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Quercetin: A Promising Treatment for the Common Cold

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... Normally, the absorption rate of QR in the intestine is between 30% and 50%, but a higher half-life of 25 h can help maintain the plasma levels of QR. It has been observed that vitamin C increases the absorption rate of QR in the intestine and elevates plasma QR levels [105]. ...
... Vitamin C also reduces flavonol's oxidative degradation, thus helping maintain higher plasma levels of flavonoids, such as QR [105]. Vitamin D is a major immunomodulatory vitamin and controls the immune system. ...
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The COVID-19 outbreak seems to be the most dangerous challenge of the third millennium due to its highly contagious nature. Amongst natural molecules for COVID-19 treatment, the flavonoid molecule quercetin (QR) is currently considered one of the most promising. QR is an active agent against SARS and MERS due to its antimicrobial, antiviral, anti-inflammatory, antioxidant, and some other beneficial effects. QR may hold therapeutic potential against SARS-CoV-2 due to its inhibitory effects on several stages of the viral life cycle. In fact, QR inhibits viral entry, absorption, and penetration in the SARS-CoV virus, which might be at least partly explained by the ability of QR and its derivatives to inhibit 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro). QR is a potent immunomodulatory molecule due to its direct modulatory effects on several immune cells, cytokines, and other immune molecules. QR-based nanopreparations possess enhanced bioavailability and solubility in water. In this review, we discuss the prospects for the application of QR as a preventive and treatment agent for COVID-19. Given the multifactorial beneficial action of QR, it can be considered a very valid drug as a preventative, mitigating, and therapeutic agent of COVID-19 infection, especially in synergism with zinc, vitamins C, D, and E, and other polyphenols.
... Mounting studies have proven the therapeutic effects of Quercetin against various dreadful diseases, including diabetes, cancer, cardiovascular diseases, etc. [35,36]. Most importantly, many in vitro and in vivo studies have supported potent antiviral properties of Quercetin [11,37,38]. The phytoestrogen Genistein (C 15 H 10 O 5 ) is a natural isoflavaone found abundantly in several plants, including lupin, fava beans, soybeans, kudzu, Psoralea, etc. ...
... Studies have shown that Genistein possesses enormous antiviral, anti-oxidant, and anthelmintic properties [39,40]. Like Quercetin, Genistein is also proven to be an ideal drug to treat various dreadful viral infections, including coronaviridae, HIV, Epsein-Barr virus, herpes simplex virus etc. [38,40]. Our in silico analysis clearly shows that both Quercetin and Genistein could bind to the catalytic and substrate binding sites of TMPRSS2. ...
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Background The Transmembrane Serine Protease 2 (TMPRSS2) of human cell plays a significant role in proteolytic cleavage of SARS-Cov-2 coronavirus spike protein and subsequent priming to the receptor ACE2. Approaching TMPRSS2 as a therapeutic target for the inhibition of SARS-Cov-2 infection is highly promising. Hence, in the present study, we docked the binding efficacy of ten naturally available phyto compounds with known anti-viral potential with TMPRSS2. The aim is to identify the best phyto compound with a high functional affinity towards the active site of the TMPRSS2 with the aid of two different docking software. Molecular Dynamic Simulations were performed to analyse the conformational space of the binding pocket of the target protein with selected molecules. Results Docking analysis using PyRx version 0.8 along with AutoDockVina reveals that among the screened phyto compounds, Genistein shows the maximum binding affinity towards the hydrophobic substrate-binding site of TMPRSS2 with three hydrogen bonds interaction ( − 7.5 kcal/mol). On the other hand, molecular docking analysis using Schrodinger identified Quercetin as the most potent phyto compound with a maximum binding affinity towards the hydrophilic catalytic site of TMPRSS2 ( − 7.847 kcal/mol) with three hydrogen bonds interaction. The molecular dynamics simulation reveals that the Quercetin-TMPRSS complex is stable until 50 ns and forms stable interaction with the protein ( − 22.37 kcal/mol of MM-PBSA binding free energy). Genistein creates a weak interaction with the loop residues and hence has an unstable binding and exits from the binding pocket. Conclusion The compounds, Quercetin and Genistein, can inhibit the TMPRSS2 guided priming of the spike protein. The compounds could reduce the interaction of the host cell with the type I transmembrane glycoprotein to prevent the entry of the virus. The critical finding is that compared to Genistein, Quercetin exhibits higher binding affinity with the catalytic unit of TMPRSS2 and forms a stable complex with the target. Thus, enhancing our innate immunity by consuming foods rich in Quercetin and Genistein or developing a novel drug in the combination of Quercetin and Genistein could be the brilliant choices to prevent SARS-Cov-2 infection when we consider the present chaos associated with vaccines and anti-viral medicines.
... The putative health promoting effects of quercetin have been reported as ranging across anti-allergic, anticancer, anti-inflammatory, antiviral, and cardiovascular protective activities [3,4]. For example, the flavonol was found to reduce the release of inflammatory cytokines (e.g., IL-8) which may alleviate infection-related symptoms and possibly suppress inflammatory responses that are often associated with viral infections [5][6][7]. In the case of rheumatoid arthritis, quercetin has been reported to inhibit neutrophil activity, and reduce the plasma levels of inflammatory cytokines [8]. ...
... In the case of rheumatoid arthritis, quercetin has been reported to inhibit neutrophil activity, and reduce the plasma levels of inflammatory cytokines [8]. Kinker (2014) has suggested that the antioxidative potential of quercetin might prevent tissue damage by scavenging free radicals. ...
