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			<p class="Type-of-Article" lang="en-GB">&nbsp;</p>
			<p class="Type-of-Article" lang="en-GB"><span class="CharOverride-1">Review Article</span></p>
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			<p class="title- ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="title- ParaOverride-1" lang="en-GB">Biological Effects and Modes of Action of Carvacrol in Animal and Poultry Production and Health - A Review</p>
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			<p class="Authors ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Authors ParaOverride-1" lang="en-GB"><span class="CharOverride-3">Mahmoud Alagawany</span><span class="CharOverride-4">1</span><span class="CharOverride-3">*, Mohamed Ezzat Abd El-Hack</span><span class="CharOverride-4">1</span><span class="CharOverride-3">, Mayada Ragab Farag</span><span class="CharOverride-4">2</span><span class="CharOverride-3">, Ruchi Tiwari</span><span class="CharOverride-4">3</span><span class="CharOverride-3">, Kuldeep Dhama</span><span class="CharOverride-4">4</span></p>
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			<p class="Affiliations ParaOverride-1" lang="en-GB"><span class="CharOverride-2">1</span>Poultry Department, Faculty of Agriculture; <span class="CharOverride-2">2</span>Forensic Medicine and Toxicology Department, Veterinary Medicine Faculty, Zagazig University, Zagazig 44111, Egypt; <span class="CharOverride-2">3</span>Department of Veterinary Microbiology, College of Veterinary Sciences, Uttar Pradesh Pandit Deen Dayal Upadhayay Pashu Chikitsa Vigyan Vishwa&#160;Vidyalaya Evam Go-Anusandhan Sansthan (DUVASU), Mathura (Uttar Pradesh) – 281001, India; <span class="CharOverride-2">4</span>Division of Pathology, Indian Veterinary Research Institute, Izatnagar, Bareilly, 243122,Uttar Pradesh, India.</p></div>
		
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			<p class="Abstract ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Abstract ParaOverride-1" lang="en-GB"><span class="CharOverride-5">Abstract</span> | The carvacrol compound is an antioxidant nutrient, used to enhance growth and productive performance via modification and activation of gastrointestinal tract structure and function and to inhibit/prevent cancer initiations. Numerous studies performed on animal diets supplemented with phytogenic supplements/feed additives containing natural antioxidants such as carvacrol demonstrated its capability to improve performance indices, feed utilization, immune functions and health of livestock as well as reducing the risks of different animal diseases like cancer and other diseases. Such properties could be due to its ability as antimicrobial, antioxidant, antifungal, immunomodulatory, anticancer and anti-inflammatory agents by preventing free radicals and hazardous compounds from interacting with cellular DNA and its ability to change the gut microflora, improving digestion coefficient and absorption of nutrient compounds. The present review illustrates the chemical and physical proprieties, modes of action, metabolism and excretion, biological properties, natural sources and beneficial aspects of carvacrol in animal and poultry production and health.</p>
  <p class="Abstract ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Abstract ParaOverride-1" lang="en-GB"><span class="CharOverride-5">Keywords </span>| Carvacrol, Nutrition, Antioxidant, Antimicrobial, Anticancer, Immunity, Health, Production performance, Animal, Poultry, Human</p>
  <p class="Abstract ParaOverride-1" lang="en-GB">&nbsp;</p>
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			<p class="Editor----Citation" lang="en-GB"><span class="CharOverride-7">Editor</span> | 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.</p>
			<p class="Editor----Citation" lang="en-GB"><span class="CharOverride-7">Special Issue</span>| 2 (2015) “Reviews on Trends and Advances in Safeguarding Terrestrial /Aquatic Animal Health and Production”</p>
			<p class="Editor----Citation" lang="en-GB"><span class="CharOverride-5">Received</span> | February 17, 2015; <span class="CharOverride-5">Revised</span> | March 18, 2015; <span class="CharOverride-5">Accepted</span> | March 19, 2015; <span class="CharOverride-5">Published</span> | March 23, 2015&#9;&#9;</p>
			<p class="Editor----Citation" lang="en-GB"><span class="CharOverride-5">*Correspondence</span> | Mahmoud Alagawany, Zagazig University, Zagazig, Egypt; <span class="CharOverride-5">Email:</span> dr.mahmoud.alagwany@gmail.com</p>
			<p class="Editor----Citation" lang="en-GB"><span class="CharOverride-5">Citation</span> | 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.  </p>
