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Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients

  • Alexey Polonikov*
    Alexey Polonikov
    Department of Biology, Medical Genetics and Ecology and Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russian Federation
    *E-mail: [email protected]. Telephone/Fax: +7(4712) 58-81-47.
    More by Alexey Polonikov
    Orcidhttp://orcid.org/0000-0001-6280-247X
Cite this: ACS Infect. Dis. 2020, 6, 7, 1558–1562
Publication Date (Web):May 28, 2020
https://doi.org/10.1021/acsinfecdis.0c00288
Copyright © 2020 American Chemical Society
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Abstract

Higher rates of serious illness and death from coronavirus SARS-CoV-2 (COVID-19) infection among older people and those who have comorbidities suggest that age- and disease-related biological processes make such individuals more sensitive to environmental stress factors including infectious agents like coronavirus SARS-CoV-2. Specifically, impaired redox homeostasis and associated oxidative stress appear to be important biological processes that may account for increased individual susceptibility to diverse environmental insults. The aim of this Viewpoint is to justify (1) the crucial roles of glutathione in determining individual responsiveness to COVID-19 infection and disease pathogenesis and (2) the feasibility of using glutathione as a means for the treatment and prevention of COVID-19 illness. The hypothesis that glutathione deficiency is the most plausible explanation for serious manifestation and death in COVID-19 patients was proposed on the basis of an exhaustive literature analysis and observations. The hypothesis unravels the mysteries of epidemiological data on the risk factors determining serious manifestations of COVID-19 infection and the high risk of death and opens real opportunities for effective treatment and prevention of the disease.

  Note

This article is made available via the ACS COVID-19 subset for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

The novel coronavirus SARS-CoV-2 (COVID-19) continues to spread throughout the globe, affecting more and more people; thus, the identification of effective drugs for disease prevention and treatment is necessary. The overwhelming majority of people infected by SARS-CoV-2 have asymptomatic, mild, or moderate disease, and only 14% and 5% of patients developed severe or critical disease, respectively. (1) Higher rates of serious illness and death from COVID-19 infection among older people and those who have comorbidities suggest that age- and disease-related biological processes make such individuals more sensitive to environmental stress factors including infectious agents like coronavirus SARS-CoV-2. Specifically, impaired redox homeostasis and associated oxidative stress appear to be important biological processes that may account for increased individual susceptibility to diverse environmental insults.
Oxidative stress is a nonspecific pathological condition reflecting an imbalance between the increased production of reactive oxygen species (ROS) and an inability of biological systems to detoxify the reactive intermediates or to repair the resulting damage. (2) Notably, ROS are closely related with aging because they mediate a stress response to age-dependent damage. (3) Mounting evidence supports the concept that oxidative stress and associated inflammation resulting from an increased production of ROS and/or decreased antioxidant defense contribute to the pathogenesis of various chronic diseases, (4) including diabetes and cardiovascular and respiratory diseases, known to increase the risk of severe illness and death in COVID-19 patients. (5) It is also known that virus-induced modulation of the host antioxidant response represents a crucial determinant for the progression of several viral diseases. (6) In this regard, the antioxidant defense system protecting against oxidative stress is of great interest in the context of understanding the mechanisms underlying nonspecific sensitivity or resistance to infectious agents.
Glutathione (a tripeptide consisting of cysteine, glycine, and glutamate) is the most abundant molecular weight antioxidant that plays a crucial role in antioxidant defense against oxidative damage of cells from ROS and is also involved in the regulation of various metabolic pathways essential for whole body homeostasis. (7) The maintenance of the highest (millimolar) concentrations of reduced glutathione (GSH) in most cell types highlights its vital and multifunctional roles in the control of various biological processes such as detoxification of foreign and endogenous compounds, protein folding, regeneration of vitamins C and E, maintenance of mitochondrial function, antiviral defense, regulation of cellular proliferation, apoptosis, and immune response. (7) Despite a number of publications reporting beneficial effects of glutathione on human health, the key role of this powerful antioxidant in human physiology and pathology and in clinical applications still remains underestimated.
The aim of this Viewpoint is to justify (1) the crucial roles of glutathione in determining individual responsiveness to COVID-19 infection and disease pathogenesis and (2) the feasibility of using glutathione as a means for the treatment and prevention of COVID-19 illness.

Does Glutathione Deficiency Worsen COVID-19 Prognosis through the Risk Factors?

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Numerous studies report that endogenous glutathione deficiency attributed to decreased biosynthesis and/or increased depletion of GSH represents a significant contributor to the pathogenesis of various diseases through mechanisms involving oxidative stress and inflammation. Figure 1 summarizes the most common causes responsible for endogenous glutathione deficiency and also the mechanisms through which this deficiency may contribute to the pathogenesis of severe COVID-19 disease.

Figure 1

Figure 1. Factors responsible for endogenous glutathione deficiency and the mechanisms through which this deficiency may contribute to COVID-19 pathogenesis and outcomes. The bottom of the figure shows that the risk factors for severe COVID-19 infection are associated with decrease/depletion of intracellular glutathione. The top of the figure shows the potential mechanisms through which glutathione deficiency could influence clinical manifestations and outcomes in COVID-10 disease. The numbers in brackets indicate PubMed references (PMID).

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Age is a well-recognized risk factor for severe illness, complications, and death from COVID-19 infection. (8) Interestingly, animal and human studies indicate that the levels of endogenous glutathione progressively decline with aging, thereby making cells in the elderly more susceptible to oxidative damage caused by different environmental factors compared to younger individuals.
Comorbidity is considered one of the major risk factors responsible for poor prognosis in COVID-19 patients. (5) Interestingly, the deficiency in endogenous glutathione is common in individuals with chronic diseases as well as in individuals with a worsening prognosis of COVID-19. This means that decreased levels of glutathione occurring in COVID-19 patients with chronic diseases could be a triggering factor that shifts redox homeostasis toward oxidative stress, thereby exacerbating lung inflammation and leading to acute respiratory distress syndrome (ARDS), multiorgan failure, and death.
Sex-related COVID-19 mortality is one of the common epidemiologic findings around the globe, (9) suggesting sexual dimorphism in susceptibility to severe illness. It has been observed that men are significantly more likely to suffer severe effects of COVID-19 infection and experience a higher mortality rate that women. (9) In addition, men have lower plasma levels of reduced glutathione (GSH) than women, making men more susceptible to oxidative stress and inflammation.
Smoking is also considered a risk factor for severe complications and death from COVID-19. (10) Cigarette smoke is known to deplete the cellular glutathione pool in the airways, exacerbating oxidative damage and inflammation in the lung, which is likely the reason why smokers with COVID-19 more likely require intensive medical interventions.
Dietary factors may also contribute to endogenous glutathione deficiency in patients with severe COVID-19 illness. In particular, an insufficient consumption of fresh vegetables and fruits, natural sources of glutathione, seems to be an important but not yet established risk factor responsible for glutathione deficiency in patients with severe COVID-19 illness.
Thus, the relationship between risk factors and serious manifestations and death in COVID-19 patients could be attributable to a common cause, glutathione deficiency.

What Is the Primary Cause of Severe COVID-19 Illness: Glutathione or Vitamin D Deficiency?

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The novel hypothesis that vitamin D (VD) deficiency is responsible for severe manifestations and death in COVID-19 patients has been proposed (11) and is actively being discussed by the scientific community. Several studies reported that glutathione levels positively correlate with active vitamin D. (12,13) It has also been found that lower levels of l-cysteine (a rate-limiting precursor of GSH) and GSH correlated with lower vitamin D binding protein (VDBP) and VD levels in T2D patients (14) . l-cysteine supplementation is known to improve GSH status through upregulation of expression of VDBP, vitamin D 25-hydroxylase, and vitamin D receptor, thereby increasing vitamin D levels and decreasing inflammatory biomarkers in diabetic rats. (15) Interestingly, a recent experimental study (16) showed that GSH deficiency and the associated increased oxidative stress epigenetically alters vitamin D regulatory genes and, as a result, the suppressed gene expression decreases VD biosynthesis, ultimately leading to a secondary deficiency of vitamin D. It is important to note that the replenishment of GSH by l-cysteine treatment beneficially altered epigenetic enzymes methyltransferases and increased the expression of VD-metabolism genes. This study provides important information that glutathione is essential for the control of endogenous vitamin D biosynthesis and demonstrates potential benefits of GSH treatment in reducing the deficiency of vitamin D. Taken together, these findings suggest that glutathione deficiency rather than vitamin D deficiency is a primary cause underlying biochemical abnormalities, including the decreased biosynthesis of vitamin D, and is responsible for serious manifestations and death in COVID-19 patients.