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Background: Quercetin, a flavonoid found in plant-based foods, has a range of biological activities that may be beneficial for human health. The pharmacokinetic profile of quercetin remains, however, a limiting factor for its use as a nutritional supplement. Quercetin LipoMicel®—a novel delivery system encapsulating quercetin into a liquid micelle matrix—has been designed to address the low bioavailability issue associated with non-conjugated forms by improving the absorption of quercetin. Objective: The purpose of this study was to evaluate the solubility and gastrointestinal absorption of quercetin in a novel Quercetin LipoMicel delivery system in healthy adult volunteers by comparing it with free quercetin and another commercial quercetin product. Several pharmacokinetic parameters were compared between these three formulations. Methods: Twelve healthy adult male and female volunteers aged between 21 and 65, with BMIs under 30, participated in a non-blinded, crossover bioavailability study conducted with three quercetin products. Each treatment contained a total dose of 500 mg quercetin. Capillary whole blood samples from participants were collected serially at intervals from 0–24 hours. Quercetin concentrations were detected and measured by ultra-performance liquid chromatography (UHPLC) coupled to a Thermo QExactive Orbitrap Mass Spectrometer. Solubility of quercetin in water and simulated gastrointestinal media was determined by UHPLC. Results: Oral absorption of quercetin was significantly enhanced with the LipoMicel delivery system compared to free quercetin. Improvements in in vitro gastric stability and intestinal solubility were observed with LipoMicel, leading to significantly higher blood concentration and enhanced duration of a stable concentration of quercetin in the body. Compared to free quercetin, 8- and 9-fold increases in AUC and Cmax were attained with the LipoMicel delivery system, and 10-fold higher quercetin plasma concentrations detected at 12 hours after administration. Conclusions: Quercetin LipoMicel represents an efficient delivery system for augmenting the bioavailability of quercetin in vivo. Significantly higher blood concentrations and a sustained release of quercetin over the study period was achieved following the administration of quercetin via the LipoMicel technology. Optimization in the in vivo bioavailability of quercetin may promote its salutary effects.
... Quercetin has a pleiotropic role as an antioxidant and anti-inflammatory, modulating signaling pathways that are associated with post-transcriptional modulators affecting post-viral healing. 8 Intervention Quercetin Suggested dose Regular: 1 gm po bid; phytosome: 500 mg, bid Mechanism(s) of action against non-COVID-19 viruses Promote viral eradication or inactivation: 9,10,11,12,13 • Inhibition of viral replication Favorably modulate viral-induced pathological cellular processes: ...
Article
As the novel infection with SARS-CoV-2 emerges, objective assessment of the scientific plausibility of nutraceutical and botanical interventions for prevention and treatment is important. We evaluate twelve such interventions with mechanisms of action that modulate the immune system, impair viral replication, and/or have been demonstrated to reduce severity of illness. These are examples of interventions that, mechanistically, can help protect patients in the presence of the prevalent and infectious SARS-CoV-2 virus. While there are limited studies to validate these agents to specifically prevent COVID-19, they have been chosen based upon their level of evidence for effectiveness and safety profiles, in the context of other viral infections. These agents are to be used in a patient-specific manner in concert with lifestyle interventions known to strengthen immune response (see related article in this issue of IMCJ).
... cytokine production). For instance, besides the antiviral effects of quercetin, the flavonol was found to prevent tissue damage by scavenging free radicals, and could reduce the release of inflammatory cytokines such as interleukine IL-8 (Kinker 2014). ...
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COVID-19, the highly contagious novel disease caused by SARS-CoV-2, has become a major international concern as it has spread quickly all over the globe. However, scientific knowledge and therapeutic treatment options for this new coronavirus remain limited. Although previous outbreaks of human coronaviruses (CoVs) such as SARS and MERS stimulated research, there are, to date, no antiviral therapeutics available that specifically target these kinds of viruses. Natural compounds with a great diversity of chemical structures may provide an alternative approach for the discovery of new antivirals. In fact, numerous flavonoids were found to have antiviral effects against SARS-and MERS-CoV by mainly inhibiting the enzymes 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro). In this review, we specifically focused on the search for flavonoids, polyphenolic compounds, which are proven to be effective against human CoVs. We therefore summarized and analyzed the latest progress in research to identify flavonoids for antiviral therapy and proposed strategies for future work on medicinal plants against coronaviruses such as SARS-CoV-2. We discovered quercetin, herbacetin, and isobavachalcone as the most promising flavonoids with anti-CoV potential.
... 16,17 It has anti-infective and anti-replicative effects on a number of viruses, including RNA viruses. [16][17][18][19] Studies showed that micromolar doses of quercetin can inhibit betacoronavirus infectious activities in vitro. One study reported that quercetin blocked pseudotype SARS-CoV entry into host cells (EC 50 ¼ 83.2 mM). ...
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The coronavirus (SARS-CoV-2), which causes COVID-19, is a betacoronavirus closely related to the human severe acute respiratory syndrome (SARS)-coronavirus (SARS-CoV). The recent COVID-19 outbreak created an urgent need for treatment. To expedite the development of such treatment, pharmaceutical companies and government agencies are currently testing several existing drugs for their effect on the virus. Gene-Eden-VIR and Novirin are natural, broad-spectrum, antiviral treatments proven to be safe and effective in several clinical studies. In this article, we present evidence indicating that the 5 Gene-Eden-VIR/Novirin ingredients have anti-betacoronavirus, and specifically, anti-SARS-CoV effects. We consider this evidence as a first indication of the anti-coronavirus effects of Gene-Eden-VIR/Novirin. Next, we are planning to conduct a clinical study with users of the treatments to test the effects of Gene-Eden-VIR/Novirin on individuals at risk and those infected with the virus.
... They are reported as inhibitors of atherosclerosis and cancer [4]. Quercetin is a well-known antioxidant [5] with antiviral and anti-inflammatory activities *Address correspondence to this author at the Department of Biological and Health Sciences, Pharmacy College, Laboratory of Phytopharmaceutical Nanobiotechnology, Amapá Federal University, ZIP Code 68903-419, Macapá, Brazil; Tel: ++55-96-40092927; E-mail: caiofernandes@unifap.br [6]. Additional pharmacological effects have been associated to this flavonoid, such as inhibitory activity on catecholase and cresolase [7] and antidiarrheal effects [8]. ...
