ArticlePDF Available

Effects of Quadruple Therapy: Zinc, Quercetin, Bromelain and Vitamin C on the Clinical Outcomes of Patients Infected with COVID-19

Authors:

Abstract

ABSTRACT COVID-19 emerged in Wuhan, China in December 2019, reached epidemic proportions and spread globally as a serious life-threatening pandemic. SARS- Cov-2 is the causative virus that causes severe acute respiratory distress, pneumonia, respiratory failure, and septic shock leading to increased mortality. High risk patients include those with chronic non-communicable diseases such as diabetes, hypertension, coronary heart disease and cancers. No speci􀏐ic treatment is available and supportive care all that could be done to rescue patients. Quadriple therapy consisting of Zinc, Quercetin, Bromelain and Vitamin C showed promising results in improving clinical outcome among COVID-19 patients. Keywords: COVID-19, Cytokines, zinc, Quercetin, Bromelain, Vitamin C.
Research International Journal of Endocrinology and Diabetes
Re Int Jou of end and dia
© 2020 MSD Publica ons. All rights reserved. 018
Volume 1 Issue 1 - 1005
Mini Review
Eff ects of Quadruple Therapy: Zinc, Quercetin, Bromelain
and Vitamin C on the Clinical Outcomes of Patients
Infected with COVID-19
Amr K. Ahmed1, Yousef S. Albalawi2, Hassan A. Shora3*, Hiba. K. Abdelseed4 and
Abdulla N. Al-Kattan5
1Tuberculosis Control Program, Mobile Team, Ministry of Health, Saudi Arabia.
2Medical Hospital Director, Elmam AbdelRahman lfaiasal Hospital, Saudi Arabia.
3Department of Biochemistry, Port-said University, Egypt.
4Tuberculosis Control Program Coordinator, Riaydh Ministry of Health, Saudi Arabia.
5Pharmacology Candidate, Ministry of Health, Saudi Arabia.
*Address for Correspondence: Hassan Shora, Senior Researcher, Port-Said University & Head of Medicine and Diabetes
Center, Ismailia General Hospital, Ismailia 064, Egypt. E mail: Hassanshora56@gmail.com
Received: 01 August 2020; Accepted: 28 August 2020; Published: 29 August 2020
Citation of this article: Ahmed AK, Albalawi YS, Shora HA, Abdelseed HK, Al-Kattan AN (2020) Effects of Quadruple Therapy:
Zinc, Quercetin, Bromelain and Vitamin C on the Clinical Outcomes of Patients Infected with COVID-19. Rea Int J of End and
Diabe. 1(1): 018-021. DOI: 10.37179/rijed.000005.
Copyright: © 2020 Ahmed AK, et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Introduction
A novel infectious disease, caused by severe acute respiratory
syndrome coronavirus 2 (SARS-Cov-2), was detected in Wuhan,
China, in December 2019.  e disease (COVID-19) spread rapidly,
reaching epidemic proportions in China, and 27 other countries. No
speci c therapeutics are available, and current management includes
travel restrictions, patient isolation, and supportive medical care.
ere are several pharmaceuticals already being tested [1].
Coronavirus disease 2019 (COVID-19) is an acute respiratory
disease that can lead to respiratory failure and death. Patients with
chronic respiratory diseases, such as chronic obstructive pulmonary
disease (COPD) and asthma, would be anticipated to have an
increased risk of infection and a more severe disease [2].
ABSTRACT
COVID-19 emerged in Wuhan, China in December 2019, reached epidemic proportions and spread globally as a serious life-threatening
pandemic. SARS- Cov-2 is the causative virus that causes severe acute respiratory distress, pneumonia, respiratory failure, and septic shock
leading to increased mortality. High risk patients include those with chronic non-communicable diseases such as diabetes, hypertension,
coronary heart disease and cancers. No speciic treatment is available and supportive care all that could be done to rescue patients. Quadriple
therapy consisting of Zinc, Quercetin, Bromelain and Vitamin C showed promising results in improving clinical outcome among COVID-19
patients.
Keywords: COVID-19, Cytokines, zinc, Quercetin, Bromelain, Vitamin C.
Citation: Ahmed AK, Albalawi YS, Shora HA, Abdelseed HK, Al-Kattan AN (2020) Effects of Quadruple Therapy: Zinc,
Quercetin, Bromelain and Vitamin C on the Clinical Outcomes of Patients Infected with COVID-19. Rea Int J of End and Diabe.
1(1): 018-021. DOI: 10.37179/rijed.000005.
019
Volume 1 Issue 1 - 1005
Re Int Jou of end and dia
© 2020 MSD Publica ons. All rights reserved.
e pathogen, a novel coronavirus (SARS-CoV-2), was identi ed
by local hospitals using a surveillance mechanism for “pneumonia
of unknown etiology” that was established in the wake of the 2003
SARS outbreak with the aim of allowing timely identi cation of novel
pathogens [3].
e immune system plays a critical role in protecting the
human body from infectious diseases [4]. T-cell counts are reduced
signi cantly in COVID-19 patients, and the surviving T-cells appear
functionally exhausted. Non-ICU patients with total T cells counts
lower than 800/μ L may still require urgent intervention, even in
the immediate absence of more severe symptoms due to a high risk
for further deterioration in condition [5]. Further research on the
severity of comorbidities and all medication received by the patients
is mandatory to shed light on these associations [2] (Figure 1).
