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			<p class="Type-of-Article">&nbsp;</p>
			<p class="Type-of-Article"><span class="CharOverride-1">Review Article</span></p>
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			<p class="title- ParaOverride-1">&nbsp;</p>
			<p class="title- ParaOverride-1">Flavonoids: Health Promoting Phytochemicals for Animal Production-a Review</p>
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			<p class="Authors ParaOverride-1">&nbsp;</p>
			<p class="Authors ParaOverride-1"><span class="CharOverride-2">Asghar Ali Kamboh</span><span class="CharOverride-3">1</span><span class="CharOverride-2">,</span><span class="CharOverride-3"> </span><span class="CharOverride-2">Muhammad Awais Arain</span><span class="CharOverride-3">2*</span><span class="CharOverride-2">, Muhammad Jameel Mughal</span><span class="CharOverride-3">3</span><span class="CharOverride-2">, Ali Zaman</span><span class="CharOverride-3">4</span><span class="CharOverride-2">, Zeeshan Mahmood Arain</span><span class="CharOverride-3">1</span><span class="CharOverride-2">, Abdul Hameed Soomro</span><span class="CharOverride-3">5</span></p>
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			<p class="Affiliations ParaOverride-1"><span class="CharOverride-5">1</span>Department of Veterinary Microbiology, Faculty of Animal Husbandry and Veterinary Sciences, Sindh Agriculture University Tandojam 70060, Pakistan; <span class="CharOverride-5">2</span>Department of Livestock and Fisheries, Government of Sindh; <span class="CharOverride-5">3</span>Laboratory of Animal Pathology, College of Veterinary Science, Sichuan Agriculture University, Yaan, China; <span class="CharOverride-5">4</span>Gomal College of Veterinary Sciences, Gomal University Dera Ismail Khan, KPK, Pakistan; <span class="CharOverride-5">5</span>Ministry of National Food Security and Research, Animal Quarantine Department, Karachi, Pakistan.</p>
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			<p class="Abstract ParaOverride-1">&nbsp;</p>
			<p class="Abstract ParaOverride-1"><span class="CharOverride-6">Abstract</span> | Flavonoids are phytochemicals derived from plants that known to possess several surprising health effects. They have been divided into several sub-classes, among those isoflavones (soy flavonoids) and flavanones (citrus flavonoids) have aroused great interest due to their immense availability and multidimensional properties. They exert their effects both as purified molecules and as plant extracts. Their well known properties includes anti-inflammation, antioxidation, antimicrobial, antiallergic and immunomodulation, have indicated both in animal and human models. Their modulatory role in several biological processes has also been identified like  oxidation, detoxification of enzymes, apoptosis, host  immune system  and  several others.  Their potential to interfere with  numerous  cellular  processes  such as protection of genomic  vitality suggest  that flavonoids  may  used  as  dietary compounds  for promotion of health and preclusion of several infectious and non-infectious diseases. They are known to enhance the gut morphology and functionality, mucosal and cellular immunity, immune organs size and amelioration of heat stress in farm animals; that suggested them health promoting phytochemicals for animal production.</p>
		  <p class="Abstract ParaOverride-1">&nbsp;</p>
			<p class="Abstract ParaOverride-1"><span class="CharOverride-6">Keywords </span>| Animal Production, Flavonoids, Antioxidation, Immunomodulation, Gut</p>
		  <p class="Abstract ParaOverride-1">&nbsp;</p>
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			<p class="Editor----Citation"><span class="CharOverride-7">Editor</span> | Asghar Ali Kamboh, Sindh Agriculture University, Tandojam, Pakistan.</p>
			<p class="Editor----Citation"><span class="CharOverride-6">Received</span> | December 02, 2014; <span class="CharOverride-6">Revised</span> | January 11, 2015; <span class="CharOverride-6">Accepted</span> | January 12, 2015; <span class="CharOverride-6">Published</span> | January 29, 2015&#9;&#9;</p>
			<p class="Editor----Citation"><span class="CharOverride-6">*Correspondence</span> | Muhammad Awais Arain, Department of Livestock and Fisheries, Government of Sindh, Pakistan; <span class="CharOverride-6">Email:</span> awaisarain@yahoo.com </p>
			<p class="Editor----Citation"><span class="CharOverride-6">Author contribution</span> | First 2 authors Asghar Ali Kamboh and Muhammad Awais Arain contributed equally.</p>
			<p class="Editor----Citation"><span class="CharOverride-6">Citation</span> | Kamboh AA, Arain MA, Mughal MJ,  Zaman A, Arain ZM, Soomro AH (2015). Flavonoids: health promoting phytochemicals for animal production -a review. J. Anim. Health Prod. 3(1): 6-13.</p>
