Review on Emu Products for Use As Complementary and Alternative Medicine

Nutrition 31 (2015) 21–27

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Nutrition

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Review Review on emu products for use as complementary and alternative medicine

Manish Kumar Jeengar M.S. (Pharm.) a, P. Sravan Kumar a, Dinesh Thummuri M.S. (Pharm.) a, Shweta Shrivastava M.S. (Pharm.) a, Lalita Guntuku M.S. (Pharm.) a, Ramakrishna Sistla Ph.D. b, V.G.M. Naidu Ph.D. a,* a Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education & Research (NIPER-Hyderabad), Balanagar, India b Pharmacology Division, Indian Institute of Chemical Technology, Hyderabad, India article info abstract

Article history: Emu (Dromaius novaehallandiae), the flightless bird native to Australia and found in many Received 10 January 2014 countries, is receiving much attention for its nutritional benefits as well as its medicinal value. Emu Accepted 1 April 2014 oil contains high amounts of polyunsaturated fatty acids and antioxidants. It has potent anti- inflammatory actions and thus can be used topically and orally to treat conditions such as Keywords: mucositis, inflammatory bowel syndrome, and auricular inflammation, and to prevent Emu oil chemotherapy-induced bone loss. Emu oil also has a hypocholesterolemic effect, transdermal PUFAs penetration-enhancing activity, cosmetic and insect repellent activity, and so on. However, its MUFA Inflammation mechanism(s) of actions are unclear and have not, to our knowledge, been studied to date. Previous Antioxidant studies suggest that the fatty acids of the u-9, u-6, and u-3 series, which are present in emu oil, Penetration enhancer may act on cyclooxygenase, lipoxygenase, and lipoxin pathways to bring about its anti- GPR120 inflammatory and other beneficial actions. The aim of this review was to provide a brief summary of the current knowledge of research on emu products, mainly emu oil, for the possible use as a complementary and alternative natural medicine for various chronic diseases. In this review we also highlighted the future research scope of emu oil for its possible antidiabetic activity. Thus, emu oil is an attractive pharmacologic agent to further explore for its therapeutic activity to treat various ailments. Ó 2015 Elsevier Inc. All rights reserved.

Introduction attributed to its body fat content. Emus store their fat on their back, which is known as the back pad. Because of where the fat is Ratites are a diverse group of flightless birds belonging to the stored, emu meat is very lean and devoid of fat. Emus have both superorder Palaeognathae and order struthioniformes. They have nutritional value and health benefits [4]. flat breast bones with no keel, giving the wing muscles nothing to anchor to, and thus they are unable to fly. Emus belong to ratite group of flightless birds, along with ostrich, rhea, kiwi, Emu egg choique and cassowary [1]. The emu (“bush chook”), Dromaius novaehallandiae, is a free-roving, cursorial bird indigenous to The emu egg is dark green in color and weighs about 400 to Australia for 80 million years [2]. Native aboriginals and white 650 g. The color of the egg results from the presence of methyl settlers used the liquid fat from emus topically for various ail- ester in the pigment biliverdin in the egg shell. Emus lay one egg ments such as wound healing, to alleviate pain, and for muscu- every 3 or 5 d during breeding season, i.e., between April and ’ loskeletal disorders. Emu is the second-largest extant bird in the October. The egg s shell contains about 95% calcium carbonate in world by height. The only extant species is D. novaehallandiae the form of calcite, as well as two different C-type lectin-like [3,4]. An adult emu weighs about 45 kg, of which 10 kg can be proteins that are common among ratite group. Emu eggs contain 29% to 47% albumen. Chemically, albumen contains 0.05% of lysosome and 3.1% of sialic acid, whereas the egg white * Corresponding author. Tel.: þ91 944 051 7979; fax: þ91 40 23073751. of the domestic hen contains 3.4% lyosome and 0.29% sialic E-mail address: [email protected] (V. G. M. Naidu). acid [4].

