text:
Frontiers in Plant Science
Plant Metabolism and Chemodiversity
This article is part of the Research Topic
Plant Science's Contribution to Fighting Viral Pandemics: COVID-19 as a Case Study View all 15 Articles
Fernando Ponz
Instituto Nacional de Investigación y Tecnología Agroalimentaria (INIA), Spain
Miguel A. Martín-Acebes
Second Military Medical University, China
Carvacrol as an Immunomodulator Agent
Carvacrol as an Anti-Inflammatory Agent
The Safety Profile of Carvacrol
Pharmacokinetics of Carvacrol
Front. Plant Sci., 16 February 2021 | https://doi.org/10.3389/fpls.2020.601335
Carvacrol, a Plant Metabolite Targeting Viral Protease (Mpro) and ACE2 in Host Cells Can Be a Possible Candidate for COVID-19
Hayate Javed1*, Mohamed Fizur Nagoor Meeran2, Niraj Kumar Jha3 and Shreesh Ojha2*
1Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
2Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
3Department of Biotechnology, School of Engineering and Technology (SET), Sharda University, Knowledge Park III, Greater Noida, India
The recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started in December 2019, resulting in the coronavirus disease-19 (COVID-19) pandemic. Coronaviruses are solely accountable for rising mortality and socioeconomic saddles. Presently, there are few repurposed drugs such as remdesivir or favipiravir approved for the treatment of COVID-19, although vaccines and plasma therapy is also subject to emergency approval. However, some potential natural treatments and cures have also been proposed. Molecules of natural origin showed therapeutic importance such as antiviral, anti-inflammatory, and antioxidant activity, and could be useful drug candidates for treating COVID-19. In recent years, essential oils have shown promising therapeutic effects against many viral diseases. Carvacrol is one of the monoterpene phenol with abundant presence in essential oils of many aromatic plants, including thyme and oregano. It is being used as food flavoring, additive, and preservatives. Carvacrol is also used as a fragrance in cosmetic products. A number of research studies have shown biological actions of carvacrol with its therapeutic potential is of clinical significance. The in vitro and in vivo studies have shown multiple pharmacological properties such as anticancer, anti-fungal, anti-bacterial, anti-oxidant, anti-inflammatory, vasorelaxant, hepatoprotective, and spasmolytic. This review highlights the various biological and pharmacological properties of carvacrol within the scope of COVID-19.
The novel virus strain, SARS-CoV-2 is responsible for the recent outbreak of respiratory infectious disease known as "coronavirus disease 19" (COVID 19) (Boopathi et al., 2020; Hemida and Ba Abduallah, 2020). Globally, the health and healthcare systems are under serious threat due to this major outbreak (Lu et al., 2020; Zhu et al., 2020). The pandemic has affected millions of individuals because of compulsory quarantine and isolation, and also devastated the healthcare facilities. The pandemic have a severe impact on the world economy and will continue to impact if the spread of this novel virus is not stopped or a valuable treatment is not discovered. Coronaviruses are transmitted to humans through respiratory droplets and are single-stranded positive-sense RNA viruses. Patients infected with SARS-CoV-2 display many symptoms including fever, dry cough, diarrhea, loss of smell, and complications mainly beginning with acute respiratory distress following a rapid and robust rise in the levels of proinflammatory cytokines (Das et al., 2020; Jean et al., 2020; Zhang et al., 2020). The morphology of the coronavirus consists of transmembrane spike glycoproteins (S protein), which project outside from the surface of the virus (Tortorici and Veesler, 2019). SARS-CoV and SARS-CoV-2 both display structural morphology in their S proteins and preserved ectodomains. In light of previous studies, the binding inhibition of SARS-CoV to its host cell receptor angiotensin-converting enzyme-2 (ACE2) appears most relevant, as the cellular entry of SARS-CoV-2 also requires ACE2 (Hoffmann et al., 2020; Walls et al., 2020). The epithelial cells of the respiratory tract express ACE2, an exopeptidase, which may provide a potentially viable pharmacological approach to control the cell entry of SARS-CoV-2. Infections with SARS-CoV-2 may affect the gastrointestinal tract, central nervous system, kidney, liver, and heart (Tang et al., 2020). In comparison to SARS-CoV or MERS-CoV, SARS-CoV-2 is highly infectious and communicable (Baez-Santos et al., 2015).
In studies on the replication and infection processes of SARS-CoV-2, numerous mechanisms have been suggested that could be targeted on a pharmacological basis for prevention and treatment. The viral S protein is required by the mast cells of macrophages, pneumocytes, and pulmonary cells in infections. A diverse range of viruses require host cell proteases to activate the S glycoprotein for cellular entry (Bertram et al., 2012; Yamaya et al., 2015; Zhou et al., 2015). The membrane fusion and host cell entry require cleavage and activation of the spike protein (S protein) of SARS-CoV and are mediated by transmembrane protease/serine subfamily member 2 (TMPRSS2), an airway and alveolar cell serine protease (Matsuyama et al., 2010; Glowacka et al., 2011; Shulla et al., 2011). SARS-CoV-2 also involves TMPRSS2 for the priming of spike protein (S) driven cellular entry (Hoffmann et al., 2020).
A clinically established and commercially available, serine protease inhibitor, camostat mesylate, has partially inhibited the infection by HCoV-NL63 and SARS-CoV in HeLa cell lines, which express TMPRSS2 and ACE2 (Kawase et al., 2012). Camostat mesylate has also significantly inhibited the TMPRSS2 in human lung Calu-3 cells and lowered the infection with SARS-CoV-2 (Hoffmann et al., 2020). The viral host cell entry could be blocked by agents that inhibit TMPRSS2. Upon host cell entry, viral RNA (single-stranded) starts the replication process and subsequent translation of polyproteins which are eventually broken into full effecter proteins by the action of viral proteases (Baez-Santos et al., 2015). A viral infection is initiated by the interaction of S protein with ACE2 on the host cell cytoplasmic membrane.
Therapeutic strategies that disrupt the interaction of S protein with ACE2 could be of therapeutic importance. Recently, it was shown that the S protein of SARS-CoV-2 binding affinity to ACE2 is 10-20-times greater in comparison to the S protein of SARS-CoV indicating that the SARS-CoV-2 contagiousness is much higher than SARS-CoV (Tang et al., 2020). Recently, an in vivo study showed that multiple drugs including ritonavir/lopinavir and remdesivir targeted the MERS-CoV (Sheahan et al., 2020), and inhibited the RdRp of Ebola virus as well as the proteases of SARS-CoV-2 in humans. Moreover, these drugs are also recognized as potential drug candidates against SARS-CoV-2. The therapeutic efficacy of these drugs is now under investigation in two international clinical trials (SOLIDARITY Trial and DisCoVeRy Trial).
Numerous efforts are currently ongoing to accelerate the discovery and development of effective preventive and therapeutic candidate drugs against SARS-CoV-2 infections (Altay et al., 2020). In the past few months, since the emergence of COVID-19, several compounds have provided promising alternatives such as chloroquine, hydroxychloroquine, ritonavir, remdesivir, tocilizumab, interferon-β, ivermectin, lopinavir, ribavirin, and azithromycin (Wu et al., 2020). The repurposing of drugs has to date mainly concentrated on the pharmacological properties including antivirals, antibiotics, anti-inflammatory, and immunomodulators (Fan et al., 2020). The use of the above-mentioned drugs in COVID-19 patients is mostly empirical due to its lack of randomized controlled trials to demonstrate the efficacy and safety of these treatments. Taking into account COVID-19 related mortality, effective medications are required to improve the prognosis of patients and to curb the spread of the virus (Fan et al., 2020). Given the pharmacological perspective, all these drugs have the potential to either block the virus from entering host cells or prevent viral replication and/or attenuate the exacerbation of the host's immune response (Fan et al., 2020).
The pathogenesis and complications caused by SARS-CoV-2 are primarily based on an immune-inflammatory cascade. Taking this into account, therapeutic approaches should be focused on this cascade by attenuating inflammation and immune modulation (Allegra et al., 2020; Song et al., 2020). Numerous researches are currently in progress across different institutions around the world to identify novel drug candidates as well as vaccine for COVID-19. Learning from the discovery of Tamiflu®, phytochemicals, and natural products with antiviral, anti-inflammatory, and immunomodulatory properties should be investigated for the prevention and cure of SARS-CoV-2 infections. Among all these therapeutic approaches, natural products, mainly essential oils (EOs) have drawn much interest because of their robust use as anti-inflammatory, immunomodulator, and antioxidant as well as a source of novel antimicrobial, anti-inflammatory, and immunomodulator agents (Allegra et al., 2014; Sadgrove and Jones, 2019). EOs are well recognized for their strong antiviral, anti-inflammatory, and immunomodulatory activities (de Lavor et al., 2018; Asif et al., 2020; Gandhi et al., 2020). EO displays numerous beneficial effects in different diseases and produces systemic effects, consequently, it has been proposed as a possible candidate for evaluation in prevention and treatment of COVID-19 (Agatonovic-Kustrin et al., 2019).
In viral infections, EO may have an important role as therapeutics in ameliorating the redox immune-inflammatory cascade by interfering with the pathways related to inflammatory processes in allergic and infectious airways. EO has shown time-tested safety and efficacy and because of that, it has been used in traditional medicine and food for a long time (Dosoky and Setzer, 2018). EOs are predominantly found in aromatic plants and are a complex mixture of lipophilic as well as volatile terpene compounds. They have been consumed via diets and recognized for potent antioxidant, anti-inflammatory, immunomodulatory, and antimicrobial properties (Aziz et al., 2018). Numerous experimental studies along with some clinical trials showed that EOs could be important therapeutic agents for immune system-related diseases (de Lavor et al., 2018; Gandhi et al., 2020). EOs supplementation along with other compounds are also very well recognized for their activity against bacteria and viruses that lead to respiratory infections. These have reported safe, and synergistic with potent antihistamine, and antioxidant properties (Boskabady et al., 2003; Leigh-de Rapper and van Vuuren, 2020).
Among many active principles of EOs, one of the compounds, carvacrol, received special attention due to recent reports of its specific binding with Mpro, a protease enzyme in the viral genome belonging to non-structural proteins showing a significant effect in the replication and maturation of SARS-CoV-2 (Kumar et al., 2020). In another recent study, carvacrol, a bioactive molecule in the EO of Ammoides verticillata Briq. was reported to inhibit ACE2 activity and suggested that it may block the host cell entry of SARS-CoV-2 (Abdelli et al., 2020). Both these studies demonstrate the potential of carvacrol on virus machinery as well as virus entry and the replication in the host cells. Moreover, Kulkarni et al. (2020) have reported that various monoterpenoid phenols including carvacrol have the potential to inhibit the binding of viral spike (S) glycoprotein to the host cell. Carvacrol has been docked against the S1 receptor binding domain of the spike protein, which is the key target for novel antiviral drugs, to ascertain their inhibitory effects based on their binding affinities.
Carvacrol (C10H14O), a monoterpenoid of the phenolic group [2-methyl-5-(1-methylethyl) phenol], found in an EO of ajwain (Carum copticum (L.) Benth. and Hook. f. ex C.B. Clarke), oregano (Origanum vulgare L.), Shirazi thyme (Zataria multiflora Boiss.), thyme (Thymus vulgaris L.), black cumin (Nigella sativa L.), wild bergamot [Citrus aurantium bigaradia (Loisel.) Brandis], pepperwort (Lepidium flavum Torr.), and other plants (Butt and Sultan, 2010; Tang et al., 2011; Fachini-Queiroz et al., 2012; Boskabady et al., 2014; Khazdair et al., 2018).
The biosynthetic pathway of carvacrol has been elucidated recently. Carvacrol is biosynthesized from isopentenyl diphosphate (IDP) and dimethylallyl diphosphate (DMADP), which are derived from the methylerythritol phosphate (MEP) pathway located in plastids (Rohmer et al., 1993; Dudareva et al., 2005). In the MEP pathway, which is involved in the biosynthesis of carvacrol, 1-deoxy-D-xylulose-5-phosphate (DXP) is irreversibly converted into 2-C-methyl-D-erythritol-4-phosphate (MEP) by a 1-deoxy-D-xylulose-5-phosphate reductoisomerase enzyme (DXR). This step has been described as the first committed step in the MEP pathway (Takahashi et al., 1998). Geranyl diphosphate synthase (GDS) is a key enzyme in this biosynthetic pathway, which catalyzes the head-to-tail condensation of IDP and DMADP to geranyl diphosphate (GDP) as the universal precursor of monoterpenes (Lichtenthaler, 1999). Subsequently, γ-terpinene synthase, which is a member of the monoterpene synthase family produces γ-terpinene through the cyclization of GDP. Furthermore, enzymes such as CYP71D180 and CYP71D181 belonging to the cytochrome P450 (CYP) monooxygenases, are also involved in further modification of γ-terpinene backbone to yield carvacrol (Crocoll et al., 2010).
Carvacrol is used as a microbicidal agent, and fragrance ingredient in cosmetic formulations (Andersen, 2006). Carvacrol is generally considered safe for consumption. It has been approved by the Federal Drug Administration for its use in food and is included by the Council of Europe in the list of chemical flavorings that can be found in alcoholic beverages, baked goods, chewing gum, condiment relish, frozen dairy, gelatin pudding, non-alcoholic beverages, and soft candy (Ultee et al., 2002; De Vincenzi et al., 2004). The structure and various pharmacological properties of carvacrol are represented in Figure 1.
Figure 1. An illustrative flow diagram showing the various pharmacological properties of carvacrol and its chemical structure (center). Adopted and modified from Suntres et al. (2015).
In this article, it has been hypothesized that carvacrol could be a candidate for use as a preventive agent or therapeutic adjuvant in SARS-CoV-2 endowed with potent anti-inflammatory, antiviral, and immunomodulating properties to reduce the harshness and progression of the disease. In the present hypothesis the potential pharmacological and molecular mechanisms targeting oxidative stress, inflammation, immune system, and viremia or infectivity has been presented based on available literature that may provide logical speculation of its use in COVID-19. The proposed possible mechanisms of carvacrol on infection, immunity, and inflammation are presented in Figure 2.
Figure 2. The possible mechanism of carvacrol on infection, immunity and inflammation in context to COVID-19.
The first line of defense is the immune system of the body, which plays an important role in all types of infections including SARS-CoV-2. Immuno-modulation is a process that targets and augments immune response to prevent infections in immuno-deficiencies. In the case of allergies or autoimmune diseases immuno-modulation aims to inhibit the immune system, where the target is to lessen the immune system. At the initial stage of SARS-CoV-2 infection, M1 phenotypic macrophages show up and release ROS, IL-8, IL-6, nitric oxide, MCP-1, IL-1, TNF-α, and CXCL-10, which modulate the host defense against the virus, however, at the same time, it also enhances lung injury. Inflammation is primarily initiated by TNF-α. Moreover, TNF-α is also a key player in cell death mediator, differentiation, and immune modulation. Anti-inflammatory macrophages (M2) are activated once the pathogenic agent is eliminated and eventually control the process of healing and restore the lung tissue. In addition, the innate immune system is significantly controlled by natural killer (NK) cells. At the time of infection, an innate immune response is initiated by eliminating the virally infected cells. Carvacrol administration to lipopolysaccharide (LPS) treated RAW 264.7 macrophages showed significant inhibition of LPS induced release of ROS, TNF-α, IL-1β, and NO. Moreover, carvacrol inhibited the nuclear translocation of the NF-κB (p65) subunit from the cytoplasm (Somensi et al., 2019).