			<p class="Editor----Citation" lang="en-GB"><span class="CharOverride-7">DOI</span> | <a href="http://dx.doi.org/10.14737/journal.aavs/2015/3.2s.73.84"><span class="Hyperlink">http://dx.doi.org/10.14737/journal.aavs/2015/3.2s.73.84</span></a></p>
			<p class="Editor----Citation" lang="en-GB"><span class="Editor---Citation CharOverride-5" lang="en-US">ISSN </span><span class="Editor---Citation CharOverride-5" lang="en-US">(</span><span class="Editor---Citation CharOverride-5" lang="en-US">Online</span><span class="Editor---Citation CharOverride-5" lang="en-US">)</span> | 2307-8316; <span class="Editor---Citation CharOverride-5" lang="en-US">ISSN </span><span class="Editor---Citation CharOverride-5" lang="en-US">(Print) </span> | 2309-3331</p>
			<p class="Editor----Citation" lang="en-GB"><span class="CharOverride-7">Copyright </span>© 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.</p>
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			<p class="Heading-1--Introduction----" lang="en-GB">&nbsp;</p>
		  <p class="Heading-1--Introduction----" lang="en-GB">INTRODUCTION</p>
			<p class="Caps-on-First-Para ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Caps-on-First-Para ParaOverride-1" lang="en-GB"><span class="_idGenDropcap-1">C</span>arvacrol is a <a href="http://en.wikipedia.org/wiki/Monoterpene">monoterpenoid</a> phenol predominantly found in oregano (<a href="http://en.wikipedia.org/wiki/Origanum_vulgare"><span class="CharOverride-11">Origanum vulgare</span></a>), <a href="http://en.wikipedia.org/wiki/Thyme">thyme</a> (<a href="http://en.wikipedia.org/wiki/Thymus_vulgaris"><span class="CharOverride-11">Thymus vulgaris</span></a>), <a href="http://en.wikipedia.org/wiki/Pepperwort">pepperwort</a> (<a href="http://en.wikipedia.org/wiki/Lepidium_flavum"><span class="CharOverride-11">Lepidium flavum</span></a>) and <a href="http://en.wikipedia.org/wiki/Monarda_fistulosa">wild bergamot</a>, also produced naturally by isolation of essential oil from some plants (<a href="#Kintzios-SE--2002-"><span class="Hyperlink">Kintzios, 2002</span></a>; <a href="#Sokmen-M--Serkedjieva-J--Daferera-D--Gulluce-M-2004"><span class="Hyperlink">Sokmen et al., 2004</span></a>; <a href="#Barnes-J-Anderson-LA--Phillipson-JD--2007-"><span class="Hyperlink">Barnes et al., 2007</span></a>; <a href="#Tang-X--Chen--S--Wang-L--2011"><span class="Hyperlink">Tang et al., 2011</span></a>; <a href="#Jamali-CA--El-Bouzidi-L--Bekkouche-K--Lahcen-H--Markouk-M--Wohlmuth-H--Leach-D--Abbad-A--2012"><span class="Hyperlink">Jamali et al., 2012</span></a>; <a href="#Kim-E--Choi-Y--Jang-J--Park-T--2013-.-Carv"><span class="Hyperlink">Kim et al., 2013</span></a>). The carvacrol amount in marjoram and hop marjoram (<a href="http://en.wikipedia.org/wiki/Dittany_of_Crete"><span class="CharOverride-11">Dittany of Crete</span></a>) are 50 and 70%, respectively. While, the oil extracted from thyme plant contains carvacrol percentage between 5 -75 (<a href="#Le-n-Rodr-guez-A-de--Escalante-Minakata-P--2008"><span class="Hyperlink">León-Rodríguez, 2008</span></a>). Several <span class="CharOverride-11">in vitro</span> and <span class="CharOverride-11">in vivo</span> 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 (<a href="#Luna-A1--L-baque-MC--Zygadlo-JA--Marin-RH--2010"><span class="Hyperlink">Luna et al., 2010</span></a>; <a href="#Soltanab-YA--Morsybc-AS--Araujo-RC--Elzaiatab-HM--Sallama-SMA--Louvandinib-H--Abdallab-AL--2011"><span class="Hyperlink">Soltanab et al., 2011</span></a>; <a href="#Hashemipour-H1--Kermanshahi-H--Golian-A--Veldkamp-T--2013"><span class="Hyperlink">Hashemipour et al., 2013</span></a>; <a href="#Bravo-D--Pirgozliev-V--Rose-SP--2014-"><span class="Hyperlink">Bravo et al., 2014</span></a>). </p>
		  <p class="Caps-on-First-Para ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Body-Text ParaOverride-1" lang="en-GB">Carvacrol is molecule that has crucial bioactivities on poultry and animal physiology and metabolism (<a href="#Reiner-GN--Labuckas-DO--Garcia-DA--2009-."><span class="Hyperlink">Reiner et al., 2009</span></a>), 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 (<a href="#Rhee-KS--Anderson-LM--Sams-AR--1996-."><span class="Hyperlink">Rhee et al., 1996</span></a>; <a href="#Yanishlieva-NV--Marinova-EM--Gordon-MH--Raneva-VG--1999-."><span class="Hyperlink">Yanishlieva et al., 1999</span></a>). 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, <a href="#Bavadekar-S--2012-."><span class="Hyperlink">Bavadekar (2012)</span></a> reported that carvacrol promotes <a href="http://en.wikipedia.org/wiki/Apoptosis">cell</a> death in prostate cancer cells.</p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Body-Text ParaOverride-1" lang="en-GB">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 (<a href="#Ashour-EA--Alagawany-M--Reda-FM--Abd-El-Hack-ME--2014"><span class="Hyperlink">Ashour et al., 2014</span></a>; <a href="#Farag-MR--Alagawany-MM-Dhama-K--2014-."><span class="Hyperlink">Farag et al., 2014</span></a>; <a href="#Alagawany-MM--Farag-MR--Dhama-K--Abd-El-Hack-ME--Tiwari-R--Alam-GM--2015a"><span class="Hyperlink">Alagawany et al., 2015a</span></a>, <a href="#Alagawany-MM--Farag-MR--Dhama-K--2015b"><span class="Hyperlink">2015b</span></a>; <a href="#Dhama-K--Shyma-K-Latheef--Saminathan-2015"><span class="Hyperlink">Dhama et al., 2015</span></a>). 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.</p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Heading-1--Introduction----" lang="en-GB"><span class="mw-headline CharOverride-14">CARVACROL SOURCES</span></p>
