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BIOLOGÍA FARMACÉUTICA 2021, VOL. 59, NO. 1, 285- https://doi.org/10.1080/13880209.2021. ARTÍCULO DE REVISIÓN
Revisión de los efectos antiinflamatorios, antioxidantes e inmunomoduladores
de Allium cepa y sus principales componentes
Narges Marefatia,b, Vahideh Ghorania,b, Farzaneh Shakeric,d, Marzie Boskabadye,f, Farzaneh Kianiang, Ramin
Rezaeeh and Mohammad Hosein Boskabady
a,
b Centro de Investigación Biomédica, Universidad de Ciencias Médicas de Mashhad, Mashhad, Irán; (^) bDepartamento de Fisiología, Facultad de Medicina, Universidad de Ciencias Médicas de Mashhad, Mashhad, Irán; (^) Centro de Investigación de Productos Naturales y Plantas Medicinales, Universidad de Ciencias Médicas del Norte de Khorasan, Bojnurd, Irán; dDepartamento^ de Fisiología, Facultad de Medicina, Universidad de Ciencias Médicas del Norte de Khorasan, Bojnurd, Irán; Centro de Investigación de Materiales eDental^ y Departamento de Odontología Pediátrica, Facultad de Odontología, Universidad de Ciencias Médicas de Mashhad, Mashhad, Irán; Departamento^ de Odontología Pediátrica de la Facultad de Odontología de la Universidad de Ciencias Médicas de Mashhad; gDepartamento^ de Fisiología, Facultad de Medicina, Universidad de Ciencias Médicas de Teherán, Teherán, Irán; hUnidad de Investigación Clínica, Facultad de Medicina, Universidad de Ciencias Médicas de Mashhad, Mashhad, Irán ABSTRACTO Contexto: Allium cepa L. (Liliaceae), conocida como cebolla, se consume en todo el mundo. La cebolla y sus derivados incluyendo saponinas, agliconas, quercetina, cepanas, flavonoides, organosulfuros y compuestos fenólicos, mostraron varias propiedades farmacológicas y efectos terapéuticos. Objetivo: Se presentan los efectos antiinflamatorios, antioxidantes e inmunomoduladores de A. cepa y sus principales componentes, junto con los mecanismos moleculares subyacentes. Métodos: Se revisaron bases de datos como Web of Knowledge, Medline/PubMed, Scopus y Google Scholar para buscar artículos publicados entre 1996 y finales de julio de 2020, utilizando las palabras clave Allium cepa, quercetina, antiinflamatorio, antioxidante e inmunomodulador. Resultados: A. cepa y sus constituyentes principalmente quercetina mostraron efectos antiinflamatorios mediados por la reducción de recuentos totales y diferenciales de GB, inhibición de quimiotaxis de leucocitos polimorfonucleares, Las vías COX y LOX previenen la formación de leucotrienos y tromboxanos, prostaglandina E2 (PGE2) como onVCAM-1, NF-jB, MARK,d STAT-1, JNK, p38 y osteoclastogénesis. A. cepa y sus derivados mostraron efecto antioxidante al disminuir la peroxidación de lípidos, NAD(P)H, MDA, NO, LPO y eNOS, pero potenciando antioxidantes como las actividades SOD, CAT, GSH, GPx, GSPO, TrxR, SDH, GST y GR y el nivel de tiol. Los efectos inmunomoduladores de la planta y la quercetina también se mostraron por la reducción de las citoquinas Th2, IL-4, IL-5 e IL-13, así como los niveles de IL-6, IL-8, IL-10, IL-1b y TNF-a e IgE, pero el aumento de las células CD4, el nivel de IFN-c y la relación IFN-c/IL4 (Th1/Th2). Conclusiones: El efecto de la cebolla y sus constituyentes sobre el estrés oxidativo, el sistema inflamatorio y el sistema inmunológico se mostraron indicando su valor terapéutico en el tratamiento de diversas enfermedades asociadas con el estrés oxidativo, la inflamación y la desregulación inmune. HISTORIAL DE ARTÍCULOS Recibido 25 febrero 2020 Revisado 13 mayo 2020 Aceptado 5 enero 2021 PALABRAS CLAVE Cebolla; flavonoides; fenólico; inflamación; estrés oxidativo; quercetina Introducción Allium cepa L. (Liliaceae) se conoce comúnmente como cebolla. La familia Liliaceae incluye más de 250 géneros y 3700 especies (Nasri et al. 2012 ; Akash et al. 2014 ; Bisen y Esmeralda 2016 ). La cebolla, una de las plantas cultivadas más antiguas (Lanzotti 2006 ), se originó en Asia central (Benkeblia 2004 ; Albishi et al. 2013 ) y actualmente se cultiva en todo el mundo, especialmente en zonas con climas moderados (Nasri et al. 2012 ; Bisen y Esmeralda 2016 ). A. cepa se caracteriza por su color (amarillo, rojo o blanco) y sabor (dulce o no dulce) (Benkeblia 2004 ; Albishi et al. 2013 ). Se consume fresco en polvo, como aceite esencial (Corea et al. 2005 ; Takahashi y Shibamoto 2008 ), y como especia para potenciar el sabor de los alimentos debido a su olor y sabor (Bouba et al. 2014 ). A. cepa contiene varios componentes (Benmalek et al. 2013 ) y muestra varias propiedades farmacológicas. El uso más antiguo de A. cepa fue reportado desde el antiguo Egipto donde fue utilizado debido a sus propiedades antimicrobianas, antiinflamatorias y otras propiedades curativas (Dorsch et al. 1988 ). Desde la antigüedad, también ha sido reconocido como un tratamiento eficaz para enfermedades estomacales, infecciones de garganta y hepatitis (Akash et al. 2014 ). En la medicina china, el té A. cepa se usa contra la fiebre, el dolor de cabeza, el cólera, la disentería, el resfriado común y la artritis (Corzo-Martınez et al. 2007 ). Esta planta también se utilizó como antifúngico (Lanzotti 2006 ), anticancerígeno, antiinflamatorio (Elberry et al. 2014 ), antioxidante, antiespasmódico (Albishi et al. 2013 ; Benmalek et al. 2013 ), antimicrobiano, antimutagénico (Shri y Bora 2008 ), antidiabético (Ali et al. 2000 ; El-Aasr et al. 2010 ; Nasri et al. 2012 ), antiplaquetario (Galmarini et al. 2001 ) y antiasmático (Takahashi y Shibamoto 2008 ). Además, A. cepa mostró propiedades antimicrobianas, antitrombóticas, antitumorales, anti- hiperlipídicas, anti-artríticas, anti-hiperglucémicas anticancerígenas (Upadhyay 2017). CONTACTO Mohammad Hosein Boskabady boskabadymh@mums.ac.ir Centro de Investigación Biomédica Aplicada, Universidad de Ciencias Médicas de Mashhad, Irán 2021 El Autor(es). Publicado por Informa UK Limited, operando como Taylor & Francis Group.
