No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Mechanism of the antiviral effect of hydroxytyrosol on influenza virus appears to involve morphological change of the virus
Abstract
Hydroxytyrosol (HT), a small-molecule phenolic compound, inactivated influenza A viruses including H1N1, H3N2, H5N1, and H9N2 subtypes. HT also inactivated Newcastle disease virus but not bovine rotavirus, and fowl adenovirus, suggesting that the mechanism of the antiviral effect of HT might require the presence of a viral envelope. Pretreatment of MDCK cells with HT did not affect the propagation of H9N2 virus subsequently inoculated onto the cells, implying that HT targets the virus but not the host cell. H9N2 virus inactivated with HT retained unaltered hemagglutinating activity and bound to MDCK cells in a manner similar to untreated virus. Neuraminidase activity in the HT-treated virus also remained unchanged. However, in the cells inoculated with HT-inactivated H9N2 virus, neither viral mRNA nor viral protein was detected. Electron microscopic analysis revealed morphological abnormalities in the HT-treated H9N2 virus. Most structures found in the HT-treated virus were atypical of influenza virions, and localization of hemagglutinin was not necessarily confined on the virion surface. These observations suggest that the structure of H9N2 virus could be disrupted by HT.
... Sometimes, polyphenols interfere with the attachment of a virus to host cells by binding to the viral capsid (envelope). Hydroxytyrosol is particularly effective against enveloped viruses such as influenza, human immunodeficiency virus, and coronavirus [36,37]. ...
... The antiviral activities of HXT were studied by Kentaro Yamada and colleagues with influenza A virus, New Castle disease virus, bovine rotavirus, and chicken adenovirus [36]. Although HXT proved successful in combating enveloped viruses, it proved ineffective with non-enveloped viruses. ...
... These results indicate that the viral envelope is the primary target of HXT. The H9N2 virus treated with HXT showed antiviral properties, including a reduction in mRNA production and the absence of viral nucleoproteins [36]. ...
Phytochemicals from plant extracts are becoming increasingly popular in the world of food science and technology because they have positive effects on human health. In particular, several bioactive foods and dietary supplements are being investigated as potential treatments for chronic COVID. Hydroxytyrosol (HXT) is a natural antioxidant, found in olive oil, with antioxidant anti-inflammatory properties that has been consumed by humans for centuries without reported adverse effects. Its use was approved by the European Food Safety Authority as a protective agent for the car-diovascular system. Similarly, arginine is a natural amino acid with anti-inflammatory properties that can modulate the activity of immune cells, reducing the production of pro-inflammatory cytokines such as IL-6 and TNF-α. The properties of both substances may be particularly beneficial in the context of COVID-19 and long COVID, which are characterised by inflammation and oxidative stress. While L-arginine promotes the formation of • NO, HXT prevents oxidative stress and inflammation in infected cells. This combination could prevent the formation of harmful peroxynitrite, a potent pro-inflammatory substance implicated in pneumonia and COVID-19-associated organ dysfunction, as well as reduce inflammation, improve immune function, protect against free radical damage and prevent blood vessel injury. Further research is needed to fully understand the potential benefits of HXT and arginine in the context of COVID-19.
... Hydroxytyrosol (36) (Yamada et al. 2009) and glycyrrhizin are moderate repressors of NDV. ...
... Simple phenols are mainly strong inhibitors of IV in vitro such as gallic acid (1) (You et al. 2018), hydroxytyrosol (36) (Yamada et al. 2009) and ellagic acid , the latter active in vivo . Protocatechuic acid given at the dose of 20 mg/kg twice daily by oral gavages at 12 h intervals for 7 d protected mice against IV (Ou et al. 2014). ...
... Mainly phenolics such as baicalein (Johari et al. 2012), epicatechin (35) (Ferraz et al. 2019), hesperitin (29) (Castrillo et al. 2015), silvestrol (8) (Elgner et al. 2018), gallic acid (1) (Hsu et al. 2015), and hydroxytyrosol (36) (Yamada et al. 2009). Flavanols evoke viral envelope desquamation, shape distortion, and destruction as well as flavones. ...
Context
The emergence of zoonotic viruses in the last decades culminating with COVID-19 and challenges posed by the resistance of RNA viruses to antiviral drugs requires the development of new antiviral drugs.
Objective
This review identifies natural products isolated from Asian and Pacific medicinal plants with in vitro and in vivo antiviral activity towards RNA viruses and analyses their distribution, molecular weights, solubility and modes of action.
Materials and methods
All data in this review was compiled from Google Scholar, PubMed, Science Direct, Web of Science, ChemSpider, PubChem and library search from 1961 to 2022.
Results
Out of about 350 molecules identified, 43 phenolics, 31 alkaloids, and 28 terpenes were very strongly active against at least one type of RNA virus. These natural products are mainly planar and amphiphilic, with a molecular mass between 200 and 400 g/mol and target viral genome replication. Hydroxytyrosol, silvestrol, lycorine, tylophorine and 12-O-tetradecanoylphorbol 13-acetate with IC50 below 0.01 µg/mL and selectivity index (S.I.) above 100 have the potential to be used for the development of anti-RNA virus leads.
Discussion and conclusions
The medicinal plants of Asia and the Pacific are a rich source of natural products with the potential to be developed as lead for the treatment of RNA viral infections.
... Yamada et al. demonstrated that hydroxytyrosol (HT) was able to inactivate different influenza A viruses, including H1N1, H3N2, H5N1, and H9N2, and also the Newcastle disease virus, suggesting that the mechanism of the antiviral effect of this polyphenol may require the presence of a viral envelope for its action [55]. At the same time, a pre-treatment of MDCK (Madin-Darby Canine Kidney cells) with HT did not affect the spread of H9N2 when subsequently inoculated; although, the H9N2 virus inactivated with hydroxytyrosol maintained its hemagglutinating activity unaltered and bound to MDCK cells in a similar way to untreated virus, implying that HT targets the virus and not the host cell [55]. ...
... Yamada et al. demonstrated that hydroxytyrosol (HT) was able to inactivate different influenza A viruses, including H1N1, H3N2, H5N1, and H9N2, and also the Newcastle disease virus, suggesting that the mechanism of the antiviral effect of this polyphenol may require the presence of a viral envelope for its action [55]. At the same time, a pre-treatment of MDCK (Madin-Darby Canine Kidney cells) with HT did not affect the spread of H9N2 when subsequently inoculated; although, the H9N2 virus inactivated with hydroxytyrosol maintained its hemagglutinating activity unaltered and bound to MDCK cells in a similar way to untreated virus, implying that HT targets the virus and not the host cell [55]. ...
... Electron microscopy analysis showed morphological abnormalities in the HT-treated H9N2 virus, with most of the structures found in the virions being atypical. These results suggest that the viral structure is altered by HT [55]. ...
There is currently a worldwide consensus and recognition of the undoubted health benefits of the so-called Mediterranean diet, with its intake being associated with a lower risk of mortality. The most important characteristics of this type of diet are based on the consumption of significant amounts of fruit, vegetables, legumes, and nuts, which provide, in addition to some active ingredients, fiber and a proportion of vegetable protein, together with extra virgin olive oil (EVOO) as the main sources of vegetable fat. Fish and meat from poultry and other small farm animals are the main sources of protein. One of the main components, as already mentioned, is EVOO, which is rich in monounsaturated fatty acids and to a lesser extent in polyunsaturated fatty acids. The intake of this type of nutrient also provides an important set of phytochemicals whose health potential is widely spread and agreed upon. These phytochemicals include significant amounts of anthocyanins, stilbenes, flavonoids, phenolic acids, and terpenes of varying complexities. Therefore, the inclusion in the diet of this type of molecules, with a proven healthy effect, provides an unquestionable preventive and/or curative activity on an important group of pathologies related to cardiovascular, infectious, and cancerous diseases, as well as those related to the metabolic syndrome. The aim of this review is therefore to shed light on the nutraceutical role of two of the main phytochemicals present in Olea europaea fruit and leaf extracts, polyphenols, and triterpenes, on healthy animal growth. Their immunomodulatory, anti-infective, antioxidant, anti-aging, and anti-carcinogenic capabilities show them to be potential nutraceuticals, providing healthy growth.
... Hydroxytyrosol can also have antiviral activity. Certain research studies 33 suggest that the mechanism of this effect might require the presence of a viral envelope. ...
... The influenza virus protein has a binding site for hydroxytyrosol in the domain essential for cell entry, which means that hydroxytyrosol affects the influenza virus. The results obtained in this study also suggest that the antiviral effect of hydroxytyrosol on the H9N2 virus can be attributed to the direct effect of hydroxytyrosol on the virus 33 . The morphology of the hydroxytyrosol-treated H9N2 virus has been analyzed under the electron microscope. ...
... The results suggested that the structure of the viral envelope could be disrupted by hydroxytyrosol. Suppression of viral mRNA synthesis and lack of viral nucleoprotein observed in cells inoculated with hydroxytyrosol-treated H9N2 virus may be the result of poor viral binding, viral uncoating or problems with other steps of viral infection 33 . ...
Objective:
The aim of the study was to show the effect that two naturally occurring compounds, a cyclodextrin and hydroxytyrosol, can have on the entry of SARS-CoV-2 into human cells.
Materials and methods:
The PubMed database was searched to retrieve studies published from 2000 to 2020, satisfying the inclusion criteria. The search keywords were: SARS-CoV, SARS-CoV-2, coronavirus, lipid raft, endocytosis, hydroxytyrosol, cyclodextrin. Modeling of alpha-cyclodextrin and hydroxytyrosol were done using UCSF Chimera 1.14.
Results:
The search results indicated that cyclodextrins can reduce the efficiency of viral endocytosis and that hydroxytyrosol has antiviral properties. Bioinformatic docking studies showed that alpha-cyclodextrin and hydroxytyrosol, alone or in combination, interact with the viral spike protein and its host cell receptor ACE2, thereby potentially influencing the endocytosis process.
Conclusions:
Hydroxytyrosol and alpha-cyclodextrin can be useful against the spread of SARS-CoV-2.
... Olive polyphenols are also known to play a role in preventing chronic human diseases such as cardiovascular diseases and inflammatory diseases [6]. Several in vitro and in vivo studies confirmed that phenolic compounds from olive reduce the effect of oxidative stress associated with pathological disorders including atherosclerosis [7,8], cancer [9,10], inflammatory diseases [11][12][13], neurodegenerative diseases [14], and they have some anti-microbial and anti-viral properties [15][16][17][18]. ...
... A large number of methods have been developed for measure ROS production, which are based on detection by colorimetry, fluorescence or chemiluminescence, depending on the probe used [16][17][18][19][20]. The ideal technique should be highly sensitive, specific for one ROS species, and should not interfere with cellular functions. ...
... The ideal technique should be highly sensitive, specific for one ROS species, and should not interfere with cellular functions. Among these techniques, luminolamplified chemiluminescence has been largely used to detect ROS production [16][17][18][19]. Luminol (5-amino-2,3-dihydro-1,4-phthalazine-dione) is a redox-sensitive compound that emits blue luminescence when oxidized. ...
Olive mill wastewater (OMW) is produced seasonally by the olive oil producing countries. A large amount of liquid waste results from olive oil extraction, with a very high organic load which renders it difficult to treat. Wastewater represents also a significant source of polyphenols (pp). Oleuropein and hydroxytyrosol are
polyphenols wich are major biological active components of olives, olive oil and
OMW.The extraction of polyphenols will improve the wastewater biodegradation and
reduce its phytotoxicity.
The aim of this study was to extract pp from OMW and investigate the effect of this
extract, hydroxytyrosl and oleurpeine on human polynuclear neutrophil (PN) functions
such as reactive oxygen species (ROS) production, degranulation and chemotaxis.
PN were isolated from healthy donors and were incubated with increased
concentrations of polyphenol extract or hydroxytyrosol and oleuropeine. ROS
production was measured by luminol-amplified chemiluminescence, cytochrome c reduction, and flow cytometer. Hydroxytyrosol and oleuropeine are tested on other PN functions: degranulation was assessed by measuring myeloperoxidase activity
and Western blots, chemotaxis was assessed by the under-agarose chemotaxis
assay. Phosphorylated proteins were assessed by gel electrophoresis and Western
blots.
Our results showed that pp extracted from OMW exerts a strong antioxidant effect and they could have an anti-inflammatory effect by inhibiting PN ROS production by scavenging hydrogen peroxide, thus limiting their toxic effects. We show that in
addition to their ROS scavenging effect, oleuropein and hydroxytyrosol significantly inhibited the bacterial peptide N-formyl-methionyl-leucylphenylalanine (fMLF)-induced
degranulation of azurophilic and specific granules as measured by myeloperoxidase and lactoferrin release, respectively. We also show that oleuropein and hydroxytyrosol reduced fMLF-induced neutrophil chemotaxis. Interestingly, both agents impaired the fMLF-induced AKT, p38MAPKinase, and ERK1/2 phosphorylation, signaling molecules that are involved in pathways regulating PN functions. Our data suggest that the anti-inflammatory properties of olive pp are not only restricted to their ROS scavenging effect, but also involve the inhibition of two other major pro-inflammatory PN functions.