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Polyphenols are a large group of structurally diverse natural products, including flavonoids. One of most bioactive compound of this class is the flavonol quercetin, a recognized antioxidant. Despite several studies were carried out aiming to develop nanoformulations with secondary metabolites, to our knowledge, quercetin was not used as raw material for nanodispersion production without coating polymers. This type of nanosize formulation is often prepared using organic solvents and quercetin nanodispersions were prepared by emulsification evaporation technique, using 16.22 experimental factorial design, ("surfactant type" evaluated at 6 levels, "surfactant amount" and "stirring speed" evaluated at 2 levels). Variance analysis, after one day of nanodispersions preparation, revealed that only the surfactant type was statistically significant on particle size, while none of factors presented statistically significant effect on polydispersity index. Variance analysis after seven days of nanodispersions preparation revealed that either surfactant type and surfactant amount presented significantly effect on particle size, while only surfactant type influenced polydispersity index. Some nanodispersions presented small diameter and narrow size distribution, suggesting potential stability of some systems. Special attention was given to nanodispersion prepared with 3 % (w/w) of polyethylene glycol 400 monooleate (expressed as function of surfactant concentration at aqueous phase). It presented mean droplet size of 129.4 ± 0.5 nm and polydispersity index of 0.173 ± 0.018, after 7 days of preparation. Low polydispersity index indicates a high homogeneity concerning particle size distribution and also suggests stability of the system. Moreover, absence of coating polymers and utilization of a low energy method would be an advantage in terms of reducing costs for industrial application, without any nanosize impairment.
... A viable syphilis control option became available in the 20th century with the discovery of penicillin Rhinovirus infections have afflicted humanity since the dawn of civilization, and helpful to treat diseases that were difficult to treat even with medicine In Trinidad where there was a two-tier system of health care, a public health care system in which all services are delivered by the state and are cost free to clients. The first accurate description of syphilis was provided by the Venetian military surgeon Marcello Cumano, who had taken his troops to the battle of Fornovo and fought alongside the armies of Charles VIII of France and the League of Venice one must also consider that there is still much to learn about the pathogenicity and enzoonotic transmission cycles connected to the natural occurrence of this disease [60][61][62][63][64][65] . The major forms of disease are predominantly paranasal sinus, allergic bronco-pulmonary or pulmonary infections but cardiac, orthopedic, and ophthalmic infectious diseases spreading through air are commonly known as air borne diseases and some of the air borne ancient diseases includes anthrax, influenza, measles, smallpox and tuberculosis. ...
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The following study throws a light upon the inflammation causing allergies and diseases such as asthma, Allergic Rhinitis, respiratory syncytial virus, airway hyper-reactivity and their treatment for inflammation and symptoms seducing drugs and medication such as Allergen specific immunotherapy, Allergen Immunotherapy, Topical Corticosteroids, NAC anti-oxidant in left pulmonary artery ligation (LPAL), Subcutaneous immunotherapy (SIT), corticosteroid (ICS) and miraculous effects of these potential therapeutic treatments in affecting changes in metabolism of the patient etc.
... The causative agent, M. leprae multiplies very slowly and the incubation period of the disease is about five years; moreover, symptoms can take as long as twenty years to appear it is a chronic granulomatous infectious disease caused by Mycobacterium leprae that mainly infects skin macrophages and Schwann cells in peripheral nerves. Created in 1921 by the in vitro attenuation of a virulent Mycobacterium bovis in France, genetic and environmental factors play an important role for bacterial occurrence in the gut of haematophagous insects may have an important role in epidemiology of human infectious diseases [30][31][32] . The predominant accumulation of aggregated proteins is observed in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, treated by verapamil, verapamils R-isomer, and norverapamil (a metabolite of verapamil) help inhibit this macrophage-induced drug tolerance to RIF, rifabutin, and INH [33][34][35][36] . ...
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The following study enlightens the aspect of diseases that have effected and wreaked havoc number of times upon the world during ancient and medieval period are tending to reemerge into the present world and not only limited to this but also convergence of their study towards transformation of the microorganism. Historical diseases such Yaws, Pinta, Leprosy, and Tuberculosis that still exist and pose a threat of reemergence with infectious capacity of greater magnitude and also the existence of ancient treatment that used to and still have the capacity of curing these diseases. This article also compares the degree of effect the ancient diseases had when compared to similar types of infectious diseases ravaging today in the clinical studies.
... This bioactive compound has extensively described in the literature due to a broad spectrum of biological effects on a human body. It is well known that quercetin as an antioxidant [2] has the antiinflammatory [3,4], antiallergic [5], antirheumatic, anti-viral [6] and anti-cancer [7] activities. Also, it has the positive effects to the development of diabetes and its consequences [8], reduction of blood clotting and creation of uric acid, as well as to the number functions of enzyme in the organism. ...
Article
Quercetin is a typical plant flavonoid with a wide variety of pharmacological activities, including anti-inflammatory, anti-oxidative, anti-cancer and anti-age activity. It can be used for treatment of cardiovascular disorders. However, the application of quercetin in pharmacy is limited because of its poor aqueous solubility, low bioavailability, low permeability and instability. In order to overcome the mentioned limitations, an inclusion complex of quercetin with (2-hydroxypropyl)-β-cyclodextrin in a molar ratio of 1:1 have been prepared at room temperature by co-precipitation from ethanol solution. The inclusion complex was prepared at room temperature for 24 h by the co-precipitation method from ethanol solution. The obtained complex were evaporated and dried before the structural characterization. Based on the obtained results of FT-IR, DSC, 1H-NMR and XRD analysis, it can be concluded that the inclusion complex was formed by establishing the interaction between quercetin and (2-hydroxypropyl)-β-cyclodextrin. The phase solubility study indicates that the complexation of quercetin leads to increase the solubility of quercetin in water about 129-fold in the aqueous solution of HP-β-CD (10 mmol dm−3). Also, the photostability of quercetin was improved after its complexation with this cyclodextrin.