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polifenoles. La cebolla amarilla tiene los niveles más altos de flavonoides, 11 veces más altos que el de la cebolla blanca. La cebolla roja contiene cantidades significativas de antocianina y tiene un contenido de flavonoides del 10% (Yang et al. 2004 ; Slimestad et al. 2007 ). Dos grupos de sustancias químicas que son abundantes en cebollas y tienen beneficios para la salud de los seres humanos, incluyen flavonoides y sulfóxidos de alquilista cisteína (Griffiths et al. 2002 ). Cerca de 31 proteínas únicas en la epidermis inferior (LE) y la epidermis superior (UE) de las escamas de bulbo de cebolla se identificaron que participan en la síntesis de pigmento, respuesta al estrés y la división celular. Las diferencias en la isomerasa de chalcone-flavanona y la flavona O-metiltransferasa 1- similar en la LE de la escala de cebolla, se mostraron responsables de los colores rojo y amarillo de las cebollas. Además, las diferencias en la proteína 1-similar a la UDP-ara-binopiranosa mutasa y la b-1,3-glucanasa en la LE, pueden estar relacionadas con las diferencias en los tamaños celulares en LE y UE de cebollas rojas y amarillas (Wu et al. 2016). También se demostró que las cebollas contienen alisulfuros y flavonoides, incluida la quer-cetina, que ejercen actividades antioxidantes y podrían reducir la apoptosis de los hepatocitos; también, cebolla contiene saponinas y sapogeninas esteroides, y b-clorogenina que es una sapogenina esteroide característica. Los otros constituyentes de A. cepa son compuestos organosulfurados, incluyendo DATS, disulfuro de dialilo (DADS), ajoene y salicilmercaptocisteína (SAMC), con efecto de detención del ciclo celular en células cancerosas (Upadhyay 2017 ). Los polifenoles totales son 444,3-1591 mg/kg en el ajo (A. sativum L.), el cebollino (A. schoenoprasum L.), la cebolla silvestre (A. ursinum L.) y la cebolla roja, amarilla y blanca (A. cepa L.) que disminuyen en el orden de cebolletas > cebolla roja > cebolla amarilla > cebolla silvestre
cebolla blanca (Lenkova et al. 2016 ). El análisis fitoquímico de A. cepa L. y A. cornutum utilizando cromatografía líquida de alto rendimiento (HPLC), mostró que dos conjugados de quercetina, (1) y (2), representan alrededor del 80% del contenido total de flavonol en ambas cebollas (Fredotovic et al. 2017 ). Las concentraciones más altas de quercetina, quercetina 3-b-D- glucósido, luteolina y kaempferol en cv. 'NHRDF Red' (11,885.025 mg/kg), 'Hissar-20. (1432,875 mg/kg), 'Pusa Riddhi' (1669,925 mg/kg) y 'Bhima Shakti' (709, mg/kg), se encontraron en la piel seca de 15 cultivares de cebolla de la India cuando su concentración de flavoides, contenido fenólico total (TPC) y contenido total de flavon (TFC) se examinaron. Además, el cv. 'NHRDF Red' tenía el contenido más alto, mientras que el cv 'Bhima Shubhra' tenía el contenido más bajo de TPC y TFC (Sagar et al. 2020 ). Los componentes detallados de A. cepa figuran en el cuadro 1. Efectos antiinflamatorios de A. cepa La inflamación es una reacción defensiva del cuerpo para eliminar los factores dañinos y restablecer la homeostasis doméstica. En el proceso de inflamación, el flujo sanguíneo aumenta en el sitio dañado debido a la liberación de agentes vasodilatadores, mejora la permeabilidad capilar y se aumenta la migración de los glóbulos blancos al sitio inflamado; estos conducen a la aparición de los síntomas clásicos de la inflamación a saber, enrojecimiento, calor, hinchazón, dolor, y en algunos casos, rigidez, y en última instancia, daño a la zona afectada (O'Byrne y Dalgleish 2001 ). Estos cambios son inducidos por citoquinas y otros mediadores inflamatorios (Dalgleish y O'Byrne 2002 ). Las citoquinas se clasifican en dos categorías principales: citoquinas pro-inflamatorias y antiinflamatorias. Varias citoquinas incluyendo interleucina (IL)-1, factor de necrosis tumoral alfa (TNF-a), IL-6 e IL-8, y quimioquinas tales como factor estimulante de colonias de granulocitos (G-CSF) y estimulante de colonias de granulocitos macrófagos (factor GM-CSF) juegan un papel clave en las reacciones inflamatorias agudas (Rothwell et al. 1996 ). Varios
BIOLOGÍA FARMACÉUTICA 287 Cuadro 1. Principales componentes de Allium cepa. Principales compuestos Compuestos menores Referencia. Agua El Nilo y el Parque ( 2014 ) Proteínas El Nilo y el Parque ( 2014 ), Ashwini y Sathishkumar ( 2014 ) Hidratos de carbono Inulina, fructooligosacáridos, isorhamnetin-4-glucósido, El Nilo y el Parque ( 2014 ) galactosa, glucosa y manosa Hormona vegetal Glycoquinine Corzo-Martınez et al. ( 2007 ) Lectina Esteroides Catecol, ácido protocatecénico, tiocianato y Ashwini y Sathishkumar ( 2014 ), Nilo y Parque ( 2014 ), aldehído de tioopiono Benmalek et al. ( 2013 ) Fitoestrógenos Coumestrol, zearalenol, isoflavonas y humulona Ashwini y Sathishkumar ( 2014 ), Nilo y Parque ( 2014 ), Benmalek et al. ( 2013 ) Vitaminas Complejo A, B, C y E Ashwini y Sathishkumar ( 2014 ), Nilo y Parque ( 2014 ), Benmalek et al. ( 2013 ) Minerales Selenio, fósforo, hierro, calcio y cromo El Nilo y el Parque ( 2014 ), Ashwini y Sathishkumar ( 2014 ) Flavonoides Quercetin, apigenin, rutin, myricetin, kaempferol, catechin, Ashwini y Sathishkumar ( 2014 ); Lanzotti ( 2006 ), resveratrol, epigalocatecol-3-gallato, luteolina y Benmalek et al. ( 2013 ), Corzo-Martınez et al. ( 2007 ), genisteína Yamamoto y Yasuoka ( 2010 ), Nilo y Parque ( 2014 ), Quercetina aglicona, quercetina diglucósida, quercetina 4 Rodas y Precio ( 1996 ), Wiczkowski et al. ( 2008 ), Shi glucósido y monoglucósido de isorhamnetina o et al. ( 2016 ), Rodrıguez Galdon et al. ( 2008 ), Ko et al. kaempferol monoglycoside ( 2011 ), Rodrigues et al. ( 2017 ), Slimestad et al. ( 2007 ) Compuestos organosulfúricos