homeostasis. Glutathione also promotes detoxification, protein folding, regeneration of vitamins C and E, antiviral defence, regulation of cellular proliferation, and immune response. Hence its importance during infection increase a lot. There are need to the supplements which can maintain the levels of glutathione, vitamin C and E, and other essential components to balance the homeostasis. Glutaup nanoshots is a product which is the novel combination of glutathione, vitamin C, resveratrol and solar vitis (PhytoCellTec) as 8 ml oral solution. Nanoshots can be provided as prophylactic, supportive, or as rehabilitation therapies and enhance immunity by increasing the level of glutathione in body. It helps in improving lung function and reduction in mechanical ventilation. Physician guidance is required to seek the treatment with nanoshots.
Keywords: Glutathione, COVID-19, Immunity, Oxidative stress
Introduction
In December 2019, the first case of novel Coronavirus Disease 2019 (COVID-19) was reported in Wuhan, China, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). Since then, a total of 250,154,972 cases are recorded globally, with 5,054,267 deaths so far [1] and the counting is increasing day by day globally. These deaths are recorded by government agencies and the real toll of deaths might be on higher side than the actual number of these confirmed deaths reported. This gap could be due to limited testing and problems associated with the attribution of cause of death reported during first and second waves. Since its first reporting in China, the COVID-19 spread globally and penetrated through more than 200 countries, and forced World Health Organization (WHO) declare it as a pandemic. The healthcare system collapsed globally and the lockdown was imposed in most of the countries to avoid the contacts and breaking the chain of the virus. At this time, the world seems to be connected virtually by different medium. The infection was at a rapid pace and did not spare anyone including the general public, and the healthcare professionals (doctors, nursing and paramedical staff). Globally, a lot of frontline workers, who were fighting against the virus, sacrificed their lives, serving the humanity. India was no behind the rest of the world [2].
Coronaviruses, a group of viruses, is named due to its crown-like spikes on surface and constitute 4 groups namely alpha, beta, gamma, and delta. This nomenclature was proposed by the expert group that was convened by WHO. This expert group of scientists include WHO Virus Evolution Working Group (now known as the Technical Advisory Group on Virus Evolution), the WHO COVID-19 reference laboratory network, and representatives from GISAID, Nextstrain, Pango and additional experts in virological, microbial nomenclature [3]. The most common human coronaviruses are:
Apart from these, the other types of human coronaviruses include:
Apart from the common human to human transmission, the animals that are infected with coronaviruses can serves as a medium to mutate and originate in a new human coronavirus. The examples of these types include SARS-CoV, 2019-nCoV, and MERS-CoV [3]. As a property of viruses, SARS-CoV2 also undergo mutation and update themselves to constantly change over time. As the virus has the opportunity to penetrate through a large population and causing infection, it has more chances to replicate itself to undergo changes [4]. The published literatures and available data reported that the SARS-CoV-2 has the capacity to mutate at the rate of 1-2 mutations per month [5]. As per WHO, the variants of concerns are presented in table 1.
Table 1: Variants of Concern
Source: https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/
The principal target of the SARS-CoV-2 is respiratory system, but it also affect other parts of body including cardiovascular, renal, gastrointestinal tract (GI), hepatobiliary, and central nervous system. Patients with infection and who have typical clinical signs suspicious of COVID-19 (cough, fever, sore throat, loss of smell and taste, myalgia) should be immediately tested for SARS‑CoV-2. Along with, the patients without symptoms (asymptomatic) should also be tested for SARS‑CoV-2. The diagnosis testing of COVID-19 can be done by molecular testing, serology testing, laboratory assessments, imaging modalities, chest X-rays, chest computed tomography (CT), lung ultrasound etc. The standard diagnostic testing is done by nasopharyngeal swab for SARS-CoV-2 nucleic acid using a real-time polymerase chain reaction (PCR) assays which are validated by the United States Food and Drug Administration (FDA) with emergency use authorizations (EUAs) [6].