Vit c
Vitamin C exerts its antiviral properties by supporting lymphocyte
activity, increasing interferon-α production, modulating cytokines,
reducing in ammation, improving endothelial dysfunction, and
restoring mitochondrial function [9].
ere are also suggestions that vitamin C may be directly
viricidal.  e in vitro e ects constitute a re ection of both the supra-
physiological concentrations of ascorbate and the interaction between
vitamin C and metal-containing culture media—both of which are
pro-oxidant, generating reactive oxygen species [10].
Quercetin (Que)
Quercetin (Que), (also known as 3,3’,4’5,7-pentahydroxy avone),
is a widely distributed plant  avonoid, found in several vegetables,
leaves, seeds, and grains, where it is conjugated with residual sugars
to form Que glycosides. Studies suggest that Que supplementation
may promote antioxidant, anti-in ammatory, antiviral, and
immunoprotective e ects. Quercetin has been studied in various
types and models of viral infection due to its promising antiviral
e ects in inhibiting polymerases, proteases, reverse transcriptase,
suppressing DNA gyrase, and binding viral capsid proteins [11].
Recently, Que has been shown to inhibit in vitro production
of cyclooxygenase (COX) and lipoxygenase (LOX) which are
typically induced by in ammation.  e anti-in ammatory e ect
has been supported by in vivo experiments as well. Examples of
Que’s inhibitory qualities include the signi cant blocking of pro
in ammatory cytokines in cultured  broblasts. 10 𝜇M Que down
regulated the production of COX-2, the Nuclear Factor kappa B (NF-
𝜅B), and NO. 10–25 𝜇M Que inhibited the level of NO and TNF-𝛼.
Other properties of 50 and 100 𝜇M Que include reducing
the secretion of IL6 and TNF-𝛼 in LPS-stimulated RAW 264.7
microphages, while at 25 and 50 𝜇M it proved to be the most
e cient blocker of TNF-𝛼 secretion in macrophages. Finally, at
low concentrations, Que (less than 50 𝜇M) also stimulated anti-
in ammatory cytokine IL-10. Similarly, 25𝜇M Que blocked IL-1𝛽,
IL-6, IFN-𝛾, and TNF-𝛼 secretion in human whole blood induced by
LPS [12].
Quercetin can also inhibit pro in ammatory cytokines. A six-
week regiment of 150 milligrams of Que taken daily by human
subjects signi cantly lowered cytokine TNF-𝛼 serum concentrations
[12]. Quercetin e ectively inhibited LPS-induced DC activation by
reducing the production of proin ammatory cytokines/chemokines
and the expression levels of MHC class II and costimulatory
molecules. In addition, quercetin uniquely blocked endocytosis
by Dendritic Cells DCs and the LPS-induced DC migration was
diminished by quercetin treatment [13].
Quercetin has been shown clinically to block human mast cell
cytokine release, possibly inhibiting the clinical manifestation of
cytokine storm. Severe COVID-19 disease progression is associated
with increased levels of C-Reactive protein, D-Dimer, Ferritin, IL-
2, and IL-6. Quercetin has been shown in studies to reduce all these
markers [14].
Figure 1: Cytokine storm.
Discussion
The role of Zinc:
Since the discovery of the  rst reported case with zinc-de ciency
in Iran by Prasad et al. in 1961 [6], we have learned a lot about Zinc,
and we have much more le to learn. Zinc is the second most abundant
common trace mineral in the human body, with vital biological
functions from cell growth and development to cell homeostasis and
immune response [7].
Mechanical ventilation is a necessary intervention to support
patients with lung injury and the acute respiratory distress syndrome
(ARDS) but can also exacerbate injury through mechanical stress-
activated signaling pathways. It is showed that stretch applied to
cultured human lung cells, and to mouse lungs in vivo, induces
robust expression of metallothionein, a potent antioxidant and
cyto-protective molecule critical for cellular zinc homeostasis.
Furthermore, genetic de ciency of murine metallothionein genes
exacerbated lung injury caused by injurious mechanical ventilation,
identifying an adaptive role for these genes in limiting lung injury.
Stretch induction of metallothionein required zinc and the zinc
binding transcription factor MTF-1. We further show that dietary
zinc-de ciency in mice potentiates ventilator-induced lung injury,
and that plasma zinc levels were signi cantly reduced in human
patients with ARDS compared to healthy and non-ARDS ICU
controls [8].
Citation: Ahmed AK, Albalawi YS, Shora HA, Abdelseed HK, Al-Kattan AN (2020) Effects of Quadruple Therapy: Zinc,
Quercetin, Bromelain and Vitamin C on the Clinical Outcomes of Patients Infected with COVID-19. Rea Int J of End and Diabe.