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Citation: Kottakis, G.; Kambouri, K.; Giatromanolaki, A.; Valsami, G.; Kostomitsopoulos, N.; Tsaroucha, A.; Pitiakoudis, M. Effects of the Antioxidant Quercetin in an Experimental Model of Ulcerative Colitis in Mice. Medicina 2023, 59, 87. Abstract: Background and Objectives: Quercetin, a member of the flavanol family found in many fruits, vegetables, leaves and grains has been found to have a wide range of biological effects on human physiology. The aim of this study was to investigate the effects of quercetin, when administered orally in the form of the water-soluble inclusion complex with hydroxypropyl-b-cyclodextrin (Que-HP-β-CD), in an experimental model of ulcerative colitis in mice. Materials and Methods: Animals received either Dextran Sodium Sulphate (DSS), to induce colitis, + Que-HP-β-CD (Group A), DSS alone (Group B) or no intervention (control, Group C) for 7 days. All animals were weighed daily, and evaluation of colitis was performed using the Disease Activity Index (DAI). On day 7 a blood sample was taken from all animals, they were then euthanised, the large intestine was measured , and histological and immunochemical analyses were performed. Results: The DAI demonstrated an increase over time for the groups receiving DSS (Groups A and B) compared with the control group (Group C), with a significant degree of protection being observed in the group that also received quercetin (Group A): The DAI over time slope for Group B was higher than that for Group A by 0.26 points/day (95% Cl 0.20-0.33, p < 0.01). Weight calculations and immunohistochem-istry results validated the DAI findings. Conclusions: In conclusion, the administration of quercetin in an ulcerative colitis model in mice presents a therapeutic/prophylactic potential that warrants further investigation.
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Background Cystic fibrosis is an autosomal recessive monogenic disease marked by a mutation in the cystic fibrosis transmembrane conductance regulator gene. Cystic fibrosis transmembrane conductance regulator gene mutations affect respiratory, digestive and reproductive functions and impede bicarbonate, bile acid and sweat secretion. Moreover, the current trend indicates that CF is no longer only a paediatric disease; but has progressively become a disease that also affects adults. This calls to address the condition with an appropriate nutraceutical approach. Objective The study aims to find and collate nutritional targets in the management of Cystic Fibrosis. Method Studies highlighting the benefits of nutrients or nutraceuticals in the management of Cystic Fibrosis were included from previously published research articles (1971 to 2020). Data including nutrients, nutraceuticals, study design, study model, sample size, age, dose and duration of the dose of the supplement were extracted from the studies included and explored to understand their role. Results About 26 studies are being included in the present review. It was found that nutrient interventions comprising nutraceuticals including dietary fibre, proteins and amino acids (taurine, arginine, glutathione), fats (medium-chain triglycerides, polyunsaturated fatty acids (omega-3 fatty acids)), phytochemicals (apigenin, genistein, quercetin, curcumin, allicin, beta-carotene, Pulmonaria officinalis L, Epigallocatechin-3-gallate), micronutrients including vitamin A, vitamin D, vitamin K, magnesium and zinc in addition to antioxidants exhibit improvement in the symptomatic condition of cystic fibrosis patients. Conclusion The advent of nutraceuticals in the food industry and studies indicating their promising benefits have paved a path for targeted therapies in cystic fibrosis.
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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.
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Unlabelled: Barrier dysfunction of airway epithelium may increase the risk for acquiring secondary infections or allergen sensitization. Both rhinovirus (RV) and polyinosinic-polycytidilic acid [poly(I·C)], a double-stranded RNA (dsRNA) mimetic, cause airway epithelial barrier dysfunction, which is reactive oxygen species (ROS) dependent, implying that dsRNA generated during RV replication is sufficient for disrupting barrier function. We also demonstrated that RV or poly(I·C)-stimulated NADPH oxidase 1 (NOX-1) partially accounts for RV-induced ROS generation. In this study, we identified a dsRNA receptor(s) contributing to RV-induced maximal ROS generation and thus barrier disruption. We demonstrate that genetic silencing of the newly discovered dsRNA receptor Nod-like receptor X-1 (NLRX-1), but not other previously described dsRNA receptors, abrogated RV-induced ROS generation and reduction of transepithelial resistance (R(T)) in polarized airway epithelial cells. In addition, both RV and poly(I·C) stimulated mitochondrial ROS, the generation of which was dependent on NLRX-1. Treatment with Mito-Tempo, an antioxidant targeted to mitochondria, abolished RV-induced mitochondrial ROS generation, reduction in R(T), and bacterial transmigration. Furthermore, RV infection increased NLRX-1 localization to the mitochondria. Additionally, NLRX-1 interacts with RV RNA and poly(I·C) in polarized airway epithelial cells. Finally, we show that NLRX-1 is also required for RV-stimulated NOX-1 expression. These findings suggest a novel mechanism by which RV stimulates generation of ROS, which is required for disruption of airway epithelial barrier function. Importance: Rhinovirus (RV), a virus responsible for a majority of common colds, disrupts the barrier function of the airway epithelium by increasing reactive oxygen species (ROS). Poly(I·C), a double-stranded RNA (dsRNA) mimetic, also causes ROS-dependent barrier disruption, implying that the dsRNA intermediate generated during RV replication is sufficient for this process. Here, we demonstrate that both RV RNA and poly(I·C) interact with NLRX-1 (a newly discovered dsRNA receptor) and stimulate mitochondrial ROS. We show for the first time that NLRX-1 is primarily expressed in the cytoplasm and at the apical surface rather than in the mitochondria and that NLRX-1 translocates to mitochondria following RV infection. Together, our results suggest a novel mechanism for RV-induced barrier disruption involving NLRX-1 and mitochondrial ROS. Although ROS is necessary for optimal viral clearance, if not neutralized efficiently, it may increase susceptibility to secondary infections and alter innate immune responses to subsequently inhaled pathogens, allergens, and other environmental factors.