			<p class="Editor----Citation"><span class="CharOverride-7">DOI</span> | <a href="http://dx.doi.org/10.14737/journal.jahp/2015/3.1.6.13">http://dx.doi.org/10.14737/journal.jahp/2015/3.1.6.13</a></p>
			<p class="Editor----Citation"><span class="Editor---Citation CharOverride-6">ISSN </span>| 2308–2801</p>
			<p class="Editor----Citation"><span class="CharOverride-7">Copyright </span>© 2015 </span>Kamboh 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----">&nbsp;</p>
			<p class="Heading-1--Introduction----">&nbsp;</p>
			<p class="Heading-1--Introduction----">WHAT ARE FLAVONOIDS </p>
		  <p class="Heading-1--Introduction----">&nbsp;</p>
			<p class="Caps-on-First-Para ParaOverride-1"><span class="_idGenDropcap-1">P</span>hytochemicals are the substances found naturally in all fruits, vegetables and medicinal plants that, ingested daily or rarely, may exhibit a potential for modulating the human metabolism in a way favorable for the preclusion of chronic and degenerative diseases. These days, many  studies are conducted on thousands of phytochemicals that may have important physiological and biochemical effects. Among phytochemicals, several compounds, including flavonoids, polyphenols, stilbenes, carotenoids and anthocyanins, are known to be important for a number of health promoting effects.</p>
		  <p class="Caps-on-First-Para ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">Flavonoids have aroused enormous interest in the preceding decade because of their multidimensional health effects on human and animal health, and omnipresence in the plant kingdom. They are called as  “functional  ingredients”  and “health promoting  biomolecules”  in recent literature due to their potential role in promoting  health and preventing chronic degenerative diseases (<a href="#Nijveldt-RJ--van-Nood-E--van-Hoorn-DE--Boelens-PG--van-Norren-K--van-Leeuwen-PA--2001-."><span class="Hyperlink">Nijveldt et al., 2001</span></a>). These are polyphenolic compounds with a very little molecular  weight  based  on  a  flavan  moiety  (i.e.,  2-phenyl-benzo-<span class="CharOverride-9">γ</span>-pyrane). The basic structure of bioflavonoids consists of three rings, two benzene rings that linked together through a third heterocyclic oxygen containing pyrane ring (<a href="#Kuhnau-J--1976-."><span class="Hyperlink">Kuhnau, 1976</span></a>). Flavonoids have been divided into several sub-classes based on their C-ring structure (<a href="#Table-1-"><span class="Hyperlink">Table 1</span></a>); however, some of them are relatively important due to their universal occurrence in plant-based diets (<a href="#Middleton-E--Kandaswami-C--Theoharides-T--2000-"><span class="Hyperlink">Middleton et al., 2000</span></a>). Over 8,000 different flavonoids have been identified, many of which occur in fruits, vegetables, grains, tea, coffee and wine (<a href="#Croft-KD--1998"><span class="Hyperlink">Croft, 1998</span></a>).    </p>
			<p class="Body-Text ParaOverride-1">&nbsp;</p>
		  <p class="Body-Text ParaOverride-1">&nbsp; </p>
			<p class="Heading-1--Introduction----">BIOLOGICAL EFFECTS OF FLAVONOIDS</p>
		  <p class="Heading-1--Introduction----">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">The flavonoids have shown to possess anti-inflammatory, antioxidant, antibacterial, antiviral, hepatoprotective, antiallergic, antithrombotic, anticarcinogenic and immunomodulator activities in a number of <span class="CharOverride-10">in vitro</span> and animal model studies (<a href="#Cushnie-TPT--Lamb-AJ--2005-."><span class="Hyperlink">Cushnie and Lamb, 2005</span></a>). Their modulatory role in several biological processes has also been identified like  oxidation, detoxification  of enzymes, apoptosis, host  immune system  and  several others.  Their potential  to  interfere  with  numerous  cellular  processes  such as protection of genomic  vitality suggest  that flavonoids  may  used  as  dietary compounds  for  the  preclusion  of  cancer  and chronic degenerative  diseases (<a href="#Tapas-AR--sakarkar-DM--Kakde-RB--2008-"><span class="Hyperlink">Tapas et al., 2008</span></a>). Animal studies have declared that, flavonoids cause the inhibition  of  degranulation  of  mast cells,  basophils  and  neutrophils. These could  protect the  rat  brain  from  LPS (lipopolysaccharide) -induced shock through attenuation of lipid peroxidation and nitric oxide generation (<a href="#Abd-El-Gawad--HM---Khalifa--AE--2001-"><span class="Hyperlink">Abd El-Gawad  et al., 2001</span></a>). Furthermore, they have shown improved biological actions upon combination with each other that indicates their potential to form synergisms (<a href="#Alvarez-MA--Debattista-NB--Pappano-NB--2008-."