1(1): 018-021. DOI: 10.37179/rijed.000005.
020
Volume 1 Issue 1 - 1005
Re Int Jou of end and dia
© 2020 MSD Publica ons. All rights reserved.
Balancing systemic iron levels within narrow limits is critical
for maintaining human health.  ere are no known pathways to
eliminate excess iron from the body and therefore iron homeostasis is
maintained by modifying dietary absorption so that it matches daily
obligatory losses. Several dietary factors can modify iron absorption.
Polyphenols are plentiful in human diet and many compounds,
including Que – the most abundant dietary polyphenol – are potent
iron chelators [15].
Quercetin is a zinc ionophore and could have similar antiviral
activity of chloroquine but described as safe choice in the treatment
of viral infections [16].
Bromelain
Bromelain activates the in ammatory mediators, including
interleukin (IL)-1β, IL-6, interferon (INF)-γ and tumor necrosis
factor (TNF)-α in mouse macrophage and human peripheral blood
mononuclear cells (PBMC) (Barth).  ese results indicated that
bromelain potentially activates the healthy immune system in
association with the rapid response to cellular stress. Conversely,
bromelain reduces IL-1β, IL-6 and TNF-α secretion when immune
cells are already stimulated in the condition of in ammation-induced
over production of cytokines [17].
It was also found that bromelain upregulated p53 and Bax
with consequent activation of Caspase 3 and Caspase 9 with
concomitant decrease in BCL2. Marked inhibition of cyclooxygenase
2 (COX2) expression with inactivation of NF Kappa B by blocking
phosphorylation and degradation of IK B α were blocked by
bromelain. Furthermore, bromelain ameliorated extracellular signal
of regulated protein kinase ERK1/2, P38 mitogen activated protein
kinase MAPK and Akt activity. So, it modulated defective cellular
signaling cascades [18].
Bromelain prevents or minimizes the severity of angina pectoris
and transient ischemic attack (TIA). It is useful in the prevention and
treatment of thrombophlebitis. It may also break down cholesterol
plaques and exerts a potent  brinolytic activity. A combination of
bromelain and other nutrients protect against ischemia / reperfusion
injury in skeletal muscle. Bromelain in uences blood coagulation by
increasing the serum  brinolytic ability and by inhibiting the synthesis
of  brin, a protein involved in blood clotting [19, 20] (Figure 2).
Conclusion
e dreadful pandemic caused by SARS-CoV2 led to extremely
high morbidity and mortality worldwide.  ere is no speci c therapy
and only supportive treatment to rescue patients’ life is the only
available option. A novel Quadriple therapy consisting of Zinc,
Quercetin, Bromelain and Vitamin C shows a promising positive
therapeutic e ect. is mini review is the basis of our running clinical
controlled trial and results will be available nearly.
References
1. Haibo Z, Josef MP, Yimin Li, Nanshan Z, Arthur SS (2020) Angiotensin-
converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular
mechanisms and potential therapeutic target Intensive Care Med 46:
586-590. Link: https://bit.ly/3lrcRu5
2. Halpin DMG, Faner R, Sibila O, Badia JR, Agusti A (2020) Do chronic
respiratory diseases or their treatment affect the risk of SARS-CoV-2
infection? Lancet Respir Med 8: 436-438. Link: https://bit.ly/3bgv8FX
3. Qun Li, Xuhua G, Peng W, Xiaoye W, Lei Z, et al. (2020) Early
Transmission Dynamics in Wuhan, China, of Novel Coronavirus-
Infected Pneumonia. N Engl J Med 382: 1199-1207. Link: https://bit.
ly/3jnQ4gK
4. Aysooda H, Omid S, Akram NB, Sepideh S, Gabriel SB, et al. (2019)
Immunomodulatory Effects of Flavonoids: Possible Induction of
T CD4+ Regulatory Cells Through Suppression of mTOR Pathway
Signaling Activity. Front Immunol 10: 51. Link: https://bit.
ly/3lnEMem
5. Diao B, Wang C, Tan Y, Xiewan C, Ying Liu, et al. (2020) Reduction
and Functional Exhaustion of T Cells in Patients with Coronavirus
Disease 2019 (COVID-19) Front. Immunol 11: 827. Link: https://bit.
ly/3gFYAWK
6. PRASAD AS, HALSTED JA, NADIMI M (1961) Syndrome of iron
deiciency anemia, hepatosplenomegaly, hypogonadism, dwarism
and geophagia. Am. J. Med 31: 532–546. Link: https://bit.ly/3hD2fWz
7. Roohani N, Hurrell R, Kelishadi R, Schulin R (2013) Zinc and its
importance for human health: An integrative review. J. Res. Med. Sci
18: 144–157. Link: https://bit.ly/2QB4LRa
8. Englert J, Boudreault F, Pinilla-Vera M, Alvin TK, Colleen I, et al.
(2016) ID: 60 Zinc deiciency primes the lung for ventilator-induced
injury. Journal of Investigative Medicine 64: 973. Link: https://bit.
ly/2Qx0hLx
9. Carr AC, Maggini S (2017) Vitamin C and Immune Function. Nutrients.
9: 1211. Link: https://bit.ly/31CvDGM
10. Furuya A, Uozaki M, Yamasaki H, Arakawa T, Arita Koyama MAH
(2008) Antiviral effects of ascorbic and dehydroascorbic acids in vitro.