... Olives, virgin olive oil, wine Phenolic alcohols HIV-1 [34] H1N1, H3N2, H5N1, H9N2, NDV [35] Interaction with SARS-CoV-2 spike protein and human ACE-2 receptor (in silico approach) [36] Reduction of PL pro -dependent adverse effects in long-COVID (in vitro approach) [37] Apigenin Parsley, celery, onions, oranges, tea, chamomile, spinach, basil Flavones ASFV, HCV, PEDV, FMD virus, HIV, IV, EBV, SARS-CoV (experimental and in silico approach) [38] HBV [39] Interaction with SARS-CoV-2 NSP10 (in silico approach) [40] Inhibition of SARS-CoV-2 M pro (in silico approach) [41] Inhibition of SARS-CoV-2 M pro (in vitro approach) [42] Luteolin Capsicum, carrots, apple, cabbage, onion leaves, parsley, basil, spinach Flavones HSV-2 [43] HIV-1, EBV [39] IAV, JEV, DENV, HBV, SARS-CoV [38] Inhibition of COVID-19 M pro protease (in silico approach) [44,45] Interaction with SARS-CoV-2 RdRp (in vitro approach) [46] Pectolinarin Cirsium setidens Nakai Flavones SARS-CoV (experimental and in silico approach) [47] Inhibition of SARS-CoV-2 M pro and spike (S) glycoprotein (in silico approach) [ Inhibition of SARS-CoV-2 M pro (in silico approach) [54] Binds to ACE2 receptor (in vitro approach) [55] Inhibition of SARS-CoV-2 envelope protein E (in silico approach) [22] Inhibition of SARS-CoV-2 M pro (in silico approach) [ [90] RSV (experimental and in silico approach) [91] SARS-CoV [92] Inhibition of SARS-CoV-2 spike protein/ACE2 binding and interaction with TMPRSS2 (in silico and in vitro approach) [93] Naringenin Sweet oranges, oregano, sorghums, grape wines, clementine, tangerine, saffrons, white lupines, dates, elderberries Flavanones HCV (in silico approach) [70] YFV (experimental and in silico approach) [90] ZIKV (experimental and in silico approach) [94] DENV [95] HSV [29] CHIKV [89] Inhibition of COVID-19 M pro (in silico approach) [ [39] EV71 [106] Interaction with SARS-CoV-2 spike protein and human ACE-2 receptor (in silico approach) [107] Inhibition of SARS-CoV-2 replication (in vitro approach) [108][109][110] Ellagic acid Raspberries, strawberries, cranberries, walnuts, pecans, pomegranates ...
... In relation to genetic and antigenic variation, the current 18 subtypes of IAV HA (H1-H18) are divided into group 1 (H1, H2, H5, H6, H8, H9, H11, H12, H13, H16, H17, and H18) and group 2 (H3, H4, H7, H10, H14, and H15), while IAV of NA has 11 subtypes (N1-N11) [134]. Gallic acid has been shown to exhibit inhibitory effects against both influenza type A and B viruses, disrupting the viral particles [28], while hydroxytyrosol inactivates influenza A viruses, including H1N1, H3N2, H5N1, and H9N2 subtypes with an effect virucidal rather than antiviral [35]. Apigenin, luteolin, kaempferol, epicatechin, (-)-epicatechin-3-O-gallate (ECG), epigallocatechin-3-gallate (EGCG), cirsimaritin, and eugenol also show activity against IV inhibiting replication [38,39,50,83,129]. ...
Natural products and plant extracts exhibit many biological activities, including that related to the defense mechanisms against parasites. Many studies have investigated the biological functions of secondary metabolites and reported evidence of antiviral activities. The pandemic emergencies have further increased the interest in finding antiviral agents, and efforts are oriented to investigate possible activities of secondary plant metabolites against human viruses and their potential application in treating or preventing SARS-CoV-2 infection. In this review, we performed a comprehensive analysis of studies through in silico and in vitro investigations, also including in vivo applications and clinical trials, to evaluate the state of knowledge on the antiviral activities of secondary metabolites against human viruses and their potential application in treating or preventing SARS-CoV-2 infection, with a particular focus on natural compounds present in food plants. Although some of the food plant secondary metabolites seem to be useful in the prevention and as a possible therapeutic management against SARS-CoV-2, up to now, no molecules can be used as a potential treatment for COVID-19; however, more research is needed.
... HT can inhibit the activity of various viruses, including HIV-1, H 1 N 1 , H 3 N 2 , and H 9 N 2 subtypes and Newcastle disease virus (Bedoya, et al., 2016). In dog kidney cells (MDCK), the mRNA and protein of H 9 N 2 virus could not be detected after HT treatment (Yamada, et al., 2009). The morphological changes of H 9 N 2 virus were observed using electron microscopy, which revealed that the structure of H 9 N 2 virus may be damaged by HT (Yamada, Ogawa, Hara, Yoshida, Yonezawa, Karibe, Nghia, Yoshimura, Yamamoto and Yamada, 2009). ...
... In dog kidney cells (MDCK), the mRNA and protein of H 9 N 2 virus could not be detected after HT treatment (Yamada, et al., 2009). The morphological changes of H 9 N 2 virus were observed using electron microscopy, which revealed that the structure of H 9 N 2 virus may be damaged by HT (Yamada, Ogawa, Hara, Yoshida, Yonezawa, Karibe, Nghia, Yoshimura, Yamamoto and Yamada, 2009). ...
In this study, the anti-inflammatory and antiapoptotic effects of hydroxytyrosol (HT)
in Mycoplasma gallisepticum (MG)-infected chicken were investigated, and the
underlying molecular mechanisms were explored. The results revealed severe
ultrastructural pathological changes after MG infection in the lung tissue of chicken,
including inflammatory cell infiltration, thickening of the lung chamber wall, visible
cell swelling, mitochondrial cristae rupture and ribosome shedding. MG possibly
2
activated the nuclear factor κB (NF-κB)/nucleotide-binding oligomerization
domain-like receptor protein 3 (NLRP3)/interleukin (IL)-1β signaling pathway in the
lung. However, HT treatment significantly ameliorated MG-induced pathological
damage of the lung. HT reduced the magnitude of pulmonary injury after MG
infection by reducing apoptosis and releasing the proinflammatory factors. Compared
with the MG-infected group, the HT-treated group exhibited significant inhibition of
the expression of NF-κB/NLRP3/IL-1β signaling-pathway-related genes; for example,
the expressions of NF-κB, NLRP3, caspase-1, IL-1β, IL-2, IL-6, IL-18, and TNF-α
significantly decreased (P < 0.01 or < 0.05). In conclusion, HT effectively inhibited
MG-induced inflammatory response and apoptosis and protected the lung by blocking
the activation of NF-κB/NLRP3/IL-1β signaling pathway and reducing the damage
caused by MG infection in chicken. This study revealed that HT may be a suitable and
effective anti-inflammatory drug against MG infection in chicken.
Key words: Hydroxytyrosol; Mycoplasma gallisepticum; chicken lung; inflammation;
NF-κB/NLRP3/IL-1β signaling pathway
... Hydroxytyrosol has broad-spectrum antiviral activity, especially against enveloped viruses, like influenza virus, HIV and coronaviruses. For instance, it may induce morphological changes that reduce influenza virus infectivity 9 . The exact mechanism of action is unclear but seems to require the presence of the envelope. ...
... These results further sustain our preliminary studies that suggested reduced risk of contracting the infection and reduced duration of symptoms, probably due to fewer membrane lipid rafts containing ACE2 associated with α-cyclodextrin treatment, while in addition hydroxytyrosol may have direct antiviral effects 9,18,19 . ...
Objective:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new coronavirus responsible for the current pandemic of coronavirus disease 2019 (COVID-19). This virus attacks cells of the airway epithelium by binding transmembrane angiotensin-converting enzyme 2 (ACE2). Hydroxytyrosol has anti-viral properties. Alpha-cyclodextrin can deplete sphingolipids and phospholipids from cell membranes. The aim of the present experimental study was to evaluate the efficacy of α-cyclodextrin and hydroxytyrosol in improving defenses against SARS-CoV-2 infection in in vitro cell models and humans.
Patients and methods:
For in vitro experiments on Vero E6 cells, RNA for RT-qPCR analysis was extracted from Caco2 and human fibroblast cell lines. For study in humans, the treatment group consisted of 149 healthy volunteers in Northern Cyprus, considered at higher risk of SARS-CoV-2 infection than the general population. The volunteers used nasal spray containing α-cyclodextrin and hydroxytyrosol for 4 weeks. The control group consisted of 76 healthy volunteers who did not use the spray.
Results:
RT-qPCR experiments on targeted genes involved in endocytosis showed a reduction in gene expression, whereas cytotoxicity and cytoprotective tests showed that the compounds exerted a protective effect against SARS-CoV-2 infection at non-cytotoxic concentrations. None of the volunteers became positive to SARS-CoV-2 RT-qPCR assay during the 30 days of treatment.
Conclusions:
Treatment with α-cyclodextrin and hydroxytyrosol nasal spray improved defenses against SARS-CoV-2 infection and reduced synthesis of viral particles.
... Oleuropein, the main phenolic compound present at olive, is formed by esterification of hydroxytyrosol and a glycosylated monoterpene, the elenolic acid (EA). 16,20 It is hypothesised that the real antimicrobial effect of oleuropein would be due to its components hydroxytyrosol 23 and EA, although there are still no studies carried out with EA obtained from natural sources. Early research with calcium elenolate salts revealed its antiviral activity, including influenza and parainfluenza, in vitro and in animal models. ...
... The proposed mechanism of inhibition in hydroxytyrosol would be related to abnormalities provoked by the substance in the surface of the virion envelope. 23 The anti-influenza effect of Isenolic ® can be attributed to its EA content, because the extract showed an EA dosedependent inhibition. The role of several elenolic derivates against the influenza viruses is known since decades, especially in works done with the calcium salt of EA. ...
Seasonal flu is caused by influenza infection, a virus that spreads easily in human population with periodical epidemic outbreaks. The high mutational rate of influenza viruses leads to the emergence of strains resistant to the current treatments. Due to that, scientific research is focusing on the development of new anti-influenza agents as alternative or complementary treatments. Olive tree ( Olea europaea L.) has been a source of ancestral remedies due to its antimicrobial activity. Thus, the aim of this study was to test the anti-influenza activity of a standardized olive leaf extract rich in elenolic acid (EA), Isenolic ® , compared with oseltamivir. Isenolic ® extract was characterized by High Performance Liquid Chromatography (HPLC)-Mass Spectrometry and its content in EA was determined by HPLC. Cytotoxicity, viral neuraminidase inhibitor activity and cell viability protection against influenza infection of Isenolic ® were tested in vitro using sialic acid overexpressing Madin-Darby Canine Kidney cells. Isenolic ® formulations showed a 4% and 8% dry basis. Oseltamivir and Isenolic ® extracts showed anti-influenza activity. The 8% Isenolic ® formulation showed a dose-dependent neuraminidase inhibitor activity higher than the 4% formulation, and preserved cell viability under viral infection. Thus, Isenolic ® become a promising natural alternative to existing influenza treatments.
... In this study, the SARS-CoV-2 inactivating activities of HIDROX and HT, especially the superiority of HIDROX to pure HT, was shown in vitro (Figures 1 and 2). We previously showed that HT inactivated enveloped viruses, namely, IAV and Newcastle disease virus, and not non-enveloped viruses, namely, bovine rotavirus and fowl adenovirus [17]. In this report, the hemagglutination activity of HA protein and neuraminidase activity of NA protein, expressed on the surface of IAV, seemed unaffected by HT, and the impact of HT on viral structural proteins was unclear. ...
... To identify the binding sites of HT to SARS-CoV-2 structural proteins, computational docking analysis will be useful in the future. Our previous study revealed the possibility that the viral envelope was the site of action of HT because nonenveloped viruses are unaffected by HT [17]. Moreover, HIDROX or HT treatment disrupts the SARS-CoV-2 genome ( Figure 5). ...
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally. Although measures to control SARS-CoV-2, namely, vaccination, medication, and chemical disinfectants are being investigated, there is an increase in the demand for auxiliary antiviral approaches using natural compounds. Here we have focused on hydroxytyrosol (HT)-rich aqueous olive pulp extract (HIDROX®) and evaluated its SARS-CoV-2-inactivating activity in vitro. We showed that the HIDROX solution exhibits time- and concentration-dependent SARS-CoV-2-inactivating activities, and that HIDROX has more potent virucidal activity than pure HT. The evaluation of the mechanism of action suggested that both HIDROX and HT induced structural changes in SARS-CoV-2, which changed the molecular weight of the spike proteins. Even though the spike protein is highly glycosylated, this change was induced regardless of the glycosylation status. In addition, HIDROX or HT treatment disrupted the viral genome. Moreover, the HIDROX-containing cream applied on film showed time- and concentration-dependent SARS-CoV-2-inactivating activities. Thus, the HIDROX-containing cream can be applied topically as an antiviral hand cream. Our findings suggest that HIDROX contributes to improving SARS-CoV-2 control measures.
... 20 In other similar research, they have not found this difference in the influenza virus treated with HT or with CuZeo textiles. 35,39 Just as important as HA is NA, the abundant glycoprotein on the surface of influenza viruses. It has an enzymatic activity that promotes the release of viral progeny from a host cell during the final stage of viral replication and the spread of infection to new cells. ...
Purpose
Synthesis and characterization of silver (Ag)/titanium dioxide (TiO2) nanocomposite (ATA) to investigate its antiviral activity against the H1N1 influenza virus and antiviral mechanisms.
Materials and Methods
A water-dispersible ATA was prepared by a photocatalytic reduction process from AgNO3 and TiO2. The characterization of ATA was performed by ultraviolet-visible spectroscopy, X-ray diffraction, high-resolution transmission electron microscopy and energy-dispersive X-ray spectroscopy. The antiviral activities and the antiviral mechanism of ATA were investigated in detail by light microscopy, transmission electron microscopy and biological techniques such as cell cytotoxicity, 50% tissue culture infectious dose detection, western blot and reverse transcription-polymerase chain reaction.
