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

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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.
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Endogenous Deciency of Glutathione as the Most Likely Cause of
Serious Manifestations and Death in COVID-19 Patients
Alexey Polonikov*
Cite This: https://dx.doi.org/10.1021/acsinfecdis.0c00288
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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. Specically, 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 deciency 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 eective treatment and prevention of the disease.
The novel coronavirus SARS-CoV-2 (COVID-19) con-
tinues to spread throughout the globe, aecting more and
more people; thus, the identication of eective drugs for
disease prevention and treatment is necessary. The over-
whelming 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 environ-
mental stress factors including infectious agents like
coronavirus SARS-CoV-2. Specically, impaired redox homeo-
stasis 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 nonspecic pathological condition
reecting 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 inammation 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 non-
specic 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 (milli-
molar) concentrations of reduced glutathione (GSH) in most
cell types highlights its vital and multifunctional roles in the
control of various biological processes such as detoxication of
foreign and endogenous compounds, protein folding, regener-
ation 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 benecial eects 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.
Received: May 8, 2020
Viewpoint
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DOES GLUTATHIONE DEFICIENCY WORSEN
COVID-19 PROGNOSIS THROUGH THE RISK
FACTORS?
Numerous studies report that endogenous glutathione
deciency attributed to decreased biosynthesis and/or
increased depletion of GSH represents a signicant contributor
to the pathogenesis of various diseases through mechanisms
involving oxidative stress and inammation. Figure 1
summarizes the most common causes responsible for
endogenous glutathione deciency and also the mechanisms
through which this deciency may contribute to the patho-
genesis of severe COVID-19 disease.
Age is a well-recognized risk factor for severe illness,
complications, and death from COVID-19 infection.
8
Interest-
ingly, 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 dierent 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 deciency 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 inammation and leading to acute
respiratory distress syndrome (ARDS), multiorgan failure, and
death.
Sex-related COVID-19 mortality is one of the common
epidemiologic ndings around the globe,
9
suggesting sexual
dimorphism in susceptibility to severe illness. It has been
observed that men are signicantly more likely to suer severe
eects 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
inammation.
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 inammation in the lung,
which is likely the reason why smokers with COVID-19 more
likely require intensive medical interventions.
Dietary factors mayalsocontributetoendogenous
glutathione deciency in patients with severe COVID-19
illness. In particular, an insucient consumption of fresh
vegetables and fruits, natural sources of glutathione, seems to
be an important but not yet established risk factor responsible
for glutathione deciency 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 deciency.
WHAT IS THE PRIMARY CAUSE OF SEVERE
COVID-19 ILLNESS: GLUTATHIONE OR VITAMIN D
DEFICIENCY?
The novel hypothesis that vitamin D (VD) deciency is
responsible for severe manifestations and death in COVID-19
patients has been proposed
11
and is actively being discussed by
the scientic 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 inamma-
tory biomarkers in diabetic rats.
15
Interestingly, a recent
experimental study
16
showed that GSH deciency and the
Figure 1. Factors responsible for endogenous glutathione deciency and the mechanisms through which this deciency may contribute to COVID-
19 pathogenesis and outcomes. The bottom of the gure shows that the risk factors for severe COVID-19 infection are associated with decrease/
depletion of intracellular glutathione. The top of the gure shows the potential mechanisms through which glutathione deciency could inuence
clinical manifestations and outcomes in COVID-10 disease. The numbers in brackets indicate PubMed references (PMID).
ACS Infectious Diseases pubs.acs.org/journal/aidcbc Viewpoint
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B
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 deciency of vitamin D. It is important to note
that the replenishment of GSH by L-cysteine treatment
benecially 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 benets of GSH treatment in
reducing the deciency of vitamin D. Taken together, these
ndings suggest that glutathione deciency rather than vitamin
Ddeciency 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
Several studies indicate that higher levels of glutathione may
improve an individuals 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
dierent 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 inammatory 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, gluta-
thione precursor) signicantly reduced the incidence of
clinically apparent inuenza and inuenza-like episodes,
especially in elderly high-risk individuals. In addition,
pathophysiological conditions such as lung cell injury and
inammation in patients with severe ARDS were identied as
the targets of NAC treatment. In particular, the deciency of
reduced glutathione in the alveolar uid in ARDS patients was
found to enhance lung cell injury by ROS/oxidative stress and
inammation, and this damage could be eectively prevented
and treated by the administration of NAC (Figure 1).Gluta-
).Glutathione deciency could also promote the increased
activation of von Willebrand Factor causing coagulopathy in
COVID-19 patients.