Int J Mol Med. 22: 541–545. Link: https://bit.ly/31yX98d
11. Colunga BRML, Berrill M, Catravas JD, Marik PE (2020) Quercetin and
Vitamin C: An Experimental, Synergistic Therapy for the Prevention
and Treatment of SARS-CoV-2 Related Disease (COVID-19). Frontiers
in Immunology 11: 1451. Link: https://bit.ly/2QxVppr
12. Chen S, Jiang H, Wu X, Fang J (2016) Therapeutic Effects of Quercetin
on Inlammation, Obesity, and Type 2 Diabetes. Mediators Inϔlamm
2016: 9340637. Link: https://bit.ly/2EzcZaf
13. Huang RY, Yu YL, Cheng WC, OuYang CN, Fu E, et al. (2010)
Immunosuppressive effect of quercetin on dendritic cell activation
and function. J Immunol. 184: 6815-6821. Link: https://bit.ly/3jzRh51
14. Zuyi W, Bodi Z, Shahrzad A, Nikolaos S, Alan Butcher, et al. (2012)
Quercetin Is More Effective than Cromolyn in Blocking Human
Mast Cell Cytokine Release and Inhibits Contact Dermatitis and
Figure 2: Quercetin and bromealin for blocking the interleukin.
Citation: Ahmed AK, Albalawi YS, Shora HA, Abdelseed HK, Al-Kattan AN (2020) Effects of Quadruple Therapy: Zinc,
Quercetin, Bromelain and Vitamin C on the Clinical Outcomes of Patients Infected with COVID-19. Rea Int J of End and Diabe.
1(1): 018-021. DOI: 10.37179/rijed.000005.
021
Volume 1 Issue 1 - 1005
Re Int Jou of end and dia
© 2020 MSD Publica ons. All rights reserved.
Photosensitivity in Humans. PLoS One 7: e33805. Link: https://bit.
ly/32wunUZ
15. Lesjak M, Rukshana H, Sara B, Vernon S, Edward S, et al. (2014)
Quercetin Inhibits Intestinal Iron Absorption and Ferroportin
Transporter ExpressionIn Vivo and In Vitro. PLoS ONE 9: e102900.
Link: https://bit.ly/2YI9SUu
16. Dabbagh-Bazarbachi H, Gael C, Isabel MQ, Mayreli O, Ciara KOH, et
al. (2014) “Zinc ionophore activity of quercetin and epigallocatechin-
gallate: from Hepa 1-6 cells to a liposome model.” J Agric Food Chem.
62: 8085-8093. Link: https://bit.ly/2EzfuJF
17. Onken JE, Greer PK, Calingaert B, Hale LP (2008) Bromelain treatment
decreases secretion of pro-inlammatory cytokines and chemokines
by colon biopsies in vitro. Clin Immunol 126: 345-352. Link: https://
bit.ly/3gCCrsz
18. Pavan R, Jain S, Shraddha, Kumar A (2012) Properties and therapeutic
application of bromelain: a review. Biotechnol Res Int. 2012: 976203.
Link: https://bit.ly/3b4COdY
19. Rathnavelu V, Alitheen NB, Sohila S, Kanagesan S, Ramesh R (2016)
Potential role of bromelain in clinical and therapeutic applications
(Review) Biomed. Reports 5: 283-288. Link: https://bit.ly/3hDc0UO
20. Hu PA, Chen CH, Guo BC, Kou YR, Lee TS (2020) Bromelain Confers
Protection Against the Non-Alcoholic Fatty Liver Disease in Male
C57BL/6 Mice. Nutrients. 12: 1458. Link: https://bit.ly/3gCeGRh
... In vitro studies demonstrated that quercetin inhibited recom human (rh) ACE2 activity [74,75]. More recently, the clinical trials (NCT04468 NCT04377789) including quercetin, were involved in both prophylaxis and treat COVID-19 [76][77][78]. ...
... In vitro studies demonstrated that quercetin inhibited recombinant human (rh) ACE2 activity [74,75]. More recently, the clinical trials (NCT04468139 and NCT04377789) including quercetin, were involved in both prophylaxis and treatment of COVID-19 [76][77][78]. ...
... Quercetin, in combination with zinc, bromelain and vitamin C, is recruited in clinical trials [77]. Several clinical trials on resveratrol, artemisinin, glycyrrhizin, colchicine, berberine, and tetrandrine have been designed and are going on. ...