Tiosulfinatos, cepaenes, cisteína, S-metilcisteína Ashwini y Sathishkumar ( 2014 ), Lanzotti ( 2006 ), Nilo sulfóxido, disulfuro de dialilo, sulfuro de alilo-metilo, alilo y Park ( 2014 ), Benmalek et al. ( 2013 ) disulfuro de propilo, gamma-L-glutamil-trans-S-1- sulfóxido de propenil-L-cisteína, cisteína S-propenil sulfóxido, S-alk(en)il cisteína sulfóxidos, S-alil cisteína sulfóxido Alicina Diallyl disulphide, diallyl trisulphide and ajoene Ashwini y Sathishkumarn ( 2014 ), Lanzotti ( 2006 ), Nilo and Park ( 2014 ), Corzo-Martınez et al. ( 2007 ), Benmalek et al. ( 2013 ) Compuestos fenólicos Fenoles, ácidos fenólicos, antocianinas y Lanzotti ( 2006 ), Nile and Park ( 2014 ) ácido hidroxicinámico Antioxidantes lipofílicos Disulfuros de dialquilo, agliconas, antocianinas, saponinas y Ashwini y Sathishkumar ( 2014 ), Lanzotti ( 2006 ), fistulosina (octadecil 3-hidroxiindol) Takahashi y Shibamoto ( 2008 ), Benmalek et al. ( 2013 ), Ernst and Feldheim ( 2000 ), Corzo-Martınez et al. ( 2007 ), Dorsch et al. ( 1990 ), Yamamoto y Yasuoka ( 2010 ), Nile and Park ( 2014 ), Griffiths et al. ( 2002 ), Augusti ( 1996 ), Rhodes and Price ( 1996 ), Khaki et al. ( 2009 ), Kuhnau ( 1976 ), Arjmandi et al. ( 1996 ) estudios mostraron efectos paliativos de la cebolla y sus ingredientes activos sobre la inflamación y sugirieron que las plantas de Allium son eficaces en el tratamiento de trastornos inflamatorios a menores costos con efectos secundarios limitados, en comparación con los medicamentos químicos (Ali et al. 2000 ), como se detalla a continuación. Efectos antiinflamatorios de la planta Administración de extracto acuoso de bulbo de cebolla roja (EAC; 150 y 300 mg/kg) disminuyeron los recuentos de eosinófilos y linfocitos en la sangre y el líquido de lavado broncoalveolar (BALF) en un modelo de asma de rata de Wistar (Dawud et al. 2016 ). Los efectos antiinflamatorios y antibacterianos de A. cepa se mostraron en estudios previos y se mencionó que esta planta se usó ampliamente para curar enfermedades catarrales, gripe, angina, catarro, tos e hipertrofia prostática (Kumar et al. 2010 ). El extracto de metanol A. cepa (50, 250 y 500 mg/ml) también mostró un efecto protector sobre la neuroinflamación en las células microgliales BV-2 tratadas con lipopolisacáridos (LPS) al reducir las citoquinas pro-inflamatorias TNF-a, IL-6 e IL-1-b (Jakaria et al. 2019 ). Se observó que los extractos cutáneos de A. cepa disminuyeron el nivel de ARNm de ciclooxigenasa-2 (COX-2) en células macrófagas de J774A.1 ratón tratadas con LPS (Albishi et al. 2013 ). En otro estudio, la intubación intragástrica del jugo de bulbos de cebolla fresca a una dosis diaria de 1 mL de enzima convertidora de sngiotensina (CE) durante 14 días, inhibió las vías COX y lipoxigenasa (LOX) e impidió la formación de leucotrienos y tromboxanos en un Sprague-macho
288 N. MAREFATI ET AL. kg) inhibited both acute and chronic pain and significantly decreased hind-paw thickness in male albino mice (Nasri et al. 2012 ). Steam distillate from freeze-dried A. cepa (methanol and water) attenuated 15-lipoxygenase type I activity which is an inflammatory mediator (Takahashi and Shibamoto 2008 ). Alcohol, chloroform and water extract of bulbs of A. cepa (300 mg/kg) showed wound healing activities in Wister albino rats which indicated the effect of the plant on initial phases of wound formation as an acute inflammatory process (Shenoy et al. 2009 ). The anti-inflammatory properties of the plant against carra- geenan-induced paw edoema in rats, were also investigated. Fresh onion juice was able to significantly decrease hind-paw thickness and demonstrated better results compared to the standard treatment, diclofenac (10 mg/kg). The anti-inflammatory effect of onion was attributed to it potential in preventing the formation of leukotrienes and thromboxanes via inhibition of COX and LOX pathways (Alpsoy et al. 2013 ). Anti-inflammatory effects of the constituents of A. cepa It was reported that anti-inflammatory properties of Allium species are due to the presence of effective compounds such as tannin, flavonoids, anthocyanin, saponin, etc. (Aathira et al. 2020 ). A. cepa contains various flavonoids which can help in treatment of oxidative stress-mediated diseases, as well as inflammation, and thermal and mechanical hyperalgesia associated diseases (Vazhappilly et al. 2019 ). Thiosulfinates and cepaenes found in A. cepa, can inhibit production of arachidonic acid as well as its downstream pro- inflammatory prostaglandins and leukotrienes (Wilson and Demmig-Adams 2007 ). Thiosulfinates and cepaenes (100 mM) exerted anti-inflammatory properties mediated through inhibition of chemotaxis of human polymorphonuclear leukocytes. It was also shown that cepaenes inhibit COX and LOX enzymes (Dorsch et al. 1990 ). Quercetin, a well-known constituent of A. cepa showed several biological activities including reduction of swelling (inflammation), lung tightness and cholesterol and sugar levels in the blood (Hashemzaei et al. 2017 ; Aathira et al. 2020 ). Quercetin (0, 0.1, 1, 10, 25 and 50 mM) significantly suppressed nuclear factor kappa-light-chain-enhancer of activated B cells (NF-jB) induced by receptor activator of NF-jB ligand (RANKL) in MC3T3-E1 preosteoblastic cell line (Yamaguchi and Weitzmann 2011 ), (Figure 1). Quercetin also acts as a potent antioxidant and anti-inflammatory agent. This compound decreased the production of inflammatory cytokines such as IL-1a, IL-4, and TNF-a and inhibited the proliferation and Figure 1. The anti-inflammatory effects of Allium cepa in different cells.: Decrease. COX-2: cyclooxygenase-2, IL-6: interleukin-6, NF-jB: nuclear factor kappa-light- chain-enhancer of activated B cells, TNF-a: tumour necrosis factor-alpha, VCAM-1: vascular cell adhesion protein 1.