><span class="Hyperlink">Alvarez et al., 2008</span></a>). Research has indicated that plant flavonoids cause the activation of bacterial (Rhizobium) modulated genes involved in the management of nitrogen fixation, which suggests important associations between particular flavonoids and the expression of mammalian genes; however, the real contribution of such compounds  in  health  maintenance  and  their potential for gene-nutrient interactions are still unclear. Epidemiological studies have also indicated that these phenolic compounds may play  an  important   role  in  the  health  and  preclusion  of  chronic dis orders (<a href="#Nijveldt-RJ--van-Nood-E--van-Hoorn-DE--Boelens-PG--van-Norren-K--van-Leeuwen-PA--2001-."><span class="Hyperlink">Nijveldt et al., 2001</span></a>; <a href="#Middleton-E--Kandaswami-C--Theoharides-T--2000-"><span class="Hyperlink">Middleton et al., 2000</span></a>).Recently, interest has been focused mainly on two large groups of flavonoids, i.e., soy flavonoids and citrus flavonoids.</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Heading-2--History-in-MM-">Soy Flavonoids</p>
			<p class="Body-Text ParaOverride-1">Among edible plants, legumes, particularly soybean, contains an extensive amount of hormone-like phenolic agents called phytoestrogens. They fall under two main categories i.e., isoflavones (commonly called soy flavonoids) and lignans. Isoflavones, commonly known as soy flavonoids are a large and very distinct subclass of flavonoids family. It has several important members including genistein, daidzen, glyciten etc. Isoflavone are metabolized in the intestine to a biologically active mammalian metabolites with a weak estrogenic activity. These could strongly manipulate the host enzymes, protein synthesis, cell proliferation and differentiation, and angiogenesis (<a href="#Knight-DC--Eden-JA--1996-"><span class="Hyperlink">Knight and Eden, 1996</span></a>; <a href="#Magee-PJ---Rowland--IR--2004-."><span class="Hyperlink">Magee and Rowland, 2004</span></a>). Like flavonoids they have also antioxidative, anticarcinogenic and antimicrobial properties. They are also known to important for hormone dependent diseases like menopausal symptoms, cardiovascular disease, cancer,   and osteoporosis. Substantial epidemiologic evidences have also indicated that high urine or plasma concentrations of isoflavone metabolites have a association with lower risk of cancer and heart diseases (<a href="#Setchell-KDR--Cassidy-A--1999-"><span class="Hyperlink">Setchell and Cassidy, 1999</span></a>). </p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">The chemical structure of isoﬂavones is markedly similar to mammalian estrogen. On the basis of structure, it is not surprising that isoﬂavones bind to estrogen receptors; though, their effects are more those of partial estrogen agonists and antagonists. This concept attracts steroid biochemists and endocrinologists for use of isoflavones in hormone-related disorders (<a href="#Mendelson-CR--1996-."><span class="Hyperlink">Mendelson, 1996</span></a>). In addition to their classical genomic properties these have many nonclassical actions, including effects on cell signaling pathways and plasma membranes (<a href="#Setchell-KDR--2001-"><span class="Hyperlink">Setchell, 2001</span></a>). </p>
			<p class="Body-Text ParaOverride-1">&nbsp;</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Figure--and-Table-Heading"><span class="CharOverride-6"><a id="Table-1-"></a>Table 1:</span> Main groups of ﬂavonoids, the individual compounds, and food sources</p>
			<table width="657" height="353" class="Table-Style-1" id="table-1">
				<colgroup>
					<col class="_idGenTableRowColumn-1" />
					<col class="_idGenTableRowColumn-2" />
					<col class="_idGenTableRowColumn-3" />
				</colgroup>
				<tbody>
					<tr class="_idGenTableRowColumn-4">
						<td>
							<p class="Basic-Paragraph"><span class="CharOverride-11">Flavonoids sub-class</span></p>
						</td>
						<td>
							<p class="Basic-Paragraph"><span class="CharOverride-11">Commonly occurring compound </span></p>
						</td>
						<td>
							<p class="Basic-Paragraph"><span class="CharOverride-11">Main food source</span></p>
						</td>
					</tr>
					<tr class="_idGenTableRowColumn-5">
						<td>
							<p class="Basic-Paragraph"><span class="CharOverride-12">Flavones</span></p>
						</td>
						<td>
							<p class="Basic-Paragraph"><span class="CharOverride-12">Apigenin, Sibelin, Chrysin, Rutin, Luteolin</span></p>
						</td>
						<td>
							<p class="Basic-Paragraph"><span class="CharOverride-12">Apple skins, Berries, Broccoli, Celery, Fruit peels, Cranberries, Grapes, Lettuce, Olives, Onions, Parsley</span></p>
