Review Article

 

Biological Effects and Modes of Action of Carvacrol in Animal and Poultry Production and Health - A Review

 

Mahmoud Alagawany1*, Mohamed Ezzat Abd El-Hack1, Mayada Ragab Farag2, Ruchi Tiwari3, Kuldeep Dhama4

1Poultry Department, Faculty of Agriculture; 2Forensic Medicine and Toxicology Department, Veterinary Medicine Faculty, Zagazig University, Zagazig 44111, Egypt; 3Department of Veterinary Microbiology, College of Veterinary Sciences, Uttar Pradesh Pandit Deen Dayal Upadhayay Pashu Chikitsa Vigyan Vishwa Vidyalaya Evam Go-Anusandhan Sansthan (DUVASU), Mathura (Uttar Pradesh) – 281001, India; 4Division of Pathology, Indian Veterinary Research Institute, Izatnagar, Bareilly, 243122,Uttar Pradesh, India.

Editor | Ruchi Tiwari, College of Veterinary Sciences, Department of Veterinary Microbiology and Immunology Uttar Pradesh Pandit Deen Dayal Upadhayay Pashu Chikitsa, Vigyan Vishvidhyalaya Evum Go-Anusandhan Sansthan (DUVASU), Mathura (U.P.) – 281001, India.

Special Issue| 2 (2015) “Reviews on Trends and Advances in Safeguarding Terrestrial /Aquatic Animal Health and Production”

Received | February 17, 2015; Revised | March 18, 2015; Accepted | March 19, 2015; Published | March 23, 2015

*Correspondence | Mahmoud Alagawany, Zagazig University, Zagazig, Egypt; Email: [email protected]

Citation | Alagawany M, El-Hack MEA, Farag MR, Tiwari R, Dhama K (2015). Biological effects and modes of action of carvacrol in animal and poultry production and health - a review. Adv. Anim. Vet. Sci. 3(2s): 73-84.

DOI | http://dx.doi.org/10.14737/journal.aavs/2015/3.2s.73.84

ISSN (Online) | 2307-8316; ISSN (Print) | 2309-3331

Copyright © 2015 Alagawany et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

 

INTRODUCTION

 

Carvacrol is a monoterpenoid phenol predominantly found in oregano (Origanum vulgare), thyme (Thymus vulgaris), pepperwort (Lepidium flavum) and wild bergamot, also produced naturally by isolation of essential oil from some plants (Kintzios, 2002; Sokmen et al., 2004; Barnes et al., 2007; Tang et al., 2011; Jamali et al., 2012; Kim et al., 2013). The carvacrol amount in marjoram and hop marjoram (Dittany of Crete) are 50 and 70%, respectively. While, the oil extracted from thyme plant contains carvacrol percentage between 5 -75 (León-Rodríguez, 2008). Several in vitro and in vivo studies described different bioactivity of carvacrol nutrient, including antibacterial, antioxidant, antiseptic, antispasmodic, growth promoter, antifungal, antiviral, anti-inflammatory, expectorant, antitussive, immunomodulatory and chemopreventive as well as modifier of rumen microbial fermentation and reduction of methane emission (Luna et al., 2010; Soltanab et al., 2011; Hashemipour et al., 2013; Bravo et al., 2014).

 

Carvacrol is molecule that has crucial bioactivities on poultry and animal physiology and metabolism (Reiner et al., 2009), this compound could have antioxidant action on poultry meat when added in the diet. Carvacrol plays a critical role as natural antioxidant in the reduction of lipid peroxidation which leading to oxidative destruction of cellular membranes (Rhee et al., 1996; Yanishlieva et al., 1999). Moreover, the deleterious effect of these compounds may lead to increase in the production of toxic metabolites (free radicals) and also to apoptosis. On the other hand, Bavadekar (2012) reported that carvacrol promotes cell death in prostate cancer cells.

 

Several studies have been reported the addition of some phytogenic additives or their products such as cold pressed oil, essential oil or extracts to animal and poultry diets that improved live body weight, body weight gain, feed conversion ratio, immune response, antioxidant status, carcass traits and quality, and lowered morbidity and mortality rates (Ashour et al., 2014; Farag et al., 2014; Alagawany et al., 2015a, 2015b; Dhama et al., 2015). The current review covers many important aspects including the mechanisms of action, metabolism and excretion, biological activities and beneficial applications of carvacrol in animal and poultry production and health.

 

CARVACROL SOURCES

 

Carvacrol is a component of some medicinal plants, such as black cumin (Nigella sativa), oregano (Origanum compactum), Monarda didyma, Origanum dictamnus, Origanum microphyllum, Origanum onites, Origanum scabrum, Origanum vulgare, thyme (Thymus glandulosus), savory (Satureja hortensis) (Aligiannis et al., 2001; De Vincenzi et al., 2004; Coskun et al., 2008; Liolios et al., 2009; Figiel et al., 2010). Also, carvacrol has been produced by chemical and biotechnological synthesis via metabolic engineered microorganisms (More et al., 2007).

 

CHEMICAL AND PHYSICAL CHARACTERISTICS

 

Carvacrol is an isomer and derivative of phenol, the chemical formula of carvacrol (cymophenol) is C6H3CH3 (OH) (C3H7), a monoterpenoid phenol (Bouchra et al., 2003; De Vincenzi et al., 2004). Carvacrol is also named 5-isopropyl-2-methylphenol or 2-Methyl-5-(1-methylethyl)-phenol according to International Union of Pure and Applied Chemistry (IUPAC). The structural formula of carvacrol is shown in Figure 1.

 

 

Carvacrol is a liquid and has the same taste of thymol. The density of carvacrol ranges from 0.976g/cm3 at 20°C to 0.975g/cm3 at 25°C. Carvacrol boils at 237~238°C, while its melting point is 1. It can be volatile with steam. Carvacrol is highly lipophilic; the solubility of carvacrol is very high in carbon tetrachloride, ethanol, diethyl ether, acetone; but insoluble in water (Ultee et al., 2000). Yadav and Kamble (2009) reported that formation of carvacrol could be resulted from alkylation of o-cresol with propylene or isopropyl alcohol (IPA) over solid acid catalysts.

 

MODES OF ACTION AND BIOLOGICAL ACTIVITIES

 

Several modes of action could be obtained by using phytogenic additives, such as affecting feed consumption, enhancing digestive enzymes secretion and increasing the motility of the digestive tract; antimicrobial activity, antiviral activity, antioxidative activity, endocrine and immune stimulation; anthelminthic, coccidiostat and anti-inflammatory activity (Akyurek and Yel, 2011). Basmacioğlu et al. (2010) affirmed that antioxidative and antimicrobial efficacy of the active component of plant extracts or essential oils had been used in a lot of in vitro or in vivo experiments, but some questions still remain unanswered concerning the mode of action, optimal dosage, and pathway of metabolism of these additives in poultry.