Article
Full-text available
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified in China as the etiologic agent of the recent COVID-19 pandemic outbreak. Due to its high transmissibility, this virus quickly spread throughout the world, causing considerable health issues. The scientific community exerted noteworthy efforts to obtain therapeutic solutions for COVID-19, and new scientific networks were constituted. No certified drugs to efficiently inhibit the virus were identified, and the development of de-novo medicines requires approximately ten years of research. Therefore, the repurposing of natural products could be an effective strategy to handle SARS-CoV-2 infection. This review aims to update on current status of the natural occurring compounds recognizing SARS-CoV-2 druggable targets. Among the clinical trials actually recruited, some natural compounds are ongoing to examine their potential role to prevent and to treat the COVID-19 infection. Many natural scaffolds, including alkaloids, terpenes, flavonoids, and benzoquinones, were investigated by in-silico, in-vitro, and in-vivo approaches. Despite the large data set obtained by a computational approach, experimental evidences in most cases are not available. To fill this gap, further efforts to validate these results are required. We believe that an accurate investigation of naturally occurring compounds may provide insights for the potential treatment of COVID-19 patients.
... What was found to be significant in this study was that zinc sulfate added to hydroxychloroquine and azithromycin was associated with a decrease in mortality or transition to hospice among patients who did not require ICU level of care [106]. Other clinical trials are currently recruiting members to test whether zinc can be an effective symptomatic treatment for COVID-19 [41][42][43]. ...
Article
Full-text available
The coronavirus disease 2019 (COVID-19) has caused a pandemic and upheaval that health authorities and citizens around the globe are still grappling with to this day. While public health measures, vaccine development, and new therapeutics have made great strides in understanding and managing the pandemic, there has been an increasing focus on the potential roles of diet and supplementation in disease prevention and adjuvant treatment. In the literature, the impact of nutrition on other respiratory illnesses, including the common cold, pneumonia, and influenza, has been widely demonstrated in both animal and human models. However, there is much less research on the impact related to COVID-19. The present study discusses the potential uses of diets, vitamins, and supplements, including the Mediterranean diet, glutathione, zinc, and traditional Chinese medicine, in the prevention of infection and severe illness. The evidence demonstrating the efficacy of diet supplementation on infection risk, disease duration, severity, and recovery is mixed and inconsistent. More clinical trials are necessary in order to clearly demonstrate the contribution of nutrition and to guide potential therapeutic protocols.
... Based on immune-modulatory characteristics of the bromelain, it can modify immunological responses in patients such as those with COVID-19 who present with manifestations of lymphocytosis and leukopenia (21). According to the results obtained in our study, this effect of bromelain was observed so that the patients in the sample group had lower WBC counts and higher lymphocytes, so they were in a better situation in this view between 72 hours and 120 hours after drug consumption. ...
Article
Full-text available
The severity of COVID-19 disease and its mortality may be due to a localized vascular problem owing to the activation of bradykinin B1 receptors on endothelial cells in the lungs that occur following inflammation. Bromelain acts as an anti-inflammatory factor and can lower the level of bradykinin in the serum and tissues. Patients with the novel coronavirus (COVID-19) referred to Masih Daneshvari Hospital in Tehran were included in the study after providing full explanations and obtaining written consent. The 40 patients with mild to moderate symptoms were randomly divided into the control group (No: 20) and sample (No: 20). In the sample group, a dose of 200 mg bromelain was given to patients every 8 hours. In the control group, placebo capsules were administered exactly at the above intervals. Clinical and paraclinical factors (including SaO2, RR body temperature, MAP, HR, CRP, ESR, AST, ALT, Bil, BUN, Cr, WBC, Lymph, LDH, Plt were evaluated on a regular basis for up to five days. The results were evaluated using t-test and SPSS21 software. After treatment, the sample (Bromelain) group indicated significant improvement in SaO2, RR, HR, AST, ALT, BUN, ESR, LDH, and WBC and Lymphocyte count (P<0.05). Other factors did not have a significant difference with the control group. Bromelain causes improvement in some clinical symptoms such as respiratory parameters and para clinical items of mild to moderate hospitalized COVID-19 patients, so it can be a promising treatment. Furthered evaluation of larger groups is recommended.
... 150 Que, Zinc, Bromelain, and Vitamin C A quadruple therapy consisting of zinc, Que, bromelain, and vitamin C has been suggested to show a promising positive therapeutic effect in patients. 151 Others However, Que has low bioavailability and, therefore, requires special formulations to achieve clinically effective blood levels. A trial with a phytosomal Que formulation has been started for COVID-19 patients. ...
Article
Full-text available
Quercetin, a naturally occurring dietary flavonoid, is well known to ameliorate chronic diseases and aging processes in humans, and its antiviral properties have been investigated in numerous studies. In silico and in vitro studies demonstrated that quercetin can interfere with various stages of the coronavirus entry and replication cycle such as PLpro, 3CLpro, and NTPase/helicase. Due to its pleiotropic activities and lack of systemic toxicity, quercetin and its derivatives may represent target compounds to be tested in future clinical trials to enrich the drug arsenal against coronavirus infections. There is evidence that quercetin in combination with, for example, vitamins C and D, may exert a synergistic antiviral action that may provide either an alternative or additional therapeutic/preventive option due to overlapping antiviral and immunomodulatory properties. This review summarizes the antiviral significance of quercetin and proposes a possible strategy for the effective utilization of natural polyphenols in our daily diet for the prevention of viral infection.