						</td>
					</tr>
					<tr class="_idGenTableRowColumn-6">
						<td>
							<p class="Basic-Paragraph"><span class="CharOverride-12">Flavonols</span></p>
						</td>
						<td>
							<p class="Basic-Paragraph"><span class="CharOverride-12">Isorhamnetin, Kaempferol, Myricetin, Quercetin</span></p>
						</td>
						<td>
							<p class="Basic-Paragraph"><span class="CharOverride-12">Nearly ubiquitous in all plant foods</span></p>
						</td>
					</tr>
					<tr class="_idGenTableRowColumn-5">
						<td>
							<p class="Basic-Paragraph"><span class="CharOverride-12">Flavanones</span></p>
						</td>
						<td>
							<p class="Basic-Paragraph"><span class="CharOverride-12">Hesperetin, Fisetin, Narigin, Naringenin, Taxifolin, Neohesperidin, Neoeriocitrin</span></p>
						</td>
						<td>
							<p class="Basic-Paragraph"><span class="CharOverride-12">Citrus fruits and tomatoes</span></p>
						</td>
					</tr>
					<tr class="_idGenTableRowColumn-7">
						<td>
							<p class="Basic-Paragraph"><span class="CharOverride-12">Isoflavones</span></p>
						</td>
						<td>
							<p class="Basic-Paragraph"><span class="CharOverride-12">Daidzein, Genistein, glyciten, Biochanin A, Formononentin</span></p>
						</td>
						<td>
							<p class="Basic-Paragraph"><span class="CharOverride-12">Soybean and soy foods</span></p>
						</td>
					</tr>
					<tr class="_idGenTableRowColumn-8">
						<td>
							<p class="Basic-Paragraph"><span class="CharOverride-12">Flavanol</span></p>
						</td>
						<td>
							<p class="Basic-Paragraph"><span class="CharOverride-12">Catechin, Epicatechin, Epigallocatechin-3-gallate, Epicatechin-3-gallate</span></p>
						</td>
						<td>
							<p class="Basic-Paragraph"><span class="CharOverride-12">Teas, red grapes and red wines</span></p>
						</td>
					</tr>
					<tr class="_idGenTableRowColumn-9">
						<td>
							<p class="Basic-Paragraph"><span class="CharOverride-12">Anthocyanins </span></p>
						</td>
						<td>
							<p class="Basic-Paragraph"><span class="CharOverride-12">Cyanidin, Delphinidin, Petunidin, Pelargonidin, Malvidin, Peonidin</span></p>
						</td>
						<td>
							<p class="Basic-Paragraph"><span class="CharOverride-12">Berries (blueberries, Red grapes, Strawberries)</span></p>
						</td>
					</tr>
				</tbody>
			</table>
			<p class="Figure--and-Table-Heading ParaOverride-1">&nbsp;</p>
		  <p class="Figure--and-Table-Heading ParaOverride-1"><span class="CharOverride-5">1 </span>Anonynmous, (2014)</p>
			<p class="Heading-2--History-in-MM-">&nbsp;</p>
		  <p class="Heading-2--History-in-MM-">Citrus Flavonoids</p>
			<p class="Body-Text ParaOverride-1">Citrus flavonoids belongs to flavonoid sub-class flavanones. In nature, these are found in glycoside and aglycone forms. Among aglycone forms, quercetin, naringenin and hesperitin are the main flavonoids. Whereas, the glycoside forms can be further classified into rutinosides and neohesperidosides (<a href="#Djoukeng-JD--Arbona-V--Argamasilla-R--Gomez-Cadenas-A--2008"><span class="Hyperlink">Djoukeng et al., 2008</span></a>). Neohesperidosides (e.g., naringin, neohesperidin and neoeriocitrin) contain  a  sugar  neohesperidose  (rhamnosyl-a-1, 2  glucose)  and  they  are  bitter in  taste, while  rutinosides  (rutin, hesperidin  and  didymin)  contain  a  disaccharide  residue  e.g., rutinose  (ramnosyl-a-1,6  glucose)  which makes them  tasteless (<a href="#Macheix-J--Fleuriet-A--Billot-J--1990"><span class="Hyperlink">Macheix et al., 1990</span></a>).</p>
		  <p class="Body-Text ParaOverride-1">&nbsp; </p>
			<p class="Body-Text ParaOverride-1">Citrus flavonoids fall under the flavonoid subclass of flavanones and usually these are found in diglycoside form, that results the typical taste of citrus fruits (<a href="#Macheix-J--Fleuriet-A--Billot-J--1990"><span class="Hyperlink">Macheix et al., 1990</span></a>). Knowledge of citrus fruits is paramount to understand their role in human and animal health and it is well established that some of the nutrients in citrus promote health and provide protection against chronic diseases. Hesperidin, a well known citrus flavonoid is known to be very important for health maintenance. Insufficiency of this compound in the human diet has been  linked  with abnormal  capillary  leakiness  as  well  as  pain  in  the extremities  causing  aches,  weakness  and  leg  cramps (<a href="#Simitzis-PE--Symeon-GK--Charismiadou-MA--2011-"><span class="Hyperlink">Simitzis et al., 2011</span></a>). Several <span class="CharOverride-10">in vitro</span> and <span class="CharOverride-10">in vivo</span> experiments have indicate that citrus fruits could exhibit many health promoting activities including inhibition of initiation, promotion and hyperproliferation of cancer cells (<a href="#De-Leo-F--Del-Bosco-FS--2005--1"><span class="Hyperlink">De Leo and Del Bosco, 2005</span></a>; <a href="#Jayaprakasha-GK--Ohnishi-Kameyama-M--Ono-H--Yoshida-M--Rao-LJ--2006-"><span class="Hyperlink">Jayaprakasha et al., 2006</span></a>). It has been estimated that  health  promoting effects of  citrus  juices  derived  from  the  interaction of several chemopreventive agents, including flavonoids and isoflavonoids; however studies evaluating the role of pure substances are still required.  </p>