Emu meat Table 1 Composition (%) of fatty acids in emu oil

Emus are a good source of nutrition, and its meat is very Fatty acid Amount (%) flavorful. Emu meat is lean, low in cholesterol, and has a favorable Palmitic (16:0) 24.0 fatty acid profile [5]. Lipids present in emu meat include both u-3 Palmitoleic acid (16:1; u-7) 4.3 and u-6 fatty acids such as a-linolenic, linoleic, arachidonic, and Stearic acid (18:0) 8.5 Oleic (18:1; u-9) 49.1 docosahexaenoic acids (DHAs), the levels of which are greater Linoleic (18:2; u-6) 9.5 than those present in chicken and beef [6,7]. The ratio of poly- a-Linolenic (18:3; u-3) 1.1 unsaturated fatty acids (PUFAs) to saturated fatty acids was found Saturated 32.5 to be 0.72, which is higher than chicken meat at 0.57 and beef at MUFA 53.4 0.3 [6]. Heme iron (cf. 3.4–5.0 mg iron/100 g) is present in abun- PUFA 10.6 dant amounts in emu meat compared with beef. Different mus- MUFA, monounsaturated fatty acid; PUFA, polyunsaturated fatty acid cles have different amounts of meat pigment (varying from 22 to 29 mg/g of tissue) and increases with the age of the animal from 6 include diarrhea, severe pain, nausea, and bloating [17].Thereare to 14 mo. The American Heart Association recommends con- currently several unmet needs for the prevention and treatment of sumption of emu meat because of its low fat content and because chemotherapy-induced gastrointestinal mucositis [18];however, it is a good source of proteins, vitamins, heme iron, and creatine. some agents such as keratinocyte growth factor-1 [19], insulin-like Emu meat also is a rich source of vitamins A and E. growth factor-1 [20], whey growth factor extract [21], and vela- In view of the presence of a significant amount of creatine, fermin (fibroblast growth factor-20) [22] are being investigated. emu meat is considered beneficial for athletes who indulge in Emu oil has been explored as a possible alternative therapy for high-endurance sports. The high concentration of creatine aug- chemotherapy-induced mucositis, and it has been reported that ments lean body mass, and also increases performance in various orally administered emu oil decreased acute inflammation and activities. Emu meat contains higher amounts of myoglobin altered selected small intestinal parameters in 5-fluorouracil (sarcoplasmic heme protein, important for both oxygen storage (5-FU)-induced mucositis in a rat model [23]. and oxygen delivery functions in skeletal muscles), which gives Inflammatory bowel disease the meat its dark color, similar to that of red meat [8].