		  <p class="Heading-1--Introduction----" lang="en-GB">&nbsp;</p>
			<p class="Body-Text ParaOverride-1" lang="en-GB">Carvacrol is a component of some medicinal plants, such as  black<span class="CharOverride-11"> </span>cumin<span class="CharOverride-11"> </span>(<span class="CharOverride-11">Nigella sativa</span>),<span class="CharOverride-11"> </span>oregano<span class="CharOverride-11"> </span>(<span class="CharOverride-11">Origanum compactum</span>), <span class="CharOverride-11">Monarda didyma, Origanum dictamnus, Origanum microphyllum, Origanum onites, Origanum scabrum, Origanum vulgare</span>, thyme<span class="CharOverride-11"> </span>(<span class="CharOverride-11">Thymus glandulosus</span>), savory (<span class="CharOverride-11">Satureja hortensis</span>) (<a href="#Aligiannis-N--Kalpoutzakis-E--Mitaku-S--Chinou-IB--2001"><span class="Hyperlink">Aligiannis et al., 2001</span></a>; <a href="#De-Vincenzi-M--Stammati-A--De-Vincenzi-A--Silano-M--2004-"><span class="Hyperlink">De Vincenzi et al., 2004</span></a>; <a href="#Coskun-S--Girisgin-O--K-rkc-oglu-M--Malyer-H--Girisgin-AO--Kirimer-N--Baser-KH--2008-."><span class="Hyperlink">Coskun et al., 2008</span></a>; <a href="#Liolios-CC--Gortzi-O--Lalas-S--Tsaknis-J--Chinou-I--2009"><span class="Hyperlink">Liolios et al., 2009</span></a>; <a href="#Figiel-A--Antoni-S--Antonio-GO--Carbonell-Barrachina---Ngel-A--2010-."><span class="Hyperlink">Figiel et al., 2010</span></a>). Also, carvacrol has been produced by chemical and biotechnological synthesis via metabolic engineered microorganisms (<a href="#More-UB--Narkhede-HP--Dalal-DS--Mahulikar-PP--2007-"><span class="Hyperlink">More et al., 2007</span></a>).</p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Heading-1--Introduction----" lang="en-GB"><span class="mw-headline CharOverride-16">CHEMICAL AND PHYSICAL CHARACTERISTICS</span></p>
		  <p class="Heading-1--Introduction----" lang="en-GB">&nbsp;</p>
			<p class="Body-Text ParaOverride-1" lang="en-GB">Carvacrol is an isomer and derivative of phenol, the chemical formula of carvacrol (cymophenol) is C6H3CH3 (OH) (C3H7), a <a href="http://en.wikipedia.org/wiki/Monoterpene">monoterpenoid</a> phenol (<a href="#Bouchra-C--Achouri-M--Idrissi-HLM--Hmamouchi-M--2003"><span class="Hyperlink">Bouchra et al., 2003</span></a>; <a href="#De-Vincenzi-M--Stammati-A--De-Vincenzi-A--Silano-M--2004-"><span class="Hyperlink">De Vincenzi et al., 2004</span></a>). 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 <a href="#Figure-1-"><span class="Hyperlink">Figure 1</span></a>.</p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<div class="pt" > <a href="http://nexusacademicpublishers.com/uploads/figures/20150323220853.png" target="new"><img class="img_display" src="http://nexusacademicpublishers.com/uploads/figures/20150323220853.png" width="80" height="80"></a>
            
          <p class="Figure--and-Table-Heading ParaOverride-1" lang="en-GB"><span class="CharOverride-5"><a id="Figure-1-"></a>Figure 1:</span><a href="http://nexusacademicpublishers.com/uploads/figures/20150323220853.png"> Basic structural formula of carvacrol and its derivative</a></p>
       </div>

			
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">Carvacrol is a liquid and has the same taste of thymol. The density of carvacrol ranges from 0.976g/cm<span class="CharOverride-2">3</span> at 20°C to 0.975g/cm<span class="CharOverride-2">3 </span>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 <a href="http://en.wikipedia.org/wiki/Carbon_tetrachloride">carbon tetrachloride</a>, <a href="http://en.wikipedia.org/wiki/Ethanol">ethanol</a>, <a href="http://en.wikipedia.org/wiki/Diethyl_ether">diethyl ether</a>, <a href="http://en.wikipedia.org/wiki/Acetone">acetone</a>; but insoluble in water (<a href="#Ultee-A--Gorris-LMG--Smid-EJ--1998-"><span class="Hyperlink">Ultee et al., 2000</span></a>). <a href="#Yadav-GD--Kamble-SB--2009-"><span class="Hyperlink">Yadav and Kamble (2009)</span></a> reported that formation of carvacrol could be resulted from alkylation of o-cresol with propylene or isopropyl alcohol (IPA) over solid acid catalysts. </p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Heading-1--Introduction----" lang="en-GB"><span class="mw-headline CharOverride-16">MODES OF ACTION AND BIOLOGICAL ACTIVITIES</span></p>