			<p class="Body-Text ParaOverride-1">&nbsp;</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Heading-1--Introduction----">INTERACTION OF FLAVONOIDS WITH OTHER COMPOUNDS</p>
		  <p class="Heading-1--Introduction----">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">Recent literature has indicated that polyphenols and flavonoids could interact synergistically with other compounds like drugs (<a href="#Alvarez-MA--Debattista-NB--Pappano-NB--2008-."><span class="Hyperlink">Alvarez et al., 2008</span></a>), vitamins (Fujisawa et al., 2006) and with other flavonoids (<a href="#Mikstacka-R--Rimando-A--Ignatowicz-E--2010"><span class="Hyperlink">Mikstacka et al., 2010</span></a>). However, some of their interactions lead to antagonistic effects. These activity-related interactions (synergism, additive or antagonism) of flavonoids with other compounds and co-antioxidants have not fully elucidated yet, but it is generally recognized that, it depends upon the structures of the compounds and on the micro-environment of the reaction system (<a href="#Fujisawa-S--Ishihara-M--Atsumi-T--Kadoma-Y--2006"><span class="Hyperlink">Fujisawa et al., 2006</span></a>). A recent study has suggested that synergistic or antagonistic antioxidative effects depend upon concentration; low concentrations exhibit synergistic antioxidative effects while the high concentration demonstrates additive effects (<a href="#Mikstacka-R--Rimando-A--Ignatowicz-E--2010"><span class="Hyperlink">Mikstacka et al., 2010</span></a>), however, these observations need to be elucidated further for a firm conclusion. Some other recent studies have reported the synergistic effects of flavonoids for antioxidation (<a href="#Mikstacka-R--Rimando-A--Ignatowicz-E--2010"><span class="Hyperlink">Mikstacka et al., 2010</span></a>), platelet aggregation (<a href="#Pignatelli-P--Pulcinelli-FM--Celestini-A--Lenti-L--Ghiselli-A--Gazzaniga-PP--Violi-F.--2000-"><span class="Hyperlink">Pignatelli et al., 2000</span></a>), antimicrobial activity (<a href="#Alvarez-MA--Debattista-NB--Pappano-NB--2008-."><span class="Hyperlink">Alvarez et al., 2008</span></a>) and for enhanced quality and shelf life of meat (<a href="#Kamboh-AA--Zhu-WY--2013a"><span class="Hyperlink">Kamboh and Zhu, 2013a</span></a>). These studies have opened a new era of research for enhanced effects  of phytochemicals and other compounds in reduced cost (in terms of low doses) to improve animal health and production.  </p>
			<p class="Body-Text ParaOverride-1">&nbsp;</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Heading-1--Introduction----">GUT MODULATORY ACTIVITY OF FLAVONOIDS </p>
		  <p class="Heading-1--Introduction----">&nbsp;</p>
			<p class="Body-Text ParaOverride-1"> In poultry, at the time of hatching the intestinal morphology is not yet fully developed and undergoes dramatic changes in the post-hatch period. It is estimated that villus surface area (villus height x villus width) increases in all regions until 3 days of age (<a href="#Lan-Y--2004-.-G"><span class="Hyperlink">Lan, 2004</span></a>). Increased villus height or villus width suggests an increased surface area capable of greater absorption of available nutrients which regulate the nutritional status, improve development and health of the bird. On the other hand, short villi with deeper crypts may lead to deprived nutrient absorption and increased secretion in the gastrointestinal tract, resulting poor growth and performance (<a href="#Awad-WA--Ghareeb-K--Bohm-J--2011-"><span class="Hyperlink">Awad et al., 2011</span></a>). The crypt is known to be a villus factory and a large crypt indicates rapid tissue turnover and a high demand for new tissue. Intestinal epithelial cells originate at the base of the crypts as immature proliferative cells, differentiate and migrate along the villus surface upward to the villus tip, and are finally extruded into the intestinal lumen (<a href="#Hu-Z--Guo-Y--2007-"><span class="Hyperlink">Hu and Guo, 2007</span></a>). Though, the data on the effects of purified flavonoids on histological morphometry of the small intestine is very scarce. But in recent studies, several researchers have reported the gut promotory effects of herbal plants containing adequate amounts of flavonoids in several species of farm animals and poultry; and suggested the antioxidant polyphenols as an important tool to modulate the functional architecture of the small intestine (<a href="#Awad-WA--Ghareeb-K--Bohm-J--2011-"><span class="Hyperlink">Awad et al., 2011</span></a>; <a href="#Viveros-A--Chamorro-S--Pizarro-M--Arija-I--Centeno-C--Brenes-A--2011-"><span class="Hyperlink">Viveros et al., 2011</span></a>). Some more recent studies have declared that purified flavonoids genistein and hesperidin (<a href="#Kamboh-AA--Zhu-WY--2014-."