Additionally, the virally infected cells are eliminated by the NK cells. Carvacrol treatment has been shown to attenuate the levels of pro- and anti- inflammatory cytokines in an animal model of experimental autoimmune encephalomyelitis. Carvacrol could be considered as a booster of autoimmunity as it ameliorated the levels of numerous cytokines such as IL-17, IFN-γ, TGF-β, IL-6, IL-10, and IL-4 (Mahmoodi et al., 2019). Carvacrol containing plant Zataria multiflora Boiss. also showed an immunomodulatory effect by augmenting the levels of IFN-γ and FOXP3 as well as IL-4, TGF-β, and IL-17 and could be useful in correcting immune dysregulation (Khazdair et al., 2018). In addition, carvacrol also showed strong anti-inflammatory and antioxidant properties, which could be beneficial in the cure of diseases associated with enhanced oxidative stress along with inflammatory and altered immune status (Khazdair et al., 2018). Adaptive immune responses (Giamarellos-Bourboulis et al., 2020; Kuri-Cervantes et al., 2020; Liao et al., 2020), mainly of T cells (Giamarellos-Bourboulis et al., 2020; Mathew et al., 2020), showed a significant role in the infection of SARS-CoV-2, similar to the infection of respiratory diseases. Carvacrol has been shown to reduce the transcription factors of TH cell-related cytokines in ovalbumin immunized mice, thus suppressing the antigen-specific immune response, this indicates the potential of carvacrol to ameliorate the critical immune responses ascribed to the over activation of T-cells (Gholijani and Amirghofran, 2016).
The inflammatory process is tackled through innate immune response and is consequently responsible for the release of inflammatory mediators (cytokines, ROS etc.) by the various cells of the immune system (neutrophils, macrophages, lymphocytes) that activates the adaptive immunity but enhances inflammation. T helper cells in turn result in the activation of various other types of cells (monocytes, B cells, etc.) by releasing cytokines, such as TNF-α, IL-1β, and IL-2, which institute the inflammatory cascade (Bradley, 2008).
Numerous studies have shown that the anti-inflammatory activity of carvacrol, derivatives of carvacrol, and plants containing a high amount of carvacrol in LPS-induced macrophages or monocytes or eosinophils, inhibit proinflammatory cytokines, inflammatory mediators, iNOS and COX-2, the production of NO and prostaglandin E2, and CD18 frequency on human lymphocytes (Lima Mda et al., 2013; Damasceno et al., 2014; Gholijani and Amirghofran, 2016; Li et al., 2018; Somensi et al., 2019). The hepatoprotective effect of carvacrol was observed in D-galactosamine-induced hepatotoxicity in rats. Carvacrol has been found to reduce CYP2E1 and enhance PPAR-α expression in alleviating liver damage (Aristatile et al., 2014). Carvacrol was also found as a COX-2 suppressor and PPAR-γ activator. Carvacrol has been shown to suppress the LPS induced mRNA and protein expression of COX-2 in human macrophage-like U937 cells, indicating that carvacrol ameliorates the expression of COX-2 via its agonistic effect on PPAR-γ (Hotta et al., 2010).
The role of activating PPAR-α and lipolysis has been shown to reduce the hepatitis C virus genotype-associated lipid metabolic disorder in liver diseases (Patra et al., 2019). PPAR-α activation has also been shown to beneficially influence inflammatory alveolar epithelial cells and suggest the potential usefulness of PPAR-α in acute respiratory distress syndrome (Hecker et al., 2015). Carvacrol a natural dietary molecule has no adverse effects and could be beneficial for synthetic PPAR-α. Carvacrol has been also found to activate PPAR-α and reduce the expression of mRNA and the protein of inflammatory mediator COX-2 induced by LPS (Hotta et al., 2010). Overall, carvacrol's role as a PPAR-α agonist has also shown promising effects in regulating lipid metabolism in addition to its regulatory role on the immune system, cell proliferation, and differentiation, atherosclerosis vascular homeostasis, and inflammation (Lee et al., 2015; Gholijani and Amirghofran, 2016; Li et al., 2018). Moreover, Nigella sativa L., commonly known as black cumin, and its EO component carvacrol have shown strong pharmacological properties against dyslipidemia and respiratory disorders.
Carvacrol may also maintain the immune system balance through its role in immunomodulation (Butt and Sultan, 2010). Hence, carvacrol could be beneficial for limiting the orchestrated immune-inflammatory cascade in COVID-19.
Carvacrol as an Antiviral Agent
EOs and extracts of plant origin have been investigated for various pharmacological activities including anti-viral activities (Oltmans et al., 1986). Carvacrol was one of the compounds of the EOs that has an antiviral effect against herpes simplex virus types 1 (HSV-1). A study conducted by Pilau et al. (2011) on Mentha pulegium L. EOs showed that carvacrol is the main compound and its antiviral effect on humans and animals was investigated. They concluded that these EOs can inhibit different human and animal viruses such as rotavirus, bovine diarrhea virus, and respiratory syncytial virus in vitro (Pilau et al., 2011). The mechanism of action and anti-viral activities of carvacrol derived from oregano oil has been explored against murine norovirus (MNV), a non-enveloped virus. Carvacrol was found to help deactivate MNV, a human NoV surrogate, within 1 h of exposure, directly affecting the viral capsid and thereafter RNA (Gilling et al., 2014). Carvacrol inhibits MNV binding to host cells via hiding the capsid, however, there was no altered structural morphology of the virus reported (Gilling et al., 2014).
Carvacrol is a relatively safe agent of plant origin and classified as generally regarded as safe. Even though several antimicrobial agents are not preferred for safety reasons, in this situation, carvacrol would be a good choice as antimicrobials. For example, the application of antimicrobials on foods or food contact surfaces, or it could be used in place of corrosive compounds on surfaces. Carvacrol, isolated from oregano oil, has shown to possess strong antimicrobial activity against multiple pathogenic bacterial species (Ultee et al., 2002; Knowles et al., 2005; Cox and Markham, 2007; Ravishankar et al., 2009; Garcia-Garcia et al., 2011; Mild et al., 2011) and could be beneficial for possible use as a surface (fomite) sanitizer and natural food to manage norovirus (NoV). The mechanism of action of carvacrol on bacteria is quite different due to the complex components and structure of the bacterial cell wall. Further, there are also reports available that show a direct action of carvacrol on the bacterial membrane and cell wall (Ultee et al., 2002; Cox and Markham, 2007; Garcia-Garcia et al., 2011).
There are numerous beneficial effects of EOs such as antioxidant, antimicrobial, and antimutagenic effects. However, apart from this pharmacological efficacy, EOs may have possible toxicity, for example, genotoxicity/mutagenicity (Llana-Ruiz-Cabello et al., 2015). Carvacrol has been used for a long time in diets as well as for medicinal purposes to support health and well-being. It is one of the vital constituents of numerous herbal formulations. It has been demonstrated that a high concentration of carvacrol (460 μM) may have mutagenicity and genotoxicity effects on the intestinal cell line Caco-2, as it caused DNA damage (Llana-Ruiz-Cabello et al., 2015). However, there were no adverse effects reported in human lymphocytes and hepatocytes as well as the lung fibroblast of Chinese hamsters (LLana-Ruiz-Cabello et al., 2014; Maisanaba et al., 2015).
Carvacrol possesses favorable pharmacokinetic and physicochemical properties to be developed as a drug, based on the popular rules including Lipinski's, Veber's, and Egan's (Egan et al., 2000; Lipinski et al., 2001; Veber et al., 2002) depict drug-like properties. In the intestine, carvacrol is gradually absorbed following oral administration (1.5 g) in rabbits. However, 30% remain in the GI tract and 25% excreted by urine after 22 h (Suntres et al., 2015).
In another study, multiple doses of sesame oil derived carvacrol were administered orally into rabbits (1,500 and 5,000 mg) and rats (500 mg). The results showed its distribution in the intestines, stomach, and urine, with little quantity in the muscle, liver, and lung. The intestinal delivery of carvacrol in animals was significantly enhanced by alginate–whey protein microcapsules with a diameter in the range of 250 and 800 μm, which contain 72 and 76 g/kg of carvacrol, respectively (Wang et al., 2009). Uncapsulated carvacrol has been shown to absorb or metabolize over 95% in duodenum and stomach. Even though microcapsules completely freed the compound in the intestinal tract, a better recovery has been observed in the small intestine than large intestine with larger microcapsules in particular (Wang et al., 2009). It was found that uncapsulated carvacrol greatly absorbed/metabolized in the upper GI tract of pigs upon oral ingestion, while alginate–microcapsules were found to reduce the absorption of carvacrol in the stomach and proximal intestine and enhanced the percentage of carvacrol reached to the distal small intestine (Zhang et al., 2016).
According to Austgulen et al. (1987), the metabolism of carvacrol occurs following two types of pathways. The primary metabolic pathway is the conjugation of the phenolic group with glucuronic acid (C6H10O7) and sulfate (SO42–), when administered at a low dose, the metabolism of carvacrol covers the terminal methyl groups' oxidation to primary alcohols (Austgulen et al., 1987). Carvacrol (1 mmol/kg) administration to albino rats showed its excretion in urine in their original form or the form of glucuronide and sulfate conjugates (Austgulen et al., 1987). Dong et al. (2012) revealed the cytochrome P450 role in carvacrol and its isomer thymol metabolism, in microsomes of the human liver. The isoform, CYP2A6 was observed in a primary drug-metabolizing enzyme and generated metabolites following oxidation of carvacrol (Dong et al., 2012).
Among numerous compounds screened to date using in silico tools, carvacrol appears to target both, the viral protein as well as the viral entry factors in humans. Carvacrol has also been shown to possess favorable physicochemical properties and appears to be a druggable compound. There is a paucity of preclinical data on the potential of carvacrol on infection, inflammation, and immunity in the context of COVID-19. Thus, the therapeutic efficacy of carvacrol must be tested in currently available preclinical animal models for SARS-CoV-2 infection (Cleary et al., 2020; Munoz-Fontela et al., 2020; Yuan et al., 2020), to explore whether the candidate compounds can be used as a preventive agent or therapeutic adjuvant. To conclude the use in COVID-19, it should be investigated and validated in the preclinical models of COVID-19, despite strong evidence for their anti-inflammatory, immunomodulatory, and antiviral properties in other disease models. However, based on the potent immunomodulatory, anti-inflammatory, and antimicrobial properties and additional in silico observations, carvacrol seem to be a suitable candidate for further investigation.
In summary, based on the wide range of experimental studies, carvacrol, and its metabolites appear to exert protective effects against inflammation, immune dysfunction, and infection within the scope of COVID-19. The strong anti-inflammatory properties mediating multiple mechanisms such as the reduction in pro-inflammatory cytokines, chemokines, and adhesion molecules along with inhibition of macrophage infiltration, neutrophil-endothelial cell interaction, provide a plausible reason to inhibit the cytokine storm, a major player of severity, complications, and death in COVID-19.
Carvacrol as a potent antioxidant and immunomodulator may enhance the host cellular immunity against infections. Carvacrol's capability in interfering with ACE2 receptors in the host, along with its antiviral properties due to its interaction with viral protease and antibacterial properties further strengthen the candidature of carvacrol in viremia and secondary infections, which eventually lead to complications and fatal outcomes. This review highlight the pharmacological principles and observations outlined in published studies, which plausibly suggest possible anti-inflammatory, antiviral, and immunomodulatory properties in context to COVID-19.
When taken into account, the numerous properties of carvacrol such as immunomodulatory, anti-inflammatory, and antiviral effects, along with its molecular mechanisms, indicate that it could be an important therapeutic candidate for COVID-19. In addition, the pharmacological actions, negligible toxicity, drug likeliness properties of carvacrol indicate that it could be used as a nutraceutical or pharmacological agent and/or adjuvant against COVID-19. However, the use of carvacrol in COVID-19 remains inconclusive until preclinical and clinical data is available on its efficacy and safety and does not advice the use of carvacrol in any forms for COVID-19.
HJ drafted the manuscript and performed the correction. MFNM drew the scheme, edited the manuscript, and performed the literature survey. NKJ wrote the manuscript, and edited and improved the scheme artwork. SO conceptualized, wrote, and edited the manuscript, and performed the literature survey and ideation of scheme. All authors contributed to the article and approved the submitted version.
We are grateful to the United Arab Emirates University, UAE for providing facilities.
Abdelli, I., Hassani, F., Bekkel Brikci, S., and Ghalem, S. (2020). In silico study the inhibition of angiotensin converting enzyme 2 receptor of COVID-19 by Ammoides verticillata components harvested from Western Algeria. J. Biomol. Struct. Dynam. 2, 1–14. doi: 10.1080/07391102.2020.1763199
Agatonovic-Kustrin, S., Kustrin, E., and Morton, D. W. (2019). Essential oils and functional herbs for healthy aging. Neur. Regen. Res. 14, 441–445. doi: 10.4103/1673-5374.245467
Allegra, A., Di Gioacchino, M., Tonacci, A., Musolino, C., and Gangemi, S. (2014). NF-κβ signaling and chronic inflammatory diseases: exploring the potential of natural products to drive new therapeutic opportunities. Drug Discover. Today 19, 373–378. doi: 10.1016/j.drudis.2013.11.002
Allegra, A., Di Gioacchino, M., Tonacci, A., Musolino, C., and Gangemi, S. (2020). Immunopathology of SARS-CoV-2 infection: immune cells and mediators, prognostic factors, and immune-therapeutic implications. Int. J. Mol. Sci. 21:4782. doi: 10.3390/ijms21134782
Altay, O., Mohammadi, E., Lam, S., Turkez, H., Boren, J., Nielsen, J., et al. (2020). Current status of COVID-19 therapies and drug repositioning applications. iScience 23:101303. doi: 10.1016/j.isci.2020.101303
Andersen, A. (2006). Final report on the safety assessment of sodium p-chloro-m-cresol, p-chloro-m-cresol, chlorothymol, mixed cresols, m-cresol, o-cresol, p-cresol, isopropyl cresols, thymol, o-cymen-5-ol, and carvacrol. Int. J. Toxicol. 25(Suppl. 1), 29–127. doi: 10.1080/10915810600716653
Aristatile, B., Al-Assaf, A. H., and Pugalendi, K. V. (2014). Carvacrol ameliorates the PPAR-A and cytochrome P450 expression on D-galactosamine induced hepatotoxicity rats. Afr. J. Tradit. Complemen. Alternat. Med. 11, 118–123. doi: 10.4314/ajtcam.v11i3.18
Asif, M., Saleem, M., Saadullah, M., Yaseen, H. S., and Al Zarzour, R. (2020). COVID-19 and therapy with essential oils having antiviral, anti-inflammatory, and immunomodulatory properties. Inflammopharmacology 28, 1153–1161. doi: 10.1007/s10787-020-00744-0
Austgulen, L. T., Solheim, E., and Scheline, R. R. (1987). Metabolism in rats of p-cymene derivatives: carvacrol and thymol. Pharmacol. Toxicol. 61, 98–102. doi: 10.1111/j.1600-0773.1987.tb01783.x
Aziz, Z. A. A., Ahmad, A., Setapar, S. H. M., Karakucuk, A., Azim, M. M., and Lokhat, D. (2018). Essential oils: extraction techniques, pharmaceutical and therapeutic potential – a review. Curr. Drug Metab. 19, 1100–1110. doi: 10.2174/1389200219666180723144850
Baez-Santos, Y. M., St John, S. E., and Mesecar, A. D. (2015). The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds. Antiv. Res. 115, 21–38. doi: 10.1016/j.antiviral.2014.12.015
Bertram, S., Heurich, A., Lavender, H., Gierer, S., Danisch, S., Perin, P., et al. (2012). Influenza and SARS-coronavirus activating proteases TMPRSS2 and HAT are expressed at multiple sites in human respiratory and gastrointestinal tracts. PLoS one 7:e35876. doi: 10.1371/journal.pone.0035876
Boopathi, S., Poma, A. B., and Kolandaivel, P. (2020). Novel 2019 coronavirus structure, mechanism of action, antiviral drug promises and rule out against its treatment. J. Biomol. Struct. Dynam. 8, 1–10. doi: 10.1080/07391102.2020.1758788
Boskabady, M. H., Alitaneh, S., and Alavinezhad, A. (2014). Carum copticum L.: a herbal medicine with various pharmacological effects. BioMed Res. Int. 2014:569087. doi: 10.1155/2014/569087
Boskabady, M. H., Ramazani, M., and Tabei, T. (2003). Relaxant effects of different fractions of essential oil from Carum copticum on guinea pig tracheal chains. Phytother. Res. 17, 1145–1149. doi: 10.1002/ptr.1238
Bradley, J. R. (2008). TNF-mediated inflammatory disease. J. Pathol. 214, 149–160. doi: 10.1002/path.2287
Butt, M. S., and Sultan, M. T. (2010). Nigella sativa: reduces the risk of various maladies. Crit. Rev. Food Sci. Nutr. 50, 654–665. doi: 10.1080/10408390902768797
Cleary, S. J., Pitchford, S. C., Amison, R. T., Carrington, R., Robaina Cabrera, C. L., Magnen, M., et al. (2020). Animal models of mechanisms of SARS-CoV-2 infection and COVID-19 pathology. Br. J. Pharmacol. 177, 4851–4865. doi: 10.1111/bph.15143
Cox, S. D., and Markham, J. L. (2007). Susceptibility and intrinsic tolerance of Pseudomonas aeruginosa to selected plant volatile compounds. J. Appl. Microbiol. 103, 930–936. doi: 10.1111/j.1365-2672.2007.03353.x