Phylogenetically and structurally, SARS-CoV-2 has similarity with SARS-CoV and MERS‑CoV. SARS-CoV-2 enters into the hosts' cells by binding with SARS-CoV-2 spike or S protein (S1) to the Angiotensin-converting enzyme 2 (ACE2) receptors on the respiratory epithelium. Other than the respiratory epithelium, ACE2 receptors are also expressed by other organs (upper esophagus, enterocytes from the ileum, myocardial cells, proximal tubular cells of the kidney, and urothelial cells of the bladder) [6-7]. After viral attachment, there is priming of spike protein S2 subunit by the host transmembrane serine protease 2 (TMPRSS2) which facilitates cell entry and subsequent viral replication endocytosis with the assembly of virions [8]. In the lungs and other tissues of the body, the spike receptor-binding domain (RBD) facilitates the binding to the ACE2 receptor. Functional processing is allowed by spike protein of an amino acid site (polybasic site) and human enzyme furin (protease). The entire process enables the exposure of the fusion sequences and, therefore, the fusion of the viral and cell membranes, a necessary passage for the virus to enter the cell.
The pathogenesis of SARS-CoV-2 induced pneumonia is important to understand and can be divided in 2 stages. In early stage, viral replication results in direct virus-mediated tissue damage and this is followed by a late stage when an immune response is triggered by the infected host cells, resulting in release of cytokines (tumor necrosis factor-α [TNF α], granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukins, and interferons). In the severe condition of COVID-19 infection, cytokine storm can be occurred due to over activity of immune system that causes release of high levels of cytokines, especially IL-6 and TNF-α, and ultimately cause systemic and local inflammatory response [9-10].
Glutathione and SARS-CoV-2
Glutathione is a tripeptide and consists of glutamate, cysteine and glycine, and is an antioxidant that helps in homeostasis and exists in reduced (GSH) and oxidized (GSSG) states in most of the organisms [11]. The de novo synthesis, GSSG, regeneration from the oxidized form, and extracellular GSH uptake are the factors that maintain intracellular GSH balance. In body, glutathione plays an important role, as a cytoprotective, through various mechanisms. The changes in GSH homeostasis are considered to be associated with neurodegenerative diseases, AIDS, liver and heart disease, aging, diabetes mellitus and cancer due to its strong cytoprotective effects [11]. Additionally, Glutathione can also prevent damage to important cellular components caused by reactive oxygen species (ROS) and their derivatives.
When the cells are infected by SARS viruses (that bind ACE2), it results in two effects: inhibition of ACE2 activity and decrease of ACE2 expression in infected cells [12-14]. In SARS-infected patients, high levels of IL-6 in the acute stage associated with lung lesions were found. By the reduction of ROS production, GSH inhibits NF-kB activation and subsequently keeps the cytokine storm under control [15]. The effects of GSH are presented in figure 1.
Figure 1: Effect of GSH
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402141/
There are many functions of GSH and seeing their impact on the severe inflammation in COVID-19, it’s important to throw light on those considering relation to the symptoms appeared in COVID-19. By neutralizing ROS, GSH protects the cells and further establish the relationship between ROS production and pro-inflammatory cytokine activation [16]. Glutathione S-transferase plays an important role to catalyse GSH conjugation to lipophilic xenobiotics and helps in the excretion or further facilitates metabolism of various drugs. GSH can act as a cofactor for many enzymes (prostaglandin H synthase) that helps in regulating vascular functions [11]. GSH helps in synthesizing S-nitrosoglutathione (GSNO), which plays an important role in nitric oxide (NO) signalling. In presence of GSH, NO can effectively modulate vessels and neuronal functions, and as per the local calcium influx, it helps in regulating the blood flow [11].