Article
Full-text available
Bioactive compounds, such as phenolic compounds, are phytochemicals found in significant amounts in cereals and pseudocereals and are usually evaluated by spectrophotometric (UV-VIS), HPLC, and LC-MS techniques. However, their bioavailability in grains is quite limited. This restriction on bioavailability and bioaccessibility occurs because they are in conjugated polymeric forms. Additionally, they can be linked through chemical esterification and etherification to macro components. Techniques such as thermoplastic extrusion, germination, fermentation, and hydrolysis have been widely studied to release phenolic compounds in favor of their bioavailability and bioaccessibility, minimizing the loss of these thermosensitive components during processing. The increased availability of phenolic compounds increases the antioxidant capacity and favor their documented health promoting.
Article
Full-text available
It is well known that both Fagopyrum esculentum species, buckwheat achenes and buckwheat germs, contain flavonoids, and that they can be considered functional foods. In the present study we have analyzed the total content of polyphenols (TPC) and flavonoids (TFC), as well as the antioxidant activity of buckwheat ahcenes originating from the Balti region, Republic of Moldova, and also of the buckwheat sprouts over seven days of germination. The content of phytochemicals in achenes and germinated buckwheat after three and seven days was determined by HPLC–MS analysis. Using the Folin–Ciocalteu method, we recorded an increase in TPC of 360%, and of 436% in TFC after seven days of buckwheat ahcene germination. We aimed to investigate the free radical scavenging properties of methanolic extracts from ahcenes and sprouted buckwheat. We identified and quantified flavonoids and lignans such as rutin, orientin, isoorientin, vitexin, quercetin, quercitrin, isorhamnetin, lutein, apigenin, catechins, coumestrol—which have countless beneficial effects on human health—using HPLC–MS. FTIR analysis also revealed the accumulation of phenolic compounds during germination. This is the first study on the identification and quantification of phytochemicals from buckwheat achenes and sprouts from the Balti region of the Republic of Moldova.
Article
Emergence of severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection, COVID‐19, has become the global panic since December 2019, which urges the global healthcare professionals to identify novel therapeutics to counteract this pandemic. So far, there is no approved treatment available to control this public health issue; however, a few antiviral agents and repurposed drugs support the patients under medical supervision by compromising their adverse effects, especially in emergency conditions. Only a few vaccines have been approved to date. In this context, several plant natural products‐based research studies are evidenced to play a crucial role in immunomodulation that can prevent the chances of infection as well as combat the cytokine release storm (CRS) generated during COVID‐19 infection. In this present review, we have focused on flavonoids, especially epicatechin, epigallocatechin gallate, hesperidin, naringenin, quercetin, rutin, luteolin, baicalin, diosmin, ge nistein, biochanin A, and silymarin, which can counteract the virus‐mediated elevated levels of inflammatory cytokines leading to multiple organ failure. In addition, a comprehensive discussion on available in silico, in vitro, and in vivo findings with critical analysis has also been evaluated, which might pave the way for further development of phytotherapeutics to identify the potential lead candidatetoward effective and safe management of the SARS‐CoV‐2 disease.
Article
The spread of a new strain of coronavirus, SARS-CoV-2, a pandemic poses serious health problem for all humanity. In comparison with the previous outbreaks of coronavirus infection in 2002 and 2012, COVID-19 infection has high rates of lethality, contagiousness and comorbidity. The effective methods of prevention and treatment are extremely limited. Oxidative stress is actively involved in the mechanisms of initiation and maintenance of violations of homeostatic reactions in respiratory viral infections. It is important to stop systemic inflammation aimed at "extinguishing" the cytokine "storm", caused by the production of reactive oxygen species. Antioxidant defense medications such as vitamin C, N-acetylcysteine, melatonin, quercetin, glutathione, astaxanthin, polyphenols, fat-soluble vitamins, and polyunsaturated fatty acids have proven well in experimental and clinical studies of influenza, pneumonia, and other respiratory disorders. The use of medications with antioxidant activity could be justified and most probably would increase the effectiveness of the fight against new coronavirus.
Article
Full-text available
The outbreak of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has led to coronavirus disease-19 (COVID-19); a pandemic disease that has resulted in devastating social, economic, morbidity and mortality burdens. SARS-CoV-2 infects cells following receptor-mediated endocytosis and priming by cellular proteases. Following uptake, SARS-CoV-2 replicates in autophagosome-like structures in the cytosol following its escape from endolysosomes. Accordingly, the greater endolysosome pathway including autophagosomes and the mTOR sensor may be targets for therapeutic interventions against SARS-CoV-2 infection and COVID-19 pathogenesis. Naturally existing compounds (phytochemicals) through their actions on endolysosomes and mTOR signaling pathways might provide therapeutic relief against COVID-19. Here, we discuss evidence that some natural compounds through actions on the greater endolysosome system can inhibit SARS-CoV-2 infectivity and thereby might be repurposed for use against COVID-19.