><span class="Hyperlink">Kamboh and Zhu, 2014</span></a>) and flavonoids-rich fermented Ginkgo biloba leaves (<a href="#Zhang-X--Zhao-L--Cao-F--Ahmad-H--Wang-G--Wang-T--2014-"><span class="Hyperlink">Zhang et al., 2014</span></a>) could promote the intestinal morphology and absorptive function in growing broilers. Interestingly, while both studies indicated the potential of flavonoids to minimize the deleterious effects  of  LPS  and  improved  intestinal  development in immune-stressed chickens. Likewise, another study suggested the spasmogenic effects of <span class="CharOverride-10">Berberis lycium</span> in rabbits and guinea pigs; and suggested its use to modulate gut environment to control diarrhea,  intestinal  cramps  and other gastrointestinal disorders in animals (<a href="#Shafeeq-ur-Rahaman-M--Chaudhary-MA--Ahmad-B--Alamgeer-A--2013-"><span class="Hyperlink">Shafeeq-ur-Rahaman et al., 2013</span></a>). The exact mechanism by which these polyphenols modulate the intestinal architecture is not known, but it is hypothesized that morphometric improving effects might be the protective effect of these compounds of pro-apoptotic oxidant stress to gut epithelial cells (<a href="#Miller-MJS--Angeles-FM--Reuter-BK--Bobrowski-P--Sandoval-M--2001-."><span class="Hyperlink">Miller et al., 2001</span></a>) or modulating the intestinal microflora that play an instructive role in the regulation of villus morphology (<a href="#Hooper-LV--Wong-MH--Thelin-A--Hansson-L--Falk-PG---Gordon-JI--2001-"><span class="Hyperlink">Hooper et al., 2001</span></a>). </p>
			<p class="Body-Text ParaOverride-1">&nbsp;</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Heading-1--Introduction----">ANTIOXIDATIVE ACTIVITY OF FLAVONOIDS</p>
		  <p class="Heading-1--Introduction----">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">All aerobic organisms, including human beings generate free radicals and other reactive oxygen species like hydroxyl radical (OH•), the superoxide radical (O<span class="CharOverride-13">2</span>•), the nitric oxide radical (NO•) and the lipid peroxyl radical (LOO•) under certain conditions (<a href="#Rong---T----Zeyuan---D--2004-."><span class="Hyperlink">Rong and Zeyuan, 2004</span></a>). These are the by-products of normal processing of oxygen in the body that we breathe and the food we eat. Environmental pollutants, industrial chemicals, ultraviolet light and exercise also contribute to the production of free radicals in the body (<a href="#Mojzisova-G--Kuchta-M--2001"><span class="Hyperlink">Mojzisova and Kuchta, 2001</span></a>). The process by which these radical damage the cellular structures are not fully understood, but it is generally recognized that cellular damages cause a change in the net charge of the cell, thus chang the osmotic pressure of the cell that lead to swelling and ultimate death of cell.  Furthermore, free radical attract various inﬂammatory mediators that lead to inﬂammation and tissue damage (<a href="#Nijveldt-RJ--van-Nood-E--van-Hoorn-DE--Boelens-PG--van-Norren-K--van-Leeuwen-PA--2001-."><span class="Hyperlink">Nijveldt et al., 2001</span></a>). </p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">In order to protect from ROS, living organisms endowed with extensive antioxidant defense mechanisms to neutralize the damaging effects of toxic oxygen species. These include enzymes such as superoxide dismutase, glutatione peroxidase and catalase; and some non-enzymatic counterparts like glutathione, ascorbic acid, and <span class="CharOverride-9">α</span>-tocopherol (<a href="#Mikstacka-R--Rimando-A--Ignatowicz-E--2010"><span class="Hyperlink">Mikstacka et al., 2010</span></a>).  However, when the balance between ROS and antioxidants is altered, a state of oxidative stress appeared, that possibly lead to permanent cellular damages. There is growing evidence that oxidative stress is the causative agent in a number of human and animal diseases, such as chronic inflammatory disorders, cancer, atherosclerosis, ischemic injury, aging, and neurodegenerative diseases (<a href="#Kamboh-AA--2012-."