Glutathione plays an important and critical role in determining individual responsiveness to COVID-19 infection and can be used as a mean for prevention and treatment of COVID-19 infection [17]. There are various studies reporting the role of endogenous glutathione deficiency which attribute decreased biosynthesis and/or increased depletion of GSH. These processes represent a significant contributor to the pathogenesis of various diseases by oxidative stress and inflammation [17]. There are different types of risk factors involved which, along with glutathione deficiency worsen the COVID-19 prognosis. These factors include age, comorbidities, sexual dimorphism, smoking, and dietary factors [17]. By assessing the relationship between these risk factors and serious manifestations, glutathione deficiency can be a major cause for worsening of COVID-19 and ultimate deaths [17]. Along with these factors and decreased biosynthesis of vitamin D, glutathione deficiency can contribute to the serious manifestations and death in COVID-19 patients. The causes for glutathione deficiency and its ultimate relation to the pathogenesis of COVID-19 disease is presented in figure 2.
Figure 2: Causes for Glutathione deficiency and its relation to the pathogenesis of COVID-19 disease
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263077/
Glutathione: Important Properties (Antiviral, Anti-inflammatory, and Anticoagulant)
Improvement in individual’s responsiveness to viral infections has been attributed to the higher levels of glutathione in various studies. Glutathione is considered to protect the host immune cells by its anti-oxidant activity and is vital for functioning of various cells of the immune system [17]. Glutathione is involved in inhibition of replication of various viruses at different stages. Thus, the antiviral mechanism of glutathione helps in preventing increased viral loads and subsequently prevent the cytokine storm into the lungs [17]. One study showed that the incidence of influenza and influenza-like episodes were significantly reduced in high-risk individuals by administering the N-acetylcysteine (NAC, a glutathione precursor) as a 6-month preventive therapy [18]. This further strengthen the antiviral activity of glutathione. In COVID-19 patients, deficiency of glutathione can also promote the increased activation of von Willebrand Factor that can lead to coagulopathy [17].
The balance between ACE and ACE2 is different in each person and the difference can be more prone to inflammation if ACE prevails, especially in COVID-109 patients. The best approach to prevent and to treat infection of COVID-19 is reduction in the oxidative stress secondary to the imbalance between ACE and ACE2 [11]. Oxidative stress constitutes a failure of anti-oxidation defence systems to keep ROS and reactive nitrogen in check. As the glutathione acts as a master oxidant in all tissues, the reduced form in high concentration validate its critical role in regulation of various process including detoxification, antiviral defence, immune response, and protein folding [11].
Glutathione as a Mode for the Treatment and Prevention of COVID-19 Illness
Treatment with anti-oxidants is considered to provide beneficial effects on various diseases attributable by inflammation and consequent to impaired redox homeostasis [19-21]. NAC, a thiol with antioxidant properties, is a substrate in GSH biosynthesis and its protective effects are demonstrated on asthma models of animals by restoring the oxidant-antioxidant balance [22]. In humans also, the administration of NAC and GSH has demonstrated its efficacy in cardiovascular, pulmonary and viral diseases [11]. The correlation between oxidative stress and pathogenesis is established in various pulmonary disease. Patients with idiopathic pulmonary fibrosis (IPF) were reported to have significant low levels of GSH in lung fluids. Various studies have also reported that treatment with anti-oxidants is protective against fibrosis [11]. A case report study observed the efficacy of repeated use of both 2000 mg oral and intravenous injection of glutathione in relieving the severe respiratory symptoms in COVID-19 patients, demonstrating its anti-oxidant properties in COVID-19 [23]. Another approach to restore glutathione synthesis and its concentrations are intake of the products like dietary supplementation that are rich in glutathione precursors (cysteine and glycine) are another approach to restore glutathione synthesis and concentrations. Some studies have demonstrated its effectiveness to reduce the oxidative stress in aged and diseases associated patients with low GSH concentration [24]. NAC is reported to be used in bronchitis; a meta‑analysis reported the reduction in incidence and severity of flares (exacerbations) compared to placebo by administering the standard 1200 mg dose of NAC [25]. As NAC is one of the substrates of GSH biosynthesis, a dose of 1000 mg (corresponding to daily turnover in healthy adults) is a reasonable dose for preventive and therapeutic approach [11].