Antiviral, Anti-Inflammatory, and Anticoagulant Properties of Glutathione

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Several studies indicate that higher levels of glutathione may improve an individual’s responsiveness to viral infections. In particular, glutathione is known to protect host immune cells through its antioxidant mechanism and is also responsible for optimal functioning of a variety of cells that are part of the immune system. It is important to note that there is evidence that glutathione inhibits replication of various viruses at different stages of the viral life cycle (Figure 1), and this antiviral property of GSH seems to prevent increased viral loads and the subsequent massive release of inflammatory cells into the lung (“cytokine storm”).
The antiviral activity of glutathione was demonstrated in a study of De Flora et al. (17) who showed that a 6 month preventive administration of N-acetylcysteine (NAC, glutathione precursor) significantly reduced the incidence of clinically apparent influenza and influenza-like episodes, especially in elderly high-risk individuals. In addition, pathophysiological conditions such as lung cell injury and inflammation in patients with severe ARDS were identified as the targets of NAC treatment. In particular, the deficiency of reduced glutathione in the alveolar fluid in ARDS patients was found to enhance lung cell injury by ROS/oxidative stress and inflammation, and this damage could be effectively prevented and treated by the administration of NAC (Figure 1).Glutathione deficiency could also promote the increased activation of von Willebrand Factor causing coagulopathy in COVID-19 patients.

Glutathione Deficiency Exacerbates COVID-19 Illness: My Observations

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Kursk State Medical University has been involved in a project on genetics of redox homeostasis in type 2 diabetes (T2D) since December, 2016. In April 2020, four patients from the control group were confirmed to have COVID-19. Blood samples were collected from the patients and used to measure total plasma ROS and GSH levels immediately after blood sampling. All four patients were females, nonsmokers, and without chronic diseases. Table 1 shows a description of the cases. Patients with moderate and severe COVID-19 illness had lower levels of glutathione and higher ROS and ROS/GSH ratio in plasma than patients with mild disease, clearly indicating glutathione deficiency and oxidative stress signs in patients with serious disease manifestations. Notably, only the patient with severe illness and a marked glutathione decrease is still severely sick, whereas the other patients with high/moderate levels of GSH have recovered.
Table 1. Clinical and Laboratory Characteristics of Four COVID-19 Patientsa
cases disease severity BMI, kg/m2/family history (FH) day of clinical onset after contact with infected patient clinical symptoms day when symptoms disappeared parameters of redox status, μmol/Lb
1. female M. (age 34) mild 23.8 8 fever 38 °C, mild myalgia 6 GSH, 0.712; ROS, 2.075; ROS/GSH ratio, 2.9
2. female P. (age 47) mild 21.0 10 fever 37.3 °C, mild fatigue 4 GSH, 0.933; ROS, 1.143; ROS/GSH ratio, 1.2
3. female C. (age 44) severe 22.5, FH for diabetes 4 daily fever between 37.1 and 38.5 °C, dry cough, hoarseness, significant myalgia and fatigue (radiographic findings of pneumonia) still sick, 24th day of illness (03.05.2020) GSH, 0.079 (!); ROS, 2.73; ROS/GSH ratio, 34.6 (!)
4. female R. (age 56) moderate-to-severe 33.0, FH for diabetes 7 fever up to 39 °C, a severe dry cough, dyspnea, significant fatigue and tachycardia (radiographic findings of pneumonia) 16 GSH, 0.531; ROS, 3.677 (!); ROS/GSH ratio, 6.9 (!)
a

All four cases were nonsmokers without a history of chronic diseases. COVID-19 infection was confirmed by a PCR test in all cases.

b

The parameters were measured 2 months before the patients became infected with coronavirus SARS-CoV-2.

Hypothesis

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Endogenous glutathione deficiency appears to be a crucial factor enhancing SARS-CoV-2-induced oxidative damage of the lung and, as a result, leads to serious manifestations, such as acute respiratory distress syndrome, multiorgan failure, and death in COVID-19 patients. When the antiviral activity of GSH is taken into account, individuals with glutathione deficiency seem to have a higher susceptibility for uncontrolled replication of SARS-CoV-2 virus and thereby suffer from an increasing viral load. The severity of clinical manifestations in COVID-19 patients is apparently determined by the degree of impaired redox homeostasis attributable to the deficiency of reduced glutathione and increased ROS production. This assumption can be supported by our findings. In particular, COVID-19 patients with moderate and severe illness had lower levels of glutathione, higher ROS levels, and greater redox status (ROS/GSH ratio) than COVID-19 patients with a mild illness. Long-term and severe manifestations of COVID-19 infection in one of our patients with marked glutathione deficiency suggest that the degree of glutathione decrease correlates negatively with viral replication rate and that an increasing viral load exacerbates oxidative damage of the lung. This finding suggests that the virus cannot actively replicate at higher levels of cellular glutathione, and therefore, milder clinical symptoms are observed with lower viral loads.
Glutathione deficiency is an acquired condition attributable to decreased biosynthesis and/or increased depletion of the endogenous GSH pool influenced by risk factors such as aging, male sex, comorbidity, and smoking alone or in combinations. Glutathione deficiency in COVID-19 patients with serious illness may also be a result of decreased consumption of fresh vegetables and fruits (especially during winter and spring seasons), which contributes to over 50% of dietary glutathione intake.The hypothesis suggests that SARS-CoV-2 virus poses a danger only for people with endogenous glutathione deficiency, regardless which of the factors aging, chronic disease comorbidity, smoking or some others were responsible for this deficit. The hypothesis provides novel insights into the etiology and mechanisms responsible for serious manifestations of COVID-19 infection and justifies promising opportunities for effective treatment and prevention of the illness through glutathione recovering with N-acetylcysteine and reduced glutathione.
Since the antiviral effect of glutathione is nonspecific, there is reason to believe that glutathione is also active against SARS-CoV-2. Therefore, restoration of glutathione levels in COVID-19 patients would be a promising approach for the management of the novel coronavirus SARS-CoV-2. Notably, long-term oral administration of N-acetylcysteine has already been tested as an effective preventive measure against respiratory viral infections. (1) N-Acetylcysteine is widely available, safe, and cheap and could be used in an “off-label” manner. Moreover, parenteral injection of NAC or reduced glutathione (GSH is more bioavailable than NAC) could be an efficient therapy for COVID-19 patients with serious illness. Horowitz et al. (18) just published a paper confirming this hypothesis: the authors reported the efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia. Nonetheless, the proposed hypothesis has to be confirmed in larger epidemiological and experimental studies, and also, clinical trials are needed to objectively assess the efficacy of N-acetylcysteine and reduced glutathione for the treatment and prevention of COVID-19 infection.

Author Information

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  • Corresponding Author
    • Alexey Polonikov - Department of Biology, Medical Genetics and Ecology and Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russian Federation;  Orcidhttp://orcid.org/0000-0001-6280-247X;  Email: [email protected]
    • Notes
      The author declares no competing financial interest.

    Acknowledgments

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    I am grateful to my colleague Dr. Iuliia Azarova at Kursk State Medical University for sharing clinical and laboratory data of the patients with me.