Article
Full-text available
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) represents an emergent global threat which is straining worldwide healthcare capacity. As of May 27th, the disease caused by SARS-CoV-2 (COVID-19) has resulted in more than 340,000 deaths worldwide, with 100,000 deaths in the US alone. It is imperative to study and develop pharmacological treatments suitable for the prevention and treatment of COVID-19. Ascorbic acid is a crucial vitamin necessary for the correct functioning of the immune system. It plays a role in stress response and has shown promising results when administered to the critically ill. Quercetin is a well-known flavonoid whose antiviral properties have been investigated in numerous studies. There is evidence that vitamin C and quercetin co-administration exerts a synergistic antiviral action due to overlapping antiviral and immunomodulatory properties and the capacity of ascorbate to recycle quercetin, increasing its efficacy. Safe, cheap interventions which have a sound biological rationale should be prioritized for experimental use in the current context of a global health pandemic. We present the current evidence for the use of vitamin C and quercetin both for prophylaxis in high-risk populations and for the treatment of COVID-19 patients as an adjunct to promising pharmacological agents such as Remdesivir or convalescent plasma.
Article
Full-text available
We aimed to investigate the effect of bromelain, the extract from stems of pineapples on the high-fat diet (HFD)-induced deregulation of hepatic lipid metabolism and non-alcoholic fatty liver disease (NAFLD), and its underlying mechanism in mice. Mice were daily administrated with HFD with or without bromelain (20 mg/kg) for 12 weeks, and we found that bromelain decreased the HFD-induced increase in body weight by ~30%, organ weight by ~20% in liver weight and ~40% in white adipose tissue weight. Additionally, bromelain attenuated HFD-induced hyperlipidemia by decreasing the serum level of total cholesterol by ~15% and triglycerides level by ~25% in mice. Moreover, hepatic lipid accumulation, particularly that of total cholesterol, free cholesterol, triglycerides, fatty acids, and glycerol, was decreased by 15–30% with bromelain treatment. Mechanistically, these beneficial effects of bromelain on HFD-induced hyperlipidemia and hepatic lipid accumulation may be attributed to the decreased fatty acid uptake and cholesteryl ester synthesis and the increased lipoprotein internalization, bile acid metabolism, cholesterol clearance, the assembly and secretion of very low-density lipoprotein, and the β-oxidation of fatty acids by regulating the protein expression involved in the above mentioned hepatic metabolic pathways. Collectively, these findings suggest that bromelain has therapeutic value for treating NAFLD and metabolic diseases.
Article
Full-text available
Background: The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed great threat to human health. T cells play a critical role in antiviral immunity but their numbers and functional state in COVID-19 patients remain largely unclear. Methods: We retrospectively reviewed the counts of T cells and serum cytokine concentration from data of 522 patients with laboratory-confirmed COVID-19 and 40 healthy controls. In addition, the expression of T cell exhaustion markers were measured in 14 COVID-19 cases. Results: The number of total T cells, CD4+ and CD8+ T cells were dramatically reduced in COVID-19 patients, especially in patients requiring Intensive Care Unit (ICU) care. Counts of total T cells, CD8+ T cells or CD4+ T cells lower than 800, 300, or 400/μL, respectively, were negatively correlated with patient survival. T cell numbers were negatively correlated to serum IL-6, IL-10, and TNF-α concentration, with patients in the disease resolution period showing reduced IL-6, IL-10, and TNF-α concentrations and restored T cell counts. T cells from COVID-19 patients had significantly higher levels of the exhausted marker PD-1. Increasing PD-1 and Tim-3 expression on T cells was seen as patients progressed from prodromal to overtly symptomatic stages. Conclusions: T cell counts are reduced significantly in COVID-19 patients, and the surviving T cells appear functionally exhausted. Non-ICU patients with total T cells counts lower than 800/μL may still require urgent intervention, even in the immediate absence of more severe symptoms due to a high risk for further deterioration in condition.
Article
Full-text available
Background: The initial cases of novel coronavirus (2019-nCoV)-infected pneumonia (NCIP) occurred in Wuhan, Hubei Province, China, in December 2019 and January 2020. We analyzed data on the first 425 confirmed cases in Wuhan to determine the epidemiologic characteristics of NCIP. Methods: We collected information on demographic characteristics, exposure history, and illness timelines of laboratory-confirmed cases of NCIP that had been reported by January 22, 2020. We described characteristics of the cases and estimated the key epidemiologic time-delay distributions. In the early period of exponential growth, we estimated the epidemic doubling time and the basic reproductive number. Results: Among the first 425 patients with confirmed NCIP, the median age was 59 years and 56% were male. The majority of cases (55%) with onset before January 1, 2020, were linked to the Huanan Seafood Wholesale Market, as compared with 8.6% of the subsequent cases. The mean incubation period was 5.2 days (95% confidence interval [CI], 4.1 to 7.0), with the 95th percentile of the distribution at 12.5 days. In its early stages, the epidemic doubled in size every 7.4 days. With a mean serial interval of 7.5 days (95% CI, 5.3 to 19), the basic reproductive number was estimated to be 2.2 (95% CI, 1.4 to 3.9). Conclusions: On the basis of this information, there is evidence that human-to-human transmission has occurred among close contacts since the middle of December 2019. Considerable efforts to reduce transmission will be required to control outbreaks if similar dynamics apply elsewhere. Measures to prevent or reduce transmission should be implemented in populations at risk. (Funded by the Ministry of Science and Technology of China and others.).
