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
... [11][12][13] It exerts its antioxidant effect by removing free radicals and maintaining oxidative balance, and its anti-inflammatory and anti-allergic effects by inhibiting the lipoxygenase and cyclooxygenase pathway. 12,14 In clinical studies, quercetin has been shown to have antiviral 15,16 and anti-inflammatory effects 16 , relieve respiratory symptoms 16 , prevent poor prognosis 17 and reduce hospitalization 18 in COVID-19 patients. ...
Article
Full-text available
Objectives: The COVID-19 pandemic has rapidly become a global health crisis. Currently, there are no proven, reliable, specific treatments for COVID-19. Alongside drug interventions, supportive treatments are implemented during the disease. Quercetin, recognized for its antiviral, anti-inflammatory, anti-aging, and antioxidant properties, is under evaluation in this study for its potential impact on preventing, influencing the course, and mitigating the severity of COVID-19. Methods: A thorough search was conducted across scientific databases, including PubMed, Embase, Web of Science, SAGEpub, Copernicus, Cochrane Library, ScienceDirect, Elsevier, Scopus, Google Scholar, EBSCOhost, Crossref, Ovid-LWW, and DergiPark databases, between 1 November 2021 and 1 April 2022 to ensure a comprehensive inclusion of relevant studies. Results: Thirteen randomized controlled clinical trials (five published, eight unpublished) were identified. Existing literature supports quercetin’s role as a potent free radical scavenger with robust antioxidant properties. It exhibits anti-inflammatory characteristics by inhibiting lipid peroxidation and restraining pro-inflammatory enzymes such as lipoxygenase and phospholipase A2. Scholarly discourse suggests that quercetin supplementation within the 500-1500 mg range leads to favorable outcomes, including quicker patient discharge, reduced inflammation, increased respiratory rate, accelerated viral clearance, and an improved disease prognosis. However, it is noted that intervention durations vary across studies. Conclusions: The analysis of the studies suggested that quercetin is a promising therapeutic agent that can cause a decrease in disease symptoms, frequency of hospitalization, hospital stay, need for non-invasive oxygen treatment, need for intensive care, and mortality. Nonetheless, more clinical studies are needed to better understand quercetin’s curative effects on COVID-19 infection.
... Montelukast can inhibit the NF-κB signaling pathway and decrease the release of pro-inflammatory cytokines, which is in agreement with the results of Barré et al, indicating that expressing the role of montelukast in inhibiting COVID-19 serious outcomes. [20][21][22][23] Bradykinin is a potent vasoactive mediator that is normally degraded by the ACE. The dysregulated bradykinin signaling is hypothesized to take part in COVID-19 respiratory complications. ...
Article
Introduction: The activation of bradykinin B1 receptors on endothelial cells in the lung following inflammation is a major cause of the severity and mortality of COVID-19. It has already been shown that bromelain and montelukast as two anti-inflammatory agents can be effective in controlling this condition. Methods: 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. All 40 patients with moderate symptoms were randomly divided into the placebo (n=20) and intervention (n=20) groups. In the sample group, a dose of 200 mg oral bromelain was given to patients every 8 hours and one tablet of montelukast 10 mg 1 hour before or after dinner for 5 days. In the control group, placebo capsules were administered exactly at the above intervals. The results were evaluated using a t test and SPSS21 software. Results: After treatment, the sample (bromelain and montelukast) group represented significant improvements in C-reactive protein (CRP), lactate dehydrogenase (LDH), and lymphocyte count (P<0.05), while the other factors did not have significant differences with the control group. Conclusion: Bromelain and montelukast can improve the condition of hospitalized COVID-19 patients by the positive effect on oxygen saturation, lymphocytes, serum levels of CRP, and LDH.
... Arjuna and some other herbs can in principle reduce or avoid such damage, it has been shown in different Indian studies (Gour et al., 2021;Peter et al., 2021). This has promoted Indian scientists to promote chemical extract ingredients from potent herbs as COVID-19 remedy elixir (Ahmed et al., 2020). ...