Results
These results showed the successful synthesis of ATA nanocomposite with uniform particle size and distribution. It demonstrated the highly efficient antiviral activity of ATA in a dose- and time-dependent manner, as indicated by the reduction of viral titer and the reduction of cytopathic effects caused by viral infection. In the presence of ATA, the structure of the H1N1 influenza virus is directly destroyed and even disintegrated, with the damaged surface membrane proteins and fuzzy contour. It reduces the infection efficiency of influenza by suppressing the activity and expression of hemagglutinin and neuraminidase. The results of mechanistic studies suggested that ATA nanocomposite primarily interferes with virus attachment to viral receptors on the cell surface.
Conclusion
Our study suggests that ATA may be a good antiviral candidate against the influenza virus. Compared with AgNPs alone, our synthesized ATA nanocomposites can achieve similar viral inactivation rates using only a much smaller concentration of AgNPs, greatly reducing the amount of AgNPs and their potential side effects. It has great practical value for attaching ATA to the high-efficiency particulate air network in the air purifier, which can kill the virus attached to it and limit its spread.
... Phenols are well-known to inhibit viral infection of a target host cell in a variety of ways [95][96][97][98][99], including the disruption of the virus lipid bilayer envelopes [100,101] and preventing viral attachment to the host cell [97,102]. Furthermore, the inhibition of various viral protein activities results in the disruption of the viral life cycle, which ultimately prevents the multiplication and release of the virus [85,102,103]. ...
Most plants have developed unique mechanisms to cope with harsh environmental conditions to compensate for their lack of mobility. A key part of their coping mechanisms is the synthesis of secondary metabolites. In addition to their role in plants’ defense against pathogens, they also possess therapeutic properties against diseases, and their use by humans predates written history. Viruses are a unique class of submicroscopic agents, incapable of independent existence outside a living host. Pathogenic viruses continue to pose a significant threat to global health, leading to innumerable fatalities on a yearly basis. The use of medicinal plants as a natural source of antiviral agents has been widely reported in literature in the past decades. Metabolomics is a powerful research tool for the identification of plant metabolites with antiviral potentials. It can be used to isolate compounds with antiviral capacities in plants and study the biosynthetic pathways involved in viral disease progression. This review discusses the use of medicinal plants as antiviral agents, with a special focus on the metabolomics evidence supporting their efficacy. Suggestions are made for the optimization of various metabolomics methods of characterizing the bioactive compounds in plants and subsequently understanding the mechanisms of their operation.
... Moreover, tyrosol has many useful properties in all fields, such as antioxidant and antibacterial activities [3]. Other beneficial properties can be mentioned, such as cardioprotective [4], antiviral [5], anti-inflammatory [6], and anticancer [7] activities. Additionally, tyrosol is usually well absorbed by cells, which explains their great biological activities. ...
The utmost aim of this study is the determination of the optimum ratio and the amount of almond gum (AL), sodium alginate (SA), and sodium caseinate (SC) in the formulation of tyrosol-nanoparticles. Indeed, the increase in the ratio of AL enhanced the encapsulation efficiency and significantly reduced the mean particle diameter (dp) of tyrosol-nanoparticles. Moreover, increasing the ratio of SC at an amount of 2.0% improved the polydispersity index of tyrosol nanodispersions. Besides, the high proportions of AL at the amount of 2.0% and SC at the amount of 1.0% enhanced the antioxidant activities of tyrosol nanoparticles. Hence, the statistical results showed that the mixture of 51.20% AL and 48.80% SC at the amount of 2.0% was proven to be the optimum condition which was confirmed in practice. Under these conditions, the experimental values of encapsulation efficiency, mean dp, polydispersity index, and antioxidant activity (IC50) were: 98.10%, 91.57 nm, 0.18, and 87.90 µM, respectively. Their molecular interaction was also confirmed by FTIR and thermal analysis which proved the encapsulation of tyrosol in an amorphous form.
... Phenolic interventions generally disrupt the infectivity of the virus [94,95]. Many phenolic compounds have also been reported to inhibit viral entry into the target host cells [95][96][97][98]. These they do by interfering with viral attachment proteins, or the receptors on the host cell's surface [99,100]. ...
Plants have developed unique mechanisms to cope with the harsh environmental conditions to compensate for their lack of mobility. A key part of their coping mechanisms is the synthesis of secondary metabolites. In addition to their role in plants’ defense against pathogens, they also possess therapeutic properties against diseases, and their use by humans predates written history. Viruses are a unique class of submicroscopic agents, incapable of independent existence outside a living host. Pathogenic viruses continue to pose a significant threat on global health, leading to unprecedented fatalities on a yearly basis. The use of medicinal plants as a natural source for an-tiviral agents has been widely reported in literature in the past decades. Metabolomics is a powerful research tool for the identification of plant metabolites with antiviral potentials and can be used to isolate compounds with antiviral activities in plants and study the biosynthetic pathways involved in viral disease progression. This review discusses the use of medicinal plants as antiviral agents, with a special focus on the metabolomics evidence supporting their efficacy. Additionally, suggestions are made for the optimization of various metabolomics methods for characterizing the bio-active compounds in plants and subsequent understanding of the mechanism of their operation.
... Olive polyphenols are also known to play a role in preventing chronic human diseases such as cardiovascular diseases and inflammatory diseases [6]. Several in vitro and in vivo studies confirmed that phenolic compounds from olive reduce the effect of oxidative stress associated with pathological disorders including atherosclerosis [7,8], cancer [9,10], inflammatory diseases [11][12][13], neurodegenerative diseases [14], and they have some anti-microbial and anti-viral properties [15][16][17][18]. ...
Olive mill wastewater (OMW) is produced seasonally by the olive oil-producing countries. A large amount
of liquid waste results from olive oil extraction, with a very high organic load which renders it difficult to treat.
Wastewater represents also a significant source of polyphenols which can be revalorized and used for medical or
agro-alimentary purposes. The extraction of polyphenols will improve the wastewater biodegradation and reduce
its phytotoxicity. The objective of this study was to extract polyphenols from OMW and to investigate their effect
on reactive oxygen species (ROS) production by human neutrophil. Polyphenols were extracted from OMW by
an established technique. Neutrophils, isolated from blood of healthy volunteers, were incubated with increased
concentrations of polyphenol extract and ROS production was measured by luminol-amplified chemiluminescence
and cytochrome c reduction techniques. Results show that the polyphenol extract from OMW inhibited phorbolmyristate acetate (PMA)-stimulated neutrophil ROS production as measured by the chemiluminescence assay. The
polyphenols extract from OMW also inhibited neutrophil superoxide production as measured by the cytochrome c
reduction assay; as well as H2
O2
production as measured by flow cytometry. Also, the polyphenol extract reacted
with pure H2
O2
but did not affect superoxide anions production by the xanthine/xanthine oxidase enzymatic system.
Our results show that polyphenols extracted from OMW exert a strong antioxidant effect and they could have an
anti-inflammatory effect by inhibiting neutrophil ROS production and by scavenging hydrogen peroxide, thus limiting
their toxic effects. OMW could be used to extract polyphenols for medicinal applications.
... Olive compounds have been well reviewed and preferred as a functional food containing antiviral and immune-boosting effects [163]. Additionally, Hydroxytyrosol has been found to disrupt the viral envelope of influenza A viruses, including H1N1, H3N2, H5N1 and H9N2 [164]. Oleuropein has also been reported to inhibit the herpes simplex virus (HSV-1) via phosphorylating PKR, c-FOS and c-JUN in Hela cells [163]. ...
Respiratory diseases recently became the leading cause of death worldwide, due to the emergence of COVID-19. The pathogenesis of respiratory diseases is centred around inflammation and oxidative stress. Plant-based alongside synthetic drugs were considered as therapeutics due to their proven nutraceutical value. One such example is the olive, which is a traditional symbol of the MedDiet. Olive bioactive compounds are enriched with antioxidant, anti-inflammatory, anticancer and antiviral properties. However, there are few studies relating to the beneficial effect of olive bioactive compounds on respiratory diseases. A vague understanding of its molecular action, dosage and bioavailability limits its usefulness for clinical trials about respiratory infections. Hence, our review aims to explore olive bioactive compound’s antioxidant, anti-inflammatory and antiviral properties in respiratory disease defence and treatment. Molecular insight into olive compounds’ potential for respiratory system protection against inflammation and ensuing infection is also presented. Olive bioactive compounds mainly protect the respiratory system by subsiding proinflammatory cytokines and oxidative stress.
... The activity of this compound is related to the removal of ROS. Hydroxytyrosol is also found effective against pulmonary fibrosis and influenza (Yamada et al., 2009;Liu et al., 2015). Hence, hydorxytyrosol could be a potential natural molecule to fight against COVID-19 infection (Quiles et al., 2020). ...
Food antioxidants can prevent or/and delay free radical formation which is responsible for oxidative stress. Nowadays, natural remedy is the highest concern in many countries, as well as discouraging the intake of synthetic counterparts to avoid the burden of side effects on human health. Regular intake of dietary antioxidants could help to improve the fitness of the body, and subsequently make the body more competitive in its fight against diseases through enhanced immune response. The present review thus summarised recent knowledge on the dietary source of antioxidants, and also mechanism of action and functionalities on human health benefits. Due to the proven ability to restore mitochondrial function and cellular redox balance, food antioxidants also have great potential as natural therapies against COVID-19. However, the numbers of trials are still limited. There must be more tests with the hope that these compounds will mitigate the COVID-19 and similar outbreaks in the future.
... The activity of this compound is related to the removal of ROS. Hydroxytyrosol is also found effective against pulmonary fibrosis and influenza (Yamada et al., 2009;Liu et al., 2015). Hence, hydorxytyrosol could be a potential natural molecule to fight against COVID-19 infection (Quiles et al., 2020). ...
Food antioxidants can prevent or/and delay free radical formation which is responsible for oxidative stress. Nowadays, natural remedy becomes the highest concern in many countries, as well as discouraging the intake of synthetic counterparts to avoid the burden of side effects on human health. Regular intake of dietary antioxidants could help to improve the fitness of the body, and subsequently make the body more competitive in its fight against diseases through enhanced immune response. The present review thus summarised recent knowledge on the dietary source of antioxidants, and also mechanism of action and functionalities on human health benefits. Due to the proven ability to restore mitochondrial function and cellular redox balance, food antioxidants also have great potential as natural therapies against COVID-19. However, the numbers of trials are still limited. There must be more tests with the hope that these compounds will mitigate the COVID-19 and similar outbreaks in the future
... Some natural inhibitors can interact with lipid raft components, reducing cholesterol and glycosphingolipids in the cell membrane and thus inhibiting viral endocytosis. 73,76,77 Phytosterols, for example, interact with the components of lipid rafts, thereby reducing cholesterol content in the cell membrane 76,78 Table 3. Flavonoids also play a role in endocytic inhibition as they can fluidize the cell ...
Emergence of SARS-CoV-2 variants warrants sustainable efforts to upgrade both the diagnostic and therapeutic protocols. Understanding the details of cellular and molecular basis of the virus-host cell interaction is essential for developing variant-independent therapeutic options. The internalization of SARS-CoV-2, into lung epithelial cells, is mediated by endocytosis, especially clathrin-mediated endocytosis (CME). Although vaccination is the gold standard strategy against viral infection, selective inhibition of endocytic proteins, complexes, and associated adaptor proteins may present a variant-independent therapeutic strategy. Although clathrin and/or dynamins are the most important proteins involved in CME, other endocytic mechanisms are clathrin and/or dynamin independent and rely on other proteins. Moreover, endocytosis implicates some subcellular structures , like plasma membrane, actin and lysosomes. Also, physiological conditions, such as pH and ion concentrations, represent an additional factor that mediates these events. Accordingly, endocytosis related proteins are potential targets for small molecules that inhibit endocytosis-mediated viral entry. This review summarizes the potential of using small molecules, targeting key proteins, participating in clathrin-dependent and-independent endocytosis, as variant-independent antiviral drugs against SARS-CoV-2 infection. The review takes two approaches. The first outlines the potential role of endocytic inhibitors in preventing endocytosis-mediated viral entry and its mechanism of action, whereas in the second computational analysis was implemented to investigate the selectivity of common inhibitors against endocytic proteins in SARS-CoV-2 endocytosis. The analysis revealed that remdesivir, methyl-β-cyclodextrin, rottlerin, and Bis-T can effectively inhibit clathrin, HMG-CoA reductase, actin, and dynamin I GTPase and are more potent in inhibiting SARS-CoV-2 than chloroquine. CME inhibitors for SARS-CoV-2 infection remain understudied. Abbreviations: ACE2, angiotensin-converting enzyme 2; AP2, adaptor protein complex; ARF1, ADP-ribosylation factor 1; ARP2/3, actin nucleation factor; BAR, bin-amphiphysin-Rvs; CALM, clathrin assembly lymphoid myeloid leukemia; CCP, clathrin-coated pits; CCVs, clathrin-coated vesicles; Cdc42, cell division control protein 42 homolog; CIE, clathrin-independent endocytosis; CLICs, clathrin-independent carriers; CME, clathrin-mediated endocytosis; CvME, caveolae-mediated endocytosis; Drp-1, dynamin-related protein-1; DynII, dynamin II; Eps15, EGF-receptor phosphorylation substrate; ENDOA2, endophilin A2; FCHo2, fer/Cip4 homology domain-only proteins 1/2; FEME, fast endophilin-mediated endocytosis; GEEC CLIC/GEEC, glycophosphatidyl-inositol anchored protein-enriched endosomal compartments; GPCRs, G protein-coupled receptors; GPI-APs, glycosylphosphatidylinositol-anchored proteins; GRAF1, GTPase activating factor; GSK3β, serine/threonine protein kinase; Hsc70, heat shock protein 70; OCRL, oculocerebrorenal lowe syndrome protein; PI3KC2α, phosphatidylinositol 3-kinase C2α; SARS-CoV-2, coronavirus 2; TfR, transferrin receptor; TMPRSS2, transmembrane serine protease 2; N-WASP, wiskott-aldrich syndrome protein. Rev Med Virol. 2022;e2403. wileyonlinelibrary.com/journal/rmv
... In a recent review, it was also revealed that secondary metabolites of olive oil, specifically oleanolic acid and oleuropein, could help combat COVID-19 infection by modifying the structure of SARS-CoV-2-binding proteins, thus hindering the virion's ability to enter the host cell [65]. Furthermore, OEU along with hydroxytyrosol inhibit the fusion of viruses with cell membranes [66]. Since SARS-CoV-2 is an enveloped virus with Spike glycoproteins, OEU may inhibit its endocytosis. ...