 

 

In fact, carvacrol component is added to various ingredients, such as nonalcoholic beverages (28.54 mg/kg), baked goods (15.75 mg/kg), chewing gum (8.42 mg/kg), etc. (Fenaroli, 1995). However, the mode of action of this compound was unknown by many researchers. A good knowledge of carvacrol mode of action is very required regarding application in nutritional systems. Formerly, Ultee et al. (1998) reported the antimicrobial activity of carvacrol on pathogen Bacillus cereus. Carvacrol is a hydrophobic compound and has an effective impact on biological membranes. The modes of action and beneficial aspects of carvacrol are shown in Figure 2.

 

METABOLISM AND EXCRETION

 

The metabolism and excretion of carvacrol in the body is very quick. The major metabolic pathway of carvacrol is related to the esterification of phenolic group with glucuronic acid (C6H10O7) and sulfuric acid (H2SO4). But, a minor route of carvacrol metabolism is transformation of the end methyl groups to primary alcohols. In an experiment on male albino rats, Austgulen et al. (1987) found that rats excreted a major percent of administered carvacrol (1 mmol/kg) in urine, as its sulphate and glucuronide conjugates, with extensive oxidation of the methyl groups mainly and this gave derivatives of benzyl alcohol and 2- phenylpropanol in addition to their corresponding carboxylic acids. A minor metabolite resulting from ring hydroxylation has also been detected. Moreover, the residual of carvacrol or its derivatives in urine was very small after one day only; this phenomenon is a strong indicator of the high speed of the carvacrol metabolism and excretion during the first day.

 

Michiels et al. (2008) carried out some experiment with gastric fermentation simulation of pig. Results reported 29% degradation of carvacrol in cecum, while jejunum was not affected. When piglets received oral feeding of 13.0, 13.2, 12.5 and 12.7 mg carvacrol /kg body weight, they showed half-life between 1.84 and 2.05 hours in the whole digestive tract. Carvacrol was almost absorbed completely in the proximal small intestine and the stomach. The concentrations of plasma (total of free and conjugated compound) maximized at 1.39 hours and followed by high concentrations in the urine.

 

BENEFICIAL ASPECTS OF CARVACROL

 

Improving Nutrients Bioavailability and Growth/Productive Performance

A number of animal and poultry trials have been conducted previously to establish the dependency and functionality of carvacrol and supplementation of it in animal and poultry diets. Hashemipour et al. (2013) reported that feed supplementation with thymol + carvacrol mixture by 60, 100, and 200 mg/kg of diet improved growth performance, digestive enzyme activities, and antioxidant enzyme activities besides inhibiting lipid peroxidation in broiler chicks. The concentration of IgG in serum was enhanced in the diet supplemented with different plant extracts such as thyme and oregano compared to the control diet in mice and pigs (Namkung et al., 2004).

 

In 17 days old poults which ate a diet with supplementation of a plant extract containing carvacrol at 300 mg/kg diet, Jamroz and Kamel (2002) observed daily body weight gain and feed conversion ratio to be improved by 8.1 and 7.7 %, respectively. Lee et al. (2003a) reported that increased efficiency of feed utilization could be the explanation of thymol and carvacrol effects on performance. Hernandez et al. (2004) stated that the improvement of broiler performance fed diets supplemented with several additives such as thymol and carvacrol, pepper essential oils (200 mg/kg), and rosemary extracts (5,000 mg/kg) could be attributed to its beneficial effects on digestibility.

 

Jaafari et al. (2012) fed one day female broilers with cholesterol-free or cholesterol-rich diets supplemented with 200 ppm carvacrol for four weeks of age and observed that feed intake and weight gain were reduced but feed conversion got improved. Moreover, plasma concentration of triglyceride was lowered with no effect on plasma content of cholesterol due to dietary carvacrol addition. When carvacrol was supplemented with corn-soybean meal basal diet supplemented with carboxymethyl cellulose, there were no any significant effects on feed efficiency or plasma content of cholesterol. Lee et al. (2003b) reported a negative effect on broilers body weight when feeding on 200 ppm carvacrol /kg diet with the same dose of cinnamaldehyde. A study of Lee et al. (2004) confirmed the non-significant impact on productive performance traits i.e. live body weight, feed consumption, feed efficiency and ileal content of microbiota by feeding broiler chickens on carvacrol with thymol and organic acids. These previous studies showed an indecisive influence of carvacrol on the efficiency of feed in broiler chickens and additional studies are wanted to get assured results as suggested by Umaya and Manpal (2013). Supplementing the diet of one day old broilers with 5.0 ppm carvacrol for seven days of age, caused an improvement in body weight gain and depressed oocyte shedding, gut lesions in addition to lowering gene expression of proinflammatory cytokine during coccidiosis when challenging birds by Eimeria acervulina (Lillehoj et al., 2011). Moreover, lipid metabolism, estrogen and androgen metabolism in intestinal intraepithelial lymphocytes were regulated due to carvacrol supplementation in broilers. Feeding chickens on diet supplemented with 5.0 ppm carvacrol/ kg altered the expression of 74 genes in intestinal intra epithelial lymphocytes. Treatment with carvacrol also led to an upregualtion of many genes associated with the metabolic and endocrine system such as protease serine 3 (PRSS3) and selenoprotein X, 1 (SEPX1) (Lillehoj et al., 2011). Based on the aforementioned results, several studies should be taken place to help in understanding the carvacrol molecular mechanism in the digestive tract of chicken and simplify the development of novel dietary ways to immunomodulate host response in disease or normal cases.

 

The consumer attention has been raised within the past decades regarding the quality of meat and its products. The poultry meat content of polyunsaturated fatty acids is high; so it is susceptible to oxidative deterioration, which negatively impacts the meat quality. Broilers fed diet contained 150 ppm of carvacrol through the experimental period (1 day - 42 days of age) caused a reduction in thiobarbituric acid production which is a proof of lipid peroxidation in samples of thigh (stored for 5-10 days). Similar results obtained by Yanishlieva et al. (1999); Annalisa et al. (2009); Mastromatteo et al. (2009); Kim et al. (2010) and Akalin and Incesu (2011) revealed that carvacrol supplementation minimized lipid oxidation and microbial load in chicken patties stored at low temperature (0-3°C), as well as improving shelf life and quality of poultry meat. So, using carvacrol as a natural antioxidant could improve quality of poultry products.

 

Antiviral Activity

Herbal plants and their derivatives or extracts have been evaluated for their possible antiviral prosperities, including the cold pressed or essential oils of certain commonly used culinary herbs (Jassim and Naji, 2003; Sokovic et al., 2010). Carvacrol plays a key role as antiviral component against human rotavirus (RV). On the same context, Mexican oregano (Lippia graveolens) extract and oil as well as carvacrol component are able to reduce/inhibit the viral diseases in animal and human. Specifically, the antiviral activity of oregano and its phenolic components on acyclovir resistant herpes simplex virus type 1 (ACVRHHV-1) and human respiratory syncytial virus (HRSV) and of carvacrol on RV have been documented (Bernstein, 2009; Pilau et al., 2011).