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      Since Dec., 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiol. and clin. characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clin. course of illness, including viral shedding, have not been well described. In this retrospective, multicenter cohort study, we included all adult inpatients (≥18 yr old) with lab.-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demog., clin., treatment, and lab. data, including serial samples for viral RNA detection, were extd. from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors assocd. with in-hospital death. One hundred ninety-one patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. Ninety-one (48%) patients had a comorbidity, with hypertension being the most common (58 patients), followed by diabetes (36 patients) and coronary heart disease (15 patients). Multivariable regression showed increasing odds of in-hospital death assocd. with older age, higher Sequential Organ Failure Assessment (SOFA) score, and d-dimer >1μg/L on admission. Median duration of viral shedding was 20·0 days (IQR 17·0-24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest obsd. duration of viral shedding in survivors was 37 days. The potential risk factors of older age, high SOFA score, and d-dimer >1μg/L could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future.
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      Borges do Nascimento, I. J., Cacic, N., Abdulazeem, H. M., von Groote, T. C., Jayarajah, U., Weerasekara, I., Esfahani, M. A., Civile, V. T., Marusic, A., Jeroncic, A., Carvas Junior, N., Pericic, T. P., Zakarija-Grkovic, I., Meirelles Guimarães, S. M., Luigi Bragazzi, N., Bjorklund, M., Sofi-Mahmudi, A., Altujjar, M., Tian, M., Arcani, D. M. C., O’Mathúna, D. P., and Marcolino, M. S. (2020) Novel Coronavirus Infection (COVID-19) in Humans: A Scoping Review and Meta-Analysis. J. Clin. Med. 9, 941,  DOI: 10.3390/jcm9040941
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      Vardavas, C. I. and Nikitara, K. (2020) COVID-19 and smoking: A systematic review of the evidence. Tob. Induced Dis. 18, 20,  DOI: 10.18332/tid/119324
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      COVID-19 and smoking: A systematic review of the evidence
      Vardavas Constantine I; Vardavas Constantine I; Nikitara Katerina
      Tobacco induced diseases (2020), 18 (), 20 ISSN:.
      There is no expanded citation for this reference.
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    11. 11
      Grant, W. B., Lahore, H., McDonnell, S. L., Baggerly, C. A., French, C. B., Aliano, J. L., and Bhattoa, H. P. (2020) Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients 12, 988,  DOI: 10.3390/nu12040988
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      11
      Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths
      Grant, William B.; Lahore, Henry; McDonnell, Sharon L.; Baggerly, Carole A.; French, Christine B.; Aliano, Jennifer L.; Bhattoa, Harjit P.
      Nutrients (2020), 12 (4), 988CODEN: NUTRHU; ISSN:2072-6643. (MDPI AG)
      A review. The world is in the grip of the COVID-19 pandemic. Public health measures that can reduce the risk of infection and death in addn. to quarantines are desperately needed. This article reviews the roles of vitamin D in reducing the risk of respiratory tract infections, knowledge about the epidemiol. of influenza and COVID-19, and how vitamin D supplementation might be a useful measure to reduce risk. Through several mechanisms, vitamin D can reduce risk of infections. Those mechanisms include inducing cathelicidins and defensins that can lower viral replication rates and reducing concns. of pro-inflammatory cytokines that produce the inflammation that injures the lining of the lungs, leading to pneumonia, as well as increasing concns. of anti-inflammatory cytokines. Several observational studies and clin. trials reported that vitamin D supplementation reduced the risk of influenza, whereas others did not. Evidence supporting the role of vitamin D in reducing risk of COVID-19 includes that the outbreak occurred in winter, a time when 25-hydroxyvitamin D (25(OH)D) concns. are lowest; that the no. of cases in the Southern Hemisphere near the end of summer are low; that vitamin D deficiency has been found to contribute to acute respiratory distress syndrome; and that case-fatality rates increase with age and with chronic disease comorbidity, both of which are assocd. with lower 25(OH)D concn. To reduce the risk of infection, it is recommended that people at risk of influenza and/or COVID-19 consider taking 10,000 IU/d of vitamin D3 for a few weeks to rapidly raise 25(OH)D concns., followed by 5000 IU/d. The goal should be to raise 25(OH)D concns. above 40-60 ng/mL (100-150 nmol/L). For treatment of people who become infected with COVID-19, higher vitamin D3 doses might be useful. Randomized controlled trials and large population studies should be conducted to evaluate these recommendations.
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    12. 12
      Alvarez, J. A., Chowdhury, R., Jones, D. P., Martin, G. S., Brigham, K. L., Binongo, J. N., Ziegler, T. R., and Tangpricha, V. (2014) Vitamin D status is independently associated with plasma glutathione and cysteine thiol/disulphide redox status in adults. Clin. Endocrinol. (Oxford, U. K.) 81, 458– 466,  DOI: 10.1111/cen.12449
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      12
      Vitamin D status is independently associated with plasma glutathione and cysteine thiol/disulphide redox status in adults
      Alvarez, Jessica A.; Chowdhury, Ritam; Jones, Dean P.; Martin, Greg S.; Brigham, Kenneth L.; Binongo, Jose N.; Ziegler, Thomas R.; Tangpricha, Vin
      Clinical Endocrinology (Oxford, United Kingdom) (2014), 81 (3), 458-466CODEN: CLECAP; ISSN:0300-0664. (Wiley-Blackwell)
      Objective : Redox status and inflammation are important in the pathophysiol. of numerous chronic diseases. Epidemiol. studies have linked vitamin D status to a no. of chronic diseases. We aimed to examine the relationships between serum 25-hydroxyvitamin D [25(OH)D] and circulating thiol/disulfide redox status and biomarkers of inflammation. Design : This was a cross-sectional study of N = 693 adults (449 females, 244 males) in an apparently healthy, working cohort in Atlanta, GA. Plasma glutathione (GSH), cysteine (Cys) and their assocd. disulfides were detd. with high-performance liq. chromatog., and their redox potentials (Eh GSSG and Eh CySS) were calcd. using the Nernst equation. Serum inflammatory markers included interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor-α, assayed on a multiplex platform, and C-reactive protein (CRP), assayed com. Relationships were assessed with multiple linear regression analyses. Results : Serum 25(OH)D was pos. assocd. with plasma GSH (β ± SE: 0·002 ± 0·0004) and neg. assocd. with plasma Eh GSSG (β ± SE: -0·06 ± 0·01) and Cys (β ± SE: -0·01 ± 0·003) (P < 0·001 for all); statistical significance remained after adjusting for age, gender, race, percentage body fat and traditional cardiovascular risk factors (P = 0·01-0·02). The inverse relationship between serum 25(OH)D and CRP was confounded by percentage body fat, and full adjustment for covariates attenuated serum 25(OH)D relationships with other inflammatory markers to nonstatistical significance. Conclusions : Serum 25(OH)D concns. were independently assocd. with major plasma thiol/disulfide redox systems, suggesting that vitamin D status may be involved in redox-mediated pathophysiol.
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    13. 13
      Jain, S. K., Micinski, D., Huning, L., Kahlon, G., Bass, P. F., and Levine, S. N. (2014) Vitamin D and L-cysteine levels correlate positively with GSH and negatively with insulin resistance levels in the blood of type 2 diabetic patients. Eur. J. Clin. Nutr. 68, 1148– 1153,  DOI: 10.1038/ejcn.2014.114
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      13
      Vitamin D and L-cysteine levels correlate positively with GSH and negatively with insulin resistance levels in the blood of type 2 diabetic patients
      Jain, S. K.; Micinski, D.; Huning, L.; Kahlon, G.; Bass, P. F.; Levine, S. N.
      European Journal of Clinical Nutrition (2014), 68 (10), 1148-1153CODEN: EJCNEQ; ISSN:0954-3007. (Nature Publishing Group)
      Background/Objectives: Vitamin D, L-cysteine (LC) and glutathione (GSH) levels are lower in the blood of diabetic patients. This study examd. the hypothesis that the levels of vitamin D and LC correlate with those of GSH in the blood of type 2 diabetic patients (T2D), and that vitamin D and LC upregulate glutamate-cysteine ligase (GCLC), which catalyzes GSH biosynthesis, in cultured monocytes. Subjects/Methods: Fasting blood was obtained after written informed consent from T2D (n=79) and healthy controls (n=22). U937 monocytes were pretreated with 1,25 (OH)2 vitamin D (0-25 nM) or LC (0-500 μM) for 24 h and then exposed to control or high glucose (25 mM) for 4 h. Results: Plasma levels of vitamin D, LC, GSH and GCLC protein were significantly lower in T2D vs. those in age-matched healthy controls. Multiple linear regression analyses and adjustment for body wt. showed a significant pos. correlation between plasma levels of vitamin D (r=0.26, P=0.05) and LC (r=0.81, P=0.001) and that of GSH, and between LC and vitamin D (r=0.27, P=0.045) levels. Plasma levels of GSH (r=-0.34, P=0.01) and LC (r=-0.33, r=0.01) showed a neg. correlation with triglyceride levels. Vitamin D correlated inversely with HbA1C (-0.30, P=0.01) and homeostatic model assessment insulin resistance (r=-0.31, P=0.03), which showed a significant pos. correlation with triglycerides (r=0.44, P=0.001) in T2D. Cell culture studies demonstrate that supplementation with vitamin D and LC significantly increased GCLC expression and GSH formation in control and high-glucose-treated monocytes. Conclusions: This study suggests a pos. relationship between the concns. of the micronutrients vitamin D and LC and that of GSH. Some of the beneficial effects of vitamin D and LC supplementation may be mediated by an increase in the levels of GSH and a decrease in triglyceride levels in T2D patients.
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    14. 14
      Jain, S. K., Kahlon, G., Bass, P., Levine, S. N., and Warden, C. (2015) Can L-Cysteine and Vitamin D Rescue Vitamin D and Vitamin D Binding Protein Levels in Blood Plasma of African American Type 2 Diabetic Patients?. Antioxid. Redox Signaling 23, 688– 693,  DOI: 10.1089/ars.2015.6320
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      14