Since there is an urgent need for novel treatments to combat the current coronavirus disease 2019 (COVID-19) pandemic, in silico molecular docking studies were implemented as an attempt to explore the ability of selected bioactive constituents of extra virgin olive oil (EVOO) to act as potent SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) antiviral compounds, aiming to explore their ability to interact with SARS-CoV-2 Spike key therapeutic target protein. Our results suggest that EVOO constituents display substantial capacity for binding and interfering with Spike (S) protein, both wild-type and mutant, via the receptor-binding domain (RBD) of Spike, or other binding targets such as angiotensin-converting enzyme 2 (ACE2) or the RBD-ACE2 protein complex, inhibiting the interaction of the virus with host cells. This in silico study provides useful insights for the understanding of the mechanism of action of the studied compounds at a molecular level. From the present study, it could be suggested that the studied active phytochemicals could potentially inhibit the Spike protein, contributing thus to the understanding of the role that they can play in future drug designing and the development of anti-COVID-19 therapeutics.
... Several studies have ascertained that it has many biological activities such as antidiabetic, anticancer, and anti-inflammatory, and exerts neuroprotective effects on Alzheimer's and Parkinson's diseases [7][8][9][10][11]. Furthermore, HT exhibits: antibacterial effects against Salmonella typhi, Haemophilus influenzae, Vibrio parahaemolyticus, and Vibrio cholerae, as reported by Bisignano et al.; antiviral effects against influenza enveloped viruses, as described by Yamada et al. [12,13]. The remarkable antioxidant activity of HT lies in its "catechol" structure, where two hydroxyl groups are in the ortho position ( Figure 1). ...
Hydroxytyrosol (HT) is one of the most powerful natural antioxidants, mainly contained in olive oil and its by-products. Here, a procedure for the preparation of an HT-enriched sample is described. An acidic aqueous extract (pH 1.25) from Olive Oil Dregs (OOD), a by-product from oil mills, was prepared by incubation at 37 °C for 1 h. The total phenolic content and HT amount were 6.24 ± 0.10 mg gallic acid equivalent/g OOD and 532.98 ± 5.78 μg/g OOD, respectively. Amberlite XAD16N and XAD7HP resins were used for the recovery of HT from the raw extract. Several elution conditions were tested with both resins, and elution with 25% ethanol provided the highest HT recovery (92.50% from XAD7HP). Antioxidant activities were assessed in the pool containing the highest quantity of HT. The results were compared with those of the raw extract. Ferric reducing antioxidant power values were comparable (95.71 ± 2.50 and 96.64 ± 13.47 μg ascorbic acid equivalent/mg for HT-enriched pool and raw extract, respectively), while the radical scavenging activity was higher for the pool (92.83% ± 0.44 and 44.12% ± 1.82, respectively). The results reported here demonstrate that HT can be recovered with a high yield from OOD, providing a preparation with high radical scavenging power. In addition, it is proved that this by-product, poorly considered up to now, can be usefully exploited.
... Hydroxytyrosol and oleuropein (a glycosylated seco-iridoid) and can inhibit the fusion of viruses with cell membranes. 315 Docking studies reported that hydroxytyrosol and α-cyclodextrin, present alone or in combination, impact the viral spike glycoprotein and its receptor ACE2, in that they are potential endocytosis inhibitors. Nevertheless, further studies are necessary to confirm the antiviral potential. ...
Viral pathologies encompass activation of pro-oxidative pathways and inflammatory burst. Alleviating overproduction of reactive oxygen species and cytokine storm in COVID-19 is essential to counteract the immunogenic damage in endothelium and alveolar membranes. Antioxidants alleviate oxidative stress, cytokine storm, hyperinflammation, and diminish the risk of organ failure. Direct antiviral roles imply: impact on viral spike protein, interference with the ACE2 receptor, inhibition of dipeptidyl peptidase 4, transmembrane protease serine 2 or furin, and impact on of helicase, papain-like protease, 3-chyomotrypsin like protease, and RNA-dependent RNA polymerase. Prooxidative environment favors conformational changes in the receptor binding domain, promoting the affinity of the spike protein for the host receptor. Viral pathologies imply a vicious cycle, oxidative stress promoting inflammatory responses, and vice versa. The same was noticed with respect to the relationship antioxidant impairment-viral replication. Timing, dosage, pro-oxidative activities, mutual influences, and interference with other antioxidants should be carefully regarded. Deficiency is linked to illness severity.
... 67 Several biological activities have been attributed to olive polyphenols, such as antioxidant, anti-inflammatory, anticancer, antimicrobial, and antiviral effects, mainly against the influenza A virus and human immunodeficiency virus (HIV). [68][69][70] The commercially available product HIDROX ® contains a hydroxytyrosol-rich aqueous olive pulp extract whose biocompatibility has been demonstrated in vitro and in vivo. 71 In addition, it has been shown to confer several beneficial effects, such as anti-inflammatory action in mice 72 and improvement of routine activities in individuals with rheumatoid arthritis. ...
This review presents information from several studies that have demonstrated the antiviral activity of extracts ( Andrographis paniculata, Artemisia annua, Artemisia afra, Cannabis sativa, Curcuma longa, Echinacea purpurea, Olea europaea, Piper nigrum, and Punica granatum) and phytocompounds derived from medicinal plants (artemisinins, glycyrrhizin, and phenolic compounds) against SARS-CoV-2. A brief background of the plant products studied, the methodology used to evaluate the antiviral activity, the main findings from the research, and the possible mechanisms of action are presented. These plant products have been shown to impede the adsorption of SARS-CoV-2 to the host cell, and prevent multiplication of the virus post its entry into the host cell. In addition to antiviral activity, the plant products have also been demonstrated to exert an immunomodulatory effect by controlling the excessive release of cytokines, which is commonly associated with SARS-CoV-2 infections.
... HXT is a phenolic compound found in the leaves and fruits of olive with antioxidant, anti-inflammatory and antimicrobial activities [20,21]. The antiviral activity of olive leaf metabolites against SARS-CoV-2 was reported in several in silico computational studies [43,44]. ...
The SARS-CoV-2 pandemic has caused approximately 6.3 million deaths, mainly due to the acute respiratory distress syndrome or multi-organ failure that characterizes COVID-19 acute disease. Post-acute COVID-19 syndrome, also known as long-COVID, is a condition characterized by a complex of symptoms that affects 10–20% of the individuals who have recovered from the infection. Scientific and clinical evidence demonstrates that long-COVID can develop in both adults and children. It has been hypothesized that multi-organ effects of long-COVID could be associated with the persistence of virus RNA/proteins in host cells, but the real mechanism remains to be elucidated. Therefore, we sought to determine the effects of the exogenous expression of the papain-like protease (PLpro) domain of the non-structural protein (NSP3) of SARS-CoV-2 in polarized human airway (Calu-3), intestinal (Caco-2), and liver (HepG2) epithelial cells, and to evaluate the ability of the natural antioxidant hydroxytyrosol (HXT) in neutralizing these effects. Our results demonstrated that PLpro was able to induce a cascade of inflammatory genes and proteins (mainly associated with the interferon pathway) and increase the apoptotic rate and expression of several oxidative stress markers in all evaluated epithelial cells. Noteably, the treatment with 10 μM HXT reverted PL-pro-dependent effects almost completely. This study provides the first evidence that SARS-CoV-2 PLpro remaining in host cells after viral clearance may contribute to the pathogenetic mechanisms of long-COVID. These effects may be counteracted by natural antioxidants. Further clinical and experimental studies are necessary to confirm this hypothesis.
... A viral envelope is required for the antiviral activity of hydroxytyrosol. Oleuropein and hydroxytyrosol inhibit the fusion of viruses with cell membranes (39). Since SARS-CoV-2 is an enveloped virus with spike glycoproteins, hydroxytyrosol may inhibit its endocytosis. ...
... Several other studies have also shown that oleuropein possesses antiviral properties against respiratory syncytial virus and para-influenza type 3 virus (Ma et al., 2001;Zhao et al. 2009) found that oleuropein isolated from Jasminum officinale L. blocked effectively HBsAg secretion in HepG2 2.2.15 cells in a dose-dependent manner which could present a potential new therapeutic agent for hepatitis B virus infection. Oleuropein and hydroxytyrosol isolated from olive leaf extracts were found to bind to the conserved hydrophobic pocket on the surface of the HIV-gp41 fusion domain exhibiting a dose-dependent inhibition of HIV-1 with EC 50 s of 66-58 nM and no detectable toxicity (Lee-Huang et al., 2007;Yamada et al. 2009) reported that hydroxytyrosol was able to inactivate Newcastle disease virus and influenza A viruses, including H1N1, H3N2, H5N1, and H9N2 subtypes. In vitro and in silico studies revealed that natural polyphenols could have a good impact on the body's immune system against the SARS-CoV-2 virus . ...
The Mediterranean olive oil industries are producing annually a massive quantity of olive mill wastewater (OMWW). Unfortunately, the OMWW is released arbitrarily in the nature without any pretreatment. Thus, it exhibits a high toxicity against the whole natural ecosystem including, microorganisms, plants and animals. In order to eliminate or reduce its pollution, OMWW must be properly treated prior to its release in the nature. In this regard, different treatment methods have been developed by researchers, but some of them were costly and others were inappropriate. Thus, more efforts should be made to save the nature from this pollutant. In the light of that, the current work summaries the state of knowledge regarding the OMWW from a chemical, biological, nutraceutical point of view, and the treatment methods that were used to eliminate its risk of pollution.
... Many previous studies have shown that many of these oils and their components have antibacterial and antiviral properties [6] and [7]. Oregano (Origanumvulgare) and clove (Syzygiumaromaticum) essential oils are very efficient towards many viruses especially enveloped viruses such as; Herpes simplex virus type 1 (HSV-1) and (Newcastle) virus, but on the contrary it is ineffective against non-enveloped viruses such as; poliovirus (type-1) and adenovirus (type-3) [8]. As well as, discovery research for antiviral activity does not parallel to discovery important oil method for an in vitro and in vivo study observing an avian virus that responsible of upper respiratory infections in chickens and other birds exhibited that a exclusive compound revealed virucidal activity and was very strong in controlling virus-linked bronchitis in small chickens [9]. ...
Virus disease is transmitted disease caused by recently discovered a group of viruses infecting respiratory tract, most of the infected people have major clinical signs such as; cough, sneezes, cold, fever and sore throat. The virus can be transmitted among people through the generated droplets when an infected person (coughing and exhales) or physical contact. Natural herbal remedies has been used for a long periods of ancient human history for different purposes. The desirable properties of herbal medicine are low toxicity and natural origin, as well as it is causes few side effects due to the use of additives and preservatives in a very small quantities and this made it a favorite as an alternative treatment. The current study shows the antiviral properties of natural herbal oils such as; Lavender, Peppermint, Cinnamon, Eucalyptus and Thyme oils for the purpose of treating Virus disease.
... HTyr has been reported to have antiatherogenic, cardioprotective [145,146], anticancer [147,148], neuroprotective [149,150], antimicrobial [151,152], anti-inflammatory, and antiplatelet properties [66,153]. It is released by OLE hydrolysis, which also gives rise to OLE aglycone and elenolic acid [154]. ...
The treatment of tissue damage produced by physical, chemical, or mechanical agents involves considerable direct and indirect costs to health care systems. Wound healing involves a series of molecular and cellular events aimed at repairing the defect in tissue integrity. These events can be favored by various natural agents, including the polyphenols in extra virgin olive oil (EVOO). The objective of this study was to review data on the potential effects of different phenolic compounds that can also be found in EVOO on wound healing and closure. Results of in vitro and animal studies demonstrate that polyphenols from different plant species, also present in EVOO, participate in different aspects of wound healing, accelerating this process through their anti-inflammatory, antioxidant, and antimicrobial properties and their stimulation of angiogenic activities required for granulation tissue formation and wound re-epithelialization. These results indicate the potential usefulness of EVOO phenolic compounds for wound treatment, either alone or in combination with other therapies. Human studies are warranted to verify this proposition.
... The therapeutic strategy for was also exhibited by the hesperidin, lepidine E class of polyphenols. Yamada et al. (2009) and Bedoya et al. (2016) have revealed the efficacy of hydroxytyrosol in the treatment of viral disease as influenza. ...