GLUTATHIONE DEFICIENCY EXACERBATES
COVID-19 ILLNESS: MY OBSERVATIONS
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 conrmed 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 deciency and oxidative stress signs in
patients with serious disease manifestations. Notably, only the
Table 1. Clinical and Laboratory Characteristics of Four COVID-19 Patients
a
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/L
b
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, signicant
myalgia and fatigue (radiographic ndings 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, signicant fatigue and
tachycardia (radiographic ndings 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 conrmed by a PCR test in all cases.
b
The parameters were measured 2 months before the patients
became infected with coronavirus SARS-CoV-2.
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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.
HYPOTHESIS
Endogenous glutathione deciency 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
deciency seem to have a higher susceptibility for uncontrolled
replication of SARS-CoV-2 virus and thereby suer 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 deciency of
reduced glutathione and increased ROS production. This
assumption can be supported by our ndings. 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
deciency 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 nding 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 deciency is an acquired condition attributable
to decreased biosynthesis and/or increased depletion of the
endogenous GSH pool inuenced by risk factors such as aging,
male sex, comorbidity, and smoking alone or in combinations.
Glutathione deciency 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
deciency, regardless which of the factors aging, chronic
disease comorbidity, smoking or some others were responsible
for this decit. The hypothesis provides novel insights into the
etiology and mechanisms responsible for serious manifesta-
tions of COVID-19 infection and justies promising
opportunities for eective treatment and prevention of the
illness through glutathione recovering with N-acetylcysteine
and reduced glutathione.
Since the antiviral eect of glutathione is nonspecic, 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 manage-
ment of the novel coronavirus SARS-CoV-2. Notably, long-
term oral administration of N-acetylcysteine has already been
tested as an eective preventive measure against respiratory
viral infections.
1
N-Acetylcysteine is widely available, safe, and
cheap and could be used in an o-labelmanner. Moreover,
parenteral injection of NAC or reduced glutathione (GSH is
more bioavailable than NAC) could be an ecient therapy for
COVID-19 patients with serious illness. Horowitz et al.
18
just
published a paper conrming this hypothesis: the authors
reported the ecacy of glutathione therapy in relieving
dyspnea associated with COVID-19 pneumonia. Nonetheless,
the proposed hypothesis has to be conrmed in larger
epidemiological and experimental studies, and also, clinical
trials are needed to objectively assess the ecacy of N-
acetylcysteine and reduced glutathione for the treatment and
prevention of COVID-19 infection.
AUTHOR INFORMATION
Corresponding Author
Alexey Polonikov Department of Biology, Medical Genetics
and Ecology and Research Institute for Genetic and Molecular
Epidemiology, Kursk State Medical University, 305041 Kursk,
Russian Federation; orcid.org/0000-0001-6280-247X;
Phone: +7(4712) 58-81-47; Email: polonikov@rambler.ru
Complete contact information is available at:
https://pubs.acs.org/10.1021/acsinfecdis.0c00288
Notes
The author declares no competing nancial interest.
ACKNOWLEDGMENTS
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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... GSH has the function of "master antioxidant" in all tissues and is involved in antioxidant defense, detoxication of xenobiotics, intracellular redox homeostasis, cysteine carrier/storage, cell signaling, protein folding and function, gene expression, cell differentiation/proliferation, immune response and antiviral defense, that make it a "Samsonian (mighty) little molecule" (1,2). The high (millimolar) concentration of the reduced form highlights its central role in the control of those processes (5)(6)(7)(8). ...
... GSH exists in the thiolreduced and disulfide-oxidized (GSSG) forms (1,2); and it's free and bound to proteins (Figure 1). The reduced form GSH is the active form of the molecule, it is the most abundant and it is found inside the cells in millimolar concentrations in the range of 1-10 mM (highest concentration in liver) (5)(6)(7)(8), while extracellularly they are found in micromolar (GSH in plasma: 10-30 µM) levels (5,15,16). The active group of the molecule is represented by the thiol group (-SH) of the cysteine residue (Figure 1) which provides its reductive power. ...