      Can L-Cysteine and Vitamin D Rescue Vitamin D and Vitamin D Binding Protein Levels in Blood Plasma of African American Type 2 Diabetic Patients?
      Jain, Sushil K.; Kahlon, Gunjan; Bass, Pat; Levine, Steven N.; Warden, Cassandra
      Antioxidants & Redox Signaling (2015), 23 (8), 688-693CODEN: ARSIF2; ISSN:1523-0864. (Mary Ann Liebert, Inc.)
      Aims: Vitamin D (VD) deficiency has become a worldwide epidemic, particularly affecting African Americans (AA). VD deficiency has been implicated in the excessive rate of complications assocd. with diabetes in AA. Blood levels of VD binding protein (VDBP) and glutathione (GSH) are lower in AA compared with those in Caucasians. This study tested the hypothesis that lower GSH levels are linked to VDBP and VD deficiency in AA-type 2 diabetic (AA-T2D) patients. Blood was analyzed from T2D and nondiabetic subjects (N). Expts. examg. GSH deficiency and L-cysteine (LC) supplementation were performed using THP-1 monocytes. Results: Plasma levels of LC, GSH, VDBP, and VD were significantly lower in AA-T2D compared with age-matched AA-N or Caucasian-T2D. Lower levels of LC and GSH showed a significant pos. correlation with lower VDBP and VD levels in AA-T2D. GSH deficiency investigated using an antisense approach depleted VDBP/vitamin D receptor (VDR); LC supplementation caused significant upregulation of GSH and of VDBP/VDR, while supplementation with VD+LC caused a significantly greater GSH and VDBP/VDR upregulation compared with that of VD alone in monocytes. Innovation and Conclusion: The reported observations suggest that VD deficiency may be linked to GSH and LC status and lead to a novel hypothesis that supplementation with LC in combination with VD will be effective in increasing VD levels and reducing health disparities in AA. Antioxid. Redox Signal. 23, 688-693.
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    15. 15
      Jain, S. K., Kanikarla-Marie, P., Warden, C., and Micinski, D. (2016) L-cysteine supplementation upregulates glutathione (GSH) and vitamin D binding protein (VDBP) in hepatocytes cultured in high glucose and in vivo in liver, and increases blood levels of GSH, VDBP, and 25-hydroxy-vitamin D in Zucker diabetic fatty rats. Mol. Nutr. Food Res. 60, 1090– 1098,  DOI: 10.1002/mnfr.201500667
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      15
      L-cysteine supplementation upregulates glutathione (GSH) and vitamin D binding protein (VDBP) in hepatocytes cultured in high glucose and in vivo in liver, and increases blood levels of GSH, VDBP, and 25-hydroxy-vitamin D in Zucker diabetic fatty rats
      Jain, Sushil K.; Kanikarla-Marie, Preeti; Warden, Cassandra; Micinski, David
      Molecular Nutrition & Food Research (2016), 60 (5), 1090-1098CODEN: MNFRCV; ISSN:1613-4125. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Scope : Vitamin D binding protein (VDBP) status has an effect on and can potentially improve the status of 25(OH) vitamin D and increase the metabolic actions of 25(OH) vitamin D under physiol. and pathol. conditions. Diabetes is assocd. with lower levels of glutathione (GSH) and 25(OH) vitamin D. This study examd. the hypothesis that upregulation of GSH will also upregulate blood levels of VDBP and 25(OH) vitamin D in type 2 diabetic rats. Methods and results : L-cysteine (LC) supplementation was used to upregulate GSH status in a FL83B hepatocyte cell culture model and in vivo using Zucker diabetic fatty (ZDF) rats. Results show that LC supplementation upregulates both protein and mRNA expression of VDBP and vitamin D receptor (VDR) and GSH status in hepatocytes exposed to high glucose, and that GSH deficiency, induced by glutamate cysteine ligase knockdown, resulted in the downregulation of GSH, VDBP, and VDR and an increase in oxidative stress levels in hepatocytes. In vivo, LC supplementation increased GSH and protein and mRNA expression of VDBP and vitamin D 25-hydroxylase (CYP2R1) in the liver, and simultaneously resulted in elevated blood levels of LC and GSH, as well as increases in VDBP and 25(OH) vitamin D levels, and decreased inflammatory biomarkers in ZDF rats compared with those in placebo-supplemented ZDF rats consuming a similar diet. Conclusion : LC supplementation may provide a novel approach by which to raise blood levels of VDBP and 25(OH) vitamin D in type 2 diabetes.
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    16. 16
      Parsanathan, R. and Jain, S. K. (2019) Glutathione deficiency induces epigenetic alterations of vitamin D metabolism genes in the livers of high-fat diet-fed obese mice. Sci. Rep. 9, 14784,  DOI: 10.1038/s41598-019-51377-5
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      Glutathione deficiency induces epigenetic alterations of vitamin D metabolism genes in the livers of high-fat diet-fed obese mice
      Parsanathan Rajesh; Jain Sushil K
      Scientific reports (2019), 9 (1), 14784 ISSN:.
      Obesity has been correlating with low levels of glutathione (GSH) and 25-hydroxyvitamin D3 (25(OH)VD3). The liver is the principal site for the 25(OH)VD3 biosynthesis. This study investigated whether GSH deficiency induces epigenetic alterations that impair Vitamin D (VD) metabolism genes in the livers of HFD-fed mice. The expression of the VD metabolism genes CYP2R1 and CYP27A1 (25-hydroxylase), CYP27B1 (1-α-hydroxylase), and vitamin D receptor (VDR) were downregulated in the livers of mice fed an HFD (GSH- deficient) compared with control diet-fed group. The expression of CYP24A1 (24-hydroxylase) was significantly increased, which catabolizes both 25(OH)VD3 and 1α,25-hydroxyvitaminD3. Gene-specific hypermethylation of 25-hydroxylase, 1-α-hydroxylase, and VDR, and hypomethylation of CYP24A1 was observed in HFD-fed mice. GSH deficiency induced in cultured hepatocytes caused an increase in oxidative stress and alterations in VD regulatory genes. Similarly, elevated global DNA methylation, Dnmt activity, and 5-methylcytosine but decreased Tet activity and 5-hydroxymethylcytosine were observed in the GSH-deficient hepatocytes and the liver of HFD-fed mice. Replenishment of GSH by its prodrugs treatment beneficially altered epigenetic enzymes, and VD-metabolism genes in hepatocytes. HFD-induces GSH deficiency and epigenetically alters VD-biosynthesis pathway genes. This provides a biochemical mechanism for the VD-deficiency and potential benefits of GSH treatment in reducing 25(OH)VD3-deficiency.
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    17. 17
      De Flora, S., Grassi, C., and Carati, L. (1997) Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. Eur. Respir. J. 10, 1535– 1541,  DOI: 10.1183/09031936.97.10071535
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      Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment
      De Flora, S.; Grassi, C.; Carati, L.
      European Respiratory Journal (1997), 10 (7), 1535-1541CODEN: ERJOEI; ISSN:0903-1936. (Munksgaard)
      N-acetylcysteine (NAC), an analog and precursor of reduced glutathione, has been in clin. use for more than 30 yrs as a mucolytic drug. It has also been proposed for and/or used in the therapy and/or prevention of several respiratory diseases and of diseases involving an oxidative stress, in general. The objective of the present study was to evaluate the effect of long-term treatment with NAC on influenza and influenza-like episodes. A total of 262 subjects of both sexes (78% ≥65 yrs, and 62% suffering from non-respiratory chronic degenerative diseases) were enrolled in a randomized, double-blind trial involving 20 Italian Centers. They were randomized to receive either placebo or NAC tablets (600 mg) twice daily for 6 mo. Patients suffering from chronic respiratory diseases were not eligible, to avoid possible confounding by an effect of NAC on respiratory symptoms. NAC treatment was well tolerated and resulted in a significant decrease in the frequency of influenza-like episodes, severity, and length of time confined to bed. Both local and systemic symptoms were sharply and significantly reduced in the NAC group. Frequency of seroconversion towards A/H1N1 Singapore 6/86 influenza virus was similar in the two groups, but only 25% of virus-infected subjects under NAC treatment developed a symptomatic form, vs. 79% in the placebo group. Evaluation of cell-mediated immunity showed a progressive, significant shift from anergy to normoergy following NAC treatment. Administration of N-acetylcysteine during the winter, thus, appears to provide a significant attenuation of influenza and influenza-like episodes, esp. in elderly high-risk individuals. N-acetylcysteine did not prevent A/H1N1 virus influenza infection but significantly reduced the incidence of clin. apparent disease.
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      Horowitz, R. I., Freeman, P. R., and Bruzzese, J. (2020) Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases. Respir Med. Case Rep 30, 101063,  DOI: 10.1016/j.rmcr.2020.101063
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      18
      Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases
      Horowitz Richard I; Horowitz Richard I; Freeman Phyllis R; Bruzzese James
      Respiratory medicine case reports (2020), 30 (), 101063 ISSN:2213-0071.
      PURPOSE: Infection with COVID-19 potentially can result in severe outcomes and death from "cytokine storm syndrome", resulting in novel coronavirus pneumonia (NCP) with severe dyspnea, acute respiratory distress syndrome (ARDS), fulminant myocarditis and multiorgan dysfunction with or without disseminated intravascular coagulation. No published treatment to date has been shown to adequately control the inflammation and respiratory symptoms associated with COVID-19, apart from oxygen therapy and assisted ventilation. We evaluated the effects of using high dose oral and/or IV glutathione in the treatment of 2 patients with dyspnea secondary to COVID-19 pneumonia. METHODS: Two patients living in New York City (NYC) with a history of Lyme and tick-borne co-infections experienced a cough and dyspnea and demonstrated radiological findings consistent with novel coronavirus pneumonia (NCP). A trial of 2 g of PO or IV glutathione was used in both patients and improved their dyspnea within 1 h of use. Repeated use of both 2000 mg of PO and IV glutathione was effective in further relieving respiratory symptoms. CONCLUSION: Oral and IV glutathione, glutathione precursors (N-acetyl-cysteine) and alpha lipoic acid may represent a novel treatment approach for blocking NF-κB and addressing "cytokine storm syndrome" and respiratory distress in patients with COVID-19 pneumonia.
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    • Figure 1