... Acta ScientificHydroxytyrosol (HXT) was known to inhibit influenza-A virussub types H5N1, H1N1, H9N2, and H3N2. Kentaro Yamada., et al.[33] studied the anti-viral effects of HXT using influenza-A virus, Bovine rotavirus (BRV), New Castle Disease Virus (NDV), and fowl adenovirus (FAV). In many studies, HXT was found ineffective against non-enveloped and effective against enveloped viruses. ...
... HT did not show any cytotoxic effect on MDCK cells; it affected H9N2 virus NP protein synthesis and suppressed mRNA synthesis at 24 h.p.i. Electron microscopic analysis detects the structural disruption of the H9N2 virus by HT [113]. ...
Background
Influenza is an acute respiratory tract infection caused by the influenza virus. Vaccination and antiviral drugs are the two methods opted to control the disease. Besides their efficiency, they also cause adverse side effects. Hence, scientists turned their attention to powerful herbal medicines. This review put focus on various proven, scientifically validated anti-influenza compounds produced by the plants suggested for the production of newer drugs for the better treatment of influenza and its related antiviral diseases too.
Main body
In this review, fifty medicinal herb phytochemical constituents and their anti-influenza activities have been documented. Specifically, this review brings out the accurate and substantiates mechanisms of action of these constituents. This study categorizes the phytochemical constituents into primary and secondary metabolites which provide a source for synthesizing and developing new drugs.
Conclusion
This article provides a summary of the actions of the herbal constituents. Since the mechanisms of action of the components are elucidated, the pandemic situation arising due to influenza and similar antiviral diseases can be handled promisingly with greater efficiency. However, clinical trials are in great demand. The formulation of usage may be a single drug compound or multi-herbal combination. These, in turn, open up a new arena for the pharmaceutical industries to develop innovative drugs.
... Hydroxytyrosol interacts with the plasma membrane, localizing itself at the level of the hydrophilic heads. This would confer protection against oxidative stress and modify the chemical-physical properties of the membrane [313]. The mechanism of the antiviral effect of HT suggested that the presence of a viral envelope was necessary. ...
Background:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for the coronavirus disease of 2019 (COVID-19) that emerged in December 2019 in Wuhan, China, and rapidly spread worldwide, with a daily increase in confirmed cases and infection-related deaths. The World Health Organization declared a pandemic on the 11th of March 2020. COVID-19 presents flu-like symptoms that become severe in high-risk medically compromised subjects. The aim of this study was to perform an updated overview of the treatments and adjuvant protocols for COVID-19.
Methods:
A systematic literature search of databases was performed (MEDLINE PubMed, Google Scholar, UpToDate, Embase, and Web of Science) using the keywords: "COVID-19", "2019-nCoV", "coronavirus" and "SARS-CoV-2" (date range: 1 January 2019 to 31st October 2020), focused on clinical features and treatments.
Results:
The main treatments retrieved were antivirals, antimalarials, convalescent plasma, immunomodulators, corticosteroids, anticoagulants, and mesenchymal stem cells. Most of the described treatments may provide benefits to COVID-19 subjects, but no one protocol has definitively proven its efficacy.
Conclusions:
While many efforts are being spent worldwide in research aimed at identifying early diagnostic methods and evidence-based effective treatments, mass vaccination is thought to be the best option against this disease in the near future.
... The combination of vitamin C, curcumin, and glycyrrhizic acid stimulates interferon production and modulates the immune response, counteracting SARS-CoV-2 infections ). Hydroxytyrosol, a phenolic compound present in extra virgin olive oil, shows antioxidant, anti-inflammatory, antiatherogenic and antiviral activities (Clodoveo et al. 2015;Cicero et al. 2018;Lammi et al. 2020), also it is effective in treating some viral diseases such as influenza virus (Yamada et al. 2009). Scientific studies suggest that low carotenoid levels are associated with important conditions of oxidative stress and inflammation (Walston et al. 2006). ...
Viral diseases have always played an important role in public and individual health. Since December 2019, the world is facing a pandemic of SARS-CoV-2, a coronavirus that results in a syndrome known as COVID-19. Several studies were conducted to implement antiviral drug therapy, until the arrival of SARS-CoV-2 vaccines. Numerous scientific investigations have considered some nutraceuticals as an additional treatment of COVID-19 patients to improve their clinical picture. In this review, we would like to emphasize the studies conducted to date about this issue and try to understand whether the use of nutraceuticals as a supplementary therapy to COVID-19 may be a valid and viable avenue. Based on the results obtained so far, quercetin, astaxanthin, luteolin, glycyrrhizin, lactoferrin, hesperidin and curcumin have shown encouraging data suggesting their use to prevent and counteract the symptoms of this pandemic infection.
... HT is considered the most powerful antioxidant after gallic acid. It has been most studied and used in food, cosmetic, and pharmaceutical industries [88] after being demonstrated that HT produces a wide range of biological properties besides antioxidant such as hepatoprotective [89], cytoprotective [90], neuroprotective [91], cardioprotective [92], anti-inflammatory [93], antiviral [94], anticancer [85], and anti-obesity effect [95]. Some studies affirm that the composition of olive leaves extracts rich in several phenols and flavonoids and that it varies with the harvesting season, the leaves maturity, storage conditions, and extraction method [96]. ...
Over the last years, different nanomaterials have been investigated to design highly selective and sensitive sensors, reaching nano/picomolar concentrations of biomolecules, which is crucial for medical sciences and the healthcare industry in order to assess physiological and metabolic parameters. The discovery of graphene (G) has unexpectedly impulsed research on developing cost-effective electrode materials owed to its unique physical and chemical properties, including high specific surface area, elevated carrier mobility, exceptional electrical and thermal conductivity, strong stiffness and strength combined with flexibility and optical transparency. G and its derivatives, including graphene oxide (GO) and reduced graphene oxide (rGO), are becoming an important class of nanomaterials in the area of optical and electrochemical sensors. The presence of oxygenated functional groups makes GO nanosheets amphiphilic, facilitating chemical functionalization. G-based nanomaterials can be easily combined with different types of inorganic nanoparticles, including metals and metal oxides, quantum dots, organic polymers, and biomolecules, to yield a wide range of nanocomposites with enhanced sensitivity for sensor applications. This review provides an overview of recent research on G-based nanocomposites for the detection of bioactive compounds, providing insights on the unique advantages offered by G and its derivatives. Their synthesis process, functionalization routes, and main properties are summarized, and the main challenges are also discussed. The antioxidants selected for this review are melatonin, gallic acid, tannic acid, resveratrol, oleuropein, hydroxytyrosol, tocopherol, ascorbic acid, and curcumin. They were chosen owed to their beneficial properties for human health, including antibiotic, antiviral, cardiovascular protector, anticancer, anti-inflammatory, cytoprotective, neuroprotective, antiageing, antidegenerative, and antiallergic capacity. The sensitivity and selectivity of G-based electrochemical and fluorescent sensors are also examined. Finally, the future outlook for the development of G-based sensors for this type of biocompounds is outlined.
... 23 The higher level of oxidation inhibition was reached using 100 ppm of HT ( Figure 1). Exerting neuroprotective, anti-inflammatory, anticancer, and even antiviral (against several influenza A viruses) 24 activities, hydroxytyrosol, which is abundant in O. europaea, was recently found to be "the most actively investigated natural phenol". 25 The compound has limited antibacterial activity, 26 but its great pharmacological potential is widely recognized. ...
Thanks to the pioneering studies of Østerud and co-workers, it is now increasingly understood that natural polyphenols present in marine oils play an essential role in protecting omega-3 lipids from oxidation and autoxidation, ensuring that no proinflammatory products are formed after intake as often happens with assumption of refined omega-3 concentrates. Strong antioxidants exerting multiple biological functions, olive biophenols are ideally suited to functionalize marine oils, creating a synergy that has the potential to improve public health across the world. This study identifies suitable avenues for advancing the sustainable production of health-beneficial formulations based on newly obtained natural marine oils and olive phenolic extracts. Important educational outcomes conclude the study.
... Polyphenols, in particular, have been found to have a strong antimicrobial and antiviral activity (Chiow et al., 2016;de Oliveira et al., 2015;Jassim and Naji, 2003;Mukhtar et al., 2008;Song et al., 2005;Zhang et al., 2020;Zhong et al., 2012). Oleuropein (Omar, 2010), for example, and its derivatives (tyrosol and hydroxytyrosol) (Yamada et al., 2009) (extracted from olive leaves, Olea europaea) and eugenol (extracted from cloves, Eugenia caryophyllus L.) (Hume, 1986) have a structure similar to the conserved amino acids of the SARS− COV-19 virus S protein involved in receptor interaction (Sivanesam and Andersen, 2019). ...
Clove buds is a spice of relevance in food, traditional medicine, pharmaceutics and cosmetics and, among the spices, they have the highest content of total polyphenols with exceptional antiviral and antimicrobial properties. Various approaches have been reported for the isolation of essential oil from clove buds. Nonetheless, the qualitative and quantitative analysis of hydrosoluble polyphenols and solid residues simultaneously yielded during the extraction process has not been explored yet. This work is focused on the analysis of some variables effect on yield and composition of the clove buds essential oils on a green microwave assisted extraction, and the characterization and quantification of the different compounds obtained from the extraction process. A versatile coaxial dipole antenna, to directly apply the electromagnetic energy inside the extraction medium, was used to thermally activate the hydrodistillation. The composition profiles of clove buds essential oil and hydrosoluble polyphenols obtained during in-situ microwave assisted extraction (IMWAE) were analysed and quantified by head space gas chromatography mass spectrometry (HS-GC-MS) and liquid chromatography with UV/visible diode array/fluorescence detector (HPLC-DAD-FD). The solid residue was characterized by Fourier Transform Infrared (FTIR) spectroscopy and its composition in term of lignin, cellulose and hemicellulose was predicted. The green IMWAE process was compared with the conventional hydrodistillation (CH) in terms of yield and quality of isolated products. Thermogravimetry coupled to FTIR analyses of the evolved gases from the solid residue evidenced that the solid residue obtained from IMWAE of clove buds is richer in cellulose-hemicellulose than the residue obtained from CH. This can be because of microwaves that allow to remove a higher amount of phenolic compounds/lignin oligomers. The enthalpy of combustion values (Δ c H) (kJ/g) of IMWAE and CH residues were determined by calorimetric combustion and were compared with the-Δ c H (kJ/g) values calculated using the hemicellulose, cellulose and lignin compositions predicted by partial least square chemometrics. The Δ c H highlighted the energetic features of solid residues from IMWAE and CH for their potential uses as alternative biomass for fuel production and here firstly reported for this kind of biomass. The extraction approach here presented is environmentally friendly, highly flexible, easily controllable, time saving, and enables to break the scale-up barrier in microwave assisted industrial processes aimed to valorise aromatic herbs and eventually to exploit vegetable wasting materials. This leads to a lowering of production costs and, therefore, of the market price of isolated extracts from aromatic herbs.
... For instance, it is able to reduce HIV replication (6), and fusion in vitro (4,7,8). HT is also able to induce morphological changes that reduce influenza virus infectivity (9). It also enhances anti-inflammatory effects by decreasing the levels of pro-inflammatory cytokines IL-6 and TNF-α, as observed in animal models (10). ...
Background and aim of the work:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current pandemics of coronavirus disease. This virus is able to attack the cells of the airway epithelium by binding to the transmembrane angiotensin I converting enzyme 2 (ACE2). We developed an oral spray that could inhibit the SARS-CoV-2 endocytosis. The spray contains hydroxytyrosol for its anti-viral, anti-inflammatory and anti-oxidant properties, and α-cyclodextrin for its ability to deplete sphingolipids, that form the lipid rafts where ACE2 localizes. The aim of the present pilot multi-centric open non-controlled observational study was to evaluate the safety profile of the "Endovir Stop" spray.
Methods:
An MTT test was performed to evaluate cytotoxicity of the spray in two human cell lines. An oxygen radical absorbance capacity assay was performed to evaluate the antioxidant capacity of the spray. The spray was also tested on 87 healthy subjects on a voluntary basis.
Results:
The MTT test revealed that the spray is not cytotoxic. The ORAC assay showed a good antioxidant capacity for the spray. Endovir Stop tested on healthy volunteers showed the total absence of side effects and drug interactions during the treatment.
Conclusions:
We demonstrated that Endovir Stop spray is safe. The next step would be the administration of the efficacy of the spray by testing it to a wider range of people and see whether there is a reduced infection rate of SARS-CoV-2 in the treated subjects than in the non-treated individuals.
... медицина [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. В табл.2 приведен перечень полифенолов-антиоксидантов, для которых подтверждены их антивирусное действие, их структура и пищевые источники [34][35][36][37][38][39][40][41][42][43][44][45][46][47]. ...