... Most (80-85%) of the cellular GSH are in the cytosol, 10-15% is in the mitochondria and a small percentage is in the endoplasmic reticulum (Figure 2) (3,(24)(25)(26)(27)(28). GSSG is found mainly extracellularly. The redox state of the GSH/GSSG couple can serve as an important indicator of redox environment (29)(30)(31), and changes in this couple correlate with multiple cellular processes, including cell differentiation (32)(33)(34)(35)(36)(37), cell proliferation (32)(33)(34)(35)(36)(37), and cell apoptosis (38)(39)(40)(41)(42). GSH deficiency as evidenced by a decrease in the GSH/GSSG ratio manifests itself largely through an increased susceptibility to oxidative stress, and the resulting damage is thought to be involved in SARS-CoV-2 infection leading to COVID-19 disease (6,7,39,(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53). In addition, imbalances in GSH levels affect immune system function, and are thought to play a role in the aging process and the diseases of aging, one of the principal risk factors for the development and progression of COVID-19 disease. ...
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Full-text available
Many local and systemic diseases especially diseases that are leading causes of death globally like chronic obstructive pulmonary disease, atherosclerosis with ischemic heart disease and stroke, cancer and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 19 (COVID-19), involve both, (1) oxidative stress with excessive production of reactive oxygen species (ROS) that lower glutathione (GSH) levels, and (2) inflammation. The GSH tripeptide (γ- L-glutamyl-L-cysteinyl-glycine), the most abundant water-soluble non-protein thiol in the cell (1–10 mM) is fundamental for life by (a) sustaining the adequate redox cell signaling needed to maintain physiologic levels of oxidative stress fundamental to control life processes, and (b) limiting excessive oxidative stress that causes cell and tissue damage. GSH activity is facilitated by activation of the Kelch-like ECH-associated protein 1 (Keap1)-Nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) redox regulator pathway, releasing Nrf2 that regulates expression of genes controlling antioxidant, inflammatory and immune system responses. GSH exists in the thiol-reduced (>98% of total GSH) and disulfide-oxidized (GSSG) forms, and the concentrations of GSH and GSSG and their molar ratio are indicators of the functionality of the cell. GSH depletion may play a central role in inflammatory diseases and COVID-19 pathophysiology, host immune response and disease severity and mortality. Therapies enhancing GSH could become a cornerstone to reduce severity and fatal outcomes of inflammatory diseases and COVID-19 and increasing GSH levels may prevent and subdue these diseases. The life value of GSH makes for a paramount research field in biology and medicine and may be key against systemic inflammation and SARS-CoV-2 infection and COVID-19 disease. In this review, we emphasize on (1) GSH depletion as a fundamental risk factor for diseases like chronic obstructive pulmonary disease and atherosclerosis (ischemic heart disease and stroke), (2) importance of oxidative stress and antioxidants in SARS-CoV-2 infection and COVID-19 disease, (3) significance of GSH to counteract persistent damaging inflammation, inflammaging and early (premature) inflammaging associated with cell and tissue damage caused by excessive oxidative stress and lack of adequate antioxidant defenses in younger individuals, and (4) new therapies that include antioxidant defenses restoration.
... Redükte glutatyon (GSH, γ-glutamilsisteinilglisin), toksik maddelere ve bulaşıcı ajanlara karşı önemli koruyucu etkiler sağlar. COVİD-19'lu hastalarda GSH'ın konakçı bağışıklık hücrelerinin korunmasında rol aldığı bazı çalışmalarda bildirilmiştir (Polonikov, 2020;Jaiswal ve ark., 2020). Nasetilsistein (NAC), glutatyonun bir öncüsüdür (Poe ve Corn, 2020). ...
... Glutatyon, indirgenmiş (GSH) ve oksitlenmiş (GSSG) olmak üzere iki formda bulunur. Hücreleri oksidatif stresten korumak için GSH, ROS'u azaltır ve kendisi oksitlenmiş (GSSG) durumuna dönüşür (Polonikov, 2020). GSH seviyeleri ile hastanın COVID-19 hastalığını yenmesinin bağlantılı olduğu ve yüksek ROS/GSH oranına sahip olmanın COVID-19 semptomlarını kötüleştirdiği bildirilmiştir (75). ...