      Figure 1. Factors responsible for endogenous glutathione deficiency and the mechanisms through which this deficiency may contribute to COVID-19 pathogenesis and outcomes. The bottom of the figure shows that the risk factors for severe COVID-19 infection are associated with decrease/depletion of intracellular glutathione. The top of the figure shows the potential mechanisms through which glutathione deficiency could influence clinical manifestations and outcomes in COVID-10 disease. The numbers in brackets indicate PubMed references (PMID).

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      This article references 18 other publications.

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        Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China summary of a report of 72,314 cases from the Chinese center for disease control and prevention
        Wu, Zunyou; McGoogan, Jennifer M.
        JAMA, the Journal of the American Medical Association (2020), 323 (13), 1239-1242CODEN: JAMAAP; ISSN:1538-3598. (American Medical Association)
        The Chinese Center for Disease Control and Prevention recently published the largest case series to date of coronavirus disease 2019 (COVID-19) in mainland China (72,314 cases, updated through Feb. 11, 2020). This Viewpoint summarizes key findings from this report and discusses emerging understanding of and lessons from the COVID-19 epidemic.
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        A review is given with 53 refs. Oxidative stress, defined as a disturbance in the balance between the prodn. of reactive O species (free radicals) and antioxidant defenses, is discussed in relation to its possible role in the prodn. of tissue damage in diabetes mellitus. Important free radicals are described and biol. sources of origin discussed, together with the major antioxidant defense mechanisms. Examples of the possible consequences of free radical damage are provided with special emphasis on lipid peroxidn. Finally, the question of whether oxidative stress is increased in diabetes mellitus is discussed.
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        https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXht1yhsbs%253D&md5=44a8934087388b7389b0a44305aa0eef
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        Taking a "good" look at free radicals in the aging process
        Hekimi, Siegfried; Lapointe, Jerome; Wen, Yang
        Trends in Cell Biology (2011), 21 (10), 569-576CODEN: TCBIEK; ISSN:0962-8924. (Elsevier B.V.)
        A review. The mitochondrial free radical theory of aging (MFRTA) proposes that aging is caused by damage to macromols. by mitochondrial reactive oxygen species (ROS). This is based on the obsd. assocn. of the rate of aging and the aged phenotype with the generation of ROS and oxidative damage. However, recent findings, in particular in Caenorhabditis elegans but also in rodents, suggest that ROS generation is not the primary or initial cause of aging. Here, we propose that ROS are tightly assocd. with aging because they play a role in mediating a stress response to age-dependent damage. This could generate the obsd. correlation between aging and ROS without implying that ROS damage is the earliest trigger or main cause of aging.
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        Pisoschi, A. M. and Pop, A. (2015) The role of antioxidants in the chemistry of oxidative stress: A review. Eur. J. Med. Chem. 97, 55– 74,  DOI: 10.1016/j.ejmech.2015.04.040
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        The role of antioxidants in the chemistry of oxidative stress: A review
        Pisoschi, Aurelia Magdalena; Pop, Aneta
        European Journal of Medicinal Chemistry (2015), 97 (), 55-74CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
        A review. This Review Article is focused on the action of the reactive oxygenated species in inducing oxidative injury of the lipid membrane components, as well as on the ability of antioxidants (of different structures and sources, and following different mechanisms of action) in fighting against oxidative stress. Oxidative stress is defined as an excessive prodn. of reactive oxygenated species that cannot be counteracted by the action of antioxidants, but also as a perturbation of cell redox balance. Reactive oxygenated/nitrogenated species are represented by superoxide anion radical, hydroxyl, alkoxyl and lipid peroxyl radicals, nitric oxide and peroxynitrite. Oxidative stress dets. structure modifications and function modulation in nucleic acids, lipids and proteins. Oxidative degrdn. of lipids yields malondialdehyde and 4-hydroxynonenal, but also isoprostanes, from unsatd. fatty acids. Protein damage may occur with thiol oxidn., carbonylation, side-chain oxidn., fragmentation, unfolding and misfolding, resulting activity loss. 8-Hydroxydeoxyguanosine is an index of DNA damage. The involvement of the reactive oxygenated/nitrogenated species in disease occurrence is described. The unbalance between the oxidant species and the antioxidant defense system may trigger specific factors responsible for oxidative damage in the cell: over-expression of oncogene genes, generation of mutagen compds., promotion of atherogenic activity, senile plaque occurrence or inflammation. This leads to cancer, neurodegeneration, cardiovascular diseases, diabetes, kidney diseases. The concept of antioxidant is defined, along with a discussion of the existent classification criteria: enzymic and non-enzymic, preventative or repair-systems, endogenous and exogenous, primary and secondary, hydrosol. and liposol., natural or synthetic. Primary antioxidants are mainly chain breakers, able to scavenge radical species by hydrogen donation. Secondary antioxidants are singlet oxygen quenchers, peroxide decomposers, metal chelators, oxidative enzyme inhibitors or UV radiation absorbers. The specific mechanism of action of the most important representatives of each antioxidant class (endogenous and exogenous) in preventing or inhibiting particular factors leading to oxidative injury in the cell, is then reviewed. Mutual influences, including synergistic effects are presented and discussed. Prooxidative influences likely to occur, as for instance in the presence of transition metal ions, are also reminded.
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        Yang, J., Zheng, Y., Gou, X., Pu, K., Chen, Z., Guo, Q., Ji, R., Wang, H., Wang, Y., and Zhou, Y. (2020) Prevalence of comorbidities and its effects in coronavirus disease 2019 patients: A systematic review and meta-analysis. Int. J. Infect. Dis. 94, 91– 95,  DOI: 10.1016/j.ijid.2020.03.017
        5
        Prevalence of comorbidities and its effects in coronavirus disease 2019 patients: A systematic review and meta-analysis
        Yang, Jing; Zheng, Ya; Gou, Xi; Pu, Ke; Chen, Zhaofeng; Guo, Qinghong; Ji, Rui; Wang, Haojia; Wang, Yuping; Zhou, Yongning
        International Journal of Infectious Diseases (2020), 94 (), 91-95CODEN: IJIDF3; ISSN:1201-9712. (Elsevier Ltd.)
        A review. An outbreak of coronavirus disease 2019 (COVID-19) occurred in Wuhan, China; the epidemic is more widespread than initially estd., with cases now confirmed in multiple countries. The aim of this meta-anal. was to assess the prevalence of comorbidities in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected patients and the risk of underlying diseases in severe patients compared to non-severe patients. A literature search was conducted using the databases PubMed, EMBASE, and Web of Science through Feb. 25, 2020. Odds ratios (ORs) and 95% confidence intervals (CIs) were pooled using random-effects models. Seven studies were included in the meta-anal., including 1 576 infected patients. The results showed the most prevalent clin. symptom was fever (91.3%, 95% CI: 86-97%), followed by cough (67.7%, 95% CI: 59-76%), fatigue (51.0%, 95% CI: 34-68%) and dyspnea (30.4%, 95% CI: 21-40%). The most prevalent comorbidities were hypertension (21.1%, 95% CI: 13.0-27.2%) and diabetes (9.7%, 95% CI: 7.2-12.2%), followed by cardiovascular disease (8.4%, 95% CI: 3.8-13.8%) and respiratory system disease (1.5%, 95% CI: 0.9-2.1%). When compared between severe and non-severe patients, the pooled OR of hypertension, respiratory system disease, and cardiovascular disease were 2.36 (95% CI: 1.46-3.83), 2.46 (95% CI: 1.76-3.44) and 3.42 (95% CI: 1.88-6.22) resp. We assessed the prevalence of comorbidities in the COVID-19 patients and found that underlying disease, including hypertension, respiratory system disease and cardiovascular disease, may be risk factors for severe patients compared with non-severe patients.