		  <p class="Heading-1--Introduction----" lang="en-GB">&nbsp;</p>
			<p class="Body-Text ParaOverride-1" lang="en-GB">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 (<a href="#Akyurek-H--Yel-A--2011"><span class="Hyperlink">Aky</span><span class="Hyperlink">urek and Yel, 2011</span></a>). <a href="#Basmacio-lu-MH--Baysal-S--Misirlioglu-Z--Polat-M--Yilmaz-H--Turan-N--2010"><span class="Hyperlink">Basmacioğlu et al. (2010)</span></a> affirmed that antioxidative and antimicrobial efficacy of the active component of plant extracts or essential oils had been used in a lot of <span class="CharOverride-11">in vitro</span> or <span class="CharOverride-11">in vivo</span> experiments, but some questions still remain unanswered concerning the mode of action, optimal dosage, and pathway of metabolism of these additives in poultry. </p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<div class="pt" > <a href="http://nexusacademicpublishers.com/uploads/figures/20150323225053.png" target="new"><img class="img_display" src="http://nexusacademicpublishers.com/uploads/figures/20150323225053.png" width="80" height="80"></a>
            
       <p class="Figure--and-Table-Heading ParaOverride-1" lang="en-GB"><span class="CharOverride-5"><a id="Figure-2-"></a>Figure 2: </span><a href="http://nexusacademicpublishers.com/uploads/figures/20150323225053.png"> Modes of action and biological activities of carvacrol</a></p>
       </div>
			
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">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. (<a href="#Fenaroli-G--1995"><span class="Hyperlink">Fenaroli, 1995</span></a>). 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, <a href="#Ultee-A--Gorris-LMG--Smid-EJ--1998-"><span class="Hyperlink">Ultee et al. (1998)</span></a> reported the antimicrobial activity of carvacrol on pathogen <span class="CharOverride-11">Bacillus cereus</span>. 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 <a href="#Figure-2-"><span class="Hyperlink">Figure 2</span></a>.</p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Heading-1--Introduction----" lang="en-GB"><span class="mw-headline CharOverride-16">METABOLISM AND EXCRETION</span><span class="mw-headline"> </span></p>
		  <p class="Heading-1--Introduction----" lang="en-GB">&nbsp;</p>
			<p class="Body-Text ParaOverride-1" lang="en-GB">The metabolism and excretion of carvacrol in the body is very quick. The major metabolic pathway of carvacrol is related to the <a href="http://en.wikipedia.org/wiki/Ester">esterification</a> of <a href="http://en.wikipedia.org/wiki/Phenol">phenolic</a> group with <a href="http://en.wikipedia.org/wiki/Glucuronic_acid">glucuronic acid</a> (C<span class="CharOverride-20">6</span>H<span class="CharOverride-20">10</span>O<span class="CharOverride-20">7</span>) and sulfuric acid (<a href="http://en.wikipedia.org/wiki/Sulfuric_acid">H<span class="CharOverride-20">2</span>SO<span class="CharOverride-20">4</span></a>). But, a minor route of carvacrol metabolism is <a href="http://en.wikipedia.org/wiki/Oxidation">transformation</a> of the end <a href="http://en.wikipedia.org/wiki/Methyl">methyl</a> groups to primary <a href="http://en.wikipedia.org/wiki/Alcohols">alcohols</a>. In an experiment on male albino rats, <a href="#Austgulen-LT--Solheim-E--Scheline-RR--1987"><span class="Hyperlink">Austgulen et al. (1987)</span></a> 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. </p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Body-Text ParaOverride-1" lang="en-GB"><a href="#Michiels-J--Missotten-J--Dierick-N--Fremaut-D--Maene-P--Smet-SD--2008"><span class="Hyperlink">Michiels et al. (2008)</span></a> 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. </p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Heading-1--Introduction----" lang="en-GB">BENEFICIAL ASPECTS OF CARVACROL</p>
		  <p class="Heading-1--Introduction----" lang="en-GB">&nbsp;</p>
			<p class="Heading-2--History-in-MM-" lang="en-GB">Improving Nutrients Bioavailability and Growth/Productive Performance</p>