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Rationale: Rhinovirus infection is followed by significantly increased frequencies of positive, potentially pathogenic sputum cultures in chronic obstructive pulmonary disease (COPD). However, it remains unclear whether these represent de novo infections or an increased load of organisms from the complex microbial communities (microbiome) in the lower airways. Objectives: To investigate the effect of rhinovirus infection on the airway bacterial microbiome. Methods: Subjects with COPD (n = 14) and healthy control subjects with normal lung function (n = 17) were infected with rhinovirus. Induced sputum was collected at baseline before rhinovirus inoculation and again on Days 5, 15, and 42 after rhinovirus infection and DNA was extracted. The V3-V5 region of the bacterial 16S ribosomal RNA gene was amplified and pyrosequenced, resulting in 370,849 high-quality reads from 112 of the possible 124 time points. Measurements and main results: At 15 days after rhinovirus infection, there was a sixfold increase in 16S copy number (P = 0.007) and a 16% rise in numbers of proteobacterial sequences, most notably in potentially pathogenic Haemophilus influenzae (P = 2.7 × 10(-20)), from a preexisting community. These changes occurred only in the sputum microbiome of subjects with COPD and were still evident 42 days after infection. This was in contrast to the temporal stability demonstrated in the microbiome of healthy smokers and nonsmokers. Conclusions: After rhinovirus infection, there is a rise in bacterial burden and a significant outgrowth of Haemophilus influenzae from the existing microbiota of subjects with COPD. This is not observed in healthy individuals. Our findings suggest that rhinovirus infection in COPD alters the respiratory microbiome and may precipitate secondary bacterial infections.
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Bacterial infections following rhinovirus (RV), a common cold virus, are well documented, but pathogenic mechanisms are poorly understood. We developed animal and cell culture models to examine the effects of RV on subsequent infection with non-typeable Hemophilus influenzae (NTHi). We focused on NTHI-induced neutrophil chemoattractants expression that is essential for bacterial clearance. Mice infected with RV1B were superinfected with NTHi and lung bacterial density, chemokines and neutrophil counts determined. Human bronchial epithelial cells (BEAS-2B) or mouse alveolar macrophages (MH-S) were infected with RV and challenged with NHTi, TLR2 or TLR5 agonists. Chemokine levels were measured by ELISA and expression of IRAK-1, a component of MyD88-dependent TLR signaling, assessed by immunoblotting. While sham-infected mice cleared all NTHi from the lungs, RV-infected mice showed bacteria up to 72 h post-infection. However, animals in RV/NTHi cleared bacteria by day 7. Delayed bacterial clearance in RV/NTHi animals was associated with suppressed chemokine levels and neutrophil recruitment. RV-infected BEAS-2B and MH-S cells showed attenuated chemokine production after challenge with either NTHi or TLR agonists. Attenuated chemokine responses were associated with IRAK-1 protein degradation. Inhibition of RV-induced IRAK-1 degradation restored NTHi-stimulated IL-8 expression. Knockdown of TLR2, but not other MyD88-dependent TLRs, also restored IRAK-1, suggesting that TLR2 is required for RV-induced IRAK-1 degradation. In conclusion, we demonstrate for the first time that RV infection delays bacterial clearance in vivo and suppresses NTHi-stimulated chemokine responses via degradation of IRAK-1. Based on these observations, we speculate that modulation of TLR-dependent innate immune responses by RV may predispose the host to secondary bacterial infection, particularly in patients with underlying chronic respiratory disorders.
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Rationale: Chronic obstructive pulmonary disease (COPD) exacerbations are associated with virus (mostly rhinovirus) and bacterial infections, but it is not known whether rhinovirus infections precipitate secondary bacterial infections. Objectives: To investigate relationships between rhinovirus infection and bacterial infection and the role of antimicrobial peptides in COPD exacerbations. Methods: We infected subjects with moderate COPD and smokers and nonsmokers with normal lung function with rhinovirus. Induced sputum was collected before and repeatedly after rhinovirus infection and virus and bacterial loads measured with quantitative polymerase chain reaction and culture. The antimicrobial peptides secretory leukoprotease inhibitor (SLPI), elafin, pentraxin, LL-37, α-defensins and β-defensin-2, and the protease neutrophil elastase were measured in sputum supernatants. Measurements and main results: After rhinovirus infection, secondary bacterial infection was detected in 60% of subjects with COPD, 9.5% of smokers, and 10% of nonsmokers (P < 0.001). Sputum virus load peaked on Days 5-9 and bacterial load on Day 15. Sputum neutrophil elastase was significantly increased and SLPI and elafin significantly reduced after rhinovirus infection exclusively in subjects with COPD with secondary bacterial infections, and SLPI and elafin levels correlated inversely with bacterial load. Conclusions: Rhinovirus infections are frequently followed by secondary bacterial infections in COPD and cleavage of the antimicrobial peptides SLPI and elafin by virus-induced neutrophil elastase may precipitate these secondary bacterial infections. Therapy targeting neutrophil elastase or enhancing innate immunity may be useful novel therapies for prevention of secondary bacterial infections in virus-induced COPD exacerbations.