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        Lee, C. (2018) Therapeutic Modulation of Virus-Induced Oxidative Stress via the Nrf2-Dependent Antioxidative Pathway. Oxid. Med. Cell. Longevity 2018, 6208067,  DOI: 10.1155/2018/6208067
        6
        Therapeutic Modulation of Virus-Induced Oxidative Stress via the Nrf2-Dependent Antioxidative Pathway
        Lee Choongho
        Oxidative medicine and cellular longevity (2018), 2018 (), 6208067 ISSN:.
        Virus-induced oxidative stress plays a critical role in the viral life cycle as well as the pathogenesis of viral diseases. In response to reactive oxygen species (ROS) generation by a virus, a host cell activates an antioxidative defense system for its own protection. Particularly, a nuclear factor erythroid 2p45-related factor 2 (Nrf2) pathway works in a front-line for cytoprotection and detoxification. Recently, a series of studies suggested that a group of clinically relevant viruses have the capacity for positive and negative regulations of the Nrf2 pathway. This virus-induced modulation of the host antioxidative response turned out to be a crucial determinant for the progression of several viral diseases. In this review, virus-specific examples of positive and negative modulations of the Nrf2 pathway will be summarized first. Then a number of successful genetic and pharmacological manipulations of the Nrf2 pathway for suppression of the viral replication and the pathogenesis-associated oxidative damage will be discussed later. Understanding of the interplay between virus-induced oxidative stress and antioxidative host response will aid in the discovery of potential antiviral supplements for better management of viral diseases.
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        Forman, H. J., Zhang, H., and Rinna, A. (2009) Glutathione: overview of its protective roles, measurement, and biosynthesis. Mol. Aspects Med. 30, 1– 12,  DOI: 10.1016/j.mam.2008.08.006
        7
        Glutathione: Overview of its protective roles, measurement, and biosynthesis
        Forman, Henry Jay; Zhang, Hongqiao; Rinna, Alessandra
        Molecular Aspects of Medicine (2009), 30 (1-2), 1-12CODEN: MAMED5; ISSN:0098-2997. (Elsevier B.V.)
        This review is the introduction to a special issue concerning, glutathione (GSH), the most abundant low mol. wt. thiol compd. synthesized in cells. GSH plays crit. roles in protecting cells from oxidative damage and the toxicity of xenobiotic electrophiles, and maintaining redox homeostasis. Here, the functions and GSH and the sources of oxidants and electrophiles, the elimination of oxidants by redn. and electrophiles by conjugation with GSH are briefly described. Methods of assessing GSH status in the cells are also described. GSH synthesis and its regulation are addressed along with therapeutic approaches for manipulating GSH content that have been proposed. The purpose here is to provide a brief overview of some of the important aspects of glutathione metab. as part of this special issue that will provide a more comprehensive review of the state of knowledge regarding this essential mol.
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      8. 8
        Zhou, F., Yu, T., Du, R., Fan, G., Liu, Y., Liu, Z., Xiang, J., Wang, Y., Song, B., Gu, X., Guan, L., Wei, Y., Li, H., Wu, X., Xu, J., Tu, S., Zhang, Y., Chen, H., and Cao, B. (2020) Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395, 1054– 1062,  DOI: 10.1016/S0140-6736(20)30566-3
        8
        Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study
        Zhou, Fei; Yu, Ting; Du, Ronghui; Fan, Guohui; Liu, Ying; Liu, Zhibo; Xiang, Jie; Wang, Yeming; Song, Bin; Gu, Xiaoying; Guan, Lulu; Wei, Yuan; Li, Hui; Wu, Xudong; Xu, Jiuyang; Tu, Shengjin; Zhang, Yi; Chen, Hua; Cao, Bin
        Lancet (2020), 395 (10229), 1054-1062CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)
        Since Dec., 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiol. and clin. characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clin. course of illness, including viral shedding, have not been well described. In this retrospective, multicenter cohort study, we included all adult inpatients (≥18 yr old) with lab.-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demog., clin., treatment, and lab. data, including serial samples for viral RNA detection, were extd. from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors assocd. with in-hospital death. One hundred ninety-one patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. Ninety-one (48%) patients had a comorbidity, with hypertension being the most common (58 patients), followed by diabetes (36 patients) and coronary heart disease (15 patients). Multivariable regression showed increasing odds of in-hospital death assocd. with older age, higher Sequential Organ Failure Assessment (SOFA) score, and d-dimer >1μg/L on admission. Median duration of viral shedding was 20·0 days (IQR 17·0-24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest obsd. duration of viral shedding in survivors was 37 days. The potential risk factors of older age, high SOFA score, and d-dimer >1μg/L could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future.
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      9. 9
        Borges do Nascimento, I. J., Cacic, N., Abdulazeem, H. M., von Groote, T. C., Jayarajah, U., Weerasekara, I., Esfahani, M. A., Civile, V. T., Marusic, A., Jeroncic, A., Carvas Junior, N., Pericic, T. P., Zakarija-Grkovic, I., Meirelles Guimarães, S. M., Luigi Bragazzi, N., Bjorklund, M., Sofi-Mahmudi, A., Altujjar, M., Tian, M., Arcani, D. M. C., O’Mathúna, D. P., and Marcolino, M. S. (2020) Novel Coronavirus Infection (COVID-19) in Humans: A Scoping Review and Meta-Analysis. J. Clin. Med. 9, 941,  DOI: 10.3390/jcm9040941
        There is no corresponding record for this reference.
      10. 10
        Vardavas, C. I. and Nikitara, K. (2020) COVID-19 and smoking: A systematic review of the evidence. Tob. Induced Dis. 18, 20,  DOI: 10.18332/tid/119324
        10
        COVID-19 and smoking: A systematic review of the evidence
        Vardavas Constantine I; Vardavas Constantine I; Nikitara Katerina
        Tobacco induced diseases (2020), 18 (), 20 ISSN:.
        There is no expanded citation for this reference.
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      11. 11
        Grant, W. B., Lahore, H., McDonnell, S. L., Baggerly, C. A., French, C. B., Aliano, J. L., and Bhattoa, H. P. (2020) Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients 12, 988,  DOI: 10.3390/nu12040988
        11
        Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths
        Grant, William B.; Lahore, Henry; McDonnell, Sharon L.; Baggerly, Carole A.; French, Christine B.; Aliano, Jennifer L.; Bhattoa, Harjit P.
        Nutrients (2020), 12 (4), 988CODEN: NUTRHU; ISSN:2072-6643. (MDPI AG)
        A review. The world is in the grip of the COVID-19 pandemic. Public health measures that can reduce the risk of infection and death in addn. to quarantines are desperately needed. This article reviews the roles of vitamin D in reducing the risk of respiratory tract infections, knowledge about the epidemiol. of influenza and COVID-19, and how vitamin D supplementation might be a useful measure to reduce risk. Through several mechanisms, vitamin D can reduce risk of infections. Those mechanisms include inducing cathelicidins and defensins that can lower viral replication rates and reducing concns. of pro-inflammatory cytokines that produce the inflammation that injures the lining of the lungs, leading to pneumonia, as well as increasing concns. of anti-inflammatory cytokines. Several observational studies and clin. trials reported that vitamin D supplementation reduced the risk of influenza, whereas others did not. Evidence supporting the role of vitamin D in reducing risk of COVID-19 includes that the outbreak occurred in winter, a time when 25-hydroxyvitamin D (25(OH)D) concns. are lowest; that the no. of cases in the Southern Hemisphere near the end of summer are low; that vitamin D deficiency has been found to contribute to acute respiratory distress syndrome; and that case-fatality rates increase with age and with chronic disease comorbidity, both of which are assocd. with lower 25(OH)D concn. To reduce the risk of infection, it is recommended that people at risk of influenza and/or COVID-19 consider taking 10,000 IU/d of vitamin D3 for a few weeks to rapidly raise 25(OH)D concns., followed by 5000 IU/d. The goal should be to raise 25(OH)D concns. above 40-60 ng/mL (100-150 nmol/L). For treatment of people who become infected with COVID-19, higher vitamin D3 doses might be useful. Randomized controlled trials and large population studies should be conducted to evaluate these recommendations.