activity of lymphocytes. In addition, quercetin reduced TNF-a/IL- 10 and IL-8/IL-10 ratios in animal and human studies (Lanzotti 2006 ; Rivera et al. 2008 ; Boots et al. 2011 ). Umoh et al. ( 2019 ) showed that red onion is able to decrease inflammation by inhibition of NF-jB, MARK and STAT-1 possibly by its effective components such as quercetin. Vazquez-Prieto et al. ( 2015 ) exanimated the effects of 6-week treatment with dietary catechin, quercetin, and a mixture of both, on tumour necrosis factor alpha (TNF-a) and adipose inflammation induced by high-fructose consumption, in Wistar rats. Catechin, quercetin, and their combination at the dose of 20 mg/kg/day, improved pro-inflammatory cytokines expression such as mitogen- activated protein kinase (MCP-1), resistin, and adipose tissue inflammation. In addition, catechin, quercetin, and their combination reduced the activation of the mitogen-activated kinases (MAPKs), JNK and p38. Also, catechin, quer-cetin, and their combination prevented downregulation of PPAR-c. Treatment with quercetin (0.1%) for 8 weeks, suppressed hepatic expression of TNF-a and IL-6 and decreased inflammation in high-fat diet/streptozotocin (STZ)-induced diabetic male Sprague-Dawley rats (Jung et al. 2011 ). It was also reported that quercetin was more effective in inhibiting inflammation processes compared to onion itself (Simin et al. 2013 ). In vitro studies showed that A. cepa extract and quercetin down-regulated NF-jB level and inhibited osteoclastogenesis in inflammatory conditions induced by LPS (Oliveira, Figueiredo et al. 2015 ). The anti- inflammatory activities of quercetin were attributed to its inhibitory effects on production of eicosanoids like thromboxane B2 (TXB2), prostaglandin E2 (PGE2) and 12 (S)-hydroxy- (5Z,8Z,10E,14Z)-eicosatetraenoic acid (12-HHT) which are inflammatory mediators derived from arachidonic acid (AA) (Lesjak et al. 2018 ). A. cepa (10, 100 and 1000 mM) and quercetin (3.5, 7.5 and 15 mM) also reduced the level of inflammatory cyto- kines such as IL-4, 5 and 13 in the BALF in a murine model of asthma (Oliveira, Campos et al. 2015 ). Some reports showed that allyl methyl disulphide (100 mM) from garlic had an anti- inflammatory effect on human colon cancer cell lines HT-29 and Caco-2 by increasing IL-8/IP-10 formation and suppressing IL- mRNA level in intestinal epithelial cells. Active butanolic fraction of ethanol extract of dried and grounded onion, quercetin and luteolin showed anti-inflammatory properties comparable to ibu- profen in rat peritoneal mast cells, and anti-edematogenic effect in the early phase of carrageenan-induced paw edoema (Zhang et al. 2015 ). According to Simin et al. ( 2013 ), phenolic compounds in methanol extract of Allium flavum subsp. flavum or small yellow onion (71 and 81 mg/mL), including p-coumaric, caffeic, p- hydroxybenzoic, vanillic, protocatechuic and syringic acid, rutin, quercetin-3-O-glucoside and kaempferol-3-O-glucoside, expressed a high inhibitory potential for COX-1 and 12-lipoxyge-nase (12- LOX) activity. The methanol extract inhibited cell growth of cervix epithelioid carcinoma and colon adenocarcin-oma cells. Phenolic compounds in soluble extracts of pearl onion skin at concentrations as low as 5 mg/mL, showed an antioxidant, anti- inflammatory and DNA scission inhibitory activity and inhibition of COX-2 expression and LDL cholesterol oxidation (Albishi et al. 2013 ). Pre-treatment with the phenolic-rich extract of red onion peels (100 and 500 mg/kg) against oxidative stress induced by carbon tetrachloride (CCl 4 ) free radicals in rat liver and kidney, ameliorated tissue levels of malondialdehyde (MDA) and PHARMACEUTICAL BIOLOGY 289 significantly reduced the net carrageenan-induced edoema in the paw of rats (Ahmed et al. 2017 ). The results of the above studies indicated the effect of A. cepa and its constituents such polyphenolics and flavonoids mainly quercetin, in inflammatory disorders of cardiovascular, gastrointestinal, neuronal respiratory and urogenital systems. The anti-inflammatory effects of the plant and its constituents were mediated via modulation of different inflammatory cells and mediators. Reduction of total WBC, neutrophils and eosinophil counts and inhibition of chemotaxis of human polymorpho-nuclear leukocytes, were reported in this context. The plant and its constituents showed inhibitory effects on COX and LOX pathways and prevented formation of leukotrienes and throm-boxanes (such as TXB2), prostaglandin E2 (PGE2) and 12-HHT. Inhibitory effects of A. cepa and its constituents onVCAM-1, NF-jB, MARK,d STAT-1, JNK, p38 and osteoclastogenesis as well as downregulation of PPAR-c were also shown. The results also indicated that the anti-inflammatory effects of the plant is due to its constituents mainly quercetin. The anti-inflammatory effects of A. cepa and its constituents are shown in Table 2. Antioxidant effects of A. cepa Oxidative stress is characterised by over production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) (Karimian et al. 2012 ). These free radicals, mainly nitric oxide, superoxide anion, hydroxyl radical and hydrogen peroxide, can cause oxidative damages to nucleic acids, proteins, and lipids. Thus, excess production of free radicals under pro-inflammatory conditions may initiate various diseases (Kim et al. 2012 ; Rezaee et al. 2014 ; Ghorani et al. 2018 ). Natural antioxidants are compounds that can delay or inhibit oxidative reactions by scavenging free radicals. The most important of these compounds are phenolic acids, polyphenols, flavonoids, alkaloids and terpenoids (Del Bano et al. 2006 ; Amidi et al. 2012 ; Kim IS et al. 2012 ). Therefore, suppression of oxidative stress could be achieved by using potential sources of natural antioxidants such as medicinal plants (Zarei et al. 2013 ; Parhiz et al. 2015 ; Boskabady et al. 2019 ; Hashemzaei et al. 2020 ). Essential oils derived from these plants, are rich sources of antioxidant components with different biological activities (Hasani-Ranjbar et al. 2009 ). A. cepa contains high levels of phenolic compounds mainly flavonoids, which have antioxidant properties besides other pharmacological effects such as antibiotic, antidiabetic, anti-atherogenic and anticancer activities (Helen et al. 2000 ; Liguori et al. 2017 ). Flavones, flava-nones, flavonols, isoflavones, flavanonols, chalcones, and antho-cyanins which are subclasses of flavonoids and flavonols, are the most abundant flavonoids in A. cepa (Liguori et al. 2017 ). Several studies reported the antioxidant activities of A. cepa and its constituents and introduced the plant as a potential source of natural antioxidants (Razavi and Kenari 2016 ; Roldan et al. 2008 ; Ola-Mudathir and Maduagwu 2014 ). Alterations in oxidant/anti- oxidant markers including lipid peroxidation (LPO), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and MDA were observed by studies that investigated the effects of A. cepa and its constituents (Dadkhah et al. 2014 ). Antioxidant effects of the plant Several studies examined the antioxidant capacity of onion essential oils and extracts using different methods including diphenyl-1- picrylhydrazyl (DPPH), b-carotene bleaching assays, azinobis (3- ethyl-benzothiazoline-6-sulfonic acid) (ABTS), oxygen radical
reported the antioxidant properties of three different Spanish A. cepa cultivars including white skinned onion ‘Fuentes de Ebro’ white skinned onion ‘Calc¸ot de Valls’ and yellow skinned onion ‘Grano de Oro’. Ethyl acetate sub-fraction contained the highest number of flavonoids and the TEAC was 74.86, 24.59 and 4. mol Trolox/g for ‘Grano de Oro,’ ‘Fuentes de Ebro’ and ‘Calc¸ot de Valls,’ respectively. A potent antioxidant potential was also reported for the bulb methanol extracts of three A. cepa cultivars including ‘Pusa Red’ (red), ‘Pusa White Round’ (white) and ‘Arka Pitamber’ (yellow) (Santas et al. 2010 ) and a strong antioxidant activity was shown for red onion ‘N-530 from India (Singh et al. 2009 ). Benmalek and co-workers ( 2013 ) assessed the radical scavenging activity of A. cepa and showed an IC 50 value of 2. 10 5 mg/mL for the outer layer of red onion. Ren et al. ( 2017 ) measured the in vitro antioxidant activity of two onion varieties, Hyskin and Red Baron grown in a six-year field study. The effects of conventional, organic and mixed cultivation practices on phytochemical composition and antioxidant activity were also verified. Gawlik-Dziki et al. ( 2013 ) measured the antioxidant potential of bread enriched with A. cepa skin. The food supplement was prepared by drying onions (‘Wolska’) in an oven at 50 C followed by powdering the plant material using a laboratory mill. In these experiments, the flour used in the formula of control bread (wheat bread flour 600 g, type 750) was replaced with onion skin at 1, 2, 3, 4, and 5% levels. Bio-accessibility and bio-availability were determined in vitro using a human gastrointestinal tract model. Breads were then enriched with 80% methanol extract and antioxidant activity was measured in terms of anti-radical activity, potential to suppress lipid peroxidation, metal