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Rhinovirus (RV), which is responsible for the majority of common colds, also causes exacerbations in patients with asthma and chronic obstructive pulmonary disease. So far, there are no drugs available for treatment of rhinovirus infection. We examined the effect of quercetin, a plant flavanol on RV infection in vitro and in vivo. Pretreatment of airway epithelial cells with quercetin decreased Akt phosphosphorylation, viral endocytosis and IL-8 responses. Addition of quercetin 6h after RV infection (after viral endocytosis) reduced viral load, IL-8 and IFN responses in airway epithelial cells. This was associated with decreased levels of negative and positive strand viral RNA, and RV capsid protein, abrogation of RV-induced eIF4GI cleavage and increased phosphorylation of eIF2α. In mice infected with RV, quercetin treatment decreased viral replication as well as expression of chemokines and cytokines. Quercetin treatment also attenuated RV-induced airway cholinergic hyperresponsiveness. Together, our results suggest that quercetin inhibits RV endocytosis and replication in airway epithelial cells at multiple stages of the RV life cycle. Quercetin also decreases expression of pro-inflammatory cytokines and improves lung function in RV-infected mice. Based on these observations, further studies examining the potential benefits of quercetin in the prevention and treatment of RV infection are warranted.
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Respiratory virus infections are associated with chronic obstructive pulmonary disease (COPD) exacerbations, but a causative relationship has not been proven. Studies of naturally occurring exacerbations are difficult and the mechanisms linking virus infection to exacerbations are poorly understood. We hypothesized that experimental rhinovirus infection in subjects with COPD would reproduce the features of naturally occurring COPD exacerbations and is a valid model of COPD exacerbations. To evaluate experimental rhinovirus infection as a model of COPD exacerbation and to investigate the mechanisms of virus-induced exacerbations. We used experimental rhinovirus infection in 13 subjects with COPD and 13 nonobstructed control subjects to investigate clinical, physiologic, pathologic, and antiviral responses and relationships between virus load and these outcomes. Clinical data; inflammatory mediators in blood, sputum, and bronchoalveolar lavage; and viral load in nasal lavage, sputum, and bronchoalveolar lavage were measured at baseline and after infection with rhinovirus 16. After rhinovirus infection subjects with COPD developed lower respiratory symptoms, airflow obstruction, and systemic and airway inflammation that were greater and more prolonged compared with the control group. Neutrophil markers in sputum related to clinical outcomes and virus load correlated with inflammatory markers. Virus load was higher and IFN production by bronchoalveolar lavage cells was impaired in the subjects with COPD. We have developed a new model of COPD exacerbation that strongly supports a causal relationship between rhinovirus infection and COPD exacerbations. Impaired IFN production and neutrophilic inflammation may be important mechanisms in virus-induced COPD exacerbations.
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Secondary bacterial infection following rhinovirus (RV) infection has been recognized in chronic obstructive pulmonary disease. We sought to understand mechanisms by which RV infection facilitates secondary bacterial infection. Primary human airway epithelial cells grown at air-liquid interface and human bronchial epithelial (16HBE14o-) cells grown as polarized monolayers were infected apically with RV. Transmigration of bacteria (nontypeable Haemophilus influenzae and others) was assessed by colony counting and transmission electron microscopy. Transepithelial resistance (R(T)) was measured by using a voltmeter. The distribution of zona occludins (ZO)-1 was determined by immunohistochemistry and immunoblotting. Epithelial cells infected with RV showed 2-log more bound bacteria than sham-infected cultures, and bacteria were recovered from the basolateral media of RV- but not sham-infected cells. Infection of polarized airway epithelial cell cultures with RV for 24 hours caused a significant decrease in R(T) without causing cell death or apoptosis. Ultraviolet-treated RV did not decrease R(T), suggesting a requirement for viral replication. Reduced R(T) was associated with increased paracellular permeability, as determined by flux of fluorescein isothiocyanate (FITC)-inulin. Neutralizing antibodies to tumor necrosis factor (TNF)-alpha, IFN-gamma and IL-1beta reversed corresponding cytokine-induced reductions in R(T) but not that induced by RV, indicating that the RV effect is independent of these proinflammatory cytokines. Confocal microscopy and immunoblotting revealed the loss of ZO-1 from tight junction complexes in RV-infected cells. Intranasal inoculation of mice with RV1B also caused the loss of ZO-1 from the bronchial epithelium tight junctions in vivo. RV facilitates binding, translocation, and persistence of bacteria by disrupting airway epithelial barrier function.
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The aim of this study was to search for new antiviral agents from Chinese herbal medicine. Pure flavonoids and aqueous extracts of Caesalpinia pulcherrima Swartz were used in experiments to test their influence on a series of viruses, namely herpesviruses (HSV-1, HSV-2) and adenoviruses (ADV-3, ADV-8, ADV-11). The EC50 was defined as the concentration required to achieve 50% protection against virus-induced cytopathic effects, and the selectivity index (SI) was determined as the ratio of CC50 (concentration of 50% cellular cytotoxicity) to EC50. Results showed that aqueous extracts of C. pulcherrima and its related quercetin possessed a broad-spectrum antiviral activity. Among them, the strongest activities against ADV-8 were fruit and seed (EC50 = 41.2 mg/l, SI = 83.2), stem and leaf (EC50 = 61.8 mg/l, SI = 52.1) and flower (EC50 = 177.9 mg/l, SI = 15.5), whereas quercetin possessed the strongest anti-ADV-3 activity (EC50 = 24.3 mg/l, SI = 20.4). In conclusion, some compounds of C. pulcherrima which possess antiviral activities may be derived from the flavonoid of quercetin. The mode of action of quercetin against HSV-1 and ADV-3 was found to be at the early stage of multiplication and with SI values greater than 20, suggesting the potential use of this compound for treatment of the infection caused by these two viruses.