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      12. 12
        Alvarez, J. A., Chowdhury, R., Jones, D. P., Martin, G. S., Brigham, K. L., Binongo, J. N., Ziegler, T. R., and Tangpricha, V. (2014) Vitamin D status is independently associated with plasma glutathione and cysteine thiol/disulphide redox status in adults. Clin. Endocrinol. (Oxford, U. K.) 81, 458– 466,  DOI: 10.1111/cen.12449
        12
        Vitamin D status is independently associated with plasma glutathione and cysteine thiol/disulphide redox status in adults
        Alvarez, Jessica A.; Chowdhury, Ritam; Jones, Dean P.; Martin, Greg S.; Brigham, Kenneth L.; Binongo, Jose N.; Ziegler, Thomas R.; Tangpricha, Vin
        Clinical Endocrinology (Oxford, United Kingdom) (2014), 81 (3), 458-466CODEN: CLECAP; ISSN:0300-0664. (Wiley-Blackwell)
        Objective : Redox status and inflammation are important in the pathophysiol. of numerous chronic diseases. Epidemiol. studies have linked vitamin D status to a no. of chronic diseases. We aimed to examine the relationships between serum 25-hydroxyvitamin D [25(OH)D] and circulating thiol/disulfide redox status and biomarkers of inflammation. Design : This was a cross-sectional study of N = 693 adults (449 females, 244 males) in an apparently healthy, working cohort in Atlanta, GA. Plasma glutathione (GSH), cysteine (Cys) and their assocd. disulfides were detd. with high-performance liq. chromatog., and their redox potentials (Eh GSSG and Eh CySS) were calcd. using the Nernst equation. Serum inflammatory markers included interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor-α, assayed on a multiplex platform, and C-reactive protein (CRP), assayed com. Relationships were assessed with multiple linear regression analyses. Results : Serum 25(OH)D was pos. assocd. with plasma GSH (β ± SE: 0·002 ± 0·0004) and neg. assocd. with plasma Eh GSSG (β ± SE: -0·06 ± 0·01) and Cys (β ± SE: -0·01 ± 0·003) (P < 0·001 for all); statistical significance remained after adjusting for age, gender, race, percentage body fat and traditional cardiovascular risk factors (P = 0·01-0·02). The inverse relationship between serum 25(OH)D and CRP was confounded by percentage body fat, and full adjustment for covariates attenuated serum 25(OH)D relationships with other inflammatory markers to nonstatistical significance. Conclusions : Serum 25(OH)D concns. were independently assocd. with major plasma thiol/disulfide redox systems, suggesting that vitamin D status may be involved in redox-mediated pathophysiol.
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      13. 13
        Jain, S. K., Micinski, D., Huning, L., Kahlon, G., Bass, P. F., and Levine, S. N. (2014) Vitamin D and L-cysteine levels correlate positively with GSH and negatively with insulin resistance levels in the blood of type 2 diabetic patients. Eur. J. Clin. Nutr. 68, 1148– 1153,  DOI: 10.1038/ejcn.2014.114
        13
        Vitamin D and L-cysteine levels correlate positively with GSH and negatively with insulin resistance levels in the blood of type 2 diabetic patients
        Jain, S. K.; Micinski, D.; Huning, L.; Kahlon, G.; Bass, P. F.; Levine, S. N.
        European Journal of Clinical Nutrition (2014), 68 (10), 1148-1153CODEN: EJCNEQ; ISSN:0954-3007. (Nature Publishing Group)
        Background/Objectives: Vitamin D, L-cysteine (LC) and glutathione (GSH) levels are lower in the blood of diabetic patients. This study examd. the hypothesis that the levels of vitamin D and LC correlate with those of GSH in the blood of type 2 diabetic patients (T2D), and that vitamin D and LC upregulate glutamate-cysteine ligase (GCLC), which catalyzes GSH biosynthesis, in cultured monocytes. Subjects/Methods: Fasting blood was obtained after written informed consent from T2D (n=79) and healthy controls (n=22). U937 monocytes were pretreated with 1,25 (OH)2 vitamin D (0-25 nM) or LC (0-500 μM) for 24 h and then exposed to control or high glucose (25 mM) for 4 h. Results: Plasma levels of vitamin D, LC, GSH and GCLC protein were significantly lower in T2D vs. those in age-matched healthy controls. Multiple linear regression analyses and adjustment for body wt. showed a significant pos. correlation between plasma levels of vitamin D (r=0.26, P=0.05) and LC (r=0.81, P=0.001) and that of GSH, and between LC and vitamin D (r=0.27, P=0.045) levels. Plasma levels of GSH (r=-0.34, P=0.01) and LC (r=-0.33, r=0.01) showed a neg. correlation with triglyceride levels. Vitamin D correlated inversely with HbA1C (-0.30, P=0.01) and homeostatic model assessment insulin resistance (r=-0.31, P=0.03), which showed a significant pos. correlation with triglycerides (r=0.44, P=0.001) in T2D. Cell culture studies demonstrate that supplementation with vitamin D and LC significantly increased GCLC expression and GSH formation in control and high-glucose-treated monocytes. Conclusions: This study suggests a pos. relationship between the concns. of the micronutrients vitamin D and LC and that of GSH. Some of the beneficial effects of vitamin D and LC supplementation may be mediated by an increase in the levels of GSH and a decrease in triglyceride levels in T2D patients.
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      14. 14
        Jain, S. K., Kahlon, G., Bass, P., Levine, S. N., and Warden, C. (2015) Can L-Cysteine and Vitamin D Rescue Vitamin D and Vitamin D Binding Protein Levels in Blood Plasma of African American Type 2 Diabetic Patients?. Antioxid. Redox Signaling 23, 688– 693,  DOI: 10.1089/ars.2015.6320
        14
        Can L-Cysteine and Vitamin D Rescue Vitamin D and Vitamin D Binding Protein Levels in Blood Plasma of African American Type 2 Diabetic Patients?
        Jain, Sushil K.; Kahlon, Gunjan; Bass, Pat; Levine, Steven N.; Warden, Cassandra
        Antioxidants & Redox Signaling (2015), 23 (8), 688-693CODEN: ARSIF2; ISSN:1523-0864. (Mary Ann Liebert, Inc.)
        Aims: Vitamin D (VD) deficiency has become a worldwide epidemic, particularly affecting African Americans (AA). VD deficiency has been implicated in the excessive rate of complications assocd. with diabetes in AA. Blood levels of VD binding protein (VDBP) and glutathione (GSH) are lower in AA compared with those in Caucasians. This study tested the hypothesis that lower GSH levels are linked to VDBP and VD deficiency in AA-type 2 diabetic (AA-T2D) patients. Blood was analyzed from T2D and nondiabetic subjects (N). Expts. examg. GSH deficiency and L-cysteine (LC) supplementation were performed using THP-1 monocytes. Results: Plasma levels of LC, GSH, VDBP, and VD were significantly lower in AA-T2D compared with age-matched AA-N or Caucasian-T2D. Lower levels of LC and GSH showed a significant pos. correlation with lower VDBP and VD levels in AA-T2D. GSH deficiency investigated using an antisense approach depleted VDBP/vitamin D receptor (VDR); LC supplementation caused significant upregulation of GSH and of VDBP/VDR, while supplementation with VD+LC caused a significantly greater GSH and VDBP/VDR upregulation compared with that of VD alone in monocytes. Innovation and Conclusion: The reported observations suggest that VD deficiency may be linked to GSH and LC status and lead to a novel hypothesis that supplementation with LC in combination with VD will be effective in increasing VD levels and reducing health disparities in AA. Antioxid. Redox Signal. 23, 688-693.
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      15. 15
        Jain, S. K., Kanikarla-Marie, P., Warden, C., and Micinski, D. (2016) L-cysteine supplementation upregulates glutathione (GSH) and vitamin D binding protein (VDBP) in hepatocytes cultured in high glucose and in vivo in liver, and increases blood levels of GSH, VDBP, and 25-hydroxy-vitamin D in Zucker diabetic fatty rats. Mol. Nutr. Food Res. 60, 1090– 1098,  DOI: 10.1002/mnfr.201500667
        15