 

Oregano essential oils including carvacrol compound have been strongly promoted as natural antiviral factors effective against many viral diseases such as the pandemic H1N1 virus (Vimalanathan and Hudson, 2012). On the contrary, Sokmen et al. (2004) noted that anti-influenza virus activity was not affected by supplementation of oils or extracts derived from oregano. Gilling et al. (2014) reported that carvacrol as a natural food is very effective in inhibiting human norovirus within one hour of exposure by acting directly on the viral capsid.

 

Antimicrobial Activity

The antimicrobial effects of essential oils have been due to the presence of phenolic compounds, such as carvacrol, thymol, eugenol, curcumin and cinnamaldehyde which are presented in essential oils of oregano, thyme, clove, turmeric and cinnamon, respectively (Tsao and Zhou 2000; Lambert et al. 2001; Veldhuizen et al., 2006; Alagawany et al., 2015b). Sikkema et al. (1995), Adam et al. (1998), Weber and de Bont (1996), Ben-Arfa et al. (2006) and Nostro and Papalia (2012) mentioned that the beneficial/inhibitory effects of phenolic compounds could be attributed to the interactions between the effective compounds and cell membrane of microorganisms and is usually associated with the hydrophobicity of these compounds.

 

Arsi et al. (2014) showed that campylobacter numbers were reduced with 1% carvacrol supplementation, or a combination of both thymol and carvacrol at 0.5%. Friedman et al. (2002), Sokovic et al. (2002), Nastro et al. (2004), and Baser (2008) found antimicrobial influences of carvacrol against many species of microbes such as Pseudomonas, Aspergillus, Salmonella, Streptococci, Listeria, Bacillus and Fusarium. Burt et al. (2005 and 2007) observed that carvacrol supplement as antimicrobial component has a significant impact on harmful bacteria including Escherichia coli and Salmonella numbers in chickens, this effect may be attributed to inhibit the growth of pathogenic bacteria by carvacrol vapour. Johny et al. (2010) postulated that carvacrol and eugenol decreased (P≤ 0.05) Salmonella Enteritidis and C. jejuni counts in chicken cecal contents to <1.0 log10 cfu/ml at 50 and 75 mM and 20 and 30 mM, respectively.

 

Antioxidant Activity and Scavenging of Free Radicals

Free radicals or reactive oxygen intermediates are generated by cells during the normal metabolism. When free radicals such as superoxide radical (O2.-), hydrogen peroxide (H2O2) and hydroxyl radical (OH.) are accumulated excessively, this leads to a damage in tissue and privation of many cellular functions. Carvacrol as an antioxidant protects the cells against free radicals. Moreover, antioxidants inhibit prostaglandin synthesis and induct drug-metabolizing enzymes in addition to many biological activities as reported by Azirak and Rencuzogullari (2008).

 

Some studies assured the efficiency of carvacrol in scavenging free radicals i.e. nitric oxide, superoxide radicals, peroxyl radicals and hydrogen peroxide (Kohen and Nyska, 2002; Aristatile et al., 2010). The existence of hydroxyl group (OH) which linked to aromatic ring is suggested to be the reason for the highly antioxidant activity of carvacrol either in vitro or in vivo as explained by Aeschbach et al. (1994) and Guimaraes et al. (2010). The reaction of carvacrol with a free radical is facilitated due to its weak acid character, so donating hydrogen atoms to an unpaired electron, producing another radical that is stabilized by electron scattering generated at a molecule resonance structure (Aristatile et al., 2010).

 

Supplemental oregano by 50 to 100 mg/kg to broiler chick diets exerted an antioxidant effect in the broiler tissues (Botsoglou et al., 2002). Ruberto et al. (2000), Alma et al. (2003), and Luna et al. (2010) reported that the diet unsupplemented with carvacrol or thymol has similar effectiveness to inhibit the oxidation of lipids than the synthetic antioxidant supplementation such as butylated hydroxytoluene, ascorbic acid and vitamin E, and could be considered good natural additives to be applied in animal and poultry industry to improve the performance and health. Animals fed diet supplemented with carvacrol had greater concentrations of SOD and GSH-PX and more level of poly unsaturated fatty acids (PUFA) in the brain phospholipids than the unsupplemented control (Youdim and Deans, 2000).

 

Immunomodulatory Effect

Improving poultry immunity is one of the main goals to prevent infectious diseases. Immunodeficiency could occurr by several factors including abuse of antibiotics, vaccination failure or immune-suppressive infectious diseases. To improve the bird’s immunity and decrease the susceptibility to infectious diseases, immune stimulators could be used. Acamovic and Brooker (2005) and Silveira et al. (2013) reported that herbs rich in flavonoids such as thyme and carvacrol could improve the immune functions through acting as antioxidants and extending the activity of vitamin C.

 

Botsoglou et al. (2002) expected to find an improvement in the immune responses of chicks because of the assured antioxidant, antibacterial and antiviral activities of carvacrol which had been reported by many researchers. Lillehoj et al. (2011) pointed out that feeding birds with diets containing plant-derived phytonutrients such as carvacrol, thymol, cinnamaldehyde, capsicum and oleoresin significantly improved the immune response in chickens and lowered poultry infectious diseases. Furthermore, Hashemipour et al. (2013) reported that feeding birds with diets contained carvacrol plus thymol linearly increased (P<0.01) the primary and secondary response against SRBC antigen and IgG.

 

Anti-carcinogenic and Antiplatelet Effects

Some natural antioxidants such as carvacrol exert anticarcinogenic and platelet antiaggregating impacts (Karkabounas et al., 1997 and 2002; Evangelou et al., 1998; Liasko et al., 1998; Ipeka et al., 2005). Also, Karkabounas et al. (2006) and Michiels et al. (2008) affirmed the effect of carvacrol as anticancer and antiplatelet in vivo and in vitro during hepatocellular carcinoma, pulmonary tumors and chemical induced carcinogenesis. As well, Aydin et al. (2007) and Jayakumar et al. (2012) suggested that carvacrol exhibits antigenotoxic activity at nontoxic concentrations (<0.05 mM) but it needs more investigation.

 

Arunasree (2010), Yin et al. (2012), and Al-Fatlawi et al. (2014) pointed out genomic DNA fragmentations and caspase-3, -6 or -9 enzymes gene expression were induced by carvacrol supplementation; also carvacrol addition induced apoptosis regulatory genes in human breast cancer cell line (MCF-7) cells and retarded growth. Carvacrol plays an important therapeutic role in treating cancer including cervical cancer cells (Arunasree, 2010; Mehdi et al., 2011).

 

Hepatoprotective Effect

In a D-galactosamine induced rat model, carvacrol exhibited a hepatoprotective role either in vivo or ex vivo. Aeschbach et al. (1994), Aristatile et al. (2009a) and Guimaraes et al. (2010) revealed that using carvacrol at the level of 80 mg/kg body weight in rat helped restoring the concentrations of lipid peroxidation products, lipids content in kidney, liver and blood plasma to its normal values. In addition, enzymic and non-enzymic antioxidants concentrations induced by D- galactosamine also restored to normal by carvacrol. The aforementioned authors added that the treatment with carvacrol restored and controlled the damage of DNA and the reductions in mitochondrial enzymes which induced by D-galactosamine.