Crocoll, C., Asbach, J., Novak, J., Gershenzon, J., and Degenhardt, J. (2010). Terpene synthases of oregano (Origanum vulgare L.) and their roles in the pathway and regulation of terpene biosynthesis. Plant Mol. Biol. 73, 587–603. doi: 10.1007/s11103-010-9636-1
Damasceno, S. R., Oliveira, F. R., Carvalho, N. S., Brito, C. F., Silva, I. S., Sousa, F. B., et al. (2014). Carvacryl acetate, a derivative of carvacrol, reduces nociceptive and inflammatory response in mice. Life Sci. 94, 58–66. doi: 10.1016/j.lfs.2013.11.001
Das, S., Sarmah, S., Lyndem, S., and Singha Roy, A. (2020). An investigation into the identification of potential inhibitors of SARS-CoV-2 main protease using molecular docking study. J. Biomol. Struct. Dynam. 2020, 1–11. doi: 10.1080/07391102.2020.1763201
de Lavor, É. M., Fernandes, A. W. C., de Andrade Teles, R. B., Leal, A., de Oliveira Junior, R. G., Gama, E. S. M., et al. (2018). Essential oils and their major compounds in the treatment of chronic inflammation: a review of antioxidant potential in preclinical studies and molecular mechanisms. Oxidat. Med. Cell. Longev. 2018:6468593. doi: 10.1155/2018/6468593
De Vincenzi, M., Stammati, A., De Vincenzi, A., and Silano, M. (2004). Constituents of aromatic plants: carvacrol. Fitoterapia 75, 801–804. doi: 10.1016/j.fitote.2004.05.002
Dong, R. H., Fang, Z. Z., Zhu, L. L., Ge, G. B., Cao, Y. F., Li, X. B., et al. (2012). Identification of CYP isoforms involved in the metabolism of thymol and carvacrol in human liver microsomes (HLMs). Die Pharmazie 67, 1002–1006.
Dosoky, N. S., and Setzer, W. N. (2018). Chemical composition and biological activities of essential oils of curcuma species. Nutrients 10:1196. doi: 10.3390/nu10091196
Dudareva, N., Andersson, S., Orlova, I., Gatto, N., Reichelt, M., Rhodes, D., et al. (2005). The nonmevalonate pathway supports both monoterpene and sesquiterpene formation in snapdragon flowers. Proc. Natl. Acad. Sci. U.S.A. 102, 933–938. doi: 10.1073/pnas.0407360102
Egan, W. J., Merz, K. M. Jr., and Baldwin, J. J. (2000). Prediction of drug absorption using multivariate statistics. J. Med. Chem. 43, 3867–3877. doi: 10.1021/jm000292e
Fachini-Queiroz, F. C., Kummer, R., Estevao-Silva, C. F., Carvalho, M. D., Cunha, J. M., Grespan, R., et al. (2012). Effects of thymol and carvacrol, constituents of thymus vulgaris l. essential oil, on the inflammatory response. Evid. Based Complemen. Alternat. Med. 2012:657026. doi: 10.1155/2012/657026
Fan, S., Xiao, D., Wang, Y., Liu, L., Zhou, X., and Zhong, W. (2020). Research progress on repositioning drugs and specific therapeutic drugs for SARS-CoV-2. Fut. Med. Chem. 12, 1565–1578. doi: 10.4155/fmc-2020-0158
Gandhi, G. R., Vasconcelos, A. B. S., Haran, G. H., Calisto, V., Jothi, G., Quintans, J. S. S., et al. (2020). Essential oils and its bioactive compounds modulating cytokines: a systematic review on anti-asthmatic and immunomodulatory properties. Phytomedicine 73:152854. doi: 10.1016/j.phymed.2019.152854
Garcia-Garcia, R., Lopez-Malo, A., and Palou, E. (2011). Bactericidal action of binary and ternary mixtures of carvacrol, thymol, and eugenol against Listeria innocua. J. Food Sci. 76, M95–M100. doi: 10.1111/j.1750-3841.2010.02005.x
Gholijani, N., and Amirghofran, Z. (2016). Effects of thymol and carvacrol on T-helper cell subset cytokines and their main transcription factors in ovalbumin-immunized mice. J. Immunotoxicol. 13, 729–737. doi: 10.3109/1547691X.2016.1173134
Giamarellos-Bourboulis, E. J., Netea, M. G., Rovina, N., Akinosoglou, K., Antoniadou, A., Antonakos, N., et al. (2020). Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe 27, 992–1000.e3. doi: 10.1016/j.chom.2020.04.009
Gilling, D. H., Kitajima, M., Torrey, J. R., and Bright, K. R. (2014). Antiviral efficacy and mechanisms of action of oregano essential oil and its primary component carvacrol against murine norovirus. J. Appl. Microbiol. 116, 1149–1163. doi: 10.1111/jam.12453
Glowacka, I., Bertram, S., Muller, M. A., Allen, P., Soilleux, E., Pfefferle, S., et al. (2011). Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response. J. Virol. 85, 4122–4134. doi: 10.1128/JVI.02232-10
Hecker, M., Behnk, A., Morty, R. E., Sommer, N., Vadász, I., and Herold, S. (2015). PPAR-α activation reduced LPS-induced inflammation in alveolar epithelial cells. Exp. Lung Res. 41, 393–403. doi: 10.3109/01902148.2015.1046200
Hemida, M. G., and Ba Abduallah, M. M. (2020). The SARS-CoV-2 outbreak from a one health perspective. One Health 2020:100127. doi: 10.1016/j.onehlt.2020.100127
Hoffmann, M., Kleine-Weber, H., Schroeder, S., Kruger, N., Herrler, T., Erichsen, S., et al. (2020). SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181, 271–280.e278. doi: 10.1016/j.cell.2020.02.052
Hotta, M., Nakata, R., Katsukawa, M., Hori, K., Takahashi, S., and Inoue, H. (2010). Carvacrol, a component of thyme oil, activates PPARalpha and gamma and suppresses COX-2 expression. J. Lip. Res. 51, 132–139. doi: 10.1194/jlr.M900255-JLR200
Jean, S. S., Lee, P. I., and Hsueh, P. R. (2020). Treatment options for COVID-19: the reality and challenges. J. Microbiol. Immunol. Infect. Wei Mian Gan Ran Zhi 53, 436–443. doi: 10.1016/j.jmii.2020.03.034
Kawase, M., Shirato, K., van der Hoek, L., Taguchi, F., and Matsuyama, S. (2012). Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry. J. Virol. 86, 6537–6545. doi: 10.1128/JVI.00094-12
Khazdair, M. R., Ghorani, V., Alavinezhad, A., and Boskabady, M. H. (2018). Pharmacological effects of Zataria multiflora Boiss L. and its constituents focus on their anti-inflammatory, antioxidant, and immunomodulatory effects. Fund. Clin. Pharmacol. 32, 26–50. doi: 10.1111/fcp.12331
Knowles, J. R., Roller, S., Murray, D. B., and Naidu, A. S. (2005). Antimicrobial action of carvacrol at different stages of dual-species biofilm development by Staphylococcus aureus and Salmonella enterica serovar Typhimurium. Appl. Environ. Microbiol. 71, 797–803. doi: 10.1128/AEM.71.2.797-803.2005
Kulkarni, S. A., Nagarajan, S. K., Ramesh, V., Palaniyandi, V., Selvam, S. P., and Madhavan, T. (2020). Computational evaluation of major components from plant essential oils as potent inhibitors of SARS-CoV-2 spike protein. J. Mol. Struct. 1221:128823. doi: 10.1016/j.molstruc.2020.128823
Kumar, A., Choudhir, G., Shukla, S. K., Sharma, M., Tyagi, P., Bhushan, A., et al. (2020). Identification of phytochemical inhibitors against main protease of COVID-19 using molecular modeling approaches. J. Biomol. Struct. Dynam. 10, 1–11. doi: 10.1080/07391102.2020.1772112
Kuri-Cervantes, L., Pampena, M. B., Meng, W., Rosenfeld, A. M., Ittner, C. A. G., Weisman, A. R., et al. (2020). Comprehensive mapping of immune perturbations associated with severe COVID-19. Sci. Immunol. 5:eabd7114. doi: 10.1126/sciimmunol.abd7114
Lee, K. P., Sudjarwo, G. W., Jung, S. H., Lee, D., Lee, D. Y., Lee, G. B., et al. (2015). Carvacrol inhibits atherosclerotic neointima formation by downregulating reactive oxygen species production in vascular smooth muscle cells. Atherosclerosis 240, 367–373. doi: 10.1016/j.atherosclerosis.2015.03.038
Leigh-de Rapper, S., and van Vuuren, S. F. (2020). Odoriferous therapy: a review identifying essential oils against pathogens of the respiratory tract. Chem. Biodiver. 17:e2000062. doi: 10.1002/cbdv.202000062
Li, Y., Xu, J. Z., Gu, C. X., Liu, G. L., and Tian, K. (2018). Carvacrol suppresses inflammatory responses in rheumatoid arthritis fibroblast-like synoviocytes. J. Cell. Biochem. 120, 8169–8176. doi: 10.1002/jcb.28098
Liao, M., Liu, Y., Yuan, J., Wen, Y., Xu, G., Zhao, J., et al. (2020). Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19. Nat. Med. 26, 842–844. doi: 10.1038/s41591-020-0901-9
Lichtenthaler, H. K. (1999). The 1-deoxy-D-Xylulose-5-phosphate pathway of isoprenoid biosynthesis in plants. Ann. Rev. Plant Physiol. Mol. Biol. 50, 47–65. doi: 10.1146/annurev.arplant.50.1.47
Lima Mda, S., Quintans-Junior, L. J., de Santana, W. A., Martins Kaneto, C., Pereira Soares, M. B., and Villarreal, C. F. (2013). Anti-inflammatory effects of carvacrol: evidence for a key role of interleukin-10. Eur. J. Pharmacol. 699, 112–117. doi: 10.1016/j.ejphar.2012.11.040
Lipinski, C. A., Lombardo, F., Dominy, B. W., and Feeney, P. J. (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 46, 3–26. doi: 10.1016/s0169-409x(00)00129-0
Llana-Ruiz-Cabello, M., Gutierrez-Praena, D., Puerto, M., Pichardo, S., Jos, A., and Camean, A. M. (2015). In vitro pro-oxidant/antioxidant role of carvacrol, thymol and their mixture in the intestinal Caco-2 cell line. Toxicol. Vitro 29, 647–656. doi: 10.1016/j.tiv.2015.02.006
LLana-Ruiz-Cabello, M., Maisanaba, S., Puerto, M., Prieto, A. I., Pichardo, S., Jos, A., et al. (2014). Evaluation of the mutagenicity and genotoxic potential of carvacrol and thymol using the Ames Salmonella test and alkaline, Endo III- and FPG-modified comet assays with the human cell line Caco-2. Food Chem. Toxicol. 72, 122–128. doi: 10.1016/j.fct.2014.07.013
Lu, R., Zhao, X., Li, J., Niu, P., Yang, B., Wu, H., et al. (2020). Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 395, 565–574. doi: 10.1016/S0140-6736(20)30251-8
Mahmoodi, M., Amiri, H., Ayoobi, F., Rahmani, M., Taghipour, Z., Ghavamabadi, R. T., et al. (2019). Carvacrol ameliorates experimental autoimmune encephalomyelitis through modulating pro- and anti-inflammatory cytokines. Life Sci. 219, 257–263. doi: 10.1016/j.lfs.2018.11.051
Maisanaba, S., Prieto, A. I., Puerto, M., Gutierrez-Praena, D., Demir, E., Marcos, R., et al. (2015). In vitro genotoxicity testing of carvacrol and thymol using the micronucleus and mouse lymphoma assays. Mutat. Res. Genet. Toxicol. Environ. Mutagen. 784–785, 37–44. doi: 10.1016/j.mrgentox.2015.05.005
Mathew, D., Giles, J. R., Baxter, A. E., Oldridge, D. A., Greenplate, A. R., Wu, J. E., et al. (2020). Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications. Science 369:eabc8511. doi: 10.1126/science.abc8511
Matsuyama, S., Nagata, N., Shirato, K., Kawase, M., Takeda, M., and Taguchi, F. (2010). Efficient activation of the severe acute respiratory syndrome coronavirus spike protein by the transmembrane protease TMPRSS2. J. Virol. 84, 12658–12664. doi: 10.1128/JVI.01542-10
Mild, R. M., Joens, L. A., Friedman, M., Olsen, C. W., McHugh, T. H., Law, B., et al. (2011). Antimicrobial edible apple films inactivate antibiotic resistant and susceptible Campylobacter jejuni strains on chicken breast. J. Food Sci. 76, M163–M168. doi: 10.1111/j.1750-3841.2011.02065.x
Munoz-Fontela, C., Dowling, W. E., Funnell, S. G. P., Gsell, P. S., Riveros-Balta, A. X., Albrecht, R. A., et al. (2020). Animal models for COVID-19. Nature 586, 509–515. doi: 10.1038/s41586-020-2787-6
Oltmans, G. A., Beales, M., and Lorden, J. F. (1986). Glutamic acid decarboxylase activity in micropunches of the deep cerebellar nuclei of the genetically dystonic (dt) rat. Brain Res. 385, 148–151. doi: 10.1016/0006-8993(86)91556-8
Patra, T., Sasaki, R., Meyer, K., Ray, R. B., and Ray, R. (2019). Transforming growth factor β acts as a regulatory molecule for lipogenic pathways among Hepatitis C Virus genotype-specific infections. J. Virol. 93:e00811-19. doi: 10.1128/JVI.00811-19
Pilau, M. R., Alves, S. H., Weiblen, R., Arenhart, S., Cueto, A. P., and Lovato, L. T. (2011). Antiviral activity of the Lippia graveolens (Mexican oregano) essential oil and its main compound carvacrol against human and animal viruses. Braz. J. Microbiol. 42, 1616–1624. doi: 10.1590/S1517-838220110004000049
Ravishankar, S., Zhu, L., Olsen, C. W., McHugh, T. H., and Friedman, M. (2009). Edible apple film wraps containing plant antimicrobials inactivate foodborne pathogens on meat and poultry products. J. Food Sci. 74, M440–M445. doi: 10.1111/j.1750-3841.2009.01320.x
Rohmer, M., Knani, M., Simonin, P., Sutter, B., and Sahm, H. (1993). Isoprenoid biosynthesis in bacteria: a novel pathway for the early steps leading to isopentenyl diphosphate. Biochem. J. 295(Pt 2), 517–524. doi: 10.1042/bj2950517
Sadgrove, N. J., and Jones, G. L. (2019). From petri dish to patient: bioavailability estimation and mechanism of action for antimicrobial and immunomodulatory natural products. Front. Microbiol. 10:2470. doi: 10.3389/fmicb.2019.02470
Sheahan, T. P., Sims, A. C., Leist, S. R., Schafer, A., Won, J., Brown, A. J., et al. (2020). Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat. Commun. 11:222. doi: 10.1038/s41467-019-13940-6
Shulla, A., Heald-Sargent, T., Subramanya, G., Zhao, J., Perlman, S., and Gallagher, T. (2011). A transmembrane serine protease is linked to the severe acute respiratory syndrome coronavirus receptor and activates virus entry. J. Virol. 85, 873–882. doi: 10.1128/JVI.02062-10
Somensi, N., Rabelo, T. K., Guimaraes, A. G., Quintans-Junior, L. J., de Souza Araujo, A. A., Moreira, J. C. F., et al. (2019). Carvacrol suppresses LPS-induced pro-inflammatory activation in RAW 264.7 macrophages through ERK1/2 and NF-kB pathway. Int. Immunopharmacol. 75:105743. doi: 10.1016/j.intimp.2019.105743
Song, J. W., Zhang, C., Fan, X., Meng, F. P., Xu, Z., Xia, P., et al. (2020). Immunological and inflammatory profiles in mild and severe cases of COVID-19. Nat. Commun. 11:3410. doi: 10.1038/s41467-020-17240-2
Suntres, Z. E., Coccimiglio, J., and Alipour, M. (2015). The bioactivity and toxicological actions of carvacrol. Crit. Rev. Food Sci. Nutr. 55, 304–318. doi: 10.1080/10408398.2011.653458
Takahashi, S., Kuzuyama, T., Watanabe, H., and Seto, H. (1998). A 1-deoxy-D-xylulose 5-phosphate reductoisomerase catalyzing the formation of 2-C-methyl-D-erythritol 4-phosphate in an alternative nonmevalonate pathway for terpenoid biosynthesis. Proc. Natl. Acad. Sci. U.S.A. 95, 9879–9884. doi: 10.1073/pnas.95.17.9879
Tang, B., Bragazzi, N. L., Li, Q., Tang, S., Xiao, Y., and Wu, J. (2020). An updated estimation of the risk of transmission of the novel coronavirus (2019-nCov). Infect. Dis. Model. 5, 248–255. doi: 10.1016/j.idm.2020.02.001
Tang, X., Chen, S., and Wang, L. (2011). Purification and identification of carvacrol from the root of Stellera chamaejasme and research on its insecticidal activity. Nat. Product Res. 25, 320–325. doi: 10.1080/14786419.2010.532796
Tortorici, M. A., and Veesler, D. (2019). Structural insights into coronavirus entry. Adv. Virus Res. 105, 93–116. doi: 10.1016/bs.aivir.2019.08.002
Ultee, A., Bennik, M. H., and Moezelaar, R. (2002). The phenolic hydroxyl group of carvacrol is essential for action against the food-borne pathogen Bacillus cereus. Appl. Environ. Microbiol. 68, 1561–1568. doi: 10.1128/aem.68.4.1561-1568.2002
Veber, D. F., Johnson, S. R., Cheng, H. Y., Smith, B. R., Ward, K. W., and Kopple, K. D. (2002). Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 45, 2615–2623. doi: 10.1021/jm020017n
Walls, A. C., Park, Y. J., Tortorici, M. A., Wall, A., McGuire, A. T., and Veesler, D. (2020). Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 181, 281–292.e286. doi: 10.1016/j.cell.2020.02.058
Wang, Q., Gong, J., Huang, X., Yu, H., and Xue, F. (2009). In vitro evaluation of the activity of microencapsulated carvacrol against Escherichia coli with K88 pili. J. Appl. Microbiol. 107, 1781–1788. doi: 10.1111/j.1365-2672.2009.04374.x
Wu, R., Wang, L., Kuo, H.-C. D., Shannar, A., Peter, R., Chou, P. J., et al. (2020). An Update on current therapeutic drugs treating COVID-19. Curr. Pharmacol. Rep. 6, 56–70. doi: 10.1007/s40495-020-00216-7
Yamaya, M., Shimotai, Y., Hatachi, Y., Lusamba Kalonji, N., Tando, Y., Kitajima, Y., et al. (2015). The serine protease inhibitor camostat inhibits influenza virus replication and cytokine production in primary cultures of human tracheal epithelial cells. Pulmon. Pharmacol. Therap. 33, 66–74. doi: 10.1016/j.pupt.2015.07.001
Yuan, L., Tang, Q., Cheng, T., and Xia, N. (2020). Animal models for emerging coronavirus: progress and new insights. Emerg. Microb. Infect. 9, 949–961. doi: 10.1080/22221751.2020.1764871
Zhang, H., Penninger, J. M., Li, Y., Zhong, N., and Slutsky, A. S. (2020). Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intens. Care Med. 46, 586–590. doi: 10.1007/s00134-020-05985-9
Zhang, Y., Wang, Q. C., Yu, H., Zhu, J., de Lange, K., Yin, Y., et al. (2016). Evaluation of alginate-whey protein microcapsules for intestinal delivery of lipophilic compounds in pigs. J. Sci. Food Agricult. 96, 2674–2681. doi: 10.1002/jsfa.7385
Zhou, Y., Vedantham, P., Lu, K., Agudelo, J., Carrion, R. Jr., Nunneley, J. W., et al. (2015). Protease inhibitors targeting coronavirus and filovirus entry. Antiv. Res. 116, 76–84. doi: 10.1016/j.antiviral.2015.01.011
Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., et al. (2020). A novel coronavirus from patients with pneumonia in China, 2019. New Engl. J. Med. 382, 727–733. doi: 10.1056/NEJMoa2001017
Keywords: carvacrol, terpenoid, Mpro binding, ACE2 receptor, SARS-CoV-2
Citation: Javed H, Meeran MFN, Jha NK and Ojha S (2021) Carvacrol, a Plant Metabolite Targeting Viral Protease (Mpro) and ACE2 in Host Cells Can Be a Possible Candidate for COVID-19. Front. Plant Sci. 11:601335. doi: 10.3389/fpls.2020.601335
Received: 31 August 2020; Accepted: 18 December 2020;
Published: 16 February 2021.
Fernando Ponz, Instituto Nacional de Investigación y Tecnología Agroalimentaria (INIA), Spain
Lei Zhang, Second Military Medical University, China
Miguel A. Martín-Acebes, Instituto Nacional de Investigación y Tecnología Agroalimentaria (INIA), Spain
Copyright © 2021 Javed, Meeran, Jha and Ojha. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Hayate Javed, h.javed@uaeu.ac.ae; Shreesh Ojha, shreeshojha@uaeu.ac.ae


