ERA’S JOURNAL OF MEDICAL RESEARCH VOL.3 NO.1 Review Article

CITRUS WASTE REUSE FOR HEALTH BENEFITS AND PHARMA-/NEUTRACEUTICAL APPLICATIONS

Neelima Mahato, Kavita Sharma, Fatema Nabybaccus & Moo Hwan Cho School of Chemical Engineering, Yeungnam University, Gyeongsan-si Gyongsanbuk-do, Republic of South Korea- 712 749

ABSTRACT are the largest crops grown across the globe. It is one of the most profitable crops in terms of economy as well as popular for Address for correspondence nutritional benefits. The most interesting aspect about citrus is the Neelima Mahato availability of several varieties with attractive colours. Approximately 50 School of Chemical Engineering % of citrus remains unconsumed after processing as pith residue, peels Yeungnam University, Gyeongsan-Si, and seeds. Direct disposal of these wastes cause serious environmental Gyeongsanbuk-do, problems in terms of killing natural flora in the soil because of Republic of Korea- 712 749 antibacterial properties of oils. Seepage to underground waters Ph: +82-010-2798-8476 Email:[email protected] or open water bodies affects water quality and aquatic life, respectively. Citrus waste reuse to obtain value added-phytochemicals and pectin is one of the popular topics in industrial research, food and synthetic chemistry. The present article reviews recent advances in exploring the effects of phytochemical compounds obtained from citrus wastes in view of various health aspects.

Key words: Citrus waste, Phytochemical compounds, Hesperidin, Naringenin, Flavonoids, Polyphenols

INTRODUCTION of the fruit is sedative and fruit and seed extracts are useful in palpitation and making cardiac tonics.(2-4) Citrus have long been known for health benefits due to their nutrient contents and secondary metabolites, such Citrus belongs to family Rutaceae comprising 140 as ascorbic acid, , phenolics, flavanoids, pectin, genera and 1300 . It is one of the major fruit crop etc. Ascorbic acid helps in promoting the healing of grown in tropical and subtropical regions. The main mucosal lining by stimulating procollagen formation and varieties are sweet oranges (Citrus sinensis), subsequent synthesis of the same. (1) Various parts of the or mandarin (Citrus reticulata), (Citrus vitis), citrus fruits have been in popular use in traditional Indian (Citrus aurentifolia), and (Citrus limonum). and oriental medicines. Ripe fruits are good source of The major types of citrus fruits popularly grown are Vitamin-C, Vitamin-B complex and have curative shown in Figure 1. Annual worldwide properties for sore throat, cough, asthma, thirst, hiccough, currently amounts over 70 million tons in approximately earache, nausea and vomiting. These are also potent anti- 140 citrus producing countries.(5) Out of the total citrus scorbutic, stomachic tonic, stimulant expellant of poison, production, approximately 40-50 % is utilized in correct fetid breERA'Sath and analgesic. Distilled water extract processing and manufacturing commercial products,

Figure 1. Main varieties of citrus fruits grown across the globe.

20 CITRUS WASTE REUSE FOR HEALTH BENEFITS AND PHARMA-/NEUTRACEUTICAL APPLICATIONS such as juice, jams, marmalades, jellies, flavouring affecting aquatic life. Also, citrus wastes are very agents, beverages and health drinks, etc. difficult to dry by common conventional methods because of high moisture content. CITRUS WASTES, ENVIRONMENTAL PROBLEMS AND REUSE Hence, extraction of oils, by-products and valuable Citrus processing industries produce approximately 40 phytochemical compounds from citrus wastes is not million tons of waste worldwide. The amount of only a profitable alternative, but also a creative method residues obtained from citrus fruits constitutes almost of pollution abatement. Apart from essential oils (d- 50 % of the original fruit mass. Citrus fruits contain ~ limonene), phenolics (coumarin, phenolic acid, 40-55 % peels, ~30-35 % internal tissues and ~10 % phloroglucinol), flavanoids (hesperidin, naringenin, seeds depending upon species, variety and climatic neo-hesperidin), carotenoids (lutein, β-carotene, conditions where it is cultivated. The residue waste lycopene, zeaxanthin), limonoids (limonin, normilin, contain high amount of soluble sugars which make limonoic acid), enzymes (pectinesterase, phosphatase, them highly perishable. Also, sugars and moisture peroxidase), organic acids (citric acid, maleic acid, facilitate high rates of fermentation. High content of succinic acid), vitamins (Ascorbic acid, niacin, organic matter especially oils (limonene) which riboflavin), carbohydrates and pectins can be carry antibacterial properties, make the citrus wastes commercially extracted from the citrus wastes. (5) inappropriate for direct disposals to landfills or Some of the products created from citrus wastes are dumping underground. Such disposals have been found shown in Figure 2 and a collection of commercial to affect the natural and beneficial flora present in soil brands are collaged in Figure 3. Commercial and aquatic bodies nearby. Furthermore, the oils tend to techniques and details of extraction processes are float on the surface of water bodies and limit the described in Reference. (5) passage of oxygen from dissolving into the water