 

In fact, lake of glucose and oxygen needed for metabolism of the cell could be happened if blood flow to an organ was insufficient or stopped resulting in ischemia. Reperfusion is a term of the restoration of blood flow to the tissue after the elimination of the causative agent for ischemia. As a result to reperfusion, toxic products pass to the circulation system. During liver surgery, renal I/R injury and liver transplantations, hepatic ischemia is a frequent problem. Canbek et al. (2008), Aristatile et al. (2009b) reported that carvacrol protects liver during renal I/R injury and hepatic I/R injury through improving liver antioxidant defence and minimizing the products of lipid peroxidation.

 

Anti-inflammatory and Anti-hypernociceptive Effects

Hypersensitivity of nociceptive pathways causes inflammatory hyperalgesia or it could be called hypernociception. The immune system cells release the mediators such as interleukins, cytokines or tumor necrosis factor-α during inflammation. The previous action activates the higher order neurons which exist in the transmission of the nociceptive input and also activates the primary nociceptors. Trabace et al. (2011) stated that pain sensitivity increased in laboratory animals as a result to the aforementioned hypersensitivity of nociceptive pathways which contributes to hypernociception. The threshold sensitivity of mice exposed to carrageenan was improved by using carvacrol at the dose of 50 and 100 mg/kg comparing to indomethacin and standard drug. Marchand el al. (2005) reported that the method of carvacrol in inhibiting hypernociception is to inhibit the migration of mononuclear cells and neutrophils concluded in the production of proinflammatory cytokines such as nitric oxide and consequently a decrease in prostaglandins. The morphology of the cells did not affect due to carvacrol treatment excepting a decrease in the TNF-α levels in pleural lavage. Hotta et al. (2010), and Guimaraes et al. (2012) found an anti-hypernociceptive effect of carvacrol by decreasing the levels of enzyme responsible for inducing nitric oxide synthase and in turns the macrophages content of nitric oxide. Marchand et al. (2005), Kaufmann et al. (2011), and Uyanoglu et al. (2011) had contradicting reports regarding including the antioxidant effect of carvacrol in controlling nitric oxide production and lipid peroxidation during hypernociception.

 

Anti-obesity Effect

Obesity is a medical condition in which excess body fat accumulates to the extent that it may have a negative effect on health, leading to increased health problems. It is like other chronic diseases such as hyperlipidemia, cancers and diabetes. Umaya and Manpal (2013) stated that the main factor in enhancing obesity and attributed to the metabolic diseases in humans and animal models is the consumption of high levels of fat in the diet and they found that carvacrol caused an inhabiting of fat accumulation between cells and adipocyte differentiation in mouse embryo 3T3- L1 cells. Also, results showed that diet high in fat and supplemented with carvacrol decreased total visceral fat, plasma and liver total cholesterol, HDL-cholesterol, triglyceride and free fatty acids of mice. Moreover, carvacrol decreased the expression of adipogenesis related genes- fibroblast growth factor receptor in visceral adipose tissues. Also, carvacrol decreased the expression of receptors which stimulates the intake of fat rich diet such as galanin receptor 1 and 2.

 

Wieten et al. (2010), and Cho et al. (2012) found that free fatty acid levels and the mRNA and protein levels of toll-like receptors were reduced by carvacrol. Free fatty acids in high levels are reported in obese animals, because of their release either from high fat diet or from adipose tissues. Carvacrol as anti-obese drug needs for more detailed studies to be recommended for this purpose.

 

Conclusion

This review highlights the beneficial applications of the dietary addition of carvacrol as a natural antioxidant or growth enhancer with useful activities on feed efficiency, nutrient bioavailability, immunity, oxidative status, egg quality parameters and growth/productive performances. Furthermore, useful impacts of lowered serum and meat MDA, lipid peroxidation have been noted in poultry and animal fed rations supplemented with carvacrol, indicating the beneficial effects and important role of carvacrol dietary supplementation which could be due to its pharmacological effects and beneficial health effects, such as antimicrobial, antioxidant, anticancer, antiplatelet, antiviral, anti-inflammatory, antifungal, and growth promoting properties. Exploration of the carvacrol modes of action like nutritional, pharmacological, health benefits and biological properties may play crucial role in its beneficial usages in poultry farm and animal management systems by providing further understanding of the health applications and increasing performance parameters in agriculture species.

 

ACKNOWLEDGEMENTS

 

All the authors of the manuscript thank and acknowledge their respective Universities and Institutes.

 

REFERENCES

 

Acamovic T, Brooker JD (2005). Biochemistry of plant secondary metabolites and their effects in animals. Proc. Nutr. Soc. 64: 403–412. http://dx.doi.org/10.1079/PNS2005449

Adam K, Sivropoulou A, Kokkini S, Lanaras T, Arsenakis M (1998). Antifungal activities of Origanum vulgare subsp. hirtum, Mentha spicata, Lavandula angustifolia, and Salvia fruticosa essential oils against human pathogenic fungi. J. Agric. Food. Chem. 46:1739-1745. http://dx.doi.org/10.1021/jf9708296

Aeschbach R, Loliger J, Scott BC, Murcia A, Butler J, Halliwell B, Aruoma OI (1994). Antioxidant actions of thymol, carvacrol, 6- gingerol, zingerone and hydroxytyrosol. Food Chem. Toxicol. 32: 31-36. http://dx.doi.org/10.1016/0278-6915(84)90033-4

Akalin G, Incesu Z (2011). The effects of carvacrol on apoptosis of H-RAS and N-RAS transformed cell lines. Turk. J. Pharm. Sci. 8: 105-116.

Akyurek H, Yel A (2011). Influence of dietary thymol and carvacrol preparation and/or an organic acid blend on growth performance, digestive organs and intestinal microbiota of broiler chickens. African J. Micro. Res. 5: 979-84.

Alagawany MM, Farag MR, Dhama K, Abd El-Hack ME, Tiwari R, Alam GM (2015a). Mechanisms and Beneficial Applications of Resveratrol as Feed Additive in Animal and Poultry Nutrition: A Review. Int. J. Pharmacol. 11: 213-221. http://dx.doi.org/10.3923/ijp.2015.213.221

Alagawany MM, Farag MR, Dhama K (2015b). Nutritional and biological effects of turmeric (Curcuma longa) supplementation on performance, serum biochemical parameters and oxidative status of broiler chicks exposed to endosulfan in the diets. Asian J. Anim. Vet. Adv. 10: 86-96. http://dx.doi.org/10.3923/ajava.2015.86.96

Al-Fatlawi AA, Rahisuddin, Ayaz A (2014). Cytotoxicity and pro-apoptotic activity of carvacrol on human breast cancer cell line MCF-7. World J. Pharm. Sci. 2(10): 1218-1223.