Article
Full-text available
Spices and vegetable rich, home cooked diet prevails in Asia, especially in India which is rich in polyphenols. This could have led to higher immunity and health, which is evident from the 3-4 time lower prevalence (< 10% population) and mortality (0.1% population) than the western countries. Mainly processed foods (packed and in hotels, with preservatives or additives therein, besides refined flours and vegetable oil/ trans fats) prevalent in developed countries can damage immunity. Consequent advanced glycation endproducts (AGEs) prevalence is a health risk. Polyphenols, saponins, salicylates and greater traditional, herbal medicines in the Asian diet, besides lesser vaccination/ flu shots/ antibiotics use may protect immunity, unlike in EU/ USA. Quercetin, piperine and isothiocynate (an organosulfur compound) in red onion, black pepper and mustard seed oil respectively may be the key health ingredients and anti-microbial/ anti-viral agents. Herbal tea from Terminalia arjunaL. tree bark is identified as potential COVID-19 cure alone or as adjuvant, as triterpenes in it build immunity. The Indo-Mediterranean diet with less refined flours, red meat and liquor, tobacco than the western countries may be healthy like the Oriental (Japanese) diet. Consumption extent of spices, especially mustard, is reported by others to be negatively correlated with corona incidence across 163 countries, as we too show here. We explain the preventive effect of 3 superfoods on COVID-19: red onion, black pepper & mustard. Europe and USA population miss the benefit of antioxidant quercetin content of the pungent red onion, as mild varieties are preferred, viz., white/yellow onion/shallot. Black pepper is healthier that chilly but the latter is commonly cooked by ignorance. Mustard oil that is common in India has high COVID-19 deterrence due to glucosinolates i.e. sulfur compounds. However, canola and rapeseed prevalent in EU & USA are bred for lower glucosinolate content to avoid pungency, but with no health benefits. Keywords: COVID-19, Ayurveda, Indo-Mediterranean diet, superfoods, antibiotics
... [69] A quadruple therapy involving zinc, quercetin, bromelain and vitamin C also has been suggested to show positive therapeutic effects in COVID-19 patients. [70] Thus, QCN in combination with other drugs could help enhance the drug effects and reduce the side effects, due in large part to their synergistic action. [50] Anthraqunones and stilbenes Anthraquinones and stilbenes are two important classes of compounds with manifold, well-known biological activities and were found in several species of the genus Polygonum L., such as P. capitatum, P. chinense, P. cuspidatum, P. multiflorum, P. cillinerve and also in other medicinal plants belonging to different families. ...
Article
Objectives: Increasing literature data have suggested that the genus Polygonum L. possesses pharmacologically important plant secondary metabolites. These bioactive compounds are implicated as effective agents in preclinical and clinical practice due to their pharmacological effects such as anti-inflammatory, anticancer, antidiabetic, antiaging, neuroprotective or immunomodulatory properties among many others. However, elaborate pharmacological and clinical data concerning the bioavailability, tissue distribution pattern, dosage and pharmacokinetic profiles of these compounds are still scanty. Key findings: The major bioactive compounds implicated in the therapeutic effects of Polygonum genus include phenolic and flavonoid compounds, anthraquinones and stilbenes, such as quercetin, resveratrol, polydatin and others, and could serve as potential drug leads or as adjuvant agents. Data from in-silico network pharmacology and computational molecular docking studies are also highly helpful in identifying the possible drug target of pathogens or host cell machinery. Summary: We provide an up-to-date overview of the data from pharmacodynamic, pharmacokinetic profiles and preclinical (in-vitro and in-vivo) investigations and the available clinical data on some of the therapeutically important compounds of genus Polygonum L. and their medical interventions, including combating the outbreak of the COVID-19 pandemic.
... A. K.Ahmed et al. (2020a) indicated that quercetin 800 mg, bromelain 165 mg, zinc acetate 50 mg, and ascorbic acid 1 g once daily supplements were safe for patients infected with SARS-CoV-2 and may prevent poor prognosis. The clinical trial (registration number NCT04468139) (A. ...