... Hydroxytyrosol (HXT) was known to inhibit influenza-A virus sub types H5N1, H1N1, H9N2 and H3N2. Kentaro Yamada et al. (2009), studied the antiviral effects of HXT using influenza-A virus, New castle Disease Virus (NDV), Bovine rotavirus (BRV) and fowl adenovirus (FAV)[100]. HXT was effective against the enveloped viruses and found ineffective against non-enveloped viruses. ...
can affect replication or protease activity of coronavirus. The clinical testing and regulatory approvals for these drugs will take time. However, currently there is an urgent requirement of treatment strategies which are safe, effective and can be implemented through readily available products in market. Many plant derived products rich in secondary metabolites having potential health benefits and antimicrobial properties. The olive plant leaf extracts and olive oil are rich sources of secondary metabolites such as phenols (oleuropein and hydroxytyrosol) and terpenoids (oleanolic, maslinic and ursolic acid). These compounds have been used as an effective antiviral agents in the past. The phenolics affect the virus attachment and replication. Whereas, the terpenoids mainly affects the membrane fluidity of the virus. In the recent molecular docking studies, it was found that, these compounds effectively bound to Mpro and 3CL pro protease sites of SARS-CoV-2 and were predicted to affect the replication of the SARS-CoV-2. Apart from antiviral properties, these bioactive compounds possess various other pharmacological properties such as anti-inflammatory, anti-modulatory, anti-thrombotic and anti-oxidative. The olive oil is consumed as a source of dietary fat and is the secret behind the good health in Mediterranean people. The consumption of olive oil is safe and is believed to increase the immunity against various infectious microbes. Hence olive products can be explored in management of COVID-19. In this review the various properties of phenolic and terpenoid compounds found in olives were discussed in the context of COVID-19.
The current study explores the transformative journey of Olea europaea L. (Olive) from its traditional role in random traditional medicine to its current positioning in pharmacopeia as a pharmaceutical preparation with defined dosage and indications. The comprehensive examination covers botanical and chemical profiles, traditional uses, pharmacological activities, extraction techniques, quality control, regulatory status, clinical studies, and future directions. Various analytical methods, including spectroscopic and chromatographic approaches, are discussed for quality evaluation and detection of adulteration. Additionally, the regulatory landscape, particularly within the European Union, is outlined, emphasizing the importance of accurate labeling and geographical origin disclosure. The regulatory status of Olea europaea L. varies across regions, ranging from restrictions due to safety concerns to inclusion in pharmacopeias as traditional herbal medicine or pharmaceutical preparations. A pivotal development highlighted is the incorporation of Olive into Egyptian pharmacopeia, signifying a significant shift towards evidence-based therapy and reinforcing its acceptance in mainstream healthcare.
Influenza A virus (IAV) is one of the leading causes of respiratory illness and continues to cause pandemics around the world. Against this backdrop, drug resistance poses a challenge to existing antiviral drugs, and hence, there is an urgent need for developing new antiviral drugs. In this study, we obtained a phenolic compound SG-7, a derivative of natural compound 2-hydroxymethyl-1,4-hydroquinone, which exhibits inhibitory activity toward a panel of influenza viruses and has low cellular toxicity. Mechanistic studies have shown that SG-7 exerts its anti-IAV properties by acting on the virus itself and modulating host signaling pathways. Namely, SG-7 targets the HA2 subunit of hemagglutinin (HA) to block the fusion of viral-cellular membranes and inhibits IAV-induced oxidative stress and overexpression of pro-inflammatory factors by activating the Nrf2/HO-1 pathway and reducing NF-κB activation. In addition, SG-7 can enhance type I IFN antiviral response by inducing Nrf2 expression. Importantly, SG-7 showed the ability to inhibit viral replication in the lungs of IAV-infected mice and reduce their mortality. Therefore, SG-7 may be a promising lead compound for anti-influenza drug development.
Objective: Complementary and alternative medicine (CAM) has an increasing usage in the last decades throughout the world. Herbal medicine, the most preferred CAM, is used in the treatment of various disorders by approximately eighty percent of the world's population. In this study, it was aimed to determine the antiviral activity and wound healing potential of a special herbal oil blend prepared from Olea europaea, Nigella sativa and Rosmarinus officinalis that has been used for centuries in Middle and East Anatolia. Materials and Methods: The nontoxic concentration of herbal blend was determined by MTS assay. This concentration was investigated for its wound healing potential using in vitro scratch assay. A scratch was made on cultured keratinocyte cell layer and the herbal blend was added to medium. Pictures of cells were taken at different time points. The antiviral activity was determined using Adenovirus type 5 and Poliovirus type 1. Virus titer was calculated by Spearman-Karber method. Results: The nontoxic concentration of the blend was found to show statistically higher wound healing rate in compare to control group at the end of 12, 24 and 36 hours. According to antiviral efficacy test, four log of reduction in virus titer was seen, which meant that the mixture was quite effective against the viruses used in the study. Conclusion: The study shows that the special herbal blend speed up wound healing rate and it also has antiviral activity.
The European dependencies for raw materials supply from foreign countries have been unquestionably shown by COVID‐19 outbreak and have become particular evident from the slow response to the need for high quality personal protective equipment (PPEs). Among all medical devices, surgical face masks have earned themselves a primary role for the containment of the epidemic. In this context, our work aims at improving the barrier effect of surgical mask by depositing on their external surface a mixture of bioactive compounds, mainly polyphenols, extracted from agronomical sources. The main objective is the integration of the biorefining of agri‐food solid wastes with the potential virucidal properties of the polyphenolic extracts for the treatment of PPEs.
Coronavirus disease 2019 (COVID-19) is a recently emerged pandemic caused by a novel virus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This disease is communicable and mainly affects the respiratory tract. The outbreak of this disease has greatly influenced human health and economic activities worldwide. The absence of any medication for this infection highlights the urgent need for the development of alternative methods for managing the spread of the disease. Our immune system operates based on a complex array of cells, processes, and chemicals that continuously protect our body from invading pathogens, including viruses, toxins, and bacteria. The present study was conducted to perform a comprehensive review of all dietary treatments for boosting immunity against viral infections. No study was found to explicitly support the use of any healthy foods or supplements to protect against COVID-19. However, this study offers details on well-researched functional foods and supplements that typically improve the immune response, which could be helpful against this newly emerged pandemic.
Coronavirus disease 2019 (COVID-19) is a recently emerged pandemic caused by a novel virus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This disease is communicable and mainly affects the respiratory tract. The outbreak of this disease has greatly influenced human health and economic activities worldwide. The absence of any medication for this infection highlights the urgent need for the development of alternative methods for managing the spread of the disease. Our immune system operates based on a complex array of cells, processes, and chemicals that continuously protect our body from invading pathogens, including viruses, toxins, and bacteria. The present study was conducted to perform a comprehensive review of all dietary treatments for boosting immunity against viral infections. No study was found to explicitly support the use of any healthy foods or supplements to protect against COVID-19. However, this study offers details on well-researched functional foods and supplements that typically improve the immune response, which could be helpful against this newly emerged pandemic.
Altern Ther Health Med. 2020 Dec 29; AT6564. Online ahead of print
Antioxidants have been the subject of intense research interest due to their numerous health benefits. In this work, a series of new conjugates of hydroxytyrosol and coumarin were synthesized and evaluated for their free radical scavenging, toxicity and antioxidant mechanism in vitro. The all target compounds 14a–t exhibited better radical scavenging activity than BHT, hydroxytyrosol, and coumarin in both DPPH radical and ABTS⁺ radical cation scavenging assays. The structure-activity relationships study indicated that the number and position of hydroxyl groups on the coumarin ring were vital to a good antioxidant capacity. Furthermore, the most promising compound 14q showed less toxicity in hemolysis assay and weaker antiproliferative effects than BHT against normal WI-38 and GES cells, and enhanced viability of H2O2-induced HepG2 cells. Additionally, 14q decreased the apoptotic percentage of HepG2 cells, reduced the ROS produce and LDH release, and improved GSH and SOD levels in H2O2-treated HepG2 cells. Lastly, 14q exhibited more stability than hydroxytyrosol in methanol solution. These results revealed that conjugations of hydroxytyrosol and coumarin show better antioxidant capacity, and are the efficacious approach to finding novel potential antioxidant.
Phenolic compounds, primarily derived from the phenylpropanoid pathway and acetate pathway are plant secondary metabolites that constitute one of the most common and widespread groups of substances in plants playing an important role in plant resistance. Polyphenols are chemical compounds, belonging in the class of antioxidants, which have attracted extensive attention as natural bioactive materials. Polyphenols are found in plant tissues as well as hazardeous residues after food factory processing olive mill wastes (OMW) which are characterized as phytotoxic and considered a threat to the environment. Thus, there is currently an increasing interest in using of agricultural wastes like Olive Mill Waste Waters-OMWW containing natural polyphenols as non-hazardous organic phytochemical and plant protective substances and substances such us organic matter, minerals, and nutrients. This review article is focuses on the full utilization of OMWW, which are one of the most polluting food industry wastes, in accordance with the principle zero discharge, strategy and most central waste management option. These substances (mainly from the liquid-phase) result to eco-friendly alternatives of chemical pesticides and other agrochemicals and also contribute to the health protection of the farmers and of the consumers. The recovery of high added-value products from waste plant material such as OMWW is therefore a significant issue in non chemical disease control. Several studies worldwide have investigated and proven their bioactivity potential and their effectiveness against various plant pathogens. The development of sustainable strategies based on the reuse of OMW for plant disease control in view to reduce the use of chemical and synthetic pesticides may have considerable economic benefits.
Thanks to the pioneering studies of Østerud and co-workers it is now increasingly understood that natural polyphenols present in marine oils play an essential role in protecting omega-3 lipids from oxidation and autooxidation ensuring that no proinflammatory products are formed after intake as it often happens with assumption of refined omega-3 concentrates. Strong antioxidants exerting multiple biological functions, olive biophenols are ideally suited to functionalize marine oils creating a synergy which has the potential to foster public health across the world. This study identifies suitable avenues to advance the sustainable production of health-beneficial formulations based on newly obtained natural marine oils and olive phenolic extracts. Important educational outcomes for bioeconomy educators conclude the study.
Phenolic compounds, primarily derived from the phenylpropanoid pathway and acetate pathway are plant secondary metabolites that constitute one of the most common and widespread groups of substances in plants playing an important role in plant resistance. Polyphenols are chemical compounds, belonging in the class of antioxidants, which have attracted extensive attention as natural bioactive materials. Polyphenols are found in plant tissues as well as hazardeous residues after food factory processing olive mill wastes (OMW) wich are characterized as phytotoxic and considered a threat to the environment. Thus, there is currently an increasing interest in using of agricultural wastes like Olive Mill Waste Waters-OMWW containing natural polyphenols as non-hazardous organic phytochemical and plant protective substances and substances susch us organic matter, minerals, and nutrients. This review article is focuses on the full utilization of OMWW, which are one of the most polluting food industry wastes, in accordance with the principle zero discharge, strategy and most central waste management option. These substances (mainly from the liquid-phase) result to eco-friendly alternatives of chemical pesticides and other agrochemicals and also contribute to the health protection of the farmers and of the consumers. The recovery of high added-value products from waste plant material such as OMWW is therefore a significant issue in non chemical disease control. Several studies worldwide have investigated and proven their bioactivity potential and their effectiveness against various plant pathogens. The development of sustainable strategies based on the reuse of OMW for plant disease control in view to reduce the use of chemical and synthetic pesticides may have considerable economic benefits.
Six secoiridoid glucosides, lucidumoside C (1), oleoside dimethylester (2), neonuezhenide (3), oleuropein (4), ligustroside (5) and lucidumoside A (6), isolated from the fruits of Ligustrum lucidum (Oleaceae), were examined in vitro for their activities against four strains of pathogenic viruses, namely herpes simplex type I virus (HSV-1), influenza type A virus (Flu A), respiratory syncytial virus (RSV) and parainfluenza type 3 virus (Para 3). Antiviral activities were evaluated by the cytopathic effect (CPE) inhibitory assay. The purpose was to check if the antioxidative potency of these glucosides correlated with their antiviral potency. Results showed that none of the glucosides had any significant activity against HSV-1 and Flu A. Oleuropein, however, showed significant antiviral activities against RSV and Para 3 with IC50 value of 23.4 and 11.7 microg/ml, respectively. Lucidumoside C, oleoside dimethylester and ligustroside showed potent or moderate antiviral activities against Para 3 with IC50 values of 15.6-20.8 microg/ml. These results also documented that the anti-oxidative potency of these secoiriodoid glucosides was not directly related to their antiviral effects.
Fruit and vegetable simple and polyphenols are potent antioxidants. One of the most effective in terms of free radical scavenging is 3,4-dihydroxyphenyl ethanol or hydroxytyrosol (HT), a simple phenol found predominantly in Olea europea, or the olive plant. HT is most abundant in the aqueous fraction of olive pulp with trace amounts in the olive oil fraction and in the leaves. For these experiments, we evaluated the anti-inflammatory activity of olive vegetation water (OVW), which we showed previously to have potent antioxidant activity. Because some simple phenols and polyphenols with antioxidant activity have shown varying anti-inflammatory activities, we tested OVW and HT for their ability to inhibit the production of tumor necrosis factor-alpha (TNF-alpha), a pivotal cytokine in inflammation. In lipopolysaccharide (LPS)-treated BALB/c mice, a model system of inflammation, OVW at a dose of 125 mg/mouse (500 mg/kg) reduced serum TNF-alpha levels by 95%. In the human monocyte cell line, THP-1, OVW reduced LPS-induced TNF-alpha production by 50% at a concentration of 0.5 g/L (equivalent to approximately 0.03 g/L simple and polyphenols). OVW had no toxic effects in vitro or in vivo. When OVW was combined with glucosamine, a component of proteoglycans and glycoproteins that was shown to decrease inducible nitric oxide synthase production in cultured macrophage cells, the 2 compounds acted synergistically to reduce serum TNF-alpha levels in LPS-treated mice. These findings suggest that a combination of OVW and glucosamine may be an effective therapy for a variety of inflammatory processes, including rheumatoid and osteoarthritis.