Aligiannis N, Kalpoutzakis E, Mitaku S, Chinou IB (2001). Composition and antimicrobial activity of the essential oils of two Origanum species. J. Agric. Food Chem. 49(9): 4168–4170. http://dx.doi.org/10.1021/jf001494m

Alma MH, Mavi A, Jildirim A, Diprak M, Hirata T (2003). Screen¬ing chemical composition and in vitro antioxidant and antimi¬crobial activities of the essential oils from Oreganum Synaceum L growing in Turkey. Biol. Pharm. Bul. 26: 1725–1729. http://dx.doi.org/10.1248/bpb.26.1725

Annalisa L, Mastromatteo M, Sinigaglia M, Corbo MR (2009). Combined effects of thymol, carvacrol and grapefruit seed extract on lipid oxidation and colour stability of poultry meat preparations. Int. J. Food Sci. Tech. 44: 2256-2267. http://dx.doi.org/10.1111/j.1365-2621.2009.02067.x

Aristatile B, Numair AKS, Veeramani C, Pugalendi KV (2009a). Antihyperlipidemic effect of carvacrol on D-galactosamine induced hepatotoxic rats. J. Basic. Clin. Physiol. Pharmacol. 20: 15-27. http://dx.doi.org/10.1515/JBCPP.2009.20.1.15

Aristatile B, Numair AKS, Veeramani C, Pugalendi KV (2009b). Effect of carvacrol on hepatic marker enzymes and antioxidant status in D-galactosamine induced-hepatotoxicity in rats. Fundam. Clin. Pharmacol. 23: 757-765. http://dx.doi.org/10.1111/j.1472-8206.2009.00721.x

Aristatile B, Numair AKS, Assaf AHA, Veeramani C, Pugalendi KV (2010). Protective effect of carvacrol on oxidative stress and cellular DNA damage induced by UVB irradiation in human peripheral lymphocytes. J. Biochem. Mol. Toxic. 1-11. http://dx.doi.org/10.1002/jbt.20355

Arsi K, Donoghue AM, Venkitanarayanan K, Kollanoor JA, Fanatico AC, Blore PJ, Donoghue DJ (2014). The Efficacy of the Natural Plant Extracts, Thymol and Carvacrol against Campylobacter Colonization in Broiler Chickens. J. Food Saf. 34(4): 321-325. http://dx.doi.org/10.1111/jfs.12129

Arunasree KM (2010). Anti-proliferative effects of carvacrol on a human metastatic breast cancer cell line, MDA-MB 231. Phytomedicine. 17: 581–588. http://dx.doi.org/10.1016/j.phymed.2009.12.008

Ashour EA, Alagawany M, Reda FM, Abd El-Hack ME (2014). Effect of Supplementation of Yucca schidigera Extract to Growing Rabbit Diets on Growth Performance, Carcass Characteristics, Serum Biochemistry and Liver Oxidative Status. Asian J. Anim. Vet. Adv. 9: 732-742. http://dx.doi.org/10.3923/ajava.2014.732.742

Austgulen LT, Solheim E, Scheline RR (1987). Metabolism in rats of p-cymene derivatives: carvacrol and thymol. Pharmacol. Toxicol. 61(2): 98–102. http://dx.doi.org/10.1111/j.1600-0773.1987.tb01783.x

Aydin Y, Kutlay O, Ari S, Duman S, Uzuner K, Aydin S (2007). Hypotensive effects of carvacrol on the blood pressure of normotensive Rats. Planta Med. 73: 1365-71. http://dx.doi.org/10.1055/s-2007-990236

Azirak S, Rencuzogullari E (2008). The in vivo genotoxic effects of carvacrol and thymol in rat bone marrow cells. Environ. Toxicol. 23: 728-735. http://dx.doi.org/10.1002/tox.20380

Baik JS, Kim SS, Lee JA, Oh TH, Kim JY, Lee NH, Hyun CG (2008). Chemical composition and biological activities of essential oils extracted from Korean endemic citrus species. J. Microbiol. Biotech. 18: 74–79.

Barnes J Anderson LA, Phillipson JD (2007). Herbal medicines. 3rd ed, Pharmaceutical press, London, UK.

Baser KHC (2008). Biological and pharmacological activities of carvacrol and carvacrol bearing essential oils. Curr. Pharm. Des. 14: 3106-3120. http://dx.doi.org/10.2174/138161208786404227

Basmacioğlu MH, Baysal S, Misirlioglu Z, Polat M, Yilmaz H, Turan N (2010). Effects of oregano essential oil with or without feed enzymes on growth performance, digestive enzyme, nutrient digestibility, lipid metabolism and immune response of broilers fed on wheat-soybean meal diets. Br. Poult. Sci. 51: 67–80. http://dx.doi.org/10.1080/00071660903573702

Bavadekar S (2012). http://www.liu.edu/Brooklyn/About/News/Press-Releases/2012/April/BK-PR-Apr25-2012.aspx.

Ben-Arfa A, Combes S, Preziosi-Belloy L, Gontard N, Chalier P (2006). Antimicrobial activity of carvacrol related to its chemical structure. Lett. Appl. Microbiol. 43(2): 149-154. http://dx.doi.org/10.1111/j.1472-765X.2006.01938.x

Bernstein DI (2009). The changing epidemiology of rotavirus gastroenteritis. Introduction. Pediatr. Infect. Dis. J. 28 (3 Suppl): S49. http://dx.doi.org/10.1097/INF.0b013e3181967bda

Botsoglou NA, Florou-Paner P, Christaki E, Fletouris DJ, Spais AB (2002). Effect of dietary oregano essential oil on performance of chickens and on iron-induced lipid oxidation of breast, thigh and abdominal fat tissues. Br. Poult. Sci. 43: 223– 230. http://dx.doi.org/10.1080/00071660120121436

Bouchra C, Achouri M, Idrissi HLM, Hmamouchi M (2003). Chemical composition and antifungal activity of essential oils of seven Moroccan Labiatae against Botrytis cinerea Pers: Fr. J. Ethnopharmacol. 89(1): 165–169. http://dx.doi.org/10.1016/S0378-8741(03)00275-7

Bravo D, Pirgozliev V, Rose SP (2014). A mixture of carvacrol, cinnamaldehyde, and capsicum oleoresin improves energy utilization and growth performance of broiler chickens fed maize-based diet. J. Anim. Sci. 92(4): 1531-1536. http://dx.doi.org/10.2527/jas.2013-6244

Burt SA, Vlielander R, Haagsman HP, Veldhuizen EJ (2005). Increase in activity of essential oil components carvacrol and thymol against Escherichia coli O157:H7 by addition of food stabilizers. J. Food Prot. 68(5): 919-926.

Burt SA, Fledderman MJ, Haagsman HP, van Knapen F, Veldhuizen EJ (2007). Inhibition of Salmonella enterica serotype Enteritidis on agar and raw chicken by carvacrol vapour. Int. J. Food Microbiol. 119(3): 3 46-350.