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Panik bozukluğu (PB), DSM-IV-TR (Diagnostic and Stastistical Manual of Mental Disorders) ’de anksiyete bozuklukları başlığının altında sınıflandırılmaktadır. Panik bozukluk hastalığının genel bir özelliği yenileyici nitelikte, hiç beklenmeyen bir şekilde meydana gelen panik ataklardır. Söz konusu ataklar uzun sürmeyen, çok bunaltıcı ya da korku süreçleridir. Panik atağı esnasında bireyler, başlarına bir felaket gelebileceği hissine kapılırlar. Çarpıntı, göğüs ağrısı, nefes darlığı benzeri şikayetleri sebebiyle yaygın bir şekilde kalp krizi geçirip, ölebilecekleri düşüncesine kapılırlar. Birey taze bir nöbet geçirebilme korkusu ile (bekleme anksiyetesi), kalabalık bir ortamdan, evin dışında yalnız kalmaktan ya da yolculuk yapmaktan sakınır ki bu durum “agorafobi’’ diye adlandırılmaktadır. Panik Bozukluk 20‟li yaşlarda başlasa bile genel olarak yaşamın belirsiz bir sürecinde başlayabilmektedir. Sosyal ve mesleki fonksiyonlarda mühim problemlere sebep olabilmektedir (Kaplan ve ark., 1994; Kaplan, 2007; Köroğlu, 2007). Son yıllarda serbest oksijen radikallerinin nöropsikiyatrik olan rahatsızlıkların patofizyolojisinde mühim etkisi olduğuna yönelik bilgiler zamanla artış göstermiştir.
... Redükte glutatyon (GSH, γ-glutamilsisteinilglisin), toksik maddelere ve bulaşıcı ajanlara karşı önemli koruyucu etkiler sağlar. COVİD-19'lu hastalarda GSH'ın konakçı bağışıklık hücrelerinin korunmasında rol aldığı bazı çalışmalarda bildirilmiştir (Polonikov, 2020;Jaiswal ve ark., 2020). Nasetilsistein (NAC), glutatyonun bir öncüsüdür (Poe ve Corn, 2020). ...
... Glutatyon, indirgenmiş (GSH) ve oksitlenmiş (GSSG) olmak üzere iki formda bulunur. Hücreleri oksidatif stresten korumak için GSH, ROS'u azaltır ve kendisi oksitlenmiş (GSSG) durumuna dönüşür (Polonikov, 2020). GSH seviyeleri ile hastanın COVID-19 hastalığını yenmesinin bağlantılı olduğu ve yüksek ROS/GSH oranına sahip olmanın COVID-19 semptomlarını kötüleştirdiği bildirilmiştir (75). ...
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Bipolar bozukluk (BB), tekrarlayan gerek mani, gerek hipomani ve gerekse de depresif epizodlarla karakterize edilmiş olan kronik biçimli duygudurum bozukluğudur. Bipolar Bozukluk teşhisi alan hastaların yaklaşık olarak %80'i ilk duygudurum epizodundan sonraki 2 sene içerisinde yeni bir hastalık dönemi daha yaşadıkları açıklanmıştır (Nıce, 2014). Bipolar Bozukluk, büyük ölçüde yeti yitimine sebep olan ve de bozucu seyri esnasında büyük ölçüde mortalite tehlikesi taşıyan kronik ve nöropsikiyatrik hastalıklardan biridir. Dünya Sağlık Örgütü’nce (WHO) iş gücü kaybına en fazla neden olan hastalıklar içinde kabul görmüştür (Mathers ve ark., 2004; Weissman ve ark., 1996). Hastalıkların yüksek olan morbidite ve de mortaliteleri, doğruya doğru veya dolaylı olarak maliyetleri yüksek olan mühim ölçüde ekonomik yönünden ve sosyal yönünden yük meydana getirmektedir (Saha ve ark., 2005, Barbato, 1998). Bilhassa çinko (Zn) ve bakır (Cu) gibi eser elementler; canlı olan organizmalarda pek çok enzim yönünden vazgeçilmez olan kofaktörlerdir. Fakat nöropsikiyatrik olan hastalıkların farklı türlerde seviyeleri yorumlanmış ve seviyelerinin olması gereken seviyenin aşağısına düşmesi veya yukarısına çıkması halinde bipolar bozukluk ve de şizofreninin de içinde olmak üzere çeşitli nörolojik ve psikiyatrik bozuklukların etiyoloji ve patofizyolojisinde etkili olabileceği gösterilmiştir.