Newly pressed extra-virgin olive oil contains oleocanthal--a compound whose pungency induces a strong stinging sensation in the throat, not unlike that caused by solutions of the non-steroidal anti-inflammatory drug ibuprofen. We show here that this similar perception seems to be an indicator of a shared pharmacological activity, with oleocanthal acting as a natural anti-inflammatory compound that has a potency and profile strikingly similar to that of ibuprofen. Although structurally dissimilar, both these molecules inhibit the same cyclooxygenase enzymes in the prostaglandin-biosynthesis pathway.
To prevent the introduction of highly pathogenic avian influenza (HPAI) into Japan, we examined chicken imported from China for viruses. For virus isolation, we used embryonated chicken eggs and a total of 473 samples of frozen meat and bone marrow collected between June 2001 and July 2002. The Newcastle disease virus (NDV) was isolated from 11 (2.3%) specimens and the avian influenza virus (AIV) from 13 (2.7%) specimens. No HPAI virus was included. On the basis of pathogenicity-index tests, all of the NDV isolates were identified as velogenic strains with112RRQKR-F117sequences at the F-protein cleavage site, as is typical of virulent NDV strains. As a result of phylogenetic analysis basedon the F gene, all NDV isolates were classified as belonging to genotype VII, which is prevalent mainly in East Asia and is especially closely related to strains prevalent in China. All AIV isolates were identified as H9N2 subtypes. Intravenous inoculation tests using 3AIV isolates showed no disease symptoms in chicken. Phylogenetic analysis based on the HA gene showed all AIV isolates to belong in the cluster of isolates found mainly in chicken from China.
The Mediterranean diet, rich in fresh fruits and vegetables, has been associated with a lower incidence of cardiovascular disease and cancer, partly because of its high proportion of bioactive compounds such as vitamins, flavonoids and polyphenols. The major lipid component of such diet is the drupe-derived olive oil, that can be distinguished from other seed oils for the peculiar composition of its non-triglyceride fraction. In fact, several minor components, including polyphenols, grant the oil its particular taste and aroma. Oleuropein, the most abundant among these components, has been shown to be a potent antioxidant endowed with antiinflammatory properties. We investigated the effects of oleuropein on NO release in cell culture and its activity toward nitric oxide synthase (iNOS) expression. The results show that oleuropein dose-dependently enhance nitrite production in LPS-challenged mouse macrophages. This effect was blocked by the iNOS inhibitor L-NAME, indicating increased iNOS activity. Also, Western blot analysis of cell homogenates show that oleuropein increases iNOS expression in such cells. Taken together, our data suggest that, during endotoxin challenge, oleuropein potentiates the macrophage-mediated response, resulting in higher NO production, currently believed to be beneficial for cellular and organismal protection.
Plants in the Mediterranean basin, such as vine and olive trees, have developed an array of antioxidant defences to protect themselves from environmental stress. Accordingly, the incidence of coronary heart disease and certain cancers is lower in the Mediterranean area, where olive oil is the dietary fat of choice. As opposed to other vegetable oils, extra virgin olive oil, which is obtained by physical pressure from a whole fruit, is rich in phenolic components that are responsible for the particular stability of the oil. We have investigated the scavenging actions of some olive oil phenolics, namely hydroxytyrosol and oleuropein, with respect to superoxide anion generation, neutrophils respiratory burst, and hypochlorous acid. The low EC50s indicate that both compounds are potent scavengers of superoxide radicals and inhibitors of neutrophils respiratory burst: whenever demonstratedin vivo,these properties may partially explain the observed lower incidence of CHD and cancer associated with the Mediterranean diet.
High postprandial levels of TAG may further induce endothelial dysfunction and inflammation in subjects with high fasting levels of TAG, an effect that seems to be related to oxidative stress. The present study investigated whether minor compounds of olive oil with antioxidant activity decrease postprandial levels of soluble isoforms of intercellular adhesion molecule 1 (sICAM-1) and vascular cell adhesion molecule 1 (sVCAM-1), as surrogate markers of vascular inflammation, after a high-fat meal. A randomized crossover and blind trial on fourteen healthy and fourteen hypertriacylglycerolaemic subjects was performed. The study involved a 1-week adaptation lead-in period on a National Cholesterol Education Program Step I diet supplemented with extra-virgin olive oil (EVOO) containing 1125 mg polyphenols/kg and 350 mg tocopherols/kg, or refined olive oil (ROO) with no polyphenols or tocopherols. After a 12 h fast, the participants ate a high-fat meal enriched in EVOO or ROO (50 g/m2 body surface area), which on average provided 3700 kJ energy with a macronutrient profile of 72% fat, 22% carbohydrate and 6% protein. Blood samples drawn hourly over the following 8 h demonstrated a similar postprandial TAG response for both EVOO and ROO meals. However, in both healthy and hypertriacylglycerolaemic subjects the net incremental area under the curve for sICAM-1 and sVCAM-1 were significantly lower after the EVOO meal. In conclusion,the consumption of EVOO with a high content of minor antioxidant compounds may have postprandial anti-inflammatory protective effects.
Oxidation of low density lipoproteins maybe a factor in the development of atherosclerosis. The Mediterranean diet rich in vegetables, grains, legumes, fruits, and oils, mainly olive oil, has been suggested to reduce the incidence of coronary heart disease, because of its low saturated and high monounsaturated fatty acids content. It is also possible that the natural antioxidants in the oil help to prevent lipid oxidation, e.g. that of low density lipoproteins, thus retarding the formation of atherosclerotic plaques. First-pressed, extra-virgin olive oil contains appreciable amounts of polyphenolic compounds that prevent its autoxidation and are responsible for its high stability. We tested these compounds on low density lipoprotein oxidation and found an inhibitory effect, at low concentrations, on various indexes of lipid oxidation (vitamin E content, formation of thiobarbituric acid-reacting substances, lipid peroxides, levels of polyunsaturated fatty acids, protein modification, conjugated diene formation). Our data suggest that natural antioxidants could play a role in inhibiting the formation of cytotoxic products such as lipid peroxides thus retarding the onset of the atherosclerotic damage.
The antimicrobial potential of eight phenolic compounds isolated from olive cake was tested against the growth of Escherichia coli, Klebsiella pneumoniae, Bacillus cereus, Aspergillus flavus and Aspergillus parasiticus. The phenolic compounds included p-hydroxy benzoic, vanillic, caffeic, protocatechuic, syringic, and p-coumaric acids, oleuropein and quercetin. Caffeic and protocatechuic acids (0.3 mg/ml) inhibited the growth of E. coli and K. pneumoniae. The same compounds apart from syringic acid (0.5 mg/ml) completely inhibited the growth of B. cereus. Oleuropein, and p-hydroxy benzoic, vanillic and p-coumaric acids (0.4 mg/ml) completely inhibited the growth of E. coli, K. pneumoniae and B. cereus. Vanillic and caffeic acids (0.2 mg/ml) completely inhibited the growth and aflatoxin production by both A. flavus and A. parasiticus, whereas the complete inhibition of the moulds was attained with 0.3 mg/ml p-hydroxy benzoic, protocatechuic, syringic, and p-coumaric acids and quercetin.
Secoiridoides (oleuropein and derivatives), one of the major classes of polyphenol contained in olives and olive oil, have recently been shown to inhibit or delay the rate of growth of a range of bacteria and microfungi but there are no data in the literature concerning the possible employment of these secoiridoides as antimicrobial agents against pathogenic bacteria in man.
In this study five ATCC standard bacterial strains (Haemophilus influenzae ATCC 9006, Moraxella catarrhalis ATCC 8176, Salmonella typhi ATCC 6539, Vibrio parahaemolyticus ATCC 17802 and Staphylococcus aureus ATCC 25923) and 44 fresh clinical isolates (Haemophilus influenzae, eight strains, Moraxella catarrhalis, six strains, Salmonella species, 15 strains, Vibrio cholerae, one strain, Vibrio alginolyticus, two strains, Vibrio parahaemolyticus, one strain, Staphylococcus aureus, five penicillin-susceptible strains and six penicillin-resistant strains), causal agents of intestinal or respiratory tract infections in man, were tested for in-vitro susceptibility to two olive (Olea europaea) secoiridoides, oleuropein (the bitter principle of olives) and hydroxytyrosol (derived from oleuropein by enzymatic hydrolysis and responsible for the high stability of olive oil). The minimum inhibitory concentrations (MICs) calculated in our study are evidence of the broad antimicrobial activity of hydroxytyrosol against these bacterial strains (MIC values between 0.24 and 7.85 μg mL−1 for ATCC strains and between 0.97 and 31.25 μg mL−1 for clinically isolated strains). Furthermore oleuropein also inhibited (although to a much lesser extent) the growth of several bacterial strains (MIC values between 62.5 and 500 μg mL−1 for ATCC strains and between 31.25 and 250 μg mL−1 for clinical isolates); oleuropein was ineffective against Haemophilus influenzae and Moraxella catarrhalis.
These data indicate that in addition to the potential employment of its active principles as food additives or in integrated pest-management programs, Olea europaea can be considered a potential source of promising antimicrobial agents for treatment of intestinal or respiratory tract infections in man.
Hydroxytyrosol, a polyphenol with very interesting antioxidant properties, which naturally occurs in virgin olive oil and mainly in olive oil mill waste waters, was synthesized by reducing 3, 4-dihydroxyphenylacetic acid with LiAlH(4) in tetrahydrofuran under refluxing for 2 h. The yield of reaction was 82.8%. The spectroscopic and HPLC data of the synthesized compound proved to coincide fully with those of a pure sample obtained by the chromatographic recovery from olive oil mill waste waters (yield = 91 mg/L). This synthetic method appears to be the most convenient compared with those reported in the literature and is more convenient than the chromatographic recovery. The tri- and diacetyl derivatives of the synthetic compound were also prepared for structure-bioactivity relationship studies. A brief discussion is given on the economical and ecological aspects regarding the production of hydroxytyrosol.
On the basis of the results obtained with pilot studies conducted in vitro on human low density lipoprotein (LDL) and on cell cultures (Caco-2), which had indicated the ability of certain molecules present in olive oil to inhibit prooxidative processes, an in vivo study was made of laboratory rabbits fed special diets. Three different diets were prepared: a standard diet for rabbits (diet A), a standard diet for rabbits modified by the addition of 10% (w/w) extra virgin olive oil (diet B), a modified standard diet for rabbits (diet C) differing from diet B only in the addition of 7 mg kg(-1) of oleuropein. A series of biochemical parameters was therefore identified, both in the rabbit plasma and the related isolated LDL, before and after Cu-induced oxidation. The following, in particular, were selected: (i) biophenols, vitamins E and C, uric acid, and total, free, and ester cholesterol in the plasma; (ii) proteins, triglycerides, phospholipids, and total, free, and ester cholesterol in the native LDL (for the latter, the dimensions were also measured); (iii) lipid hydroperoxides, aldehydes, conjugated dienes, and relative electrophoretic mobility (REM) in the oxidized LDL (ox-LDL). In an attempt to summarize the results obtained, it can be said that this investigation has not only verified the antioxidant efficacy of extra virgin olive oil biophenols and, in particular, of oleuropein, but has also revealed a series of thus far unknown effects of the latter on the plasmatic lipid situation. In fact, the addition of oleuropein in diet C increased the ability of LDL to resist oxidation (less conjugated diene formation) and, at the same time, reduced the plasmatic levels of total, free, and ester cholesterol (-15, -12, and -17%, respectively), giving rise to a redistribution of the lipidic components of LDL (greater phospholipid and cholesterol amounts) with an indirect effect on their dimensions (bigger by about 12%).
(3,4-Dihydroxyphenyl)ethanol, commonly known as hydroxytyrosol (1), is the major phenolic antioxidant compound in olive oil, and it contributes to the beneficial properties of olive oil. Bioavailability and metabolism studies of this compound are extremely limited, in part, related to unavailability of radiolabeled compound. Studies with radiolabeled compounds enable use of sensitive radiometric analytical methods as well as aiding elucidation of metabolic and elimination pathways. In the present study a route for the formation of hydroxytyrosol (1), by reduction of the corresponding acid 2 with tetrabutylammonium boronate, was found. Methods for the incorporation of a tritium label in 1 were investigated and successfully accomplished. Tritiated hydroxytyrosol (1t) was synthesized with a specific activity of 66 Ci/mol. The stability of unlabeled and labeled hydroxytyrosol was also investigated.
Hydroxytyrosol is the most potent phenolic antioxidant of olive oil and olive mill waste water (OMWW) and its biological activities have stimulated research on its potential role in cardiovascular protection. However, evidence of the absorption of OMWW phenolics and on their possible in vivo activity has, until now, never been provided. Three groups male Sprague-Dawley rats were administered 1, 5, or 10 mg/Kg of the OMWW extract, respectively, providing 41.4, 207, and 414 microg/Kg of hydroxytyrosol, respectively. Urine was collected for 24 h and the urinary levels of hydroxytyrosol were quantified by mass spectrometry. Hydroxytyrosol was dose-dependently (R(2) = 0.95) absorbed and excreted in the urines mostly as a glucuronide conjugate. Further, the administration of an hydroxytyrosol-rich OMWW extract (10 mg/kg) to the rats was also associated with an increase of their plasma antioxidant capacity. Future experiments will eventually further clarify its metabolic fate and its in vivo actions.