Miracle Tea is a British independent game studio made up of Tom Andrews, Bradley Smith, Enrico Ercole and Gav Amante. They are based around Ipswich in Suffolk. They aspire to make games that touch players in deeply meaningful ways.
Miracle Tea was founded in 2016 by Tom Andrews and Bradley Smith. After collaborating on freelance projects together, they teamed up to fully develop 'Shape the Mix', a prototype game Tom Andrews had created. Soon after that, they began re-imagining the typical casual game by designing something that had more heartfelt and meaningful qualities. The game later became known as 'Ruya'.
Whilst juggling industry day jobs, they managed to develop Ruya during the nights competing under the Tranzfuser graduate programme. With the help of Enrico Ercole and Gav Amante, the team managed to complete and pitch a prototype that secured them a place to showcase at EGX in Birmingham. It was at that event the team became Tranzfuser finalists. They gained the opportunity to pitch to UK Games Fund. The team ventured up north to Edinburgh with a successful pitch that kick started their games studio.
Ruya was released on November 2nd 2017, it was featured by Apple, picked up a handful of awards and praised in the press.
These days, the team are tinkering away on a new project, taking on client work and slowly building up their business.
We like to respect your time and think of our players as forward thinking intelligent individuals. We try to reflect this in our game designs. Strong ethics in our work approach is important to us. We're a generation of game developers that want to see a change in the industry, so we are trying to lead by example for the generations below us. We embrace our limitations and multi-disciplinary skills as a small team.