ERA'S

Figure 2. Main compounds and potential usage of different parts of citrus waste.

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Commercial products from Citrus Albedo

Commercial products from Citrus Pith Residue

Commercial products from dried Citrus Peel ERA'S

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Cosmetics, skin care products and toiletries from Citrys Essential oils

Commercial products from Citrus Seeds

Figure 3. Commercial products created from citrus wastes (pulp residue, pith, peels and seeds). The photographs of the products are taken from a local supermarket in Gyeongsan city, South Korea.

*Disclaimer: Pictures of commercial products used in this article are purely for academic purpose and not meant for any advertisement or commercial benefit.

CITRUS WASTE DERIVED PHYTOCHEMICALS nails, antifungal and antibacterial lotions, soaps, FOR HUMAN HEALTH perfumes and toiletries. The phytochemicals and value added compounds Obesity, hypertension, diabetes, heart diseases, cancer, extracted fromERA'S citrus wastes are utilized in designing memory loss, anxiety, etc., are closely related to healthy foods, nutrient supplements, flavouring agents in personal lifestyle as well as food and dietary habits. foods processing, preservatives, health and power drinks Since last few decades, emphasis on the philosophy of in view of enhancing the quality of taste, aroma and curing “Prevention is better than cure” has gained huge deficiencies as well as restoring health. Citrus extracts are attention and popularity in the mind-sets of common also utilized in cosmetic formulations for skin, hair and people and instigated awareness for achieving fitness

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and good health. In this direction, nutrition and food searching innoxious and therapeutic natural products. In scientists, dieticians and specialists have continuously this regard, traditionally popular oriental herbal researched along with medical practitioners and medicines, such as Diospyros kaki Thumb. and Citrus educationists on functional foods and nutritional unshiu S. Marcov. Peels for treating obesity are being supplements that can reduce the risk of diet related thoroughly investigated for developing potentially disorders/ diseases. Foods containing antioxidants and useful medicines/formulations. Both are popular as other phyto-nutrients, such as fruits and vegetables obesity curing herbal medicines in oriental countries, have proven to provide protective effects against many especially China, Korea and Japan. These fruits contain diseases especially degenerative processes caused by several bioactive compounds including polyphenols oxidative stress.(6-8) Obesity is an outcome of faulty (esp. tannins), caratenoids, flavanoids, vitamins, life style, energy imbalance and abnormal metabolism. minerals and dietary fibres. Polymethoxyflavones, It is considered as a serious global health risk by World hydroxyl polymethoxyflavones and hydroxylated Health Organization (WHO). Obesity further increases polymethoxychalcones from Citrus sinensis has been the risk of dyslipidemia, hypertension, fatty liver reported to exhibit anticancer and antioxidant activities. disease, diabetes mellitus, cancers, osteoarthritis and (14) asthma.(9, 10) As per WHO 2014 reports there are more than 1.9 billion adults of age 18 years and above Polyphenols present in peels have shown identified as overweight and out of this, over 600 to influence carbohydrate metabolism by inhibiting the million were declared obese. Approximately 41 α- glucosidase and α-amylase enzymes responsible for million children under the age of 