			<p class="Body-Text ParaOverride-1" lang="en-GB">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. <a href="#Hashemipour-H1--Kermanshahi-H--Golian-A--Veldkamp-T--2013"><span class="Hyperlink">Hashemipour et al. (2013)</span></a> 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 (<a href="#Namkung-H--Li-M--Gong-J--Yu-H--Cottrill-M--de-Lange-CFM--2004"><span class="Hyperlink">Namkung et al., 2004</span></a>).</p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Body-Text ParaOverride-1" lang="en-GB">In 17 days old poults which ate a diet with supplementation of a plant extract containing carvacrol at 300 mg/kg diet, <a href="#Jamroz-D--Kamel-C--2002"><span class="Hyperlink">Jamroz and Kamel (2002)</span></a> observed daily body weight gain and feed conversion ratio to be improved by 8.1 and 7.7 %, respectively. <a href="#Lee-KW--Everts-H--Kappert-HJ--Frehner-M--Losa-R--Beynen-AC--2003a"><span class="Hyperlink">Lee et al. (2003a)</span></a> reported that increased efficiency of feed utilization could be the explanation of thymol and carvacrol effects on performance. <a href="#Hernandez-F--Madrid-J--Garcia-V--Orengo-J--Megias-MD--2004-"><span class="Hyperlink">Hernandez et al. (2004)</span></a> 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.</p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Body-Text ParaOverride-1" lang="en-GB"><a href="#Jaafari-A--Tilaou-M--Mouse-HA--M-bark-LA--Aboufatima-R--Chait-A--Lepoivre-M--Zyad-A--2012-"><span class="Hyperlink">Jaafari et al. (2012)</span></a> 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. <a href="#Lee-KW--Everts-H.-Kappert-HJ--Yeom-KH--Beynen-AC--2003b-."><span class="Hyperlink">Lee et al. (2003b)</span></a> 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 <a href="#Lee-KW--Eerts-H--Kappert-HJ--Beynen-AC--2004-."><span class="Hyperlink">Lee et al. (2004)</span></a> 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 <a href="#Umaya-RS--Manpal-S--2013-."><span class="Hyperlink">Umaya and Manpal (2013)</span></a>. 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 <span class="CharOverride-11">Eimeria</span> <span class="CharOverride-11">acervulina</span> (<a href="#Lillehoj-HS--Kim-DK--Bravo-DM--Lee-SH--2011-."><span class="Hyperlink">Lillehoj et al., 2011</span></a>). 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) (<a href="#Lillehoj-HS--Kim-DK--Bravo-DM--Lee-SH--2011-."><span class="Hyperlink">Lillehoj et al., 2011</span></a>). 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.</p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp; </p>
			<p class="Body-Text ParaOverride-1" lang="en-GB">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 <a href="#Yanishlieva-NV--Marinova-EM--Gordon-MH--Raneva-VG--1999-."><span class="Hyperlink">Yanishlieva et al. (1999)</span></a>; <a href="#Annalisa-L--Mastromatteo-M--Sinigaglia-M--Corbo-MR--2009-."><span class="Hyperlink">Annalisa et al. (2009)</span></a>; <a href="#Mastromatteo-M--Lucera-A--Sinigaglia-M--Corbo-MR--2009"><span class="Hyperlink">Mastromatteo et al. (2009)</span></a>; <a href="#Kim-DK--Lillehoj-HS--Lee-SH--Jang-SI--Bravo-D--2010"><span class="Hyperlink">Kim et al. (2010)</span></a> and <a href="#Akalin-G--Incesu-Z--2011-.-T"><span class="Hyperlink">Akalin and Incesu (2011)</span></a> 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.</p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Heading-2--History-in-MM-" lang="en-GB">Antiviral Activity </p>
			<p class="Body-Text ParaOverride-1" lang="en-GB">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 (<a href="#Jassim-SA--Naj--MA--2003-"><span class="Hyperlink">Jassim and Naji, 2003</span></a>; <a href="#Sokovic-M--Glamoclija-J--Marin-PD--Brkic-D--van-Griensven-LJ--2010"><span class="Hyperlink">Sokovic et al., 2010</span></a>). Carvacrol plays a key role as antiviral component against human rotavirus (RV). On the same context, Mexican oregano (<span class="CharOverride-11">Lippia graveolens</span>) 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 (<a href="#Bernstein-DI--2009"><span class="Hyperlink">Bernstein, 2009</span></a>; <a href="#Pilau-MR--Alves-SH--Weiblen-R--Arenhart-S--Cueto-AP--Lovato-LT--2011"><span class="Hyperlink">Pilau et al., 2011</span></a>).</p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Body-Text ParaOverride-1" lang="en-GB">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 (<a href="#Vimalanathan-S--Hudson-J--2012"><span class="Hyperlink">Vimalanathan and Hudson, 2012</span></a>). On the contrary, <a href="#Sokmen-M--Serkedjieva-J--Daferera-D--Gulluce-M-2004"><span class="Hyperlink">Sokmen et al. (2004)</span></a> noted that anti-influenza virus activity was not affected by supplementation of oils or extracts derived from oregano. <a href="#Gilling-DH--M-Kitajima--Torrey-JR--Bright-KR--2014-."><span class="Hyperlink">Gilling et al. (2014)</span></a> 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.</p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Heading-2--History-in-MM-" lang="en-GB">Antimicrobial Activity</p>