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Helicobacter pylori infection induces an inflammatory response in the gastric mucosa. Activation of polymorphonuclear leukocytes can produce oxidative damage to gastric tissue through intermediary radicals of oxygen and nitrogen. Vegetable extracts containing polyphenols of the flavonoid family have antibacterial activity, and the flavonoid quercetin possesses anti-H. pylori activity in vitro. The aim of this study was to analyze the effect of oral administration of pure quercetin on inflammation and lipid peroxidation induced by H. pylori in the gastric mucosa of the guinea pig. Sixty days after oral infection with H. pylori guinea pigs received 200 mg/kg of quercetin daily by mouth for 15 days. The infiltration index of inflammatory cells and bacterial density in both the pyloric antrum and corpus were histologically determined by myeloperoxidase histochemistry, hematoxylin-eosin, and modified Giemsa stains. The lipid hydroperoxide content was assessed by the orange xylenol spectrophotometric method. Quercetin significantly reduced the infiltration index of mononuclear cell and bacterial colonization in the pyloric antrum and corpus. In the antrum of infected quercetin-treated animals, a significant diminution of neutrophil leukocyte infiltration was observed compared with the infected nonquercetin-treated animals. In the antrum, the lipid hydroperoxide concentration was significantly decreased in infected animals treated with quercetin, whereas in the corpus no significant differences were observed. Our results indicate that in vivo oral quercetin administration decreases H. pylori infection in the gastric mucosa and reduces both the inflammatory response and lipid peroxidation.
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Interactions between viral respiratory tract infections in infancy and childhood, and asthma development and exacerbation, are complex and intriguing. This review aims to unravel some of these complexities. Does severe respiratory viral infection early in life predispose to later asthma development, or is it indicative of a predisposition to allergic respiratory disease? How could variables such as age and severity of viral infection affect the interaction between respiratory viral infections and asthma? How could respiratory viral infection drive allergic sensitisation? Here, we review the evidence surrounding these questions, and discuss current and future research and therapeutic approaches targeting the interplay between viral respiratory tract infection and asthma. This article is protected by copyright. All rights reserved.
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Respiratory viruses have become increasingly recognised as important agents in pulmonary exacerbations in infants and children with CF. The aim of this study was to determine the prevalence of respiratory viruses during acute pulmonary exacerbations in adults and compare the severity of these exacerbations with non-viral associated exacerbations. This was a retrospective case control study. Viral throat swabs were taken from all patients presenting with an acute pulmonary exacerbation requiring intravenous antibiotic treatment over a 12month period. There were 432 pulmonary exacerbations in 180 adults. A positive viral PCR in 42 exacerbations indicated a prevalence of 9.7%. The commonest virus isolated was rhinovirus (n=29, 69%) with influenza A/H1N1 in seven patients (16.7%). Exacerbations associated with a positive viral PCR had a greater fall in lung function at presentation with higher levels of inflammatory markers. They received more days of intravenous antibiotics, showed less response to treatment and had a shorter time to next pulmonary exacerbation compared to matched controls. Viral associated pulmonary exacerbations in adults with CF are associated with more severe pulmonary involvement and respond less well to standard treatment.
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Few studies have evaluated the contribution of multiple virus and bacterial infections in acute exacerbation of chronic obstructive pulmonary disease. This study estimated the burden of multiple viral and bacterial respiratory infections in moderate to very severe chronic obstructive pulmonary disease patients that were prospectively followed-up during a 12-month pilot study. Clinical data were collected monthly and sputum was collected at the time of each acute exacerbation event. Classical culture techniques for bacteria and multiplex polymerase chain reaction (PCR) and microarray detection assays were performed to identify viral and atypical bacterial pathogens in the sputum. Overall, 51 patients were included and 45 acute exacerbation events were investigated clinically and microbiologically. Among the 45 acute exacerbation events, 44% had evidence of viral infection involving human rhinovirus (HRV) and metapneumovirus (hMPV) in 20% and 18%, respectively. Intracellular bacteria were not found in sputum by PCR. Common bacterial pathogens were identified in 42% of acute exacerbation patients, most frequently Branhamella catarrhalis, Streptococcus pneumoniae and Haemophilus influenzae. Viral or virus and bacteria co-infections were detected in 27% of acute exacerbation events (n = 12) with HRV and hMPV involved in 92% of cases. Patients with co-infections did not present greater clinical severity scores at exacerbation and more recurrence of acute exacerbation events at 3 and 6 months than those with single infections (P > 0.4). These results suggest that HRV and hMPV may be contributors or cofactors of AECOPD. These findings indicate that viral or virus and bacterial co-infections do not impact significantly on the clinical severity of acute exacerbation of chronic obstructive pulmonary disease and recurrence at 3 and 6 months. J. Med. Virol. © 2013 Wiley Periodicals, Inc.
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The common cold, or upper respiratory tract infection, is one of the leading reasons for physician visits. Generally caused by viruses, the common cold is treated symptomatically. Antibiotics are not effective in children or adults. In children, there is a potential for harm and no benefits with over-the-counter cough and cold medications; therefore, they should not be used in children younger than four years. Other commonly used medications, such as inhaled corticosteroids, oral prednisolone, and Echinacea, also are ineffective in children. Products that improve symptoms in children include vapor rub, zinc sulfate, Pelargonium sidoides (geranium) extract, and buckwheat honey. Prophylactic probiotics, zinc sulfate, nasal saline irrigation, and the herbal preparation Chizukit reduce the incidence of colds in children. For adults, antihistamines, intranasal corticosteroids, codeine, nasal saline irrigation, Echinacea angustifolia preparations, and steam inhalation are ineffective at relieving cold symptoms. Pseudoephedrine, phenylephrine, inhaled ipratropium, and zinc (acetate or gluconate) modestly reduce the severity and duration of symptoms for adults. Nonsteroidal anti-inflammatory drugs and some herbal preparations, including Echinacea purpurea, improve symptoms in adults. Prophylactic use of garlic may decrease the frequency of colds in adults, but has no effect on duration of symptoms. Hand hygiene reduces the spread of viruses that cause cold illnesses. Prophylactic vitamin C modestly reduces cold symptom duration in adults and children.