Inflammatory bowel diseases such as ulcerative colitis and Emu oil Crohn’s disease are generally managed by immunosuppressive agents, antibiotics, corticosteroids, and 5-aminosalicylic acid Emu oil is obtained from the emu’s fat deposits, mainly subcu- [24]. In experimental animals, emu oil ameliorated dextran sul- taneous and retroperitoneal fat. Collected tissues are first subjected phate sodium-induced colitis in rats and decreased the severity to maceration or centrifugation and then liquified fat is passed of tissue damage to a significant degree. Emu oil enhanced through various filters to obtain pure oil [9]. Emu oil is a commer- colonic crypt lengthening, indicating its ability to stimulate in- cially available product in countries such as Australia and the testinal repair processes. Moreover, it has no effect on the su- United States. It possesses various beneficial characterisitics. It is an crose breath test, indicating that it maintains normal intestinal anti-inflammatory, it promotes enhancementof skinpermeation, it function [25]. Further studies are needed to evaluate the mech- is moisturizing and has cosmetic properties, and it has been used anism(s) of action of emu oil in ameliorating symptoms of in- for the treatment of various ailments for decades [4,10,11]. flammatory bowel disease. Composition of emu oil Auricular inflammation Emu oil is a bright yellow liquid [12]. It contains 98.8% and 98% of the average amount of lipids in oils obtained from subcutane- It has been reported that emu oil decreases auricular fl ous and retroperitoneal adipose tissues, respectively. The fatty in ammation in CD-1 mice. It was noted that emu oil reduced fi acid composition of emu oil depends on the diet of the bird, the auricular thickness and weight of ear plug, signi cantly, which method of extraction, and the type of adipose tissue from which was also accompanied by a 70% reduction in interleukin (IL)-1a the oil is extracted [9,13]. Emu oil is reported to contain all three and a 60% drop in tumor necrosis factor (TNF)-a compared to the omega fatty acids (i.e., u-9, u-6, and u-3), making it an excellent control group [26]. supplement. The largest component is oleic acid, a monounsaturated u-9 fatty acid (18:1), comprising >49.1% of the total Cancer chemotherapy-induced bone loss fatty acids. Emu oil also contains unsaturated fatty acids like 9.5% linoleic acid (18:2; u-6), 1.1% a-linolenic acid (18: u3), and 32.5% Cancer chemotherapy can cause osteoporosis or osteopenia. saturated fatty acids as previously reported [14] (Table 1). The 5-FU, methotrexate, cyclophosphamide, and etoposide induce non-triglyceride (TG) fractions include various compounds like osteopenia by reducing osteoblast activity and increasing oste- antioxidants, notably carotenoids, flavones, polyphenols, and oclast activity [27,28]. It has been reported that dietary emu oil phospholipids [15]. suppressed 5-FU-induced bone loss by inhibiting TNF-a production and RANK expression. It also has been suggested that the Anti-inflammatory properties of emu oil in various diseases non-TG components of emu oil may contribute to its anti-osteoclast effect [29]. Mucositis Adjuvant-induced arthritis Mucositis is the most common adverse effect of cancer chemotherapy and is characterized by the depletion of the mucous layer in The anti-inflammatory activities of different preparations of the alimentary tract [16]. Symptoms associated with mucositis emu oil applied topically have been compared using adjuvant- M. K. Jeengar et al. / Nutrition 31 (2015) 21–27 23

Fig. 1. Schematic diagram representing the stimulation of GPR120 receptor by u-3 fatty acids in alleviating inflammation. When u-3 fatty acids bind to the GPR120 receptor present on macrophages, the complex will translocate into the cytoplasm where it binds to the b-arrestin. This complex binds to TAB1, thus inhibiting binding of TAK1 to TAB1, which is the key step in the signaling pathway of TLR 4 and TNF-R for the activation of NF-kB and JNK, respectively. Thus, production of cytokines responsible for inflammation is inhibited. FA, fatty acid; GPR120, G protein-coupled receptor; IKKb, inhibitor of nuclear factor kappa-B kinase subunit beta; JNK, c-JUN N-terminal kinase; LPS, lipopolysaccharide; MKK4, mitogen-activated protein kinase kinase; NF-kB, nuclear factor kappa-B; TAB1, TAK1-binding protein; TAK1, transforming growth factor b activated kinase-1; TLR 4, toll-like receptor; TNF, tumor necrosis factor; TNF-R, tumor necrosis factor receptor. induced polyarthritis in rats. Some of the topically applied stimulated melanogenesis in the skin and hair growth, preparations showed anti-inflammatory effects comparable with reduced skin wrinkles, and rejuvenated aged and photo- orally administered ibuprofen [12]. damaged skin. Emu oil also has been recommended for the treatment of hypopigmentation and other disorders such as Other potent activities of emu oil alopecia, male pattern baldness, female baldness, and chemotherapy-induced alopecia [32]. Hypocholesterolemic effect