        L-cysteine supplementation upregulates glutathione (GSH) and vitamin D binding protein (VDBP) in hepatocytes cultured in high glucose and in vivo in liver, and increases blood levels of GSH, VDBP, and 25-hydroxy-vitamin D in Zucker diabetic fatty rats
        Jain, Sushil K.; Kanikarla-Marie, Preeti; Warden, Cassandra; Micinski, David
        Molecular Nutrition & Food Research (2016), 60 (5), 1090-1098CODEN: MNFRCV; ISSN:1613-4125. (Wiley-VCH Verlag GmbH & Co. KGaA)
        Scope : Vitamin D binding protein (VDBP) status has an effect on and can potentially improve the status of 25(OH) vitamin D and increase the metabolic actions of 25(OH) vitamin D under physiol. and pathol. conditions. Diabetes is assocd. with lower levels of glutathione (GSH) and 25(OH) vitamin D. This study examd. the hypothesis that upregulation of GSH will also upregulate blood levels of VDBP and 25(OH) vitamin D in type 2 diabetic rats. Methods and results : L-cysteine (LC) supplementation was used to upregulate GSH status in a FL83B hepatocyte cell culture model and in vivo using Zucker diabetic fatty (ZDF) rats. Results show that LC supplementation upregulates both protein and mRNA expression of VDBP and vitamin D receptor (VDR) and GSH status in hepatocytes exposed to high glucose, and that GSH deficiency, induced by glutamate cysteine ligase knockdown, resulted in the downregulation of GSH, VDBP, and VDR and an increase in oxidative stress levels in hepatocytes. In vivo, LC supplementation increased GSH and protein and mRNA expression of VDBP and vitamin D 25-hydroxylase (CYP2R1) in the liver, and simultaneously resulted in elevated blood levels of LC and GSH, as well as increases in VDBP and 25(OH) vitamin D levels, and decreased inflammatory biomarkers in ZDF rats compared with those in placebo-supplemented ZDF rats consuming a similar diet. Conclusion : LC supplementation may provide a novel approach by which to raise blood levels of VDBP and 25(OH) vitamin D in type 2 diabetes.
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        https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmtVSns7s%253D&md5=5ef052f6f548bc9b00b3af09d9e02e51
      16. 16
        Parsanathan, R. and Jain, S. K. (2019) Glutathione deficiency induces epigenetic alterations of vitamin D metabolism genes in the livers of high-fat diet-fed obese mice. Sci. Rep. 9, 14784,  DOI: 10.1038/s41598-019-51377-5
        16
        Glutathione deficiency induces epigenetic alterations of vitamin D metabolism genes in the livers of high-fat diet-fed obese mice
        Parsanathan Rajesh; Jain Sushil K
        Scientific reports (2019), 9 (1), 14784 ISSN:.
        Obesity has been correlating with low levels of glutathione (GSH) and 25-hydroxyvitamin D3 (25(OH)VD3). The liver is the principal site for the 25(OH)VD3 biosynthesis. This study investigated whether GSH deficiency induces epigenetic alterations that impair Vitamin D (VD) metabolism genes in the livers of HFD-fed mice. The expression of the VD metabolism genes CYP2R1 and CYP27A1 (25-hydroxylase), CYP27B1 (1-α-hydroxylase), and vitamin D receptor (VDR) were downregulated in the livers of mice fed an HFD (GSH- deficient) compared with control diet-fed group. The expression of CYP24A1 (24-hydroxylase) was significantly increased, which catabolizes both 25(OH)VD3 and 1α,25-hydroxyvitaminD3. Gene-specific hypermethylation of 25-hydroxylase, 1-α-hydroxylase, and VDR, and hypomethylation of CYP24A1 was observed in HFD-fed mice. GSH deficiency induced in cultured hepatocytes caused an increase in oxidative stress and alterations in VD regulatory genes. Similarly, elevated global DNA methylation, Dnmt activity, and 5-methylcytosine but decreased Tet activity and 5-hydroxymethylcytosine were observed in the GSH-deficient hepatocytes and the liver of HFD-fed mice. Replenishment of GSH by its prodrugs treatment beneficially altered epigenetic enzymes, and VD-metabolism genes in hepatocytes. HFD-induces GSH deficiency and epigenetically alters VD-biosynthesis pathway genes. This provides a biochemical mechanism for the VD-deficiency and potential benefits of GSH treatment in reducing 25(OH)VD3-deficiency.
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      17. 17
        De Flora, S., Grassi, C., and Carati, L. (1997) Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. Eur. Respir. J. 10, 1535– 1541,  DOI: 10.1183/09031936.97.10071535
        17
        Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment
        De Flora, S.; Grassi, C.; Carati, L.
        European Respiratory Journal (1997), 10 (7), 1535-1541CODEN: ERJOEI; ISSN:0903-1936. (Munksgaard)
        N-acetylcysteine (NAC), an analog and precursor of reduced glutathione, has been in clin. use for more than 30 yrs as a mucolytic drug. It has also been proposed for and/or used in the therapy and/or prevention of several respiratory diseases and of diseases involving an oxidative stress, in general. The objective of the present study was to evaluate the effect of long-term treatment with NAC on influenza and influenza-like episodes. A total of 262 subjects of both sexes (78% ≥65 yrs, and 62% suffering from non-respiratory chronic degenerative diseases) were enrolled in a randomized, double-blind trial involving 20 Italian Centers. They were randomized to receive either placebo or NAC tablets (600 mg) twice daily for 6 mo. Patients suffering from chronic respiratory diseases were not eligible, to avoid possible confounding by an effect of NAC on respiratory symptoms. NAC treatment was well tolerated and resulted in a significant decrease in the frequency of influenza-like episodes, severity, and length of time confined to bed. Both local and systemic symptoms were sharply and significantly reduced in the NAC group. Frequency of seroconversion towards A/H1N1 Singapore 6/86 influenza virus was similar in the two groups, but only 25% of virus-infected subjects under NAC treatment developed a symptomatic form, vs. 79% in the placebo group. Evaluation of cell-mediated immunity showed a progressive, significant shift from anergy to normoergy following NAC treatment. Administration of N-acetylcysteine during the winter, thus, appears to provide a significant attenuation of influenza and influenza-like episodes, esp. in elderly high-risk individuals. N-acetylcysteine did not prevent A/H1N1 virus influenza infection but significantly reduced the incidence of clin. apparent disease.
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      18. 18
        Horowitz, R. I., Freeman, P. R., and Bruzzese, J. (2020) Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases. Respir Med. Case Rep 30, 101063,  DOI: 10.1016/j.rmcr.2020.101063
        18
        Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases
        Horowitz Richard I; Horowitz Richard I; Freeman Phyllis R; Bruzzese James
        Respiratory medicine case reports (2020), 30 (), 101063 ISSN:2213-0071.
        PURPOSE: Infection with COVID-19 potentially can result in severe outcomes and death from "cytokine storm syndrome", resulting in novel coronavirus pneumonia (NCP) with severe dyspnea, acute respiratory distress syndrome (ARDS), fulminant myocarditis and multiorgan dysfunction with or without disseminated intravascular coagulation. No published treatment to date has been shown to adequately control the inflammation and respiratory symptoms associated with COVID-19, apart from oxygen therapy and assisted ventilation. We evaluated the effects of using high dose oral and/or IV glutathione in the treatment of 2 patients with dyspnea secondary to COVID-19 pneumonia. METHODS: Two patients living in New York City (NYC) with a history of Lyme and tick-borne co-infections experienced a cough and dyspnea and demonstrated radiological findings consistent with novel coronavirus pneumonia (NCP). A trial of 2 g of PO or IV glutathione was used in both patients and improved their dyspnea within 1 h of use. Repeated use of both 2000 mg of PO and IV glutathione was effective in further relieving respiratory symptoms. CONCLUSION: Oral and IV glutathione, glutathione precursors (N-acetyl-cysteine) and alpha lipoic acid may represent a novel treatment approach for blocking NF-κB and addressing "cytokine storm syndrome" and respiratory distress in patients with COVID-19 pneumonia.
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        https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB38zosVSltw%253D%253D&md5=e2612dff6acf69f8f1f9aedfec0908f4
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