chelating activity and ferric reducing power. The antioxidant activity of onion-supplemented bread was significantly higher than that seen for the control. Also, Helen et al. ( 2000 ) mentioned that 100 mg/kg onion oil given for 21 days is a potent antioxidant against oxidative injury caused by nicotine in Sprague-Dawley rats and its antioxidant activity was comparable to that of vitamin E. In vitro antioxidant activity of methanol and aqueous extracts of A. cepa was compared using various methods such as DPPH and superoxide scavenging activity. The results showed that both extracts had antioxidant activity but this capacity was higher for the methanol extract of onion (Kaur et al. 2016 ). Various in vitro studies showed the presence of higher levels of antioxi-dants in oil and extracts of A. cepa using DPPH radical scavenging activity and other methods. In vivo evidence also confirmed potential antioxidant activity of the plant in different animal models (Votto et al. 2010 ; Cheng et al. 2013 ; Ye et al. 2013 ; Soto et al. 2015 ; Lenkova et al. 2016 ; Shrestha et al. 2016 ; Ola-Mudathir et al. 2018 ). In a Sprague-Dawley rat model, the antioxidant effect of A. cepa oil on nicotine-induced damages was compared to vitamin E. The results showed that 100 mg/kg/day onion oil given for 21 days led to significant increases in antioxidants (SOD, CAT and GSH) levels suggesting that A. cepa is an effective antioxi-dant against oxidative damage induced by nicotine (Helen et al. 2000 ). Enhancement of antioxidant parameters such as SOD, CAT, thioredoxin reductase (TrxR), sorbitol dehydrogenase (SDH), and glutathione reductase (GR) and decrease of LPO were observed in the liver of mice infected with Schistosoma mansoni after treating with onion powder (2 g/100 g bw/day), (Mantawy et al. 2012 ). The protective effect of onion extract against doxo-rubicin-induced hepatotoxicity in rats, was also demonstrated. Doxorubicin, a chemotherapeutic agent, produces cardiotoxicity (Georgiadis et al. 2020 ) and hepatotoxicity via production of free oxygen radicals. However, significant reductions of MDA level, and increased levels of SOD, GSH and GPx were observed in Sprague-Dawley rats after treatment with 1 mL/day aqueous extract of onion, for 14 days (Mete et al. 2016 ). Similarly, aqueous extract of A. cepa ( and 300 mg/kg/day) caused hepato-protective effects by improvement of antioxidant parameters such as SOD, CAT, GPx, GSH and MDA in alloxan-induced diabetic rabbits (Ogunmodede et al. 2011 ). Cadmium, as a nephrotoxic agent, causes kidney damage through induction of oxidative stress. Preventive effect of A. cepa aqueous extract (1 mL for 8 weeks) against cadmium-induced renal dysfunction in a Wistar rats, was evaluated and the results showed significant improvements in plasma and tissue levels of SOD, CAT and MDA (Ige et al. 2009 ). Another study also showed that treatment of cadmium-intoxicated Wistar rats with aqueous extract of A. cepa (0.5 and 1 mL onion/100 g bw/day) for 7 days, led to a significant and dose-dependent restoration of renal oxidant (lipid peroxidation and glutathione-S transferase)/ antioxidant (SOD, CAT and GSH) parameters (Suru 2008 ). The protective effects of methanol extract of A. cepa on cyanide-induced renal toxicity, were assessed in Wistar rats. Significant increases in antioxidant enzymes (SOD, CAT and GSH) and a significant reduction of MDA and LPO in the kidney, were observed in rats treated for 14 days with 600 mg/kg/day onion extract (Ola-Mudathir and Maduagwu 2014 ). Administration of onion aqueous extract (0.5 and 1 mL onion/100 g bw/day) for 6 weeks, caused marked increases in hepatic and renal levels of GSH, GST, SOD and CAT, but PHARMACEUTICAL BIOLOGY 291 significant reductions in MDA level in Wistar rats (Suru and Ugwu 2015 ). In an in vivo study, the antioxidant effect of A. cepa juice ( mL/day) on Wistar rat testis tissue and seminiferous tubules affected by Escherichia coli, was evaluated and the results showed significant increases in total antioxidant capacity after treatment of animals with A. cepa juice. Thus, this plant showed protective effects against E. coli infection-induced oxidative stress (Shahverdi et al. 2017 ). A. cepa aqueous extract (0.5 and 1 mL onion/100 g bw/day for 7 days) against cadmium-induced damage in prostate glands of Wistar rats produced significant improvements in oxidant/antioxidant status. These results suggested a chemoprotective capacity for this plant against biochemical alterations induced by cadmium in the prostate glands (Ola- Mudathir and Suru 2015 ). Protective effects of various doses (0. and 1.0 mL/100 g bw/day for one week) of onion aqueous extracts, were also indicated on sperm and testicular oxidative damage induced by cadmium in Wistar rats, which were mediated through reduction of LPO and MDA as well as improved antioxidant parameters (Ola-Mudathir et al. 2008 ). The effects of A. cepa on the levels of oxidants and antioxi-dant markers in the BALF of ovalbumin-sensitised Wistar rats, were evaluated. Treatment with A. cepa juice (0.175, 0.35, or 0. mg/mL) significantly reduced oxidant markers such as nitrogen dioxide (NO 2 ), nitrate (NO 3 – ), and MDA but increased the levels of SOD and CAT in sensitised Wistar rats (Marefati et al. 2018 ). Treatment of STZ-induced diabetic Wistar rats with aqueous extract of onion (0.4 g/mL/day) resulted in reduction of lipid hydroperoxide and lipoperoxide concentrations but did not alter GPx (Campos et al. 2003 ). Also, the level of free radicals was diminished in plasma and tissues of alloxan-induced diabetic rats after administration of onion extract (El-Demerdash et al. 2005 ) which was in agreement with previous studies (Baynes and Thorpe 1999 ; Kumari and Augusti 2002 ). Campos and co-workers ( 2003 ) examined the effects of the consumption of onion extract (40 g/ mL for 30 days) in STZ-induced diabetic Wistar rats. It was shown that onion intake reduced SOD activity and prevented the increment of lipid hydroperoxide and lipoperoxide concentrations in treated diabetic rats. The antioxidant potential of the ethanol extract and fractions of aerial parts of A. cepa was examined by Baragob et al. ( 2015 ), in in vitro and in vivo studies. In vitro experiments used DPPH and NO radical scavenging methods, whereas the in vivo effects on antioxidant enzyme were investigated in the erythrocytes and pancreas of normal and STZ- induced diabetic albino rats. Before treatment, compared to diabetic groups, normal groups had higher levels of SOD, CAT, GSH but lower LPO level, while administration of A. cepa ethanol extract (200 mg/kg/day for 21 days) and its chloroform fraction, significantly augmented the levels of SOD, CAT and GSH and declined LPO level to near normal levels, in the diabetic groups. Vazquez-Prieto et al. ( 2011 ) indicated anti-inflammatory and antioxidant effect of onion so that oral administration of onion extract (400 mg/kg/day for 8 weeks) in fructose-fed Wistar rats led to attenuation of lipid peroxidation and NAD(P)H oxidase activity and decreased heart endothelial nitric oxide synthase (eNOS) activity that are related to oxidative stress. Also, they found that the vascular inflammation was decreased through reduction of VCAM-1 expression. In addition, the effects of processing technologies and storage conditions on antioxidant capacity of onions were investigated. Siddiq et al. ( 2013 ) showed that usage of mild-heat (50 and
PHARMACEUTICAL BIOLOGY 293 Table 3. The antioxidant effects of Allium cepa and its constituents. Preparations Doses Model of study Effects Reference Essential oil 100 mg/kg/day, gavage Nicotine-induced damages in Reduced LPO, Helen et al. ( 2000 ) Sprague–Dawley rats increased SOD, CAT and GSH Onion powder 2 g/100 g body weigh/day, Murine infected with Reduced LPO, Mantawy et al. ( 2012 ) orally Schistosoma mansoni increased SOD, TrxR, SDH, GR Aqueous 1mL/day, orally Doxorubicin-induced Reduced MDA, increased SOD, GSH Mete et al. ( 2016 ) hepatotoxicity in Sprague- and GPx Dawley rats Aqueous 100 and 300 mg/kg/day, orally Alloxan-induced diabetic rabbits Increased SOD, CAT, GPx, GSH, Ogunmodede reduced MDA content et al. ( 2011 ) Aqueous 1 mL/day, orally Cadmium-induced renal Improveed plasma and tissue levels Ige et al. ( 2009 ) dysfunction of SOD, CAT and MDA Aqueous 0.5 and 1 mL/100 g bw/day, Cadmium-induced Reduced LPO and GST, increased Suru ( 2008 ) gavage nephrotoxicity in Wistar rats SOD, CAT and GSH Methanolic 600 mg/kg/day, orally Cyanide-induced renal toxicity in Reduced LPO and MDA, increased Ola-Mudathir and Wistar rats SOD, CAT and GSH Maduagwu ( 2014 ) Aqueous 0.5 and 1 mL/100 g bw/day, Endogenous hepatic and renal Decreased MDA, increased GSH, GST, Suru and Ugwu ( 2015 ) gavage antioxidant status in SOD and CAT Wistar rats Onion juice 3 mL/day, gavage Escherichia coli induced testis Enhanced total antioxidant capacity Shahverdi et al. ( 2017 ) and seminiferous tubules damage in Wistar rats Aqueous 0.5 and 1 mL/100 g bw/day, Cadmium-induced prostate Reduced GST, increased SOD, CAT Suru and Ugwu ( 2015 ) gavage glands damage in Wistar rats and GSH Aqueous 0.5 and 1 mL/100 g bw/day, Cadmium-induced sperm and Reduced LPO, GST and MDA, Ola-Mudathir gavage testicular damage in increased SOD, CAT and GSH et al. ( 2008 ) Wistar rats Decreased NO2, NO3–, MDA, Onion juice 0.175, 0.35, or 0.7 mg/mL in Wistar rat model of asthma Marefati et al. ( 2018 ) drinking water elevated SOD and CAT Aqueous 0.4 g/ mL/day, gavage STZ-induced diabetic rats Reduced lipid hydroperoxide and Campos et al. ( 2003 ) Wistar rats lipoperoxide Onion juice 100 mL/day, orally Subjects with mild Increased total antioxidant capacity Jain et al. ( 2018 ), hypercholesterolaemia and extended time of LDL Lu et al. ( 2015 ) oxidation Onion juice 100 mL/day, orally Health subjects Improved total antioxidant capacity, Law et al. ( 2016 ) GSH and GR Quercetin 5 mg/kg Hyperuricemic Wistar rats Improved oxidative stress Haidari et al. ( 2008 ) Quercetin 1–10 lM Cortical neuronal cells Protected cells from oxidative stress Lee and Jung ( 2016 ) by inactivation of protein kinase C-e Quercetin 100 mg/kg, orally Paracetamol induced oxidative Inhibited free radicals Mehta et al. ( 2012 ) stress in Wistar rats Quercetin oxidation 0.03 nanomolar Indomethacin-induced damage Protected Caco2 cells against Fuentes et al. ( 2020 ) metabolite (BZF) in human Caco2 cells damage by antioxidant effect MAS 200 mg/kg, gavage Varicocele-induced Sprague- Improved parameters of oxidative Karna et al. ( 2019 ) Dawley rats stress such as MDA, SOD and GPx Dihydroquercetin 100 mg/kg, orally CCl4- induced hepatitis in rat Hepatoprotective effect Teselkin et al. ( 2000 ) model Polysaccharides 0.5-2.0 mg/mL In vitro study ABTS radical scavenging activity, Ma et al. ( 2018 ) DPPH radical scavenging activity, iron (Fe2þ) chelating activity, and superoxide anion radical scavenging activity STZ: streptozocin; LPO: lipid peroxidation; SOD: superoxide dismutase; CAT: catalase; GSH: glutathione; TrxR: thioredoxin reductase; SDH: sorbitol dehydrogenase; GR: glutathione reductase; MDA: malondialdehyde; GPx: glutathione peroxidase; GST: glutathione S-transferase; NO 2 , nitrogen dioxide, NO3–: nitrate; BZF: 2-(3,4-dihy- droxibenzoílo)-2,4,6-trihidroxi-3(2H)-benzo-furanona; Caco2: colonic adenocarcinoma cell line; MAS: MAS: monotropein, Astragalin (kaempferol 3-O-glucoside) and spiraeoside; ABTS: azinobis (3-ethyl-benzothiazolin-6-sulfonic acid); DPPH: diphenyl-1-picrylhydrazyl. constituents have been widely evaluated by several studies (Spelman et al. 2006 ).