><span class="Hyperlink">Kamboh, 2012</span></a>). Reparative processes may not completely eliminate the damage of biological macromolecules. A much more effective way is the prevention, such as decreasing of sources that cause free radical formation, and strengthening of the natural antioxidant mechanism by using antioxidative agents. For this reason, special attention is paid to the search of agents with powerful antioxidant potential (<a href="#Mojzisova-G--Kuchta-M--2001"><span class="Hyperlink">Mojzisova and Kuchta, 2001</span></a>).</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">The best described property of almost all flavonoids is their antioxidative activity, which reported far exceeds that of well-known antioxidant vitamins (C and E) and carotenoids in <span class="CharOverride-10">in vitro</span> and <span class="CharOverride-10">in vivo</span> studies (<a href="#Middleton-EJ--1996-.-Biolo"><span class="Hyperlink">Middleton, 1996</span></a>). These are known to scavenge or inhibit the production of several kinds of free radicals and reactive oxygen species, which are the major cause of autoimmune and chronic inflammatory diseases in humans and animals like pulmonary hypertension syndrome (also called ascites) of broilers (<a href="#Iqbal-M--Cawthon-D--Beers-K--Wideman-RF-Jr--Bottje-WG--2002"><span class="Hyperlink">Iqbal et al., 2002</span></a>). Studies in broilers have declared that isoflavone and flavanone could improve the plasma antioxidant status of growing chickens (<a href="#Kamboh-AA--Zhu-WY--2013b-."><span class="Hyperlink">Kamboh and Zhu, 2013b</span></a>) and also modify the biomarkers of heat-stress towards the positive direction (<a href="#Kamboh-AA--Hang-SQ--Bakhetgul-M--Zhu-WY--2013-."><span class="Hyperlink">Kamboh et al., 2013</span></a>) probably due to their quenching action on free radical and ROS generated by heat stress. Some other studies in laboratory and farm animals have indicated that bioflavonoids could reduce the oxidative stress; thus could improve the performance of farm animals (<a href="#Abd-El-Gawad--HM---Khalifa--AE--2001-"><span class="Hyperlink">Abd El-Gawad  et al., 2001</span></a>; <a href="#Hager-Theodorides-AL--Goliomytis-M--Delis-S--Deligeorgis-S--2014-"><span class="Hyperlink">Hager-Theodorides et al., 2014</span></a>).</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">Flavonoids inhibit oxidation through a variety of mechanisms and their protective  effects  in  biological  systems  are  ascribed  to  their  capacity  to  transfer  free  radical  electrons,  chelate  metal  catalysts,  activate  antioxidant enzymes, reduce alpha-tocopherol radicals and inhibit oxidases (<a href="#Middleton-E--Kandaswami-C--Theoharides-T--2000-"><span class="Hyperlink">Middleton et al., 2000</span></a>; <a href="#Nijveldt-RJ--van-Nood-E--van-Hoorn-DE--Boelens-PG--van-Norren-K--van-Leeuwen-PA--2001-."><span class="Hyperlink">Nijveldt et al., 2001</span></a>). Recent work has suggested that the cellular effects of ﬂavonoids may be mediated by their interactions with speciﬁc proteins that are central to some intracellular signaling cascades. In particular, ﬂavonoids may act selectively with different components of protein kinase signaling cascades, like asphosphoinositide 3-kinase, protein kinase C, Akt/protein kinase B and etc,. (<a href="#Hou-DX--Kumamoto-T--2010-"><span class="Hyperlink">Hou and Kumamoto, 2010</span></a>). </p>
			<p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Heading-1--Introduction----">IMMUNOMODULATORY ACTIVITY OF FLAVONOIDS</p>
		  <p class="Heading-1--Introduction----">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">All vertebrates possess the well defined immune system that  protect  the  host  from  infectious  agents  present  in  the environment (e.g., viruses, bacteria, fungi) and from other deleterious insults. Dietary phytochemicals with antioxidant properties such as flavonoids are known to improve the immune response in all taxa of vertebrates. The dietary polyphenols not only stimulate the immune system but also cause the modulation of detoxification enzymes, scavenging of oxidative agents and regulation of gene expression in cells (<a href="#Catoni-C--Peters-A--Schaefer-M--2008-"><span class="Hyperlink">Catoni et al., 2008</span></a>). The effect of soy (<a href="#Sakai-T--Kogiso-M---2008-"><span class="Hyperlink">Sakai and Kogiso, 2008</span></a>) and citrus fruits (<a href="#Silalahi-J--2002-."