text:
György Surányi (* 3. ledna 1954 Budapešť) je maďarský ekonom, ředitel a předseda představenstva maďarského finančního ústavu CIB Bank. V letech 1990–1991 a 1995–2001 byl guvernérem Maďarské národní banky. Na jaře 2009 byl navržen jako vhodný kandidát pro řízení nově vznikající úřednické vlády, z kandidatury však ustoupil, jelikož neměl podporu všech parlamentních stran, kterou požadoval.

Biografie
György Surányi se narodil dne 3. ledna 1954 v Budapešti. V roce 1977 vystudoval na Marx Károly Közgazdaságtudományi Egyetemen (dnes Budapesti Corvinus Egyetem) ekonomii a poté řadu let pracoval v ekonomickém výzkumném ústavu. Od roku 1980 je ženatý s Dr.Judit Marmoly a má sní dvě děti. Dcera Szilvia se narodila v roce 1983 a syn Gábor v roce 1985.

Kariéra
V letech 1990-1991 a 1995-2001 byl guvernérem Maďarské národní banky. V této funkci významně přispěl společně s tehdejším ministrem financí Lajosem Bokrosem ke snížení inflace a obnovení rovnováhy maďarské ekonomiky. Rovněž hrál klíčovou roli při hledání východiska z ekonomické krize v letech 1995 až 1996. V minulosti již mnohokrát kritizoval vládu MSZP za nedostatek přísnosti v ekonomice. V lednu 2002 varoval středoevropské země před zbrklým přijímáním eura krátce po vstupu do EU. V současné době je ředitelem a předsedou představenstva maďarského finančního ústavu CIB Bank.