Canbek M1, Uyanoglu M, Bayramoglu G, Senturk H, Erkasap N, Koken T, Uslu S, Demirustu C, Aral E, Husnu CBK (2008). Effects of carvacrol on defects of ischemiareperfusion in the rat liver. Phytomed. 15: 447-452. http://dx.doi.org/10.1016/j.phymed.2007.11.022

Cho S, Choi Y, Park S, Park T (2012). Carvacrol prevents diet-induced obesity by modulating gene expressions involved in adipogenesis and inflammation in mice fed with high-fat diet. J. Nutr. Biochem. 23: 192-201. http://dx.doi.org/10.1016/j.jnutbio.2010.11.016

Coskun S, Girisgin O, Kürkcüoglu M, Malyer H, Girisgin AO, Kirimer N, Baser KH (2008). Acaricidal efficacy of Origanum onites L. essential oil against Rhipicephalus turanicus (Ixodidae). Parasitol. Res. 103(2): 259–261. http://dx.doi.org/10.1007/s00436-008-0956-x

De Vincenzi M, Stammati A, De Vincenzi A, Silano M (2004). Constituents of aromatic plants: carvacrol. Fitoterapia. 75(7-8): 801-804. http://dx.doi.org/10.1016/j.fitote.2004.05.002

Dhama K, Shyma K Latheef, Saminathan M, Abdul Samad H, Karthik K, Tiwari R, Khan RU, Alagawany M, Farag MR, Alam GM, Laudadio V, Tufarelli V (2015). Multiple beneficial applications and modes of action of herbs in poultry health and production-A review. Int. J. Pharmacol. 11: 152-176. http://dx.doi.org/10.3923/ijp.2015.152.176

Evangelou A, Malamas M, Vezyraki P, Karkabounas S (1998). Is epinephrine-induced platelet aggregation autoregulated by its metabolic degradation products in vivo? In Vivo. 12: 321–6.

Farag MR, Alagawany MM Dhama K (2014). Antidotal effect of Turmeric (Curcuma longa) against endosulfan-induced cytogenotoxicity and immunotoxicity in broiler chicks. Int. J. Pharmacol. 10: 429-439. http://dx.doi.org/10.3923/ijp.2014.429.439

Fenaroli G (1995). Fenaroli’s handbook of flavor ingredients, 3rd ed. CRC Press, Inc., Boca Raton, Fla.

Figiel A, Antoni S, Antonio GO, Carbonell-Barrachina, ÁNgel A (2010). Composition of oregano essential oil (Origanum vulgare) as affected by drying method. J. Food Eng. 98 (2): 240–247. http://dx.doi.org/10.1016/j.jfoodeng.2010.01.002

Friedman M, Henika PR, Mandrell RE (2002). Bactericidal activities of plant essential oils and some of their isolated constituents against C. jejuni, E. coli, L. monocytogenes and S. enteritica. J. Food Prot. 65: 1545–60.

Gilling DH, M Kitajima, Torrey JR, Bright KR (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 http://dx.doi.org/10.1111/jam.12453

Guimarães AG, Oliveira GF, Melo MS, Cavalcanti SC, Antoniolli AR, Bonjardim LR, Silva FA, Santos JP, Rocha RF, Moreira JC, Araújo AA, Gelain DP, Quintans-Júnior LJ (2010). Bioassay-guided evaluation of antioxidant and antinociceptive activities of carvacrol. Basic Clin. Pharmacol. Toxicol. 107: 949-957. http://dx.doi.org/10.1111/j.1742-7843.2010.00609.x

Guimaraes AG, Xavier MA, Santana MT (2012). Carvacrol attenuates mechanical hypernociception and inflammatory response. N-S Arch. Pharmacol. 385: 253-263.

Hashemipour H1, Kermanshahi H, Golian A, Veldkamp T (2013). Effect of thymol and carvacrol feed supplementation on performance, antioxidant enzyme activities, fatty acid composition, digestive enzyme activities, and immune response in broiler chickens. Poult. Sci. 92(8):2059-69. http://dx.doi.org/10.3382/ps.2012-02685

Hernandez F, Madrid J, Garcia V, Orengo J, Megias MD (2004). Influence of two plant extracts on broiler performance, digestibility, and digestive organ size. Poult. Sci. 83: 169–174. http://dx.doi.org/10.1093/ps/83.2.169

Hotta M, Nakata R, Katsukawa M, Hori K, Takahashi S, Inoue H (2010). Carvacrol, a component of thyme oil, activates PPAR alpha and gamma, and suppresses COX-2 expression. J. Lipid Res. 51: 132-39. http://dx.doi.org/10.1194/jlr.M900255-JLR200

Ipeka E, Zeytinoglua H, Okaya S, Tuylua BA, Kurkcuoglub M, Can Baserb KH (2005). Genotoxi-city and antigenotoxicity of Origanum oil and carvacrol evaluated by Ames Salmonel-la/microsomal test. Food Chem. 93(30): 551–556. http://dx.doi.org/10.1016/j.foodchem.2004.12.034

Jaafari A, Tilaou M, Mouse HA, M’bark LA, Aboufatima R, Chait A, Lepoivre M, Zyad A (2012). Comparative study of the antitumor effect of natural monoterpenes: relationship to cell cycle analysis. Brazilian J. Pharmacog. 22: 534-540. http://dx.doi.org/10.1590/S0102-695X2012005000021

Jamali CA, El Bouzidi L, Bekkouche K, Lahcen H, Markouk M, Wohlmuth H, Leach D, Abbad A (2012). Chemical composition and antioxidant and anticandidal activities of essential oils from different wild Moroccan Thymus species. Chem. Biodivers. 9(6): 1188-1197. http://dx.doi.org/10.1002/cbdv.201200041

Jamroz D, Kamel C (2002). Plant extracts enhance broiler performance. J. Anim. Sci. 80: 4. (Ab-str.)

Jassim SA, Naj, MA (2003). Novel antiviral agents: a medicinal plant perspective. J. Appl. Microbi-ol. 95(3): 412-427. http://dx.doi.org/10.1046/j.1365-2672.2003.02026.x

Jayakumar S, Madankumar A, Asokkumar S (2012). Potential preventive effect of carvacrol against diethylnitrosamine-induced hepatocellular carcinoma in rats. Mol. Cell Biochem. 360: 51-60. http://dx.doi.org/10.1007/s11010-011-1043-7

Jensen C, Engberg R, Jakobsen K, Skibsted LH, Bertelsen G (1997). Influence of the oxidative quality of dietary oil on broiler meat storage stability. Meat Sci. 47: 211–222. http://dx.doi.org/10.1016/S0309-1740(97)00052-1

Johny AK, Darre MJ, Donoghue AM, Donoghue DJ, Venkitanarayanan K (2010). Antibacterial effect of trans-cinnamaldehyde, eugenol, carvacrol, and thymol on Salmonella Enteritidis and Campylobacter jejuni in chicken cecal contents in vitro. J. Appl. Poult. Res. 19(3): 237-244. http://ps.oxfordjournals.org/content/92/8/2059.long - xref-ref-22-1

Karkabounas S, Karabetsos D, Gogos Ch, Beka A, Evangelou A (1997). The platelet function mod-ification by chemical carcinogenesis inhibitors. Thromb. Haemost. 1: 469.