			<p class="Body-Text ParaOverride-1" lang="en-GB">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 (<a href="#Tsao-R--Zhou-T--2000"><span class="Hyperlink">Tsao and Zhou 2000</span></a>; <a href="#Lambert-RJW--Skandamis-PN--Coote-PJ--Nycs-GJE--2001-"><span class="Hyperlink">Lambert et al. 2001</span></a>; <a href="#Veldhuizen-EJ--Tjeerdsma-van-Bokhoven-JL--Zweijtzer-C--Burt-SA--Haagsman-HP--2006-"><span class="Hyperlink">Veldhuizen et al., 2006</span></a>; <a href="#Alagawany-MM--Farag-MR--Dhama-K--2015b"><span class="Hyperlink">Alagawany et al., 2015b</span></a>). <a href="#Sikkema-J--De-Bont-J--Poolman-B--1995"><span class="Hyperlink">Sikkema et al. (1995)</span></a>, <a href="#Adam-K--Sivropoulou-A--Kokkini-S--Lanaras-T--Arsenakis-M--1998"><span class="Hyperlink">Adam et al. (1998)</span></a>, <a href="#Weber-FJ--de-Bont-JAM--1996"><span class="Hyperlink">Weber and de Bont (1996)</span></a>, <a href="#Ben-Arfa-A--Combes-S--Preziosi-Belloy-L--Gontard-N--Chalier-P--2006-"><span class="Hyperlink">Ben-Arfa et al. (2006)</span></a> and <a href="#Nostro-A--Papalia-T--2012-."><span class="Hyperlink">Nostro and Papalia (2012)</span></a> 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.</p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Body-Text ParaOverride-1" lang="en-GB"><a href="#Arsi-K--Donoghue-AM--Venkitanarayanan-K--Kollanoor-JA--Fanatico-AC--Blore-PJ--Donoghue-DJ--2014"><span class="Hyperlink">Arsi et al. (2014)</span></a> showed that campylobacter numbers were reduced with 1% carvacrol supplementation, or a combination of both thymol and carvacrol at 0.5%. <a href="#Friedman-M--Henika-PR--Mandrell-RE--2002-."><span class="Hyperlink">Friedman et al. (2002)</span></a>,<span class="CharOverride-5"> </span><a href="#Sokovic-M--Glamoclija-J--Marin-PD--Brkic-D--van-Griensven-LJ--2010"><span class="Hyperlink">Sokovic et al. (2002)</span></a>, <a href="#Nastro-A--Blanco-AR--Cannatelli-MA--Enea-V--Flamini-G--Morelki-J--Sudano-Roccano-A--Alonzo-V--2004-"><span class="Hyperlink">Nastro et al. (2004)</span></a>,<span class="CharOverride-5"> </span>and<span class="CharOverride-5"> </span><a href="#Baser-KHC--2008"><span class="Hyperlink">Baser (2008)</span></a> found antimicrobial influences of carvacrol against many species of microbes such as <span class="CharOverride-11">Pseudomonas, Aspergillus, Salmonella, Streptococci</span>, <span class="CharOverride-11">Listeria</span>, <span class="CharOverride-11">Bacillus</span> and <span class="CharOverride-11">Fusarium</span>. <a href="#Burt-SA--Vlielander-R--Haagsman-HP--Veldhuizen-EJ--2005"><span class="Hyperlink">Burt et al. (2005</span></a> and <a href="#Burt-SA--Fledderman-MJ--Haagsman-HP--van-Knapen-F--Veldhuizen-EJ--2007"><span class="Hyperlink">2007</span></a>) observed that carvacrol supplement as antimicrobial component has a significant impact on harmful bacteria including<span class="CharOverride-11"> Escherichia coli</span> and <span class="CharOverride-11">Salmonella</span> numbers in chickens, this effect may be attributed to inhibit the growth of pathogenic bacteria by carvacrol vapour. <a href="#Johny-AK--Darre-MJ--Donoghue-AM--Donoghue-DJ--Venkitanarayanan-K--2010"><span class="Hyperlink">Johny et al. (2010)</span></a> postulated that carvacrol and eugenol decreased (<span class="Emphasis">P</span>≤ 0.05) <span class="Emphasis">Salmonella</span> Enteritidis and <span class="Emphasis">C. jejuni</span> counts in chicken cecal contents to &lt;1.0 log<span class="CharOverride-20">10</span> cfu/ml at 50 and 75 m<span class="Emphasis">M</span> and 20 and 30 m<span class="Emphasis CharOverride-21">M</span>, respectively.</p>
			<p class="Heading-2--History-in-MM-" lang="en-GB">&nbsp;</p>
		  <p class="Heading-2--History-in-MM-" lang="en-GB">Antioxidant Activity and Scavenging of Free Radicals</p>
			<p class="Body-Text ParaOverride-1" lang="en-GB">Free radicals or reactive oxygen intermediates are generated by cells during the normal metabolism. When free radicals such as superoxide radical (O<span class="CharOverride-20">2</span>.-), hydrogen peroxide (H<span class="CharOverride-20">2</span>O<span class="CharOverride-20">2</span>) 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 <a href="#Azirak-S--Rencuzogullari-E--2008"><span class="Hyperlink">Azirak and Rencuzogullari (2008)</span></a>.</p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Body-Text ParaOverride-1" lang="en-GB">Some studies assured the efficiency of carvacrol in scavenging free radicals i.e. nitric oxide, superoxide radicals, peroxyl radicals and hydrogen peroxide (<span class="Hyperlink">Kohen and Nyska, 2002</span>; <a href="#Aristatile-B--Numair-AKS--Assaf-AHA--Veeramani-C--Pugalendi-KV--2010-."><span class="Hyperlink">Aristatile et al., 2010</span></a>). 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 <span class="CharOverride-11">in vitro </span>or <span class="CharOverride-11">in vivo</span> as explained by <a href="#Aeschbach-R--Loliger-J--Scott-BC--Murcia-A--Butler-J--Halliwell-B--Aruoma-OI--1994"><span class="Hyperlink">Aeschbach et al. (1994)</span></a> and <a href="#Guimar-es-AG--Oliveira-GF--Melo-MS--Cavalcanti-2010"><span class="Hyperlink">Guimaraes et al. (2010)</span></a>. 