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The effect of several naturally occurring dietary flavonoids including quercetin, naringin, hesperetin, and catechin on the infectivity and replication of herpes simplex virus type 1 (HSV-I), polio-virus type 1, parainfluenza virus type 3 (Pf-3), and respiratory syncytial virus (RSV) was studied in vitro in cell culture monolayers employing the technique of viral plaque reduction. Quercetin caused a concentration-dependent reduction in the infectivity of each virus. In addition, it reduced intracellular replication of each virus when monolayers were infected and subsequently cultured in medium containing quercetin. Preincubation of tissue culture cell monolayers with quercetin did not affect the ability of the viruses to infect or replicate in the tissue culture monolayers. Hesperetin had no effect on infectivity but it reduced intracellular replication of each of the viruses. Catechin inhibited the infectivity but not the replication of RSV and HSV-1 and had negligible effects on the other viruses. Naringin had no effect on either the infectivity or the replication of any of the viruses studied. Thus, naturally occurring flavonoids possess a variable spectrum of antiviral activity against certain RNA (RSV, Pf-3, polio) and DNA (HSV-1) viruses acting to inhibit infectivity and/or replication.
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In vitro data indicate quercetin has antioxidative and anti-inflammatory functions with the potential to lower disease risk factors, but data in human beings are limited. The objective of this study was to investigate the effect of quercetin, vitamin C, and niacin supplements (500 mg quercetin, 125 mg vitamin C, and 5 mg niacin [Q-500]; 1,000 mg quercetin, 250 mg vitamin C, and 10 mg niacin [Q-1,000]), on disease risk factors in a large group of community adults (n=1,002, 60% women) varying widely in age and body mass index. Subjects were randomized into one of three groups (placebo, Q-500, or Q-1,000) and ingested supplements for 12 weeks. Blood samples were taken pre- and postsupplementation, and plasma quercetin, inflammatory markers (ie, C-reactive protein and five cytokines), diagnostic blood chemistries, blood pressure, and blood lipid profiles were measured. Plasma quercetin increased in the Q-500 and Q-1,000 groups. No differences in blood chemistries were found except for a small decrease in serum creatinine and increase in glomerular filtration rate in Q-500 and Q-1,000 groups. A small decrease in mean arterial blood pressure was measured for Q-500 and Q-1,000 groups compared to placebo. A difference in serum total cholesterol was measured between Q-500 and placebo groups, and there was small decrease in high-density lipoprotein cholesterol levels in the Q-1,000 group. Change in inflammatory measures did not differ between groups except for a slight decrease in interleukin-6 for the Q-1,000 group. Q-500 or Q-1,000 supplementation for 12 weeks had a negligible influence on disease risk factors.
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Viral respiratory tract infections are common and usually selflimited illnesses. For patients at risk of asthma, or with existing asthma, viral respiratory tract infections can have a profound effect on the expression of disease or loss of control. New evidence has shown that wheezing episodes early in life due to human rhinoviruses are a major risk factor for the later diagnosis of asthma at age 6 years. For those with existing asthma, exacerbations are a major cause of morbidity, can need acute care, and can, albeit rarely, result in death. Viral respiratory tract infections, predominantly those caused by human rhinoviruses, are associated with asthma exacerbations. There is also evidence that deficiencies in antiviral activity and the integrity of the airway epithelial barrier could make individuals with asthma more likely to have severe viral respiratory infections of the lower airway, and thus increase the risk of exacerbation. In view of the effect of respiratory viruses on many aspects of asthma, efforts to understand the mechanisms and risk factors by which these airway infections cause changes in airway pathophysiology are a first step towards improved treatment.
Article
Quercetin exhibits antitumor activity. We investigated the effect of quercetin on the in vitro and in vivo growth of two squamous cell carcinoma cell lines and a normal human lung fibroblast-like cell line. The in vivo effect was evaluated using implantable cell growth chambers implanted subcutaneously in immunocompetent rats. Quercetin was injected intraperitoneally, and multiple dosages were tested. Cells were counted on days 1, 3, 5, and 7, and growth curves were constructed. Quercetin caused inhibition of growth in both squamous cell carcinoma lines. Effect on the fibroblast-like human lung cells was noted only at the maximum concentration. Significant growth inhibition of squamous cell carcinoma was observed in implantable cell growth chambers retrieved 3 days after quercetin treatment. Quercetin appears to possess a cytotoxic effect on squamous cell carcinoma of head and neck origin both in vivo and in vitro. The inhibitory effect on malignant cells appears to be selective and dose-dependent.
Article
Flavonoid quercetin and its derivative, methylquercetin, inhibit the replication of poliovirus in several cell lines. Here, we show that replication of poliovirus is inhibited by quercetin and that the extent of this inhibition depends on the intracellular content of pirin, a quercetinase. HeLa cells contain higher content of pirin protein than normal kidney human epithelial (NKE) or 293 cells do. Poliovirus replication in HeLa cells is significantly more resistant to quercetin than its replication in NKE and 293 cells. Overexpression of pirin reduced antiviral inhibitory effect of quercetin, while siRNA-induced suppression of pirin level made poliovirus replication more sensitive to the flavonoid. The results suggest that quercetinase activity of pirin determines the resistance of poliovirus infection to quercetin.
Cold Wars: The Fight Against the Common Cold
  • D M Tyrrell
  • Fielder
Tyrrell DM, Fielder (2002) Cold Wars: The Fight Against the Common Cold. New York
  • S Ganesan
  • A N Faris
  • A T Comstock
  • A L Curtis
  • F J Martinez
Ganesan S, Faris AN, Comstock AT, Curtis AL, Martinez FJ, et al. (2011)