GlutaUp Nanoshots: a Novel Composition
GlutaUp nanoshots is a combination of glutathione, Vitamin C, resveratrol and solar vitis (PhytoCellTec) in 8 ml oral solution.
As stated in earlier sections, glutathione, a tripeptide, containing glutamate, cysteine, and glycine, has anti-oxidant and anti-inflammatory properties. It promote detoxification, protein folding, antiviral defense, and enhanced immune response. It plays an important role in ACE expression, ACE/ACE2 balance, reduction in ROS production and helps in preventing cytokine storm.
Vitamin C is effective in reducing oxidative stress, has anti-inflammatory properties and influence the cellular immunity and vascular integrity. Glutathione is considered to be act as an anti-oxidant which decrease the inflammation, and ultimately improves immune functions. Glutathione increase the immune functions by enhancing phagocytosis activities (swallowing of harmful microbes and foreign substances), promoting the growth and spread of lymphocytes, which further increase circulating antibodies and attacks on foreign bodies.
Resveratrol (3,4,5-trihydroxy-trans-stilbene), a polyphenol (natural compound) belonging to the family of stilbene, has antioxidative and anti-inflammatory properties. It is a potent antiviral against viruses (SARS-CoV); stimulate immune system by activating CD8 + T lymphocytes and NK cells and regulation of CD4+ suppressive T cells; stimulate the expression of γ-globin genes (leading to increased capacity of hemoglobin to transport oxygen in erythrocytes); and plays an important role in regulation of the RAS and activation of ACE2. It also affect the NF-κB inhibition and activation of both SIRT1 and p53 signalling pathways.
Solar vitis (PhytoCellTec), stem cells from Vitis vinifera, containing extremely high content of polyphenols, has bioactive compounds known for several pharmacological activities such as anti-oxidant, anti-inflammatory, and antimicrobial activities, during chronic illness.
During pre-COVID-19 (as prophylactic agent), during COVID-19 (as a supportive treatment), and post-COVID-19 (as rehabilitation treatment), two nanoshots per day or as per diection of physician can be given.
The mechanism of action of various components of the nanoshots is already described above. Overall, nanoshots enhance or boost immunity by increasing the level of glutathione in body. In patients with mild, moderate, and severe symptoms with oxidative stress it acts by increasing the anti-oxidative and anti-inflammatory activities. It reflects antiviral activity against SARS-CoV viruses and antimicrobial activity during secondary infection. It restore ACE/ACE2 balance in the body, has anticoagulation effect resulting from ROS activity. It also helps in reducing the harmful effects of drugs, improve lung function, and reduce mechanical ventilation. Thus very effective in maintaining glutathione level in COVID-19 patients who lost immunity and are in severe condition.
Conclusion
Deficiency of glutathione in COVID-19 infection is identified as a major concern along with other risk factors and can lead to impaired redox homeostasis and oxidative stress in COVID‑19 patients. During COVID-19 infection, it is very important to maintain the immunity and counter the different immune-mediated responses. Glutathione, being an anti‑oxidant, plays an important role against oxidative damage of cells and also regulates various metabolic pathways which are essential to maintain the body homeostasis. In summary glutathione promotes detoxification, protein folding, regeneration of vitamins C and E, antiviral defence, regulation of cellular proliferation, and immune response. During COVID-19, glutathione level should be maintained and as per physician recommendation, supplements like nanoshots can provide effective boost to the immunity. These nanoshots can be provided as prophylactic, supportive, or as rehabilitation therapies and are effective in increasing the glutathione level in the body and helps in improving lung function and reduction in mechanical ventilation. Physician guidance is required to seek the treatment with nanoshots.
References