Emu oil possesses hypocholesterolemic activity. A compar- Moisturizing and cosmetic properties ative study between emu oil and olive oil concluded that hamsters fed a refined emu oil diet had significantly reduced It was reported that emu oil is nonirritating, has good serum total cholesterol (TC) and low-density lipoprotein (LDL) moisturizing and cosmetic properties with low comedogenicity levels, with no effect on plasma high-density lipoprotein (HDL) and good penetrating ability across stratum corneum compared and TG levels compared with animals on the olive oil diet. with mineral oil. Thus, emu oil is of major interest to derma- Furthermore, emu oil reduced the ratio of TC to HDL to a sig- tologists and cosmetic scientists as a transcutaneous carrier nificant degree. Hamsters fed a refined emu oil diet showed system [33]. significantly higher levels of g-tocopherol than those fed a crude emu oil diet [30]. Emu oil as transdermal penetration enhancer Emu oil showed significant hypocholesterolemic and anti- atherosclerotic activity compared with several other animal The cream formed by combining emu oil with dermatologic oils [31]. The beneficial hypocholesterolemic and anti- active compounds such as a-hydroxy acids like lactic, glycolic, atherosclerotic activities of emu oil can be attributed to its high and pyruvic acids, water, and glycerine showed good penetrating content of monounsaturated fatty acids and PUFAs [30]. ability [34]. Emu oil has been used as a transdermal vehicle for progesterone, which could be used for relief from hot flushes, Stimulates skin and hair growth mood swings, bloating, loss of libido, vaginal dryness, and symptoms associated with menopause and premenstrual syn- Topical or parenteral administration of emu oil has been drome [35]. A topical dermal anesthetic formulation containing proven to stimulate the proliferation of skin. Emu oil 0.01% to 3% of emu oil has been proposed. Emu oil was capable of 24 M. K. Jeengar et al. / Nutrition 31 (2015) 21–27

Fig. 2. Schematic diagram representing the mechanism of action of u-3 fatty acids in insulin sensitization by acting on GPR120 receptor. When u-3 fatty acids bind to GPR120 receptor present on adipocytes PI3K is activated, which promotes increased translocation of GLUT4 channels to the plasma membrane, thus increasing glucose uptake into the þ cells. Similarly, it activates IP3 in small intestine cells increasing ca 2 concentrations causing more exocytosis of vesicles containing GLP-1. FA, fatty acid; GLP1, gucagon-like peptide-1; GLUT4, glucose transporter type 4; IP3, inositol trisphosphate; PI3K, phosphoinositide 3-kinase. increasing permeation through skin, improves shelf life of explore the scope of emu oil formulations as permeation formulation, prevents gastric irritation caused by drugs like enhancer in pharmaceutical preparations. aspirin, and can be applied directly to the area of pain on the body [36]. Emu oil has analgesic, anesthetic, and antipruritic Insect repellent property actions that have been exploited to prepare a formulation containing 20 to 70 wt% emu oil and was recommended as a spray or Emu oil serves as an excellent insect repellent when applied transdermal formula for the treatment of chronic cutaneous ul- topically. It was shown to reduce the number of mosquitoes and cers and burn wounds [37]. Emu oil and its various fractions may completely eliminated biting. Even at a low concentration of 1%, function as a carrier for antifungal, antibacterial, and antiviral emu oil was found to be effective for 30 min [40]. medications and preparations [38]. Emu oil has been paired with insulin and shown penetrating- Miscellaneous activities enhancing ability both in vitro and in vivo that could be used as alternative to injectable insulin formulations [39]. We observed Emu oil also has been reported to be effective in the treat- that emu oil can be combined with curcumin to enhance the ment of psoriasis and burns, and to enhance wound healing latter’s effect in the reduction of inflammation in adjuvant- [41,42]. In view of its antioxidant properties, emu oil may inhibit induced arthritis in an experimental animal model (data not lipid peroxidation, thus protecting against oxidative stress [11]. published). Based on these results, we prepared a nano-emulsion The variable amounts of compounds present in the non-TG formulation with emu oil as oil phase loaded with curcumin as a portion of emu oil like carotenoids, flavones, polyphenols, therapeutic drug for the treatment of arthritis. The curcumin- tocopherol, and phospholipidsTG may be responsible for the loaded nano-emulsion formulated with emu oil, when tested antioxidant effect of emu oil [15]. in carrageenan-induced arthritis model in SD rats, showed sig- The summary of various activities of emu oil are listed inTable 2. nificant reduction in inflammation compared with the formulation prepared without emu oil. These results confirm that emu Possible mechanism(s) of actions oil possesses good skin-permeation properties that can be used to enhance the delivery of drugs through the skin to enhance To our knowledge, no scientific study has been reported for bioavailability of topical applications. Development of such emu the potential mechanism(s) of action of the therapeutic effects of oil-based formulations is cost-effective and may replace expen- emu oil. In general, saturated fatty acids are proinflammatory, sive liposomal formulations. Hence, greater efforts are needed to unsaturated fatty acids are weakly proinflammatory or neutral, M. K. Jeengar et al. / Nutrition 31 (2015) 21–27 25