Hydroxytyrosol (HTyr), a natural ortho-diphenolic antioxidant with health-beneficial properties that mainly occurs in virgin olive oil and olive oil mill waste waters (also known as vegetative waters), has been enzymatically synthesized using mushroom tyrosinase. This o-diphenol (not commercially available) was obtained from its monophenolic precursor tyrosol (commercially available) in the presence of both tyrosinase and ascorbic acid. The reaction synthesis is continuous, easy to perform, and adaptable to a bioreactor for industrial purposes. The HTyr concentration is time-predicted, and the yield of reaction can be 100%. The synthesis method reported here is an alternative approach to obtain this compound in an environmentally friendly way.
Recent in vitro studies have demonstrated antioxidant properties of some virgin olive oil phenolic compounds. One of the prerequisites to extrapolate these data to an in vivo situation is the knowledge of their bioavailability in humans. In the present work we describe an analytical method which enables us to perform hydroxytyrosol and tyrosol quantitative determinations in human urine. This method was successfully used in bioavailability studies of both phenolic compounds after acute olive oil administration. Virgin olive oil was administered to healthy volunteers after a low phenolic diet. The dose administered of both phenolic compounds was estimated in reference to free forms of hydroxytyrosol and tyrosol present in virgin olive oil extracts before and after being submitted to hydrolytic conditions. These conditions mimic those occurring during digestion. Urine samples were collected before and after acute olive oil intake and analyzed by capillary gas chromatography-mass spectrometry. Hydroxytyrosol and tyrosol urinary recovery increased in response to olive oil administration, obtaining maximal values in the first 4 h. Our results further indicate that hydroxytyrosol and tyrosol are mainly excreted in conjugated form, since only 5.9 +/- 1.4% (hydroxytyrosol) and 13.8 +/- 5.4% (tyrosol) of the total amounts excreted in urine were in free form.
We have recently demonstrated, in humans, the bioavailability of hydroxytyrosol (3,4-dihydroxyphenylethanol; HT), one of the major antioxidant components of virgin olive oil. In particular, we reported that this compound is present in lipoproteins involved in atherosclerotic processes and is excreted in the urine mainly as glucuronide-conjugate. The aim of the present study was to elucidate, in humans, the metabolic fate of HT after ingestion of virgin olive oil. After administration of virgin olive oil, 24-hour urine collections of healthy volunteers were prepared for gas chromatography-mass spectrometry analyses in order to identify and quantify HT and its metabolites homovanillic alcohol (HVA1c) and homovanillic acid (HVA). The results indicate that this compound undergoes the action of catechol-O-methyl transferase (COMT), enzymes involved in the catecholamine catabolism, resulting in an enhanced excretion of HVA1c. We also found a significant increase of HVA, indicating an oxidation of the ethanolic residue of HT and/or of HVA1c in humans. The excretion of both metabolites significantly correlated with the dose of administered HT.
The activity of oleuropein, a phenolic glycoside contained in olive oil, was investigated in vitro against Mycoplasma hominis, Mycoplasma fermentans, Mycoplasma pneumoniae and Mycoplasma pirum. Oleuropein inhibited mycoplasmas at concentrations from 20 to 320 mg/l. The MICs of oleuropein to M. pneumoniae, M. pirum, M. hominis and M. fermentans were 160, 320, 20 and 20 mg/l, respectively.
A commercial plant extract derived from olive tree leaf (Olea europaea) (LExt) and its major compound, oleuropein (Ole), inhibited the in vitro infectivity of the viral haemorrhagic septicaemia virus (VHSV), a salmonid rhabdovirus. Incubation of virus with LExt or Ole before infection reduced the viral infectivity to 10 and 30%, respectively. Furthermore, LExt drastically decreased VHSV titers and viral protein accumulation (virucidal effect) in a dose dependent manner when added to cell monolayers 36 h post-infection. On the other hand, both the LExt and Ole were able to inhibit cell-to-cell membrane fusion induced by VHSV in uninfected cells, suggesting interactions with viral envelope. Therefore, we propose that O. europaea could be used as a potential source of promising natural antivirals, which have demonstrated to lack impact on health and environment. In addition, Ole could be used to design other related antiviral agents.
Oleuropein (Chemical Abstracts Service registry number 32619-42-4), a bitter-tasting secoiridoid glucoside commonly found in leaves of the olive tree as well as in olives (Olea europaea L.), was found to be hydrolyzed by the beta-glucosidase (EC 3.2.1.2.1) produced by oleuropeinolytic Lactobacillus plantarum-type strains. Three strains, designated B17, B20, and B21, were isolated from the brine of naturally ripe olives not treated with alkali. These strains were rod-shaped forms, grown at a pH 3.5 limit, and tolerated 1% oleuropein and 8% NaCl in the growth medium. The beta-glucosidase produced hydrolyzed 5-bromo-4-chloro-3-indolyl-beta-d-glucopy-ranoside as well as oleuropein. The presence of 2% glucose in the medium inhibited activity by 40 to 50%, depending on the bacterial strain. Chromatographic analysis of the trimethylsilyl derivatives of the products obtained after 7 days of incubation at 30 degrees C of strain B21 showed all the hydrolysis products of oleuropein, i.e., aglycone, iridoid monoterpen, and 3,4-dihydroxyphenylethanol (hydroxytyrosol). Oleuropein and its aglycone after 21 days of incubation decreased to trace levels with the simultaneous increase in concentration of beta-3,4-dihydroxyphenylethanol.
We report molecular modeling and functional confirmation of Ole and HT binding to HIV-1 integrase. Docking simulations identified two binding regions for Ole within the integrase active site. Region I encompasses the conserved D64-D116-E152 motif, while region II involves the flexible loop region formed by amino acid residues 140-149. HT, on the other hand, binds to region II. Both Ole and HT exhibit favorable interactions with important amino acid residues through strong H-bonding and van der Waals contacts, predicting integrase inhibition. To test and confirm modeling predictions, we examined the effect of Ole and HT on HIV-1 integrase activities including 3'-processing, strand transfer, and disintegration. Ole and HT exhibit dose-dependent inhibition on all three activities, with EC(50)s in the nanomolar range. These studies demonstrate that molecular modeling of target-ligand interaction coupled with structural-activity analysis should facilitate the design and identification of innovative integrase inhibitors and other therapeutics.
We have identified oleuropein (Ole) and hydroxytyrosol (HT) as a unique class of HIV-1 inhibitors from olive leaf extracts effective against viral fusion and integration. We used molecular docking simulation to study the interactions of Ole and HT with viral targets. We find that Ole and HT bind to the conserved hydrophobic pocket on the surface of the HIV-gp41 fusion domain by hydrogen bonds with Q577 and hydrophobic interactions with I573, G572, and L568 on the gp41 N-terminal heptad repeat peptide N36, interfering with formation of the gp41 fusion-active core. To test and confirm modeling predications, we examined the effect of Ole and HT on HIV-1 fusion complex formation using native polyacrylamide gel electrophoresis and circular dichroism spectroscopy. Ole and HT exhibit dose-dependent inhibition on HIV-1 fusion core formation with EC(50)s of 66-58nM, with no detectable toxicity. Our findings on effects of HIV-1 integrase are reported in the subsequent article.
We investigated the antiviral activity of olive leaf extract (OLE) preparations standardized by liquid chromatography-coupled mass spectrometry (LC-MS) against HIV-1 infection and replication. We find that OLE inhibits acute infection and cell-to-cell transmission of HIV-1 as assayed by syncytia formation using uninfected MT2 cells co-cultured with HIV-1-infected H9 T lymphocytes. OLE also inhibits HIV-1 replication as assayed by p24 expression in infected H9 cells. These anti-HIV effects of OLE are dose dependent, with EC(50)s of around 0.2 microg/ml. In the effective dose range, no cytotoxicity on uninfected target cells was detected. The therapeutic index of OLE is above 5000. To identify viral and host targets for OLE, we characterized gene expression profiles associated with HIV-1 infection and OLE treatment using cDNA microarrays. HIV-1 infection modulates the expression patterns of cellular genes involved in apoptosis, stress, cytokine, protein kinase C, and hedgehog signaling. HIV-1 infection up-regulates the expression of the heat-shock proteins hsp27 and hsp90, the DNA damage inducible transcript 1 gadd45, the p53-binding protein mdm2, and the hedgehog signal protein patched 1, while it down-regulates the expression of the anti-apoptotic BCL2-associated X protein Bax. Treatment with OLE reverses many of these HIV-1 infection-associated changes. Treatment of HIV-1-infected cells with OLE also up-regulates the expression of the apoptosis inhibitor proteins IAP1 and 2, as well as the calcium and protein kinase C pathway signaling molecules IL-2, IL-2Ralpha, and ornithine decarboxylase ODC1.
Olive oil is the primary source of fat in the Mediterranean diet which is associated with a low mortality for cardiovascular disease. In spite of this, data concerning olive oil consumption and primary end points for cardiovascular disease are scarce. However, a large body of knowledge exists providing evidence of the benefits of olive oil consumption on secondary end points for cardiovascular disease. The benefits of olive oil consumption are beyond a mere reduction of the low density lipoprotein cholesterol. Here, we review the state of the art concerning the knowledge of the most important biological and clinical effects related to the intake of olive oil rich diets on lipoprotein metabolism, oxidative damage, inflammation, endothelial dysfunction, blood pressure, thrombosis, and carbohydrate metabolism. The extent to which we possess evidence of the health benefits of olive oil minor components is also assessed. The wide range of anti-atherogenic effects associated with olive oil consumption could contribute to explain the low rate of cardiovascular mortality found in Southern European Mediterranean countries, in comparison with other western countries, despite a high prevalence of coronary heart disease risk factors.
Recent experimental study found that OLE (olive leaf extract) has anti-HIV activity by blocking the HIV virus entry to host cells [Lee-Huang, S., Zhang, L., Huang, P.L., Chang, Y. and Huang, P.L. (2003) Anti-HIV activity of olive leaf extract (OLE) and modulation of host cell gene expression by HIV-1 infection and OLE treatment. Biochem. Biophys. Res. Commun. 307, 1029; Lee-Huang, S., Huang, P.L., Zhang, D., Lee, J.W., Bao, J., Sun, Y., Chang, Y.-Tae, Zhang, J.Z.H. and Huang, P.L. (2007) Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol. Biochem. Biophys. Res. Commun. 354, 872-878, 879-884]. As part of a joint experimental and theoretical effort, we report here computational study to help identify and characterize the binding complexes of several main compounds of OLE (olive leaf extract) to HIV-1 envelop protein gp41. A number of possible binding modes are found by docking oleuropein and its metabolites, aglycone, elenolic acid and hydroxytyrosol, onto the hydrophobic pocket on gp41. Detailed OLE-gp41 binding interactions and free energies of binding are obtained through molecular dynamics simulation and MM-PBSA calculation. Specific molecular interactions in our predicted OLE/gp41 complexes are identified and hydroxytyrosol is identified to be the main moiety for binding to gp41. This computational study complements the corresponding experimental investigation and helps establish a good starting point for further refinement of OLE-based gp41 inhibitors.
Infections with influenza A viruses still pose a major threat to humans and several animal species. The occurrence of highly pathogenic avian influenza viruses of the H5N1 subtype capable to infect and kill humans highlights the urgent need for new and efficient countermeasures against this viral disease. Here we demonstrate that a polyphenol rich extract (CYSTUS052) from the Mediterranean plant Cistus incanus exerts a potent anti-influenza virus activity in A549 or MDCK cell cultures infected with prototype avian and human influenza strains of different subtypes. CYSTUS052 treatment resulted in a reduction of progeny virus titers of up to two logs. At the effective dose of 50 microg/ml the extract did not exhibit apparent harming effects on cell viability, metabolism or proliferation, which is consistent with the fact that these plant extracts are already used in traditional medicine in southern Europe for centuries without any reported complications. Viruses did not develop resistance to CYSTUS052 when compared to amantadine that resulted in the generation of resistant variants after only a few passages. On a molecular basis the protective effect of CYSTUS052 appears to be mainly due to binding of the polymeric polyphenol components of the extract to the virus surface, thereby inhibiting binding of the hemagglutinin to cellular receptors. Thus, a local application of CYSTUS052 at the viral entry routes may be a promising approach that may help to protect from influenza virus infections.
Com-putational study of bindings of olive leaf extract (OLE) to HIV-1 fusion protein gp41 Phytochemistry: ibuprofen-like activity in extra-virgin olive oil
- J Bao
- D W Zhang
- J Z Zhang
- P L Huang
- P L Huang
- Lee
- S K Huang
- Yamada
Bao, J., Zhang, D.W., Zhang, J.Z., Huang, P.L., Huang, P.L., Lee-Huang, S., 2007. Com-putational study of bindings of olive leaf extract (OLE) to HIV-1 fusion protein gp41. FEBS Lett. 581, 2737–2742. r44 K. Yamada et al. / Antiviral Research 83 (2009) 35–44 Beauchamp, G.K., Keast, R.S., Morel, D., Lin, J., Pika, J., Han, Q., Lee, C.H., Smith, A.B., Breslin, P.A., 2005. Phytochemistry: ibuprofen-like activity in extra-virgin olive oil. Nature 437, 45–46
- K Yamada
K. Yamada et al. / Antiviral Research 83 (2009) 35–44
- P M Furneri
- A Marino
- A Saija
- N Uccella
- G Bisignano
Furneri, P.M., Marino, A., Saija, A., Uccella, N., Bisignano, G., 2002. In vitro
antimycoplasmal activity of oleuropein. Int. J. Antimicrob. Agents 20,
293–296.
Low density lipoprotein oxidation is inhibited in vitro by olive oil constituents
- Visioli