Možná politická kariéra
Po rezignaci premiéra Ference Gyurcsányho, který odstoupil z důvodu umožnit tak sestavení nové vlády s novým předsedou a pomoci tak k prosazení důležitých reforem a škrtům ve státním rozpočtu, byly jako vhodnými kandidáty na post předsedy vlády navrženi György Surányi, Ferenc Glatz a András Vértes.
Jelikož vládní MSZP vede menšinovou vládu, bude se muset na kandidátovi dohodnout s opozicí, a to zejména s bývalým koaličním partnerem SZDSZ. Předseda SZDSZ Gábor Fodor dne 23. března v rozhlase prohlásil, "že ze tří kandidátů je pro ně přijatelný György Surányi."
Jeho kandidaturu následně dne 25. března SZDSZ podpořil. Obě strany tak drží společně v parlamentu absolutní většinu, proto měl Surányi výraznou šanci stát se příštím maďarským premiérem. Naproti tomu prezident László Sólyom prohlásil, že nejlepší cestou pro recesí postižené Maďarsko by byly předčasné volby. Ty požaduje i předseda nejsilnější opoziční strany Fidesz Viktor Orbán, pro kterého je György Surányi jako premiér rovněž nepřijatelný.
Následně dne 26. března 2009 György Surányi oznámil, že se o post ministerského předsedy ucházet nebude. Jelikož již 24. března uvedl, že se funkce premiéra ujme jen tehdy, když bude mít podporu všech parlamentních stran, a tu nemá. Maďarským premiérem byl nakonec dne 14. dubna 2009 zvolen tehdejší ministr národního rozvoje a hospodářství Gordon Bajnai.

Odkazy

Reference

Související články
 Maďarsko
 Politický systém Maďarska
 Seznam premiérů Maďarska

Externí odkazy
  Virtus.hu - Surányi György: "Nem jött el a világvége"
  Hungarian Spectrum - One possible prime minister: György Surányi

Maďarští politici
Maďarští ekonomové
Narození v roce 1954
Žijící lidé
Muži

redpajama_set_name: RedPajamaWikipedia


text:
Red Sox reacquire Bradley from Brewers for Renfroe in 4-player deal
Michael Bradburn
John Fisher / Getty Images Sport / Getty
The Boston Red Sox have brought outfielder Jackie Bradley Jr. back in a trade that sends outfielder Hunter Renfroe to the Milwaukee Brewers, the teams announced Wednesday.
In addition, the Red Sox will receive infield prospects David Hamilton and Alex Binelas.
OF Hunter Renfroe has been acquired from Boston in exchange for OF Jackie Bradley Jr., INF David Hamilton and INF Alex Binelas. pic.twitter.com/00WdrqYT5S
— Milwaukee Brewers (@Brewers) December 2, 2021
Bradley, 31, spent the first eight years of his career with the Red Sox after they drafted him 40th overall in 2011. Last winter, the former All-Star and Gold Glove winner signed a two-year, $24-million contract to join the Brewers.
However, in his first season with Milwaukee, Bradley struggled to a .163/.236/.261 slash line while also recording six homers and seven steals over 134 games. He's owed $9.5 million in 2022 after he exercised his player option. Bradley's contract also includes a $12-million mutual option for 2023 with an $8-million buyout.
Renfroe, meanwhile, is coming off a strong season in his first year in Boston. The 29-year-old hit .259/.315/.501 with 31 homers and one steal over 144 contests.
Renfroe is projected to earn $7.6 million as he heads into his second year of arbitration eligibility. However, the current collective bargaining agreement is set to expire at 11:59 p.m. ET on Wednesday, and the new rules could impact the structure of arb salaries. The owners have already reportedly voted unanimously in favor of a lockout, which will begin Thursday.
Hamilton ranked No. 16 in the Brewers' system, according to MLB Pipeline. The 24-year-old middle infielder posted a .761 OPS with eight homers and 52 stolen bases across two minor-league levels last year and showed some improvement at the plate during the Arizona Fall League.
Meanwhile, the 21-year-old Binelas sat No. 17 in Milwaukee's system. The corner infielder had a .973 OPS with nine homers and one steal over 36 games between Rookie and Low-A last year.
Ortiz on track for baseball hall election
2022 Baseball HOF: Rolen, Wagner could be big winners next week
Cast your own baseball Hall of Fame ballot 👉
Ex-Red Sox coach says MLB bullied personnel into getting vac...
Triple-A to use robot umpires in 2022
MLB nixes Rays' split-city plan with Montreal
Boras: Signing Correa 'fits all organizations'
Ortiz blasts Red Sox writer who left him off HOF ballot: 'He...
2022 Baseball HOF: Intriguing cases linger at bottom of ball...
Maddux: I almost signed with Yankees in 1992
Baseball HOF preview: Best moments from this year's 'one-and...
Star free agent Correa hires Boras as agent
Former All-Star Francisco Liriano retires
Report: Twins signing Acuna's younger brother
Report: Nationals break bank with $4.9M bonus for Cuban pros...
Report: Yankees land top international prospect Arias for $4...
Which pitchers are poised to be this year's Robbie Ray?

redpajama_set_name: RedPajamaCommonCrawl


You may use the following form to text the link of Balaji Temple to a SMS capable phone.
Balaji Temple is located in Silvassa, DN - 396230. Besides this landmark, there are five more landmarks listed in Silvassa. There's also nine attractions listed in this city in other categories. You will find the exact location of Balaji Temple on the map above.
None of our visitors shared their reviews on Balaji Temple yet. However, we have collected 5 ratings from external sources on this landmark.
Following is a list of other landmarks found within few kilometers of Balaji Temple. You may also view all landmarks in Silvassa, Dadra and Nagar Haveli.


text:
Radio Inmaculada Founders Genry and Leonor Batista and Orlando and Seidy Barrientos (and their children) are pictured with Odalis Susana Gil, center, Inmaculada TV director, at the December celebration of the station's 14th anniversary.
Georgia-based Radio Inmaculada celebrates anniversary
By IMELDA RICHARD, Special to the Bulletin | Published December 26, 2019	| En Español
WINSTON—Back in his native Dominican Republic, Genry Batista never thought he would move to the United States, let alone start a radio station to bring the Gospel message to millions of Spanish-speaking Catholics around the world. During an especially difficult time in his life, Batista felt the call to evangelize over and over again; he just didn't know how to answer this call.
In November 1993, Batista arrived in Newark, New Jersey. He joined a parish, became involved and met his wife, Leonor. Together, with their friends Orlando and Seidy Barrientos, the Batistas started the adventure that is now Radio Inmaculada.
"The sacrament of baptism calls us to bear witness of our faith. There are so many people that have not experienced yet an encounter with Christ. The Second Vatican Council invites us to evangelize others through our lives, through our actions. St. John Paul II invites not to be afraid and share the news of a living Christ with others. These are the reasons behind this initiative that started 14 years ago," Batista said. "Radio Inmaculada is here to serve our church."
Ten years ago, Leonor and Genry Batista and their radio partners moved to Atlanta and relocated the station to Georgia with the blessing of then-Archbishop Wilton D. Gregory. Leonor becomes teary when she remembers the challenges they experienced those first years in Georgia.
"Back in New Jersey we had a successful business that we left behind when we decided to move here. That also meant we had to leave behind our financial security, and to make that decision was very scary," she said. But then my spiritual advisor reminded me that Christ gave his life for me, so my fear of losing all material possessions wasn't really a big deal compared to his sacrifice.
Leonor said that six months after the move to Georgia with their families, they lost everything.
"But every time we were about to give up, God sent one of his angels to help us. He never left us alone," she said. "There were times where we didn't have anything to eat and someone will knock at our door and bring food. And whatever was happening in our personal lives, the radio station kept going on. Radio Inmaculada is a true miracle of God."
Orlando and Seidy Barrientos are the co-founders of Radio Inmaculada.
They worked together with the Batistas in another evangelization project "Jesús Quiere Sanarte" (Jesus wants to heal you).
"Radio Inmaculada is a family. Our children grew up with us working in this project and have fallen in love with it, they identify themselves with it," said Seidy.
As a couple, they produce and present a show on the radio—"Vivir el amor de Dios en familia" (Living the love of God as a family). In this show, they share the challenges faced as a couple with the audience and accompany them in their journey.
"We could have not been able to make this happen without each other. We want people to know God's love and his mercy," said Orlando.
Celebrating an anniversary
Radio Inmaculada celebrated 14 years on the air Dec. 8 with a dinner and concert in Douglasville. That day they officially launched Inmaculada TV, a digital platform that broadcasts Catholic content to Spanish-speaking Catholics around the world. Currently Radio Inmaculada supplies content to more than a dozen Spanish radio stations in Latin America and has 15 digital studios in the United States, Mexico, Venezuela and Ecuador. They have also been accredited by the Vatican to cover all of Pope Francis' trips and other events of interest for the Catholic community.
The mission of Radio Inmaculada and Inmaculada TV is to help members of the Hispanic community keep their faith alive. The team is aware that many Hispanics come to the United States to work and provide for the families left behind in their home countries. It is in this quest that they sometimes have to choose whether to work or to practice their faith. Both the radio and the TV stations transmit daily Mass, the rosary and other Catholic devotions to help the community remain engaged with the church.
Odalis Susana Gil has been part of the Radio Inmaculada family for the past 10 years, first conducting a radio show. She is now the TV station director. Gil lived with her family in Miami and decided to relocate to Atlanta in 2012, after refusing to do so for more than three years. Gil's oldest sib helped her make the decision to move, because he noticed her happiness in working for the radio station.
"My biggest joy is to be able to be there for my brothers and sisters. I am the happiest every time I am able to touch somebody's soul," she said.
Cristobal Muñoz, a parishioner of Good Shepherd Church in Cumming has been listening to Radio Inmaculada for some two years.
"Ever since my wife started volunteering with them. I encourage others to open their hearts and their minds when listening to this station so they can hear God's message" he said.
Radio Inmaculada's signal is available on its website and also through an app on Apple and Android devices. This app has been downloaded more than eight million times already. Inmaculada TV is available for download on all mobile devices and smart televisions, as well as through Roku, Apple TV, Amazon fire and Google Chrome.
Visit Radio Inmaculada online at www.radioinmaculada.net.


DJ'$ provides calendars to its customers to help coordinate sales dates. If you have a calendar and your area is not on it, you should call in two weeks prior to the week you want your delivery.
Set the starting date of your sale.
Set date for collecting order sheets.
Set date for calling in your order.
Order your sales brochures at least two weeks before you begin your sale. You may call DJ'$ at 800-634-5934 to receive your brochures. We always send extras for your convenience. Please let us know when you call if there are any changes to your address.
Let your area know a sale is coming. Most local newspapers, TV and radio stations are more than willing to help advertise for a nonprofit group at no expense to you.
Three words that can make a good sale great. E-mail is today's way to send a message about your sale and to get orders from customers you may not be able to reach in other ways.
Your students will be better received if people are aware beforehand. Be sure to stress that you are selling high quality products and that the money is used for your chapter.
Each member should be given complete instructions on how to use the sales brochure. Everyone should know how to complete the order form, what the correct prices are, when to turn in their order forms, and when to expect delivery.
To turn in your order you may call 800-634-5934 or FAX us at 918-569-4249.
An order form is provided in your packet. We will notify you the week before your delivery to let you know the exact day of delivery.
Always count your product as it comes off the truck.
Be sure to group each product by itself.
Count each item again after your entire order is unloaded.
The sale advisor and truck/delivery driver should count the order together. All discrepancies (shortages, damaged product, etc.) should be noted at this time. At times, our drivers may carry extra product on the truck. If you add to your order, please note it at this time also.
You will receive a copy of your invoice at the time of delivery. Please pay from this copy. If there are any changes to your order, our office will issue an invoice to cover any additions or a credit memo to cover any shortages and a copy will be mailed to you.


text:
Charley Crockett - Welcome to Hard Times
One of our goals at Alvies is to be a cowboy boot company for non-cowboys — to challenge the stereotype that you have to sport a huge belt buckle and a drawl to enjoy wearing boots. So we were selective when considering country music artists for our Waterloo collaboration.
But everyone at Alvies HQ (aka The Boot Cave) agreed that we had to include Charley Crockett's new record. Similar to what we're trying to do with boots, Crockett set out to make an album that would challenge the ideas of what country music is and can be. And did just that. While we think everything he has released since moving to Austin in 2017 has been great, Welcome to Hard Times is possibly his best work yet.
His intent was to make a more eclectic record, like the country albums of the 50s and 60s that paired rhumba beats with honky tonk, blues with cha-cha. The result is something that can't easily be pigeon-holed, but that producer Mark Neill calls "dark gothic country." The sound draws on honky tonk piano, blues and soul blended together with country into something all its own — something that must be heard.
A Side
Welcome to Hard Times
Run Horse Run
Tennessee Special
Fool Somebody Else
Lilly My Dear
Wreck Me
B Side
Heads You Win
Rainin' in My Heart
Paint it Blue
Blackjack County Chain
The Man That Time Forgot
The Poplar Tree
Together We Rock
Waterloo Records is an Austin institution. The musical wizards there have been slanging albums and advice since 1982. So when we wanted to highlight some of the music that makes us tap our booted and flip-flopped toes, we of course asked them to help. All the albums highlighted here are curated and sold by Waterloo through the Alvies store.