Table 2 Summary of various activities of emu oil

Disease Model Parameters Effect References 1. Gastrointestinal diseases a) Mucositis 5-FU-induced rat model Myeloperoxidase activity, Decreased myeloperoxidase [23] sucrose breath test activity, no effect on sucrose breath test. Decreased infiltration of neutrophils and reduced pro-inflammatory cytokines b) Inflammatory bowel Dextran sulphate sodium- Disease activity index, sucrose Increased colonic crypt [25] disease induced colitis breath test, histological colonic lengthening, no effect on damage severity, & crypt depth sucrose breath test 2. Experimentalpolyarthritis Adjuvant-induced arthritis in Paw diameter Four of five topical preparation [12] female Wistar rats of emu oil showed significant decrease in paw diameter 3. Hypocholesterolemic effect Cholesterol-enriched diet in TC, LDL, HDL, TG Decreased levels of TC, LDL [30,31] rats No effect on HDL, TG 4. Auricular inflammation Croton induced inflammation Ear lobe thickness, EP weights, Auricular thickness and EP [26] cytokines levels weights reduced IL-a, TNF-a level decreased 5. Cancer chemotherapy- 5-FU-induced osteopenia TNF-a, RANK expression Decreased TNF-a levels, inhibits [29] induced bone loss RANK expression, decreased osteoclast formation 6. Stimulates skin and hair Topically on C57BL/6 mice 3H-thymidine incorporation Increased pigmentation and [32] growth. hair growth 7. Moisturizing and cosmetic Human subjects, applied Ranking scale (0 ¼ poor,5¼ Better penetrating ability than [33] properties. topically on face and trunk excellent) mineral oil. Eleven subjects liked emu oil 8. Emu oil as penetration Insulin emulgel on excised skin Insulin permeation in in vitro, Increased insulin permeation, [39] enhancer of Albino rats in vitro, directly glucose levels in in vivo. decreased glucose levels. on back in vivo 9. Insect repellent activity Emu oil applied on one hand of No. of mosquitoes landed and/ Reduced landing and [40] human volunteers or bit in 30 sec eliminated biting of mosquitoes