Karkabounas S, Binolis J, Zelovitis J, Kotsis N, Charalabopoulos A, Avdikos A, Zouridakis A, Li-asko R, Giannako¬poulos X, Charalabopoulos K (2002). Inhibition and modification of ben-zo[a]pyrene-induced chemical carcinogenesis by ascorbic acid alone or in combination with a-tocopherol in Wistar rats. Exp. Oncol. 24: 274–8.

Karkabounas S, Kostoula O, Daskalou T (2006). Anticarcinogenic and antiplatelet effects of car-vacrol. Exp. Oncol. 28: 121-125.

Kaufmann D, Dogra AK, Wink M (2011). Myrtenal inhibits acetylcholinesterase, a known Alz-heimer target. J. Pharm. Pharmacol. 63: 1368-1371. http://dx.doi.org/10.1111/j.2042-7158.2011.01344.x

Kim DK, Lillehoj HS, Lee SH, Jang SI, Bravo D (2010). High-throughput gene expression analysis of intestinal intraepithelial lymphocytes after oral feeding of carvacrol, cinnamaldehyde, or Capsicum oleoresin. Poult. Sci. 89:68-81. http://dx.doi.org/10.3382/ps.2009-00275

Kim E, Choi Y, Jang J, Park T (2013). Carvacrol protects against hepatic steatosis in mice fed a high-fat diet by enhancing SIRT1-AMPK signalling. Evid. Based Complement. Alternat. Med. 1-10. http://dx.doi.org/10.1155/2013/290104

Kintzios SE (2002). Oregano: the genera Origanum and Lippia. Kintzios Se, ed. New York: Taylor and Francis. 277 p.

Kohen R, Nyska A (2002). Oxidation of Biological Systems: Oxidative stress phenome-na, antioxidants, redox reactions, and methods for their quantification. Toxicol. Pathol. 30: 620-650. http://dx.doi.org/10.1080/01926230290166724

Lambert RJW, Skandamis PN, Coote PJ, Nycs GJE (2001). A study of minimum inhibitory concen-tration and mode of action of oregano essential oil, thymol and carvacrol. J. Appl. Microbiol. 91: 453–462. http://dx.doi.org/10.1046/j.1365-2672.2001.01428.x

Lee KW, Everts H, Kappert HJ, Frehner M, Losa R, Beynen AC (2003a). Effects of dietary essen-tial oil components on growth performance, digestive enzymes and lipid metabolism in female broiler chickens. Br. Poult. Sci. 44: 450–457. http://dx.doi.org/10.1080/0007166031000085508

Lee KW, Everts H. Kappert HJ, Yeom KH, Beynen AC (2003b). Dietary carvacrol lowers body weight gain but improves feed conversion in female broiler chickens. J. Appl. Poult. Res. 12: 394-399. http://dx.doi.org/10.1093/japr/12.4.394

Lee KW, Eerts H, Kappert HJ, Beynen AC (2004). Growth performance of broiler chickens fed a carboxymethyl cellulose containing diet with supplemental carvacrol and/or cinnamaldehyde. Int. J. Poult. Sci. 3: 619-622. http://dx.doi.org/10.3923/ijps.2004.619.622

León-Rodríguez A de, Escalante-Minakata P, Jiménez-García MI, Ordo-ez-Acevedo LG, Flores Flores JL, Barba de la RA (2008). Characterization of volatile compounds from ethnic Agave alcoholic beverages by gas chromatography-mass spectrometry. Food Technol. Biotechnol. 46(4): 448-455.

Liasko R, Kabanos T, Karkabounas S, Malamas M, Tasiopoulos A, Stefanou D, Collery P, Evange-lou A (1998). Beneficial effects of a Vanadium complex with cysteine, administrated at low doses of benzo[a]pyrene — induced leiomyosarcomas in Wistar rats. Anticancer Res. 18: 3609–3614.

Lillehoj HS, Kim DK, Bravo DM, Lee SH (2011). Effects of dietary plant-derived phytonutrients on the genome-wide profiles and coccidiosis resistance in the broiler chickens. BMC Proc. 5: 4-34.

Liolios CC, Gortzi O, Lalas S, Tsaknis J, Chinou I (2009). Liposomal incorporation of carvacrol and thymol isolated from the essential oil of Origanum dictamnus L. and in vitro antimicrobial activity. Food Chem. 112(1): 77–83. http://dx.doi.org/10.1016/j.foodchem.2008.05.060

Luna A1, Lábaque MC, Zygadlo JA, Marin RH (2010). Effects of thymol and carvacrol feed sup-plementation on lipid oxidation in broiler meat. Poult Sci. 89(2): 366-70. http://dx.doi.org/10.3382/ps.2009-00130

Marchand F, Perretti M, Mahon SB (2005). Role of the immune system in chronic pain. Nat. Rev. Neurosci. 6: 521-532. http://dx.doi.org/10.1038/nrn1700

Mastromatteo M, Lucera A, Sinigaglia M, Corbo MR (2009). Combined effects of thymol, car-vacrol and temperature on the quality of non-conventional poultry patties. Meat Sci. 83: 246-254. http://dx.doi.org/10.1016/j.meatsci.2009.05.007

Mehdi SJ, Ahmad A, Irshad M, Manzoor N, Rizvi MMA (2011). Cytotoxic effect of carvacrol on human cervical cancer cells. Biology and Medicine, 3 (2s): 307-312.

Michiels J, Missotten J, Dierick N, Fremaut D, Maene P, Smet SD (2008). In vitro degradation and in vivo passage kinetics of carvacrol, thymol, eugenol and transcinnnamaldehydealong the gas-trointestinal tract of piglets. J. Sci. Food Agric. 88: 2371-81. http://dx.doi.org/10.1002/jsfa.3358

More UB, Narkhede HP, Dalal DS, Mahulikar PP (2007). Synthesis of biologically active carvacrol compounds using different solvents and supports. Synthetic Communications. 37(12): 1957-1964. http://dx.doi.org/10.1080/00397910701354608

Namkung H, Li M, Gong J, Yu H, Cottrill M, de Lange CFM (2004). Impact of feeding blends of organic acids and herbal extracts on growth performance, gut microbiota and digestive function in newly weaned pigs. Can. J. Anim. Sci. 84: 697-704. http://dx.doi.org/10.4141/A04-005

Nastro A, Blanco AR, Cannatelli MA, Enea V, Flamini G, Morelki J, Sudano Roccano A, Alonzo V (2004). Susceptibility of methicillin-resistant staphylococci to oregano essential oil, carvacrol and thymol. FEBS Lett. 230: 191–195. http://dx.doi.org/10.1016/S0378-1097(03)00890-5

Nostro A, Papalia T (2012). Antimicrobial activity of carvacrol: current progress and future prospectives. Recent. Pat. Antiinfect. Drug Discov. 7: 28–35. http://dx.doi.org/10.2174/157489112799829684