... Redükte glutatyon (GSH, γ-glutamilsisteinilglisin), toksik maddelere ve bulaşıcı ajanlara karşı önemli koruyucu etkiler sağlar. COVİD-19'lu hastalarda GSH'ın konakçı bağışıklık hücrelerinin korunmasında rol aldığı bazı çalışmalarda bildirilmiştir (Polonikov, 2020;Jaiswal ve ark., 2020). Nasetilsistein (NAC), glutatyonun bir öncüsüdür (Poe ve Corn, 2020). ...
... Glutatyon, indirgenmiş (GSH) ve oksitlenmiş (GSSG) olmak üzere iki formda bulunur. Hücreleri oksidatif stresten korumak için GSH, ROS'u azaltır ve kendisi oksitlenmiş (GSSG) durumuna dönüşür (Polonikov, 2020). GSH seviyeleri ile hastanın COVID-19 hastalığını yenmesinin bağlantılı olduğu ve yüksek ROS/GSH oranına sahip olmanın COVID-19 semptomlarını kötüleştirdiği bildirilmiştir (75). ...
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Familial Mediterranean fever (FMF) is the most familiar and widespread inheritable auto-inflammatory disease. This inherited disease is indicated by recurrent self-limiting attacks of serosal surfaces and result in inflammation. Inflammation is the physiological resistance that the organism responds to every kind of deleterious stimulus. Vitamin D deficiency or insufficiency have vital role in the initiation and enduring of certain autoimmune diseases. According to prior pertinent studies, vitamin D levels in adult FMF patients as well as children with FMF manifest hypovitaminosis D as compared with healthy peers. The frequency of vitamin D deficiency in children and adults with familial Mediterranean fever (FMF) is demonstrated and found that the serum 25-hydroxyvitamin D levels were significantly lower in FMF patients than the healthy controls and incremental colchicine dose appears to negatively affect vitamin D levels.
... Research has shown that Covid-19 severe symptoms were observed in patients with insufficient glutathione levels so that its deficiency may likely be the most cause of severe symptoms of SARS-2 illness. The responsiveness of everyone to SARS-2 infection mostly depends on his/her glutathione levels since low levels are found in people with chronic diseases that put them at higher risks of severe symptoms and death as quoted by Polonikov (2020). ...
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Inflammasome activation is one of the first steps in initiating innate immune responses. In this work, we studied the activation of inflammasomes in the airways of critically ill COVID-19 patients and the effects of N-acetylcysteine (NAC) on inflammasomes. Tracheal biopsies were obtained from critically ill patients without COVID-19 and no respiratory disease (control, n = 32), SARS-CoV-2 B.1 variant (n = 31), and B.1.1.7 VOC alpha variant (n = 20) patients. Gene expression and protein expression were measured by RT-qPCR and immunohistochemistry. Macrophages and bronchial epithelial cells were stimulated with different S, E, M, and N SARS-CoV-2 recombinant proteins in the presence or absence of NAC. NLRP3 inflammasome complex was over-expressed and activated in the COVID-19 B.1.1.7 VOC variant and associated with systemic inflammation and 28-day mortality. TLR2/MyD88 and redox NOX4/Nrf2 ratio were also over-expressed in the COVID-19 B.1.1.7 VOC variant. The combination of S-E-M SARS-CoV-2 recombinant proteins increased cytokine release in macrophages and bronchial epithelial cells through the activation of TLR2. NAC inhibited SARS-CoV-2 mosaic (S-E-M)-induced cytokine release and inflammasome activation. In summary, inflammasome is over-activated in severe COVID-19 and increased in B.1.1.7 VOC variant. In addition, NAC can reduce inflammasome activation induced by SARS-CoV-2 in vitro, which may be of potential translational value in COVID-19 patients.