><span class="Hyperlink">Silalahi, 2002</span></a>) on the different constituents of humoral and cellular immunity has been reviewed recently. Evidences suggested that epigallocatechin gallate and cyanidin glycosides rich juices could enhance the IL-2 secretion, lymphocyte proliferation and lytic activity of NK cells (<a href="#Bub-A--Watzl-B--Blockhaus-M--Briviba-K--Liegibel-U--M-ller-H--Pool-Zobel-BL--Rechkemmer-G--2003"><span class="Hyperlink">Bub et al., 2003</span></a>). A mini review by Chen and coworkers indicated that intake of flavonoid-enriched purple sweet potato leaves could produce a significant increase in proliferation responsiveness of peripheral blood mononuclear cells with enhanced secretions of immunoreactive IL-2 and IL-4 cytokines. As well, increased lytic activity in NK cells and salivary IgA secretion was also observed (<a href="#Chen-CM--Li-SC--Lin-YL--Hsu-CY--Shieh-MJ--Liu-JF--2005"><span class="Hyperlink">Chen et al., 2005</span></a>). The mechanisms underlying this phenomenon are not fully understood, but it is generally hypothesized that the intake of antioxidants may reduce the harmful effects of free radicals and ROS on the immune response that results the better performance of the immune system (<a href="#Sakai-T--Kogiso-M---2008-"><span class="Hyperlink">Sakai and Kogiso, 2008</span></a>).</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">Several animal studies also supporting that polyphenols and flavonoids are immune cocktails. In a mice study, it was observed that berry juice could increase the splenic weight and the number of splenic macrophages. There was a corresponding increase in splenic phagocytic cells with increasing doses of juice (<a href="#Chao-S--Schreuder-M--Young-G--Nakaoka-K--Moyes-L--Oberg-C--2004"><span class="Hyperlink">Chao et al., 2004</span></a>). In mouse tumor model, antitumor effects of grape seed proanthocyanidins were observed via the immunomodulatory mechanism. The study suggested that proanthocyanidins could increase the splenic lymphocyte proliferation, CD4+/CD8+ ratio, NK cell cytotoxicity, IFN-<span class="CharOverride-9">γ</span> and IL-2 productions (<a href="#Zhang-XY--Li-WG--Wub-YJ--2005-."><span class="Hyperlink">Zhang et al., 2005</span></a>). Plum, a flavonoid-rich fruit (contains 118 to 237 mg/100g) has been documented for its immune enhancing effect. In chicken study challenged with <span class="CharOverride-10">Eimeria acervulina</span>, it was observed that plum powder reduced the fecal oocyst shedding, and increased the levels of mRNAs for IL-15 and interferon-<span class="CharOverride-9">γ</span>. Furthermore, chickens fed plum diets exhibited significantly greater spleen cell proliferation (<a href="#Lee-CK--Park-KK--Hwang-JK--Lee-SK--Chung-WY--2007-."><span class="Hyperlink">Lee et al., 2007</span></a>). A recent study has demonstrated that citrus and soy flavonoids could significantly improve the immunity of LPS-challenged broilers. The study suggested the use of plant flavonoids as a feed additive to ameliorate the negative effects of circulatory low dose endotoxaemia on animal production (<a href="#Kamboh-AA--Zhu-WY--2014-."><span class="Hyperlink">Kamboh and Zhu, 2014</span></a>). Another study, addressed the IgY enhancing effects of supplemental quercetin in growing broilers, that obviously indicated the potential of quercetin to promote mucosal immunity (<a href="#Hager-Theodorides-AL--Goliomytis-M--Delis-S--Deligeorgis-S--2014-"><span class="Hyperlink">Hager-Theodorides et al., 2014</span></a>). </p>
			<p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Heading-1--Introduction----">Conclusion</p>
		  <p class="Heading-1--Introduction----">&nbsp;</p>
		  <p class="Body-Text ParaOverride-1">It has been estimated that free radicals and ROS are involved in the etiology of several human and animal diseases and also responsible for the significant reduction in animal production. Evidences have suggested that phytochemicals especially the flavonoids could reduce the oxidative stress at the cellular level, thus can improve the genomic stability and cellular integrity. These flavonoids also known to improve immunity and gut function that ultimately  reduce the risk of infectious diseases and increase animal performance. Moreover, these could produce the syngerisms with each other and other organic and synthetic growth promoters. Hence, these flavonoidal compounds, both in purified and phytoextracts–form could be the potential candidates to improve the production of farm animals.</p>
		  <p class="Body-Text ParaOverride-1"><br />
	      </p>
			<p class="Heading-1--Introduction----">Acknowledgement</p>
		  <p class="Heading-1--Introduction----">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">Sincere thanks go to Prof. Zhu Weiyun and all teaching staff of laboratory of GIT microbiology, Nanjing Agricultural University, China.</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Heading-1--Introduction----">References </p>
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