Pilau MR, Alves SH, Weiblen R, Arenhart S, Cueto AP, Lovato LT (2011). Antiviral activity of the lippia graveolens (Mexican oregano) essential oil and its main compound carvacrol against human and animal viruses. Br. J. Microbiol. 42: 1616-1624. http://dx.doi.org/10.1590/S1517-83822011000400049

Reiner GN, Labuckas DO, Garcia DA (2009). Lipophilicity of some GABAergic phenols and related compounds determined by HPLC and partition coefficients in different systems. J. Pharm. Biomed. Anal. 49: 686–691. http://dx.doi.org/10.1016/j.jpba.2008.12.040

Rhee KS, Anderson LM, Sams AR (1996). Lipid peroxidation potential of beef, chicken and pork. J. Food Sci. 61: 8–12. http://dx.doi.org/10.1111/j.1365-2621.1996.tb14714.x

Ruberto G, Baratta MT, Deans SG, Dorman HJ (2000). Antioxidant and antimicrobial activity of Foeniculum vulgare and Crith¬mum maritimum essential oils. Planta Med. 66: 683-693. http://dx.doi.org/10.1055/s-2000-9773

Sikkema J, De Bont J, Poolman B (1995). Mechanisms of membrane toxicity of hydrocarbons. Microbiol. Rev. 59: 201–222.

Silveira SRC, Andrade LN, Sousa DP (2013). A Review on Anti-Inflammatory Activity of Monoterpenes. Molecules. 18: 1227-1254. http://dx.doi.org/10.3390/molecules18011227

Sokmen M, Serkedjieva J, Daferera D, Gulluce M, Polissiou M, Tepe B, Akpulat HA, Sahin F, Sokmen A (2004). In vitro antioxidant, antimicrobial and antiviral activities of the essential oil and various extracts from herbal parts and callus cultures of Origanum acutidens. J. Agri. Food Chem. 52: 3309–3312. http://dx.doi.org/10.1021/jf049859g

Sokovic M, Tzakou O, Pitarokili D, Couladis M (2002). Antifungal activities of selected aromatic plants growing wild in Greece. Nahrung. 46: 312–20. http://dx.doi.org/10.1002/1521-3803(20020901)46:5<317::AID-FOOD317>3.0.CO;2-B

Sokovic M, Glamoclija J, Marin PD, Brkic D, van Griensven LJ (2010). Antibacterial effects of the essential oils of commonly consumed medicinal herbs using an in vitro model. Molecules. 15: 7532- 7546. http://dx.doi.org/10.3390/molecules15117532

Soltanab YA, Morsybc AS, Araujo RC, Elzaiatab HM, Sallama SMA, Louvandinib H, Abdallab AL (2011). Carvacrol and eugenol as modifiers of rumen microbial fermentation, and methane production in vitro. Foreign Agricultural Relations (FAR), Egypt, 3 – 5 October pp. 01 – 11.

Tang X, Chen, S, Wang L (2011). Purification and identification of carvacrol from the root of Stellera chamaejasme and research on its insecticidal activity. Nat. Prod. Res. 25: 320–325. http://dx.doi.org/10.1080/14786411003792140 http://dx.doi.org/10.1080/14786419.2010.532796

Trabace L, Zotti M, Morgese MG, Tucci P, Colaianna M, Schiavone S, Avato P, Cuomo V (2011). Estrous cycle affects the neurochemical and neurobehavioral profile of carvacrol-treated female rats. Toxicol. Appl. Pharm. 255: 169-75. http://dx.doi.org/10.1016/j.taap.2011.06.011

Tsao R, Zhou T (2000). Antifungal activity of monoterpenoids against postharvest pathogens Botrytis cinerea and Monilinia fructicola. J. Essent. Oil Res. 12: 113–121. http://dx.doi.org/10.1080/10412905.2000.9712057

Ultee A, Gorris LMG, Smid EJ (1998). Bactericidal activity of carvacrol towards the food-borne pathogen Bacillus cereus. J. Appl. Microbiol. 85: 211–218. http://dx.doi.org/10.1046/j.1365-2672.1998.00467.x

Ultee A, Slump RA, Steging G, Smid EJ (2000). Antimicrobial activity of carvacrol toward Bacillus cereus on rice. J. Food Prot. 63(5): 620–624.

Umaya RS, Manpal S (2013). Biological and pharmacological of actions carvacrol and its effects on poultry: an updated review. World J. Pharm. Pharmaceut. Sci. 2 (5): 3581-3595.

Uyanoglu M, Canbek M, Ceyhan E, Senturk H, Bayramoglu G, Gunduz O, Ozen A, Turgak O (2011). Preventing organ injury with carvacrol after renal ischemia/reperfusion. J. Med. Plants Res. 5: 72-80.

Veldhuizen EJ, Tjeerdsma-van Bokhoven JL, Zweijtzer C, Burt SA, Haagsman HP (2006). Structural requirements for the antimicrobial activity of carvacrol. J. Agri. Food Chem. 54(5): 1874-1879. http://dx.doi.org/10.1021/jf052564y

Vimalanathan S, Hudson J (2012). Anti-Influenza virus activities of commercial oregano oils and their carriers. J. Appl. Pharmaceut. Sci. 2(7): 214-218. http://dx.doi.org/10.7324/JAPS.2012.2734

Weber FJ, de Bont JAM (1996). Adaptation mechanisms of microorganisms to the toxic effects of organic solvents on membranes. Biochimi. Biophys. Acta. (BBA) 1286: 225–245. http://dx.doi.org/10.1016/S0304-4157(96)00010-X

Wieten L, van der Zee R, Spiering R, Wagenaar-Hilbers J, van Kooten P, Broere F, van Eden W (2010). A novel heat-shock protein coinducer boosts stress protein Hsp70 to activate T cell regulation of inflammation in autoimmune arthritis. Arthritis Rheum. 62: 1026-1035. http://dx.doi.org/10.1002/art.27344

Yadav GD, Kamble SB (2009). Synthesis of carvacrol by Friedel–Crafts alkylation of ocresol with isopropanol using superacidic catalyst UDCaT-5. J. Chem. Technol. Biot. 84: 1499-1508. http://dx.doi.org/10.1002/jctb.2210

Yanishlieva NV, Marinova EM, Gordon MH, Raneva VG (1999). Antioxidant activity and mechanism of action of thymol and carvacrol in two lipid systems. Food Chem. 64: 59-66. http://dx.doi.org/10.1016/S0308-8146(98)00086-7

Yin Q, Yan F, Zu XY, Wu Y, Wu X, Liao M, Deng S, Yin L, Zhuang Y (2012). Anti-proliferative and pro-apoptotic effect of carvacrol on human hepatocellular carcinoma cell line HepG-2. Cytotechnology. 64(1): 43-51. http://dx.doi.org/10.1007/s10616-011-9389-y

Youdim, KA, Deans SG (2000). Effect of thyme oil and thymol dietary supplementation on the antioxidant status and fatty acid composition of the ageing rat brain. Br. J. Nutr. 83: 87–93.