Know Maplewood Class of 1967 graduates that are NOT on this List? Help us Update the 1967 Class List by adding missing names.
More 1967 alumni from Maplewood HS have posted profiles on Classmates.com®. Click here to register for free at Classmates.com® and view other 1967 alumni.
The students that went to school at the West Hill high school called Maplewood High School and graduated in '67 are on this page. Register to add your name to the class of 1967 graduates list.
You can also find out what other graduates are doing now, share memories with other alumn, upload pictures from Maplewood and find other alumni.


Your daughter has the ability to achieve more than she thinks.
Your son deserves the chance to reach his full potential.
Almost all teachers will agree that the most fulfilling aspect of our profession is when a pupil breaks through a learning barrier, instilling confidence in themselves to tackle all kinds of new challenges.
Every child has the potential to experience a breakthrough like this on a daily basis but, even in classes of a relatively small size, the opportunities are greatly diminished. Primary school teachers must spread their attention across a wide range of personalities, behaviours and learning needs. No matter the skills and strategies employed by the teacher, every single minute someone's potential is not being tapped into.
From a teacher's perspective this is also frustrating because we lose countless chances to experience the most fulfilling aspect of our job.
This is why I established Catapult Tuition. One-to-one tuition works. There are no distractions. An individual's strengths and struggles are analysed. The tutor's language is tailored to meet the needs of one specific and unique child. We will not allow time pressures or curricular demands to force us to move on too soon - we only progress to the next step when the knowledge, skills and understanding are confidently cemented into place.
Furthermore, tuition works because the parent and tutor establish a routine of regular feedback that far exceeds what is possible at a primary school.


text:
King's College Latvia
British School of Latvia
BSO Inspection
Our Campus Extension
Academic Principles
The British System
The British Way
Academic Results & University Destinations
Beyond the curriculum
Information Fees
Age and Course Guidelines
King's Alumni
Fostering Development
Our main goal is to foster student development so that each individual reaches his or her full potential in every aspect of school life. The academic rigour of the classroom, adapted to suit the age and maturity of pupils, is complemented by a wide range of enhancement activities within and beyond the school, and standards of teaching and learning are regularly monitored throughout the school.
Our teaching and learning strategies are reviewed regularly.
Teaching staff access training materials from accepted best practice in other parts of the world. Informative marking of work and our monitoring system ensure that pupils achievements are carefully noted and additional support or extension work is given where necessary. Reports to parents and regular teacher-parent consultation meetings add a further dimension to the high quality monitoring of each individual pupil's progress.
Academic success is underpinned by positive relationships with staff and other pupils.
We stress and encourage positive relationships at all levels of the school. Our pastoral care arrangements and the Personal, Social and Health and Religious Education programme encourage pupils to discuss a wide range of issues, appropriate to their age, and to develop an understanding of current events and issues.
By challenging pupils to strive for excellence we achieve exceptional examination results.
Similar challenges are given in extra-curricular activities, for example the International Award (Duke of Edinburgh Award), sport, music and drama. Many of our pupils participate enthusiastically in these activities. Modern technology is harnessed to add further challenges to academic classroom work.
One of our key objectives is to develop inquiring minds in our pupils, leading to an independent approach to learning with a wide range of research skills.
The broad curriculum of the Primary years gradually becomes more focused as pupils move through the Secondary years towards final examinations in their chosen subjects. The result of this is an excellent foundation for Higher Education in the world's best universities.
King's Group
King's Training Spain
King's Training Panama
King's College International
Nexalia Services
© Copyright King's College Latvia SIA (2019) Member of COBIS and AoBSO King's College The British School of Latvia undergoes regular external inspections as a British School Overseas and is accredited by the UK Government and Department for Education (DfE). DfE Registration Number: 000/6154
We will call you back in the near future!	 Call me!


Technical support is available by contacting Mikotech Systems by phone (during our regular business hours), email or fax. Technical support is provided free for one (1) year.
Keep in mind that these are partial lists and are subject to change without notice. All support will be based on the judgment and sole discretion of Mikotech Systems and its employees.
Know basic system information: Accupoint version, Windows version, which computer is the server, the path for your Accupoint data and central locations, etc.
If you are receiving error messages from the Accupoint product, please have the EXACT error message available.
Shipping and handling, labour, installation, and customization charges are not refundable.


How do I change it so that it will only say how many times the program has ran once I typed another key then y.
There are ? odd values in the sequence.
There are ? even values in the sequence.
Would you like to run this program again?
Thanks for using the super sequence analyzer!
This progam has ran 1 times.
This progam has ran 2 times.
cout << "Programmer Name: Peter Langlands\n"
<< "CS 150 Spring 2011 Lab CRN:\n"
Move the output outside the loop.
I moved howManyoutside of the loop but then when I ran my program it gave me a 1 as a result every time. How do I fix this?
put count in main and everytime you call the function add 1 then have that number passed to howMany(int a) (howMany should take an int) like howMany(count).
I said put the output outside the loop. howMany() does more than just output.
no it, still gave me the result of 1 run every time.
So maybe you need to bring the variable count outside of howMany() so the rest of the program can see it. Since it's local to the function alone, it doesn't exist.
And I beg to differ. It does not give you 1 every time. The program doesn't even compile.
How to write this program in C++ or Java (Fibonacci)?


An essential oil is a concentrated, hydrophobic liquid containing volatile aroma compounds from plants. Essential oils are also known as volatile or ethereal oils, or simply as the "oil of" the plant from which they were extracted, such as oil of clove. An oil is "essential" in the sense that it carries a distinctive scent, or essence, of the plant. Essential oils do not as a group need to have any specific chemical properties in common, beyond conveying characteristic fragrances. They are not to be confused with essential fatty acids.
Essential oils are generally extracted by distillation. Other processes include expression, or solvent extraction. They are used in perfumes, cosmetics and bath products, for flavoring food and drink, and for scenting incense and household cleaning products.
Various essential oils have been used medicinally at different periods in history. Medical application proposed by those who sell medicinal oils range from skin treatments to remedies for cancer, and are often based on historical use of these oils for these purposes. Such claims are now subject to regulation in most countries, and have grown more vague to stay within these regulations.


On 19 April 2011, IAEA Director General Yukiya Amano began his two-day visit to Ukraine, where he addressed the Kiev Summit for Safe and Innovative Use of Nuclear Energy providing an update on the situation following the accident at the Fukushima Daiichi nuclear power plant in Japan.
He noted that since the 11 March nuclear accident, the IAEA had sent radiation monitoring teams, experts on food safety and the marine environment, as well as specialists in Boiling Water Reactors to Japan. The Agency was providing regular technical briefings to Member States and the media on the situation.
The Director General also briefed participants on an IAEA Ministerial Conference on Nuclear Safety which will be held in Vienna from 20 to 24 June. The Conference is likely to make a preliminary assessment of the Fukushima Daiichi accident, to review nuclear safety generally and to examine the international emergency response system. The Director General stressed that the IAEA will play a central role in these deliberations, as well as in future efforts to further strengthen nuclear safety.
During his initial day in Kiev, the Director General also met the French Prime Minister Francois Fillon.
On Wednesday, 20 April, the Director General will visit the Chernobyl Exclusion Zone and will then return to Kiev to meet the Ukrainian President Viktor Yanukovych and UN Secretary General Ban Ki-moon. The Director General will then join Ukrainian President, the UN Secretary General, the Secretary General of the Council of Europe, Thorbjørn Jagland, and the President of the Europe Commission, José Barroso, at an international scientific conference that focuses on the Chernobyl nuclear accident.