Article
Full-text available
Objective: Severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) affects millions of people worldwide. The article aims to review the therapeutic perspective on natural antioxidants, their mechanism of action, pharmacokinetics in management and cure of COVID‐19/ SARS‐CoV‐2 infection. Methods: We conducted a literature search including World Health Organization and National Institute of Health guidelines and clinical trials registered with ClinicalTrials.gov limited to antioxidants in COVID‐19 management. Results: Elderly, immunocompromised patients, and others with underlying health conditions or multiple comorbidities have a high mortality rate. Disrupted redox homeostasis and oxidative stress seem to be biological pathways that may increase personal vulnerability to infection. Antioxidants like vitamins C, D, E, epigallocatechin‐3 gallate, and morin have been reported to protect against COVID‐19 disease. Reactive oxygen species are immunological regulatory elements of viral replication. Natural antioxidants exhibit potential action in preventing inflammation and organ dysfunction during viral infection. They also increase glutathione level, oxygenation rate, and immunological responses in the treatment of sepsis and acute respiratory distress syndrome. Conclusion: No wonder the selection of prevention, treatment, and cure of COVID‐19 and SARS‐CoV‐2 mainly depends upon the antiviral and immunoregulatory activity which they possess. Yet, their efficacy against COVID‐19 is of great concern and demands extensive study. Transmission of Covid‐19 from host to community and its prevention and treatment using natural anti‐oxidants
... 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.
Chapter
ABSTRACT Chalcones with a C6-C3-C6 backbone are a class of plant-derived polyphenolic metabolites structurally related to flavonoids, of which two phenyl rings are connected via an α- and β-unsaturated carbonyl chain. Indeed, these secondary metabolites are precursors of flavonoids, as they are readily converted to the corresponding flavanones by the action of chalcone isomerase. Chalcones are found in various plant resources and possess a myriad of biological/pharmacological activities, including antioxidant, anticancer, antiviral, anti-inflammatory, and immunomodulatory effects. Given the outbreak of harmful viral diseases like Ebola, Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Mother Nature has been recognized as the most beneficial choice to look for potential candidates to target the variety of human viruses. So, the leaves of an Indian medicinal plant containing chalcones inhibited in vitro SARS-CoV-2 replication by blocking viral entry into host cells with high safety and low toxicity. Various researchers have also computationally studied the potency of chalcones as antiviral drugs toward SARS-CoV-2, the virus that caused COVID-19. As previously reported, prenylated chalcones (i.e., xanthoangelols B, D, E, and F) derived from Angelica keiskei inhibited in vitro the key SARS-CoV enzymes, including 3CLpro (chemotrypsin-like protease) and PLpro (papain-like protease), with IC50 ranges of 1.2‒34.1 μM. Another in vitro study reported that synthetic chalcones, for example, a new ciprofloxacin-chalcone hybrid, can dose-dependently inhibit SARS-CoV-2 3CLpro in Vero cells (IC50 value of 0.6 μM). Although chalcones may provide excellent anti-SARS-CoV-2 compounds, further research is required to investigate their efficiency and safety in clinical trials. This chapter will cover the current knowledge on chalcones and, in some cases, their synthetic derivatives against SARS-CoV-2. Furthermore, the inhibition of different enzymes, which are related to different stages of viral replication and progression of COVID-19, will be discussed.
Article
Quercetin has a wide range of potential health benefits, working as a direct or indirect agent or an adjuvant following different principles. It may be used as a generally useful or exclusive supplement, but also specifically used to treat an acute or chronic condition. Quercetin may work as a cancer chemopreventive and chemotherapeutic agent, because this versatile substance, which owns antioxidant and anti‐inflammatory properties, may also kill cancer cells and also holds senolytic properties. While both the specific chemo‐preventive or chemotherapeutic uses as a drug need clinical trials, it may be used without any contraindication as a general chemo‐preventive supplement.
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
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
The increasing rate of autoimmune disorders and cancer in recent years has been a controversial issue in all aspects of prevention, diagnosis, prognosis and treatment. Among dietary factors, flavonoids have specific immunomodulatory effects that might be of importance to several cancers. Over different types of immune cells, T lymphocytes play a critical role in protecting the immune system as well as in the pathogenesis of specific autoimmune diseases. One of the important mediators of metabolism and immune system is mTOR, especially in T lymphocytes. In the current review, we assessed the effects of flavonoids on the immune system and then their impact on the mTOR pathway. Flavonoids can suppress mTOR activity and are consequently able to induce the T regulatory subset.
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.