Article
Full-text available
Vitamin C is an essential micronutrient for humans, with pleiotropic functions related to its ability to donate electrons. It is a potent antioxidant and a cofactor for a family of biosynthetic and gene regulatory enzymes. Vitamin C contributes to immune defense by supporting various cellular functions of both the innate and adaptive immune system. Vitamin C supports epithelial barrier function against pathogens and promotes the oxidant scavenging activity of the skin, thereby potentially protecting against environmental oxidative stress. Vitamin C accumulates in phagocytic cells, such as neutrophils, and can enhance chemotaxis, phagocytosis, generation of reactive oxygen species, and ultimately microbial killing. It is also needed for apoptosis and clearance of the spent neutrophils from sites of infection by macrophages, thereby decreasing necrosis/NETosis and potential tissue damage. The role of vitamin C in lymphocytes is less clear, but it has been shown to enhance differentiation and proliferation of B- and T-cells, likely due to its gene regulating effects. Vitamin C deficiency results in impaired immunity and higher susceptibility to infections. In turn, infections significantly impact on vitamin C levels due to enhanced inflammation and metabolic requirements. Furthermore, supplementation with vitamin C appears to be able to both prevent and treat respiratory and systemic infections. Prophylactic prevention of infection requires dietary vitamin C intakes that provide at least adequate, if not saturating plasma levels (i.e., 100–200 mg/day), which optimize cell and tissue levels. In contrast, treatment of established infections requires significantly higher (gram) doses of the vitamin to compensate for the increased inflammatory response and metabolic demand.
Article
Full-text available
In previous studies, abdominal obesity has been related to total low-grade inflammation and in some cases has resulted in insulin resistance and other metabolism related disorders such as diabetes. Quercetin is a polyphenol, which is a derivative of plants, and has been shown in vitro as well as in a few animal models to have several potential anti-inflammatory as well as anticarcinogenic applications. The substance has also been shown to aid in the attenuation of lipid peroxidation, platelet aggregation, and capillary permeability. However, further research is called for to gain a better understanding of how quercetin is able to provide these beneficial effects. This manuscript reviewed quercetin’s anti-inflammatory properties in relation to obesity and type 2 diabetes.
Article
Mechanical ventilation is a necessary intervention to support patients with lung injury and the acute respiratory distress syndrome (ARDS), but can also exacerbate injury through mechanical stress-activated signaling pathways. We show that stretch applied to cultured human lung cells, and to mouse lungs in vivo, induces robust expression of metallothionein, a potent anti-oxidant and cyto-protective molecule critical for cellular zinc homeostasis. Furthermore, genetic deficiency of murine metallothionein genes exacerbated lung injury caused by injurious mechanical ventilation, identifying an adaptive role for these genes in limiting lung injury. Stretch induction of metallothionein required zinc and the zinc binding transcription factor MTF-1. We further show that dietary zinc-deficiency in mice potentiates ventilator-induced lung injury, and that plasma zinc levels are significantly reduced in human patients with ARDS compared to healthy and non-ARDS ICU controls, as well as to other critically ill patients without ARDS. Taken together, our findings identify a novel adaptive response of the lung to stretch mediated by metallothionein and zinc. These results demonstrate that failure of stretch-adaptive responses play an important role in exacerbating ventilator-induced lung injury, and identify zinc and metallothionein as targets for developing lung-protective interventions in patients requiring mechanical ventilation.
Article
A syndrome occurring in males, characterized by severe iron deficiency anemia, hypogonadism, dwarfism, hepatosplenomegaly and geophagia, has been observed in villagers in Iran suffering from malnutrition. Eleven such patients, studied in detail, are described. Despite hepatosplenomegaly, results of the liver function tests were uniformly normal except for the serum alkaline phosphatase, which was consistently elevated. The anemia was not associated with blood loss, hookworm infestation or intestinal malabsorption, and responded promptly to oral iron therapy. Although the diet contained adequate amounts of iron it is believed that the predominantly wheat diet, with its high phosphate content, interfered with absorption because of the formation of insoluble iron complexes. Correction of the anemia resulted in marked decrease in the size of the liver and spleen. Prolonged follow-up of patients receiving a well balanced diet indicates that the endocrine abnormalities of growth and sexual development are reversible. The relationship of geophagia (which occurred in nearly all patients) to this syndrome is not clear, and is discussed. The possibility of zinc deficiency is considered as an explanation of hypogonadism, dwarfism and changes in alkaline phosphate.