text:
February 20, 2023 by 0 Comments
Manchester United face a massive Premier League clash with Arsenal on Sunday amid a gruelling run of key games.
The Red Devils eased past Burnley in their first game back from the World Cup break with a 2-0 Carabao Cup victory at Old Trafford — a positive result and performance as Erik ten Hag looks to build momentum for the coming months.
Important cup wins over Charlton Athletic and Everton followed as part of a nine-game winning run in all competitions that included a 2-1 comeback victory over Manchester City. That sequence was ended when Crystal Palace held them to a 1-1 draw on January 18.
United winger Jadon Sancho was absent for all of those matches. The winger has completed 90 minutes in the Premier League just once since the start of October and has not been in the United matchday squad since the 1-1 draw with Chelsea on October 22.
He has been working individually to regain sharpness since the start of the World Cup and rejoined United team training this week, just days before the Arsenal game.
MORE: Watch every Premier League match live with fuboTV in Canada
Will Jadon Sancho play against Arsenal?
United manager Erik ten Hag was asked about Sancho's possible return following the draw with Palace at Selhurst Park.
When quizzed on whether Sancho could be in the matchday squad for the game at the Emirates Stadium, Ten Hag replied: "I can't answer that question.
"He's making the next step. Yesterday [Tuesday], for the first time, he was in team training. Team training is the final training before a game, so we will extend that in the coming days, [the] coming week, and then go step by step."
It seems most likely that Sancho's comeback will be in the Carabao Cup first leg against Nottingham Forest or the FA Cup fourth-round match at home to Reading, both of which are next week.
What's happening with Jadon Sancho?
Sancho has not been in the squad for United's past 12 games in all competitions and has only completed 90 minutes once since mid-September.
After being overlooked for England's World Cup squad, the 22-year-old began training with coaches recommended by United manager Ten Hag in a bid to improve his match sharpness, both physically and mentally. There is not yet any certainty over when he will be back in the first team, although he is back in first-team training in Manchester.
Sancho's struggles are notable given the fanfare that greeted his arrival at Old Trafford. United's attempts to sign Sancho ahead of the 2020/21 season were thwarted by Borussia Dortmund but they returned with an improved offer a year later to sign him for a reported fee of £73 million ($100 million).
After a slow start to the 2021/22 campaign, he ended the season with five goals in all competitions, despite the managerial upheaval at Old Trafford.
The early signs under Ten Hag looked positive, with Sancho starting in United's first six Premier League games of the season and scoring key goals in wins over Liverpool and Leicester City.
However, a bout of tonsillitis and the arrival of Antony saw him edged out of the starting XI, and his morale took a major blow when he was omitted from England's squad for the World Cup in Qatar. He then began training individually, following a suggestion from Ten Hag, at Dutch club OJC Rosmalen.
MORE: Arsenal vs Man United betting tips and prediction
What has Ten Hag said about Sancho?
Sancho lost his place as a starter under Ten Hag prior to the World Cup, which prompted speculation on his long-term intentions for the former Manchester City youngster.
The Dutch coach hinted at his omission from England's UEFA Nations League squad in September as a crucial downturn for Sancho as his confidence began to slip.
"Sometimes there are circumstances with fitness and mood. He is not currently in the right status or fitness state," Ten Hag said during the World Cup in December.
"I've had several talks with Jadon. He's on a physical programme and our aim is to get him back as quickly as possible, but I can't give a prognosis of when that will be.
"At the start of the season, he had goals and assists, but his key moments and key actions became less and less. It's a combination of physical, but also mental. We're trying to work and get him back to his best."
Erik ten Hag has revealed Jadon Sancho has not been "in the right fitness state" as he trains away from the Manchester United first team. pic.twitter.com/AYC7x8aptb
— Sky Sports Premier League (@SkySportsPL) December 14, 2022
Sancho was not included in United's World Cup training camp in Spain, instead travelling for a specialist programme in the Netherlands. His progress has been gradual, but Ten Hag has most been positive about his work.
Ten Hag was quizzed about the latest on Sancho following the Burnley win, but he gave a perfunctory reply when he was asked for an update on when Sancho will return to the United fold.
"Do you have any update on Sancho and when he's coming back?".
Erik ten Hag: "No".@footballdaily #MUFC 🔴🎥 pic.twitter.com/15LaEWWubI
— Fabrizio Romano (@FabrizioRomano) December 21, 2022
Asked whether he'd be in contention to play against Nottingham Forest in their Premier League return on December 27, he added: "I don't think so." Ten Hag has since made it clear they will be patient with Sancho, although his return to team training is clearly a positive development.
Jadon Sancho transfer fee
United's 2020 interest in Sancho ended when they were unable to agree a fee with Dortmund, who were eager to recoup a significant fee for a player who had shone for three years in the Bundesliga.
Despite the stand-off, United returned with an improved £73m ($100m) offer in July 2021, and Dortmund accepted, with Sancho agreeing a five-year deal at Old Trafford.
The move represented a huge profit for Dortmund. They paid around £8m/$9.6m to bring him in from the Manchester City academy in 2017.
Dortmund have established a policy of looking to sell one key player per season, with Sancho's 2021 move followed by Erling Haaland joining Manchester City in 2022, and a potential 2023 exit for Sancho's England teammate Jude Bellingham.
MORE: How World Cup star Bellingham evoked Paul Gascoigne memories for England
Jadon Sancho stats
Sancho has endured a mixed overall career at United, with just eight goals and four assists in 51 appearances across all competitions since the start of 2021/22.
Those numbers show a major dip from his Dortmund days, where Sancho plundered 50 goals and 64 assists in his four seasons in Germany.
78 – Since the start of the 2018-19 season Jadon Sancho has been directly involved in 78 goals in the Bundesliga (37 goals, 41 assists), no Englishman recorded more goals and assists in Europe's top 5 leagues in that period. Farewell. https://t.co/mqdcBhVj88 pic.twitter.com/pxXmbuRiQZ
— OptaFranz (@OptaFranz) July 1, 2021
In 2022/23, Sancho has scored three goals and set up another in 14 games for United in all competitions. He has been substituted 10 times, the most of anyone under Ten Hag, highlighting his lack of impact in many of his appearances.
However, Sancho has managed an average of 1.69 chances created per 90 minutes, which was a better return than Antony (1.41), Anthony Elanga (1.41), Marcus Rashford (1.14) and Cristiano Ronaldo (1.03), according to Opta data as of December 26.
Will Man United sell Jadon Sancho?
Sancho looks unlikely to leave United in the January window despite facing a battle to prove himself to Ten Hag. United consider him a first-team player — one in whom a significant amount of money has been invested — and the manager is giving him the chance to regain fitness and focus before coming back to push for a return to regular football.
There has been speculation United could let Sancho leave on loan in January in a bid to reinvigorate the player, much as they did with Jesse Lingard, who thrived during a spell at West Ham in the second half of 2021/22. However, with Cristiano Ronaldo having left the club, Ten Hag is unlikely to sanction further attacking departures midway through the season unless he can bring in replacements.
Still, if Ten Hag remains unconvinced by the end of the campaign, Sancho could become available for transfer, particularly with United eager to generate extra funds through player sales. The prospect of a return to the Bundesliga, perhaps to Dortmund, could appeal.
Premier League 2022/23 TV channels, live streams
Region TV Streaming
Australia — Optus Sport
Canada —
Hong Kong — Now TV
India Star Sports Disney+, Hotstar, JioTV
Malaysia Astro SuperSport Astro Go
New Zealand Sky Sport Sky Sport Now, Sky Go
Singapore StarHub StarHub TV+
UK Sky Sports, BT Sport NOW TV, Sky Go, Amazon Prime
USA USA Network, Telemundo, Universo fuboTV, Peacock
UK: Matches are carried across Sky Sports and BT Sport streaming and TV platforms, with select matches on Amazon Prime.
USA: Select matches are televised on USA Network (English) and Telemundo or Universo (Spanish), and all three channels can be streamed on fuboTV. The rest of the matches are streamed on NBC platform Peacock for subscribers.
Canada: Every Premier League game this season is live streaming exclusively via fuboTV in Canada.
Australia: Fans in Australia can stream every match live and on demand on Optus Sport.
India: Star Sports network has the rights to show Premier League matches in India. As well as an English broadcast on Star Sports Select, select matches will be available via regional feeds on Star Sports 3 (in Bengali, English, Kannada, Malayalam), Star Sports 1 (Bangla) and Star Sports 1 (Tamil).
This article was originally published by Sportingnews.com. Read the original article here.
Friday Night Notes: National Signing Day watch, the latest commitments and more
NHL Highlights | Golden Knights vs. Rangers – January 27, 2023
NFL head coach, GM interview tracker: Jets, Patriots tab former head coaches to be next offensive coordinators
Robert Horry ejected from high school basketball game for heckling referees


Ocean Front Pool Villa Suite at Six Senses Koh Samui, Koh-samui | Luxury Resort & Hotels in Thailand By Rizort.
The Ocean Front Pool Villa Suite offers a large spacious bedroom with a lounge area, walk-in closet and two bathrooms along with an indoor and outdoor shower on the upper level. A private pool and a dining area are on the lower level. This villa is perfect for couples as well as families, as the lounge area can be transformed into a second bedroom. Panoramic views of the Gulf of Thailand can be enjoyed from the bedroom and from the private pool area.


text:
Hashtag 101: What are they, and why do we need 'em?
January 13, 2014 By Leigh Caldwell 2 Comments
If you use social media, you have seen a hashtag. No, scratch that. In 2014, if you watch TV, or read magazines or attend conferences, you've seen a hashtag. But I still have folks ask me all the time what a hashtag is, why they exist, and why in the world you would want to use them. So, here's a hashtag primer for you.
What is a hashtag?
A hashtag is a word or phrase without spaces preceeded by a #. #hashtag is a Hashtag. #hashtagsarecool is also one. The idea of using # to denote a keyword actually started in the 1970s in computer programming languages. In 2007, this really smart open source guy named Chris Messina proposed using the # on Twitter as a way to mark posts belonging to a certain group. Twitter users quickly adopted them, and in 2009, Twitter started to hyperlink hashtags within Tweets to a page of search results for that hashtag. Facebook and Instagram now do that, too. You can also type a particular hashtag into the search box on Twitter or Facebook to get posts that include it.
Why do hashtags exist?
Hashtags are a way to sort out the myriad of content being posted on social media to find a group of content about a certain topic. They are essentially a way to aggregate content about one particular thing. For example, if you are interested in finding content about the upcoming Sochi Olympics, a quick look at the hashtag #Olympics on Twitter will yield all kinds of tweets about them.
Why would you use hashtags?
Well, as I said above, you can use them to find content about a particular topic. A couple of hashtags I look at every day are #twill, which started out meaning "Twitter Illinois" and has evolved to be a hashtag for posts about statewide politics in Illinois, and #southernillinois, which is growing in popularity and is pretty self-explanatory – it's about things of interest in Southern Illinois.
Media will sometimes assign a hashtag to a particular topic in hopes that they can sort out social media posts about that topic. For example, WSIL asks users to tag weather photos they post on Facebook, Instagram or Twitter with #wsilwx, and the weather team sometimes uses that user-generated content on the air. Ads for many TV shows and movies include hashtags now, as well. If you watched the #GoldenGlobes, you could have looked at that hashtag on Twitter or Facebook to see what others were saying during the show. That can be especially fun during live events like award shows, because it can be like having a live running commentary in your living room.
In-person events you may attend, like business conferences and fun stuff like festivals, will often have a hashtag for participants to use so that everyone can follow along with the online conversation. Taylor Swift's tour last year asked her audiences to tag social media posts with #redtour. Locally, HerrinFesta Italiana uses the hashtag #HerrinFesta. Some folks have even started assigning a hashtag to gatherings like weddings, so that they can more easily find pictures guests posted of the event.
A final use of hashtags is just for fun. People will hashtag posts with phrases just to be funny. A friend and I sometimes tag posts (and even texts to each other) #teamhotmess, because that's what we jokingly call ourselves. Folks will often tag posts sarcastically with #winning, a leftover remnant of Charlie Sheen's very public meltdown a few years back. And if you're still not getting this trend, let Jimmy Fallon and Justin Timberlake explain it for you:
Filed Under: Blog, Social Media Tagged With: facebook, hash tag history, hashtag, instagram, twitter
About Leigh Caldwell
Leigh M. Caldwell is Director of Social Media and Digital Marketing at Harness TechED. She is a content creator and marketing strategist with two decades of experience in social, online, print and broadcast media. Leigh is a native of West Frankfort, Illinois, and a Southern Illinois University alum.
Great explanation, and one of my all time favorite youtube vids. 🙂
Tom Harness says
Aimee, thanks for posting. The video is a classic.


One person has been killed and an additional 10 people were injured when a City of Miami dump truck slammed into a taxi cab at an intersection.
Police are still investigating the chain reaction crash that happened at the intersection of Northwest Seventh Street and 17th Avenue; however, believe that the dump truck caused the crash when it hit the yellow taxi.
Authorities were able to obtain surveillance video from a local business that captured footage of when the dump truck struck the cab belonging to Diamond Cab and then into the numerous other vehicles that were ahead of it.
A woman who was riding as a passenger in the taxi cab was killed in the accident. She has been identified as Pamela Kay Plummer, 66.
Those who were injured in the crash were transported by ambulance to Jackson Memorial Hospital. Four of the victims sustained serious injuries.
The City of Miami officials identified the driver of the dump truck as Larry Ellis.
According to Pamela Plummer's family, she had just overcome some major health issues recently. It seems unfair that just when someone is on the road to recovery, their life should be taken from them so abruptly.
When vehicles owned and operated by a city government or municipality are involved in an accident in the State of Florida, the guidelines for eligible claims against municipalities are often stricter than they are in accidents involving other types of vehicles. Such claims often allow for a much shorter window of time for injured passengers to file legal action. Accident victims or their surviving family members often need to act quickly.
If you or a loved one has been injured in an accident involving a vehicle owned by a city or municipality, you may be entitled to compensation for damages such as the recovery of medical expenses, rehabilitation, time off of work and other costs in addition to your pain and suffering.
When you call, we will match you with an attorney who will review your claim and give you several potential courses of action that can get your case filed in a timely manner that is most advantageous for you. Your initial consultation is without cost to you.