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 (<a href="#Aristatile-B--Numair-AKS--Assaf-AHA--Veeramani-C--Pugalendi-KV--2010-."><span class="Hyperlink">Aristatile et al., 2010</span></a>). </p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Body-Text ParaOverride-1" lang="en-GB">Supplemental oregano by 50 to 100 mg/kg to broiler chick diets exerted an antioxidant effect in the broiler tissues (<a href="#Botsoglou-NA--Florou-Paner-P--Christaki-E--Fletouris-DJ--Spais-AB--2002-"><span class="Hyperlink">Botsoglou et al., 2002</span></a>). <a href="#Ruberto-G--Baratta-MT--Deans-SG--Dorman-HJ--2000"><span class="Hyperlink">Ruberto et al. (2000)</span></a>, <a href="#Alma-MH--Mavi-A--Jildirim-A--Diprak-M--Hirata-T--2003-"><span class="Hyperlink">Alma et al. (2003)</span></a>, and <a href="#Luna-A1--L-baque-MC--Zygadlo-JA--Marin-RH--2010"><span class="Hyperlink">Luna et al. (2010)</span></a> 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 (<a href="#Youdim--KA--Deans-SG--2000-"><span class="Hyperlink">Youdim and Deans, 2000</span></a>).</p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Heading-2--History-in-MM-" lang="en-GB">Immunomodulatory Effect  </p>
			<p class="Body-Text" lang="en-GB">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. <a href="#Acamovic-T--Brooker-JD--2005"><span class="Hyperlink CharOverride-12" lang="en-US">Acamovic and Brooker (2005)</span></a><span class="CharOverride-12" lang="en-US"> </span>and <a href="#Silveira-SRC--Andrade-LN--Sousa-DP--2013-."><span class="Hyperlink">Silveira et al. (2013</span></a>) 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.</p>
		  <p class="Body-Text" lang="en-GB">&nbsp;</p>
			<p class="Body-Text ParaOverride-1" lang="en-GB"><a href="#Botsoglou-NA--Florou-Paner-P--Christaki-E--Fletouris-DJ--Spais-AB--2002-"><span class="Hyperlink">Botsoglou et al. (2002</span></a><span class="Hyperlink">)</span> 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. <a href="#Lillehoj-HS--Kim-DK--Bravo-DM--Lee-SH--2011-."><span class="Hyperlink">Lillehoj et al. (2011)</span></a> 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, <a href="#Hashemipour-H1--Kermanshahi-H--Golian-A--Veldkamp-T--2013"><span class="Hyperlink">Hashemipour et al. (2013)</span></a> reported that feeding birds with diets contained carvacrol plus thymol linearly increased (<span class="CharOverride-11">P</span>&lt;0.01) the primary and secondary response against SRBC antigen and IgG.</p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Heading-2--History-in-MM-" lang="en-GB">Anti-carcinogenic and Antiplatelet Effects</p>
			<p class="Body-Text ParaOverride-1" lang="en-GB">Some natural antioxidants such as carvacrol exert anticarcinogenic and platelet antiaggregating impacts (<a href="#Karkabounas-S--Karabetsos-D--Gogos-Ch--Beka-A--Evangelou-A--1997"><span class="Hyperlink">Karkabounas et al., 1997</span></a> and <a href="#Karkabounas-S--Binolis-J--Zelovitis-J--Kotsis-N-2002"><span class="Hyperlink">2002</span></a>; <a href="#Evangelou-A--Malamas-M--Vezyraki-P--Karkabounas-S--1998"><span class="Hyperlink">Evangelou et al., 1998</span></a>; <a href="#Liasko-R--Kabanos-T--Karkabounas-S--Malamas-M--1998"><span class="Hyperlink">Liasko et al., 1998</span></a>; <a href="#Ipeka-E--Zeytinoglua-H--Okaya-S--Tuylua-BA--Kurkcuoglub-M--Can-Baserb-KH--2005-"><span class="Hyperlink">Ipeka et al., 2005</span></a>). Also, <a href="#Karkabounas-S--Kostoula-O--Daskalou-T--2006-."><span class="Hyperlink">Karkabounas et al. (2006)</span></a> and <a href="#Michiels-J--Missotten-J--Dierick-N--Fremaut-D--Maene-P--Smet-SD--2008"><span class="Hyperlink">Michiels et al. (2008)</span></a> affirmed the effect of carvacrol as anticancer and antiplatelet <span class="CharOverride-11">in vivo </span>and <span class="CharOverride-11">in vitro</span> during hepatocellular carcinoma, pulmonary tumors and chemical induced carcinogenesis. As well, <a href="#Aydin-Y--Kutlay-O--Ari-S--Duman-S--Uzuner-K--Aydin-S--2007-."><span class="Hyperlink">Aydin et al. (2007)</span></a> and <a href="#Jayakumar-S--Madankumar-A--Asokkumar-S--2012-"><span class="Hyperlink">Jayakumar et al. (2012)</span></a> suggested that carvacrol exhibits antigenotoxic activity at nontoxic concentrations (&lt;0.05 mM) but it needs more investigation. </p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Body-Text ParaOverride-1" lang="en-GB"><a href="#Arunasree-KM--2010"><span class="Hyperlink">Arunasree (2010)</span></a>, <a href="#Yin-Q--Yan-F--Zu-XY--Wu-Y--Wu-X--Liao-M--Deng-S--Yin-L--Zhuang-Y--2012"><span class="Hyperlink">Yin et al. (2012)</span></a>, and <a href="#Al-Fatlawi-AA--Rahisuddin--Ayaz-A--2014-."><span class="Hyperlink">Al-Fatlawi et al. (2014)</span></a> 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 (<a href="#Arunasree-KM--2010"><span class="Hyperlink">Arunasree, 2010</span></a>; <a href="#Mehdi-SJ--Ahmad-A--Irshad-M--Manzoor-N--Rizvi-MMA--2011"><span class="Hyperlink">Mehdi et al., 2011</span></a>).</p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Heading-2--History-in-MM-" lang="en-GB">Hepatoprotective Effect </p>