Immunomodulatory effects of the plant Several in vitro and in vivo studies reported the immunomodula- tory effects of A. cepa in different diseases. In ovalbumin-sensi- tised Wistar rats, A. cepa aqueous extract (0.175, 0.35, and 0. mg/mL, oral) caused reductions in IL-4 and IgE levels, and increased the level of IFN-c and IFN-c/IL4 ratio (Th1/Th balance) indicating its stimulatory effect on Th 1 but inhibitory effect on Th 2 activity (Marefati et al. 2018 ). An in vitro study on cultured spleen cells stimulated with pokeweed (PWM) from Blomia tropicalis-sensitised BALB/c mice, demonstrated that A. cepa methanol extract (10, 100 and 1000 lg/mL) inhibited the production of Th 2 cytokines, IL-4, IL-5, and IL-13, and IgE (Oliveira, Campos et al. 2015 ). Also, oral administration of methanol extract of A. cepa (100 and 1000 mg/ kg) attenuated the levels of IL-4, IL-5, IL-13, and IgE in BALF of a murine model of Blomia tropicalis-induced asthma (Oliveira, Campos et al. 2015 ). Zinc oxide nanoparticles (ZnO-NPs) syn- thesised from the extract of A. cepa (15 mg/mL) in UVB
PHARMACEUTICAL BIOLOGY 295 Table 4. The immunomodulatory effects of Allium cepa and its constituents. Preparations Dose Study models Effects Ref. A. fistulosom 2.5, 5 and 10 mg/400 mL Murine macrophage cell line Increased TNF-a, IL-12, IFN-c Ueda et al. ( 2013 ) /mouse RAW264.7 production, phagocytosis, NK 125–1000 mg/mL cell activities, increased TNF-a, IL-12, and MCP-1 production AE 0,175, 0,35 y 0,7 mg/ml, OVA-sensitised Wistar rat Decreased IL-4 and IgE, increased Marefati et al. ( 2018 ) orally IFN-c and IFN-c/IL-4 ratio AE 20 and 40 lL, orally OVA-sensitised BALB/c mice Reduced the levels of IL-4, IL-5, Seo et al. ( 2019 ) 100 mg/ mL Murine macrophage cell line IL-10, IL-13 and IFN-c Ahn et al. ( 2015 ) RAW264. EE LPS-induced inflammatory Reduced NO production and IL-6, markers in BV-2 microglial TNF-a, and IL-1b secretion cells ME 50, 250, and 500 mg/mL Testosterone induced atypical Reduced TNF-a, IL-6, and IL-1b Jakaria et al. ( 2019 ) prostatic hyperplasia in Allium cepa Wistar rats 75, 150, and 300 mg/kg Reduced tissue expressions of IL- Elberry et al. ( 2014 ) 6, IL-8, TNF-a and, IGF- ME 10, 100 and 1000 lg/ml PWM-stimulated splenocytes Reduced IL-4, IL-5, IL-13, and IgE Oliveira, Figueiredo et al. ( 2015 ) from Bt-sensitised BALB/ c mice ME 100 and 1000 mg/kg, orally Bt-sensitised BALB/c mice Reduced the levels of IL-4, IL-5, Oliveira, Campos et al. ( 2015 ) IL-13, and IgE in BALF Allium cepa 20 g/kg, orally Brown-marbled grouper fish Increased weight gain, Apines-Amar et al. ( 2012 ) haematocrit, and total Ig EE 75, 150 y 300 mg/kg/día, Testosterone-induced APH in Increased IL-6, IL-8, and TNF-a Elberry et al. ( 2014 ) orally Wistar rat and the expression of clusterin EE 0.1, 1, 10, 50 y 100 lg/mL Murine macrophage cell line Inhibited IL-6, TNF-a, and IL-1ß Ahn et al. ( 2015 ) RAW264.7 secretion and COX-2, iNOS, NF-jB, and MAPKs expression ME 100, 500, and 1000mg/mL Murine macrophage cell line Reduced IL-6 and IL-1a Oliveira, Campos et al. ( 2015 ) RAW264.7 production, increased IL-3 and IL-4 production, Downregulated NF-jB pathway EE 0.8–409.6 lg/mL Lymphocyte isolated white Lymphocyte response to a Hanieh et al. ( 2012 ) leghorn chickens mitogen Stimulation and IL- and IFN-c gene expressions AE 250, 500 and 750 mg/kg, Wistar rat Increased the CD4 cells Mirabeau and Samson ( 2012 ) orally AE 0.1 mL /100 gBW, orally Breast cancer-induced by cell Reduced IL-4, increased IFN-c Karishchi and Bidaran ( 2018 ) line 4T Allium cepa 10 and 30 g/kg, orally Chickens immunised with Improvement of efficacy of Hanieh et al. ( 2010 ) NDV, SRBC and BA vaccines vaccines Quercetin 3.5, 7.5, 15 lg/mL PWM-stimulated splenocytes Reduced IL-4, IL-5, IL-13, and IgE Oliveira, Figueiredo et al. ( 2015 ) from Bt-sensitised BALB/ c mice Quercetin 30 mg/kg, orally Bt-sensitised BALB/c mice Reduced the levels of IL-4, IL-5, Oliveira, Figueiredo et al. ( 2015 ) IL-13, and IgE in BALF Quercetin 1.25, 2.5 and 5 mM Murine macrophage cell line Reduced IL-6 and IL-1a Oliveira, Campos et al. ( 2015 ) RAW264.7 production, increased IL-3 and IL-4 production, Downregulated NF-jB
pathway ACA (^) 1, 10, y 100 lg, i.p. CP- immunosuppressed (^) Increased serum TNF–a, IL-10, Kumar and Venkatesh ( 2016 ) Wistar rats COX–2, IgG and IgA, improved immune parameters in spleen and thymus ACA (^) 0.01, 0.1, 1 and 10 lg/well Murine macrophage cell line (^) Stimulated TNF-a and IL-12 Prasanna and Venkatesh ( 2015 ) RAW264.7 production, enhanced murine thymocytes proliferation and IFN-c and IL-2 expression FOS 0.5, 5, 50 and 250 mg/mL^ Splenocytes and thymocytes Increased PECs phagocytic Kumar et al. ( 2015 ) activity, cell proliferation or mitogenicity Ref.: References; AE: aqueous extract; ME: methanolic extract; EE: ethanoic extract; ME: methanolic extract; CE: chloroformic extract; PWM: pokeweed; Bt: Blomia tro- picalis; CP: cyclophosphamide; APH: atypical prostatic hyperplasia; FOS: onion fructo-oligosaccharides; PECs: peritoneal exudates cells; ACA: Allium cepa agglutinin; SRBC: sheep red blood cells; NDV: newcastle disease virus; SRBC: sheep red blood cells; BA: brucella abortus.
Albishi T, John JA, Al-Khalifa AS, Shahidi F. 2013. Antioxidant, anti- inflammatory and DNA scission inhibitory activities of phenolic compounds in selected onion and potato varieties. J Funct Foods. 5(2):930–939. Ali M, Thomson M, Afzal M. 2000. Garlic and onions: their effect on eicosa- noid metabolism and its clinical relevance. Prostaglandins Leukot Essent Fatty Acids. 62(2):55–73. Alpsoy S, Aktas C, Uygur R, Topcu B, Kanter M, Erboga M, Karakaya O, Gedikbasi A. 2013. Antioxidant and anti-apoptotic effects of onion (Allium cepa) extract on doxorubicin-induced cardiotoxicity in rats. J Appl Toxicol. 33(3):202–208. Amidi S, Mojab F, Bayandori Moghaddam A, Tabib K, Kobarfard F. 2012. A simple electrochemical method for the rapid estimation of antioxidant potentials of some selected medicinal plants. Iran J Pharm Res. 11(1): 117–
Apines-Amar MJS, Amar EC, Faisan JP Jr, Pakingking RV Jr, Satoh S. 2012. Dietary onion and ginger enhance growth, hemato-immunological responses, and disease resistance in brown-marbled grouper. Epinephelus Fuscoguttatus. AACL Bioflux. 5:231–239. Arjmandi BH, Alekel L, Hollis BW, Amin D, Stacewicz-Sapuntzakis M, Guo P, Kukreja SC. 1996. Dietary soybean protein prevents bone loss in an ovariectomized rat model of osteoporosis. J Nutr. 126(1):161-167. Arung ET, Furuta S, Ishikawa H, Tanaka H, Shimizu K, Kondo R. 2011. Melanin biosynthesis inhibitory and antioxidant activities of quercetin-3’-O- beta-D-glucoside isolated from Allium cepa. Z Naturforsch C J Biosci. 66(5- 6):209–214. Ashwini M, Sathishkumar R. 2014. Onion (Allium cepa)-Ethnomedicinal and therapeutic properties. In: Handbook of Medicinal plants and their Bioactive compounds. p. 27–34. Augusti KT. 1996. Therapeutic values of onion (Allium cepa L.) and garlic (Allium sativum L.). Indian J Exp Biol. 34(7):634–640. Baragob AE, Al-Wabel NA, Ahmed NA, Babiker M, Abdalkarim AS, Elboshra M. 2015. Study to investigate the pancreatic regeneration and evaluation of the antidiabetic and antihyperlipidemic potential of aerial parts of Allium cepa. Biochem Biotechnol Res. 3:19–29. Baynes JW, Thorpe SR. 1999. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes. 48(1):1–9. Benkeblia N. 2004. Antimicrobial activity of essential oil extracts of various onions (Allium cepa) and garlic (Allium sativum). LWT – Food Sci Technol. 37(2):263–268. Benkeblia N. 2005. Free-radical scavenging capacity and antioxidant properties of some selected onions (Allium cepa L.) and garlic (Allium sativum L.) extracts. Braz Arch Biol Technol. 48(5):753–759. Benmalek Y, Yahia OA, Belkebir A, Fardeau M-L. 2013. Anti-microbial and antioxidant activities of Illicium verum, Crataegus oxyacantha ssp monog- yna and Allium cepa red and white varieties. Bioeng. 4:244–248. Beretta HV, Bannoud F, Insani M, Berli F, Hirschegger P, Galmarini CR, Cavagnaro PF. 2017. Relationships between bioactive compound content and the antiplatelet and antioxidant activities of six Allium vegetable species. Food Technol Biotech. 55:266–275. Bisen PS, Emerald M. 2016. Nutritional and therapeutic potential of garlic and onion (Allium sp. CNF. 12(3):190–199. Boots AW, Drent M, de Boer VC, Bast A, Haenen GR. 2011. Quercetin reduces markers of oxidative stress and inflammation in sarcoidosis. Clin Nutr. 30(4):506–512. Boskabady MH, Kaveh M, Shakeri K, Roshan NM, Rezaee R. 2019. Hydro- ethanolic extract of Portulaca oleracea ameliorates total and differential WBC, lung pathology and oxidative biomarkers in asthmatic rats. Iran J Pharm Res. 18(4):1947. Bouba AA, Njintang NY, Nkouam GB, Mang YD, El-Sayed Mehanni AH, Scher J, Montet D, Mbofung CM. 2014. Desorption isotherms, net isos-teric heat and the effect of temperature and water activity on the antioxi-dant activity of two varieties of onion (Allium cepa L.). Int J Food Sci Technol. 49(2):444–452. Campos K, Diniz Y, Cataneo A, Faine L, Alves M, Novelli E. 2003. Hypoglycaemic and antioxidant effects of onion, Allium cepa: dietary onion addition, antioxidant activity and hypoglycaemic effects on diabetic rats. Int J Food Sci Nutr. 54(3):241–246. Cheng A, Chen X, Jin Q, Wang W, Shi J, Liu Y. 2013. Comparison of phenolic content and antioxidant capacity of red and yellow onions. Czech J Food Sci. 31(No. 5):501–508. Corea G, Fattorusso E, Lanzotti V, Capasso R, Izzo AA. 2005. Antispasmodic saponins from bulbs of red onion, Allium cepa L. var. Tropea. J Agric Food Chem. 53(4):935–940. Corzo-Martınez M, Corzo N, Villamiel M. 2007. Biological properties of onions and garlic. Trends Food Sci Technol. 18(12):609–625. PHARMACEUTICAL BIOLOGY 297 Dadkhah A, Fatemi F, Malayeri MRM, Rasooli A. 2014. Cancer chemopre- ventive effect of dietary Zataria multiflora essential oils. Turk J Biol. 38: 930–939. Dalgleish AG, O’Byrne KJ. 2002. Chronic immune activation and inflammation in the pathogenesis of AIDS and cancer. Adv Cancer Res. 84: 231–276. Dawud F, Dubo A, Yusuf N, Umar I. 2016. Effects of aqueous extract of Allium cepa (red onion) on ovalbumin induced allergic asthma in Wistar rats. Bayero J Pure App Sci. 9(2):95–101. Del Bano M, Castillo J, Benavente-Garcia O, Lorente J, Martın-Gil R, Acevedo C, Alcaraz M. 2006. Radioprotective-antimutagenic effects of rosemary phenolics against chromosomal damage induced in human lymphocytes by gamma-rays. J Agric Food Chem. 54(6):2064–2068. Dorsch W, Schneider E, Bayer T, Breu W, Wagner H. 1990. Anti-inflammatory effects of onions: inhibition of chemotaxis of human polymorpho-nuclear leukocytes by thiosulfinates and cepaenes. Int Arch Allergy Appl Immunol. 92(1):39–42. Dorsch W, Wagner H, Bayer T, Fessler B, Hein G, Ring J, Scheftner P, Sieber W, Strasser T, Weiss E. 1988. Anti-asthmatic effects of onions. Alk(en)ylsulfinothioic acid alk(en)yl-esters inhibit histamine release, leuko- triene and thromboxane biosynthesis in vitro and counteract PAF and allergen-induced bronchial obstruction in vivo. Biochem Pharmacol. 37(23):4479–4486. El-Aasr M, Fujiwara Y, Takeya M, Ikeda T, Tsukamoto S, Ono M, Nakano D, Okawa M, Kinjo J, Yoshimitsu H, et al. 2010. Onionin A from Allium cepa inhibits macrophage activation. J Nat Prod. 73(7):1306–1308. Elberry AA, Mufti S, Al-Maghrabi J, Abdel Sattar E, Ghareib SA, Mosli HA, Gabr SA. 2014. Immunomodulatory effect of red onion (Allium cepa Linn) scale extract on experimentally induced atypical prostatic hyperpla-sia in Wistar rats. Mediators Inflamm. 2014:640746–640746. El-Demerdash FM, Yousef MI, El-Naga NA. 2005. Biochemical study on the hypoglycemic effects of onion and garlic in alloxan-induced diabetic rats. Food Chem Toxicol. 43(1):57–63. Ernst M, Feldheim W. 2000. Fructans in higher plants and in human nutri- tion. J Appl Botany. 74(1/2):5–9. Cikes-Culic V, Puizina J. 2017. Chemical composition and biological activity of Allium cepa L. and Allium cornutum (Clementi ex Visiani 1842) methanolic extracts. Moléculas. 22(3):448. Fuentes J, Arias-Sante MF, Atala E, Pastene E, Kogan MJ, Speisky H. 2020. Low nanomolar concentrations of a quercetin oxidation product, which naturally occurs in onion peel, protect cells against oxidative damage. Food Chem. 11:126–166. Galmarini CR, Goldman IL, Havey MJ. 2001. Genetic analyses of correlated solids, flavor, and health-enhancing traits in onion (Allium cepa L.). Mol Genet Genomics. 265(3):543–551. (^) ł Gawlik-Dziki U, Swieca M, Dziki D, Baraniak B, Tomi o J, Czyz J. 2013. Quality and antioxidant properties of breads enriched with dry onion (Allium cepa L.) skin. Food Chem. 138(2-3):1621–1628. Georgiadis N, Tsarouhas K, Rezaee R, Nepka H, Kass GE, Dorne JL, Stagkos D, Toutouzas K, Spandidos DA, Kouretas D, et al. 2020. What is considered cardiotoxicity of anthracyclines in animal studies. Oncol Rep. 44(3): 798–
Ghorani V, Marefati N, Shakeri F, Rezaee R, Boskabady M, Boskabady MH.
- The effects of Allium cepa extract on tracheal responsiveness, lung inflammatory cells and phospholipase A2 level in asthmatic rats. Iran J Allergy Asthma Immunol. 17:221–231. Griffiths G, Trueman L, Crowther T, Thomas B, Smith B. 2002. Onions-a global benefit to health. Phytother Res. 16(7):603–615. Grzelak-Błaszczyk K, Milala J, Kosmala M, Kołodziejczyk K, Sojka M, Czarnecki A, Klewicki R, Juskiewicz J, Fotschki B, Jurgonski A. 2018. Onion quercetin monoglycosides alter microbial activity and increase anti- oxidant capacity. J Nutr Biochem. 56:81–88. Haidari F, Rashidi MR, Eshraghian MR, Mahboob SA, Shahi MM, Keshavarz SA. 2008. Hypouricemic and antioxidant activities of Allium cepa Lilliaceae and quercetin in normal and hyperuricemic rats. Saudi Med J. 29(11):1573–
Han MH, Lee WS, Jung JH, Jeong J-H, Park C, Kim HJ, Kim GSup, Jung J-M, Kwon TK, Kim G-Y, et al. 2013. Polyphenols isolated from Allium cepa L. induces apoptosis by suppressing IAP-1 through inhibiting PI3K/ Akt signaling pathways in human leukemic cells. Food Chem Toxicol. 62: 382–
Hanieh H, Narabara K, Piao M, Gerile C, Abe A, Kondo Y. 2010. Modulatory effects of two levels of dietary Alliums on immune response and certain immunological variables, following immunization, in White Leghorn chickens. Anim Sci J. 81(6):673–680.