EP, ear plug; 5-FU, 5-fluorouracil; HDL, high-density lipoprotein; IL, interleukin; LDL, low-density lipoprotein; TC, total cholesterol; TG, triglyceride; TNF, tumor necrosis factor and u-3 fatty acids are anti-inflammatory [43]. It also has been are agonists of GPR120. GPR120 is the only lipid-sensing G reported that g-linolenic acid (GLA), an essential u-6 fatty acid, protein-coupled receptor, which is highly expressed in adipose also contains anti-inflammatory activity [44]. The anti-diabetic tissue, proinflammatory macrophages, hepatic kupffer cells, and and anti-inflammatory properties of oleic acid (u-9) have been enteroendocrine L cells. Stimulation of GPR120 by DHA has been reported previously [45,46]. As emu oil contains all three omega shown to inhibit both toll-like receptor 2/3/4 and TNF-a proin- fatty acids [13], its anti-inflammatory activity can be attributed flammatory cascade. As shown in Figure 1, the mechanism to these fatty acids. These fatty acids could participate in alter- of GPR120-mediated anti-inflammation involves inhibition of nate pathways. GLA, produced in the body by linoleic acid pre- transforming growth factor b activated kinase-1 through sent in emu oil produces dihomo-gamma-linolenic acid (DGLA), b-arrestin 2-dependent effect [49]. Hence, it is likely that acti- which is a substrate for cyclooxygenase (COX) and lipoxygenase vation of GPR120 could occur by emu oil as a result of the u-3 (LOX) enzymes. It exerts anti-inflammatory activity by producing fatty acids present in it. potent ant-iinflammatory prostaglandin E1 (PGE1) [47]. The a-linolenic acid present in emu oil participates in the Emu oil and diabetes PGE3 pathway and is also a precursor of other u-3 fatty acids. The anti-inflammatory activity of u-3 PUFAs are due to their To our knowledge, there are currently no scientific results competition with arachidonic acid as a substrate for COX and 5- available on the effect of emu oil on diabetic conditions; how- LOX. These fatty acids possess anti-inflammatory potential by ever, the anti-diabetic effect of the fatty acids that are present in inhibiting 5-lLOX pathway in neutrophils and monocytes and by the composition of emu oil has been reported previously. Oleic antagonising leukotriene B -mediated functions of neutrophils. 4 acid was found to reverse the inhibitory effect on insulin pro- Additonally, u-3 fatty acids suppress the production of IL-1 by duction caused by the inflammatory cytokine (TNF-a) in both suppressing the IL-1 mRNA, as well as the expression of COX-2 in vitro and in vivo systems [45]. GLA has proven useful in insulin mRNA that is induced by IL-1 [48]. Although cell culture resistance [44] and in the prevention and treatment of diabetic studies with u-3 PUFAs have shown inhibition of COX-2 pro- neuropathy [50]. Recent studies have reported that u-3 PUFAs duction and proinflammatory cytokines including TNF-a, IL-1, IL- also exert a potent insulin-sensitizing effect via activation of 6, IL-8, and IL-12, currently no studies have reported that emu oil GPR120 receptor [49]. Stimulation of GPR120 by free fatty acids inhibits specifically COX-2 [14]. promotes secretion of GLP-1 as shown in Figure 2 (most potent insulinotropic incretin) in vitro and in vivo, and increases Gpr120 receptor–mediated anti-inflammatory effect circulating insulin [51]. Thus, the u-9, u-6, and u-3 fatty acids present in the composition of emu oil may have beneficial effects Recent studies showed that u-3 fatty acids act on GPR120, an in diabetes. Thus, emu oil deserves close attention in the inves- orphan receptor. DHA, eicosapentaenoic acid, and palmitoleate tigattion of its anti-diabetic activity. 26 M. K. Jeengar et al. / Nutrition 31 (2015) 21–27

Conclusions [16] Stringer AM, Gibson RJ, Bowen JM, Logan RM, Yeoh AS, Keefe DM. Chemotherapy-induced mucositis: the role of gastrointestinal micro- flora and mucins in the luminal environment. J Support Oncol In this review, we highlighted the importance of emu prod- 2007;5:259–67. ucts, mostly emu oil, as possible use in complementary and [17] Lalla RV, Peterson DE. Treatment of mucositis, including new medications. – alternative medicine. We demonstrated that the main thera- Cancer J 2006;12:348 54. fl [18] Gibson RJ, Keefe DMK, Lalla RV, Bateman E, Blijlevens N, Fijlstra M, et al. peutic effect shown by emu oil is its anti-in ammatory potential, Systematic review of agents for the management of gastrointestinal for which it can be used in alternative medicine, and its mucositis in cancer patients. Support Care Cancer 2013;21:313–26. penetration-enhancing property may be useful as a complement [19] Gibson RJ, Keefe DM, Clarke JM, Regester GO, Thompson FM, Goland GJ, et al. The effect of keratinocyte growth factor on tumour growth and small to conventional medicines. intestinal mucositis after chemotherapy in the rat with breast cancer. We also have demonstrated that the beneficial effect of emu oil Cancer Chemother Pharmacol 2002;50:53–8. appears to be mediated by its unsaturated fatty acids content (u- [20] Cool JC, Dyer JL, Xian CJ, Butler RN, Geier MS, Howarth GS. Pre-treatment with insulin-like growth factor-I partially ameliorates 5-fluorouracil- 9, u-6, and u-3 fatty acids) as well as its non-TG fractions like induced intestinal mucositis in rats. Growth Horm IGF Res 2005;15:72–82. carotenoids, flavones, and other natural antioxidants. Emu oil [21] Tran CD, Howarth GS, Coyle P, Philcox JC, Rofe AM, Butler RN. Dietary may act as a natural precursor to the body’s own anti- supplementation with zinc and a growth factor extract derived from inflammatory agents. 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