			<p class="Body-Text ParaOverride-1" lang="en-GB">In a D-galactosamine induced rat model, carvacrol exhibited a hepatoprotective role either <span class="CharOverride-11">in vivo </span>or <span class="CharOverride-11">ex vivo. </span><a href="#Aeschbach-R--Loliger-J--Scott-BC--Murcia-A--Butler-J--Halliwell-B--Aruoma-OI--1994"><span class="Hyperlink">Aeschbach et al. (1994)</span></a>, <a href="#Aristatile-B--Numair-AKS--Assaf-AHA--Veeramani-C--Pugalendi-KV--2010-."><span class="Hyperlink">Aristatile et al. (2009a)</span></a> and <a href="#Guimar-es-AG--Oliveira-GF--Melo-MS--Cavalcanti-2010"><span class="Hyperlink">Guimaraes et al. (2010)</span></a> 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.</p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Body-Text ParaOverride-1" lang="en-GB">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. <a href="#Canbek-M1--Uyanoglu-M--Bayramoglu-G--Senturk-H--1-2008"><span class="Hyperlink">Canbek et al. (2008)</span></a>, <a href="#Aristatile-B--Numair-AKS--Veeramani-C--Pugalendi-KV--2009b"><span class="Hyperlink">Aristatile et al. (2009b)</span></a> 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.</p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Heading-2--History-in-MM-" lang="en-GB">Anti-inflammatory and Anti-hypernociceptive Effects </p>
			<p class="Body-Text ParaOverride-1" lang="en-GB">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-<span class="CharOverride-22">α</span> 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. <a href="#Trabace-L--Zotti-M--Morgese-MG--Tucci-P--Colaianna-M--Schiavone-S--Avato-P--Cuomo-V--2011-"><span class="Hyperlink">Trabace et al. (2011)</span></a> 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. <a href="#Marchand-F--Perretti-M--Mahon-SB--2005"><span class="Hyperlink">Marchand el al. (2005)</span></a> 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-<span class="CharOverride-22">α</span> levels in pleural lavage. <a href="#Hotta-M--Nakata-R--Katsukawa-M--Hori-K--Takahashi-S--Inoue-H--2010-"><span class="Hyperlink">Hotta et al. (2010)</span></a>, and <a href="#Guimaraes-AG--Xavier-MA--Santana-MT--2012"><span class="Hyperlink">Guimaraes et al. (2012)</span></a> 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. <a href="#Marchand-F--Perretti-M--Mahon-SB--2005"><span class="Hyperlink">Marchand et al. (2005)</span></a>, <a href="#Kaufmann-D--Dogra-AK--Wink-M--2011-"><span class="Hyperlink">Kaufmann et al. (2011)</span></a>, and <a href="#Uyanoglu-M--Canbek-M--Ceyhan-E--Senturk-H--2011"><span class="Hyperlink">Uyanoglu et al. (2011)</span></a> had contradicting reports regarding including the antioxidant effect of carvacrol in controlling nitric oxide production and lipid peroxidation during hypernociception.</p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Heading-2--History-in-MM-" lang="en-GB">Anti-obesity Effect </p>
			<p class="Body-Text ParaOverride-1" lang="en-GB">Obesity is a <a href="http://en.wikipedia.org/wiki/Medical_condition">medical condition</a> in which excess <a href="http://en.wikipedia.org/wiki/Body_fat">body fat</a> 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. <a href="#Umaya-RS--Manpal-S--2013-."><span class="Hyperlink">Umaya and Manpal (2013)</span></a> 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.</p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Body-Text ParaOverride-1" lang="en-GB"><a href="#Wieten-L--van-der-Zee-R--Spiering-R--Wagenaar-Hilbers-J--van-Kooten-P--Broere-F--van-Eden-W--2010"><span class="Hyperlink">Wieten et al. (2010)</span></a>, and <a href="#Cho-S--Choi-Y--Park-S--Park-T--2012-"><span class="Hyperlink">Cho et al. (2012)</span></a> 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.</p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Heading-1--Introduction----" lang="en-GB">Conclusion</p>
		  <p class="Heading-1--Introduction----" lang="en-GB">&#9;</p>
			<p class="Body-Text ParaOverride-1" lang="en-GB">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. </p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Heading-1--Introduction----" lang="en-GB">ACKNOWLEDGEMENTS</p>
		  <p class="Heading-1--Introduction----" lang="en-GB">&nbsp;</p>
			<p class="Body-Text ParaOverride-1" lang="en-GB">All the authors of the manuscript thank and acknowledge their respective Universities and Institutes.</p>
		  <p class="Body-Text ParaOverride-1" lang="en-GB">&nbsp;</p>
			<p class="Heading-2--History-in-MM-" lang="en-GB"><span class="mw-headline CharOverride-24">REFERENCES</span></p>
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