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Despite the great progress and advancements in scientific knowledge, technology, and medicine, viral infections continue to put human health in trouble. Both acquired immunodeficiency syndrome (AIDS) and coronavirus disease-2019 (COVID-19), caused by HIV and SARS-CoV-2, two RNA viruses responsible for global pandemics respectively, have poor outcomes associated with increased oxidative stress, systemic inflammation, and immunopathology. Here, we have collected the current knowledge linking both viral infections, focusing on the role of oxidative stress and the redox balance. Furthermore, we provide information on some redox-active compounds, such as vitamins, thiol-based agents, and polyphenols, and their possible beneficial effects on both diseases. Thus, in this review, we aim to highlight the importance and impact of nutritional strategies to strengthen our immune system, especially to increase the effectiveness of pharmacological treatments, or when there are no effective treatments.
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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 NFKappaB and addressing “cytokine storm syndrome” and respiratory distress in patients with COVID-19 pneumonia.
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The world is in the grip of the COVID-19 pandemic. Public health measures that can reduce the risk of infection and death in addition to quarantines are desperately needed. This article reviews the roles of vitamin D in reducing the risk of respiratory tract infections, knowledge about the epidemiology 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 concentrations of pro-inflammatory cytokines that produce the inflammation that injures the lining of the lungs, leading to pneumonia, as well as increasing concentrations of anti-inflammatory cytokines. Several observational studies and clinical 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) concentrations are lowest; that the number 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 associated with lower 25(OH)D concentration. 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 concentrations, followed by 5000 IU/d. The goal should be to raise 25(OH)D concentrations 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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A growing body of literature on the 2019 novel coronavirus (SARS-CoV-2) is becoming available, but a synthesis of available data has not been conducted. We performed a scoping review of currently available clinical, epidemiological, laboratory, and chest imaging data related to the SARS-CoV-2 infection. We searched MEDLINE, Cochrane CENTRAL, EMBASE, Scopus and LILACS from 01 January 2019 to 24 February 2020. Study selection, data extraction and risk of bias assessment were performed by two independent reviewers. Qualitative synthesis and meta-analysis were conducted using the clinical and laboratory data, and random-effects models were applied to estimate pooled results. A total of 61 studies were included (59,254 patients). The most common disease-related symptoms were fever (82%, 95% confidence interval (CI) 56%–99%; n = 4410), cough (61%, 95% CI 39%–81%; n = 3985), muscle aches and/or fatigue (36%, 95% CI 18%–55%; n = 3778), dyspnea (26%, 95% CI 12%–41%; n = 3700), headache in 12% (95% CI 4%–23%, n = 3598 patients), sore throat in 10% (95% CI 5%–17%, n = 1387) and gastrointestinal symptoms in 9% (95% CI 3%–17%, n = 1744). Laboratory findings were described in a lower number of patients and revealed lymphopenia (0.93 × 109/L, 95% CI 0.83–1.03 × 109/L, n = 464) and abnormal C-reactive protein (33.72 mg/dL, 95% CI 21.54–45.91 mg/dL; n = 1637). Radiological findings varied, but mostly described ground-glass opacities and consolidation. Data on treatment options were limited. All-cause mortality was 0.3% (95% CI 0.0%–1.0%; n = 53,631). Epidemiological studies showed that mortality was higher in males and elderly patients. The majority of reported clinical symptoms and laboratory findings related to SARS-CoV-2 infection are non-specific. Clinical suspicion, accompanied by a relevant epidemiological history, should be followed by early imaging and virological assay.
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Background: An outbreak of coronavirus disease 2019 (COVID-19) occurred in Wuhan, China; the epidemic is more widespread than initially estimated, with cases now confirmed in multiple countries. Aims: The aim of this meta-analysis 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. Methods: A literature search was conducted using the databases PubMed, EMBASE, and Web of Science through February 25, 2020. Odds ratios (ORs) and 95% confidence intervals (CIs) were pooled using random-effects models. Results: Seven studies were included in the meta-analysis, including 1 576 infected patients. The results showed the most prevalent clinical 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) respectively. Conclusion: 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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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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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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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 physiological and pathological conditions. Diabetes is associated with lower levels of glutathione (GSH) and 25(OH) vitamin D. This study examined 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 down-regulation 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. This article is protected by copyright. All rights reserved.
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Background Since December, 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). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 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. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/L (18·42, 2·64–128·55; p=0·0033) 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 observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/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. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.