298 N. MAREFATI ET AL. Hanieh H, Narabara K, Tanaka Y, Gu Z, Abe A, Kondo Y. 2012. Immunomodulatory effects of Alliums and Ipomoea batata extracts on lymphocytes and macrophages functions in White Leghorn chickens: in vitro study. Anim Sci J. 83(1):68–76. Hansen SL. 2001. Content of free amino acids in onion (Allium cepa L.) as influenced by the stage of development at harvest and long-term storage. Acta Agr Scand B-S P. 51(2):77–83. Hasani-Ranjbar S, Larijani B, Abdollahi M. 2009. A systematic review of the potential herbal sources of future drugs effective in oxidant-related diseases. Inflamm Allergy Drug Targets. 8(1):2–10. Hashemzaei M, Far AD, Yari A, Heravi RE, Tabrizian K, Taghdisi SM, Sadegh SE, Tsarouhas K, Kouretas D, Tzanakakis G, et al. 2017. Anticancer and apoptosis-inducing effects of quercetin in vitro and in vivo. Oncol Rep. 138(2):819–828. Hashemzaei M, Mamoulakis C, Tsarouhas K, Georgiadis G, Lazopoulos G, Tsatsakis A, Asrami ES, Rezaee R. 2020. Crocin: a fighter against inflammation and pain. Food Chem Toxicol. 143: Hedges L, Lister C. 2007. The nutritional attributes of Allium species. Crop and food research confidential report. 1814. New Zealand Institute for Crop & Food Research Limited. Helen A, Krishnakumar K, Vijayammal P, Augusti K. 2000. Antioxidant effect of onion oil (Allium cepa Linn) on the damages induced by nicotine in rats as compared to alpha-tocopherol. Toxicol Lett. 116(1-2):61–68. Ianni F, Lisanti A, Marinozzi M, Camaioni E, Pucciarini L, Massoli A, Sardella R, Concezzi L, Natalini B. 2018. Amino acid content in onions as potential fingerprints of geographical origin: the case of rossa da inverno sel. Rojo Duro. Moléculas. 23(6):1259-1271. Ige S, Salawu E, Olaleye S, Adeeyo O, Badmus J, Adeleke A. 2009. Onion (Allium cepa) extract prevents cadmium induced renal dysfunction. Indian J Nephrol. 19(4):140–144. Insani EM, Cavagnaro P, Salomon VM, Langman LE, Sance M, Pazos AA, Carrari F, Filippini O, Vignera L, Galmarini CR. 2016. Variation for health- enhancing compounds and traits in onion (Allium cepa L.) germ-plasm. FNS. 07(07):577-591. Jain S, Buttar HS, Chintameneni M, Kaur G. 2018. Prevention of cardiovascular diseases with anti-inflammatory and anti- oxidant nutraceuticals and herbal products: an overview of pre-clinical and clinical studies. Recent Pat Inflamm Allergy Drug Discov. 12(2):145–157. Jakaria M, Azam S, Cho D-Y, Haque M, Kim I-S, Choi D-K. 2019. The methanol extract of Allium cepa L. protects inflammatory markers in LPS- induced BV-2 microglial cells and upregulates the antiapoptotic gene and antioxidant enzymes in N27-A cells. Antioxidantes. 8(9): 348-396. Joung EM, Jung KH. 2014. Antioxidant activity of onion (Allium cepa L.) peel extracts obtained as onion byproducts. Korean J Food Sci Tech. 46(3):364–
Jung JY, Lim Y, Moon MS, Kim JY, Kwon O. 2011. Onion peel extracts ameliorate hyperglycemia and insulin resistance in high fat diet/streptozo- tocin-induced diabetic rats. Nutr Metab (Lond). 8(1):18. Kang B-K, Kim K-B-W-R, Ahn N-K, Choi Y-U, Kim M-j, Bark S-W, Pak W- M, Kim B-R, Park J-H, Bae N-Y, et al. 2015. Anti-inflammatory effect of onion (Allium cepa) peel hot water extract in vitro and in vivo. Ksbb J. 30(4):148-154. Karimian P, Kavoosi G, Saharkhiz MJ. 2012. Antioxidant, nitric oxide scavenging and malondialdehyde scavenging activities of essential oils from different chemotypes of Zataria multiflora. Nat Prod Res. 26(22): 2144–
Karishchi KP, Bidaran S. 2018. Study of Allium cepa effect to inhibit the growth of tumor cells in BALB/c mice breast cancer model. JSUMS. 25: 63–71. Karna KK, Choi BR, You JH, Shin YS, Cui WS, Lee SW, Kim JH, Kim CY, Kim HK, Park JK. 2019. The ameliorative effect of monotropein, astraga- lin, and spiraeoside on oxidative stress, endoplasmic reticulum stress, and mitochondrial signaling pathway in varicocelized rats. BMC Complement Altern Med. 19(1):333. Kaur G, Gupta V, Christopher AF, Bansal P. 2016. Antioxidant potential of most commonly used vegetable-onion (Allium cepa L.). JOCAMR. 1(1): 1–
Khaki A, Fathi AF, Nouri M, Khaki AA, Ozanci CC, Ghafari NM, Hamadeh M. 2009. The effects of Ginger on spermatogenesis and sperm parameters of rat. IJRM. 7(1):7. Kim M-H, Jo S-H, Jang H-D, Lee MS, Kwon Y-I. 2010. Antioxidant activity and a-glucosidase inhibitory potential of onion (Allium cepa L.) extracts. Food Sci Biotechnol. 19(1):159–164. Kim IS, Yang M, Goo TH, Jo C, Ahn DU, Park JH, Lee OH, Kang SN. 2012. Radical scavenging-linked antioxidant activities of commonly used herbs and spices in Korea. Int J Food Sci Nutr. 63(5):603–609. Ko MJ, Cheigh CI, Cho SW, Chung MS. 2011. Subcritical water extraction of flavonol quercetin from onion skin. J Food Eng. 102(4):327–333. Kuhnau J. 1976. The flavonoids. A class of semi-essential food components: their role in human nutrition. World Rev Nutr Diet. 24:117–191. Kumar KS, Bhowmik D, Chiranjib B, Tiwari P. 2010. Allium cepa: a traditional medicinal herb and its health benefits. Carbohydr Res. 2:283–
Kumar VP, Prashanth KH, Venkatesh Y. 2015. Structural analyses and immunomodulatory properties of fructo-oligosaccharides from onion (Allium cepa). Carbohydr Polym. 117:115–122. Kumar VP, Venkatesh YP. 2016. Alleviation of cyclophosphamide-induced immunosuppression in Wistar rats by onion lectin (Allium cepa agglutinin). J Ethnopharmacol. 186:280–288. Kumari K, Augusti K. 2002. Antidiabetic and antioxidant effects of S-methyl cysteine sulfoxide isolated from onions (Allium cepa Linn) as compared to standard drugs in alloxan diabetic rats. NISCAIR. 40:1005–1009. Lanzotti V. 2006. The analysis of onion and garlic. J Chromatogr A. 1112(1–2):3–22. Law YY, Chiu HF, Lee HH, Shen YC, Venkatakrishnan K, Wang CK. 2016. Consumption of onion juice modulates oxidative stress and attenuates the risk of bone disorders in middle-aged and post-menopausal healthy subjects. Food Funct. 7(2):902–912. Lee BK, Jung Y-S. 2016. Allium cepa extract and quercetin protect neuronal cells from oxidative stress via PKC-e inactivation/ERK1/2 activation. Oxid Med Cell Longev. 2016: Lee B, Jung J-H, Kim H-S. 2012. Assessment of red onion on antioxidant activity in rat. Food Chem Toxicol. 50(11):3912–3919. Lee KA, Kim K-T, Kim HJ, Chung M-S, Chang P-S, Park H, Pai H-D. 2014. Antioxidant activities of onion (Allium cepa L.) peel extracts produced by ethanol, hot water, and subcritical water extraction. Food Sci Biotechnol. 23(2):615–621. Lenkova M, Bystricka J, ToTh T, Hrstkova M. 2016. Evaluation and comparison of the content of total polyphenols and antioxidant activity of selected species of the genus Allium. J Cent Eur Agric. 17(4):1119–1133. Lesjak M, Beara I, Simin N, Pintac D, Majkic T, Bekvalac K, Orcic D, Mimica- Dukic N. 2018. Antioxidant and anti-inflammatory activities of quercetin and its derivatives. J Funct Foods. 40:68–75. Liguori L, Califano R, Albanese D, Raimo F, Crescitelli A, Di Matteo M. 2017. Chemical composition and antioxidant properties of five white onion (Allium cepa L.) landraces. J Food Qual. 2017:1–9. Lisanti A, Formica V, Ianni F, Albertini B, Marinozzi M, Sardella R, Natalini B. 2016. Antioxidant activity of phenolic extracts from different cultivars of Italian onion (Allium cepa) and relative human immune cell proliferative induction. Pharm Biol. 54(5):799–806. Lu T-M, Chiu H-F, Shen Y-C, Chung C-C, Venkatakrishnan K, Wang C-K.
- Hypocholesterolemic efficacy of quercetin rich onion juice in healthy mild hypercholesterolemic adults: a pilot study. Plant Foods Hum Nutr. 70(4):395–400. Ma Y-L, Zhu D-Y, Thakur K, Wang C-H, Wang H, Ren Y-F, Zhang J-G, Wei Z-J. 2018. Antioxidant and antibacterial evaluation of polysaccharides sequentially extracted from onion (Allium cepa L.). Int J Biol Macromol. 111:92–101. Mantawy M, Aly H, Zayed N, Fahmy Z. 2012. Antioxidant and schistosomi- cidal effect of Allium sativum and Allium cepa against Schistosoma man- soni different stages. Eur Rev Med Pharmacol Sci. 16:69–80. Marefati N, Eftekhar N, Kaveh M, Boskabadi J, Beheshti F, Boskabady M.
- The effect of Allium cepa extract on lung oxidant, antioxidant, and immunological biomarkers in ovalbumin-sensitized rats. Med Princ Pract. 27(2):122–128. Mehta A, Kaur G, Chintamane M. 2012. Piperine and quercetin enhances antioxidant and hepatoprotective effect of curcumin in paracetamol induced oxidative stress. International J of Pharmacology. 8(2):101–107. Memarzia A, Amin F, Saadat S, Jalali M, Ghasemi Z, Boskabady MH. 2019. The contribution of beta-2 adrenergic, muscarinic and histamine (H1) receptors, calcium and potassium channels and cyclooxygenase pathway in the relaxant effect of Allium cepa L. on the tracheal smooth muscle. J Ethnopharmacol. 241:112012. Mete R, Oran M, Topcu B, Oznur M, Seber ES, Gedikbasi A, Yetisyigit T.
- Protective effects of onion (Allium cepa) extract against doxorubi-cin- induced hepatotoxicity in rats. Toxicol Ind Health. 32(3):551–557. Mirabeau TY, Samson ES. 2012. Effect of Allium cepa and Allium sativum on some immunological cells in rats. Afr J Tradit Complement Altern Med. 9(3):374–379. Nasri S, Anoush M, Khatami N. 2012. Evaluation of analgesic and anti- inflammatory effects of fresh onion juice in experimental animals. Afr J Tradit Complement Altern Med. 6:1679–1684. Nile SH, Park SW. 2014. Total, soluble, and insoluble dietary fibre contents of wild growing edible mushrooms. Czech J Food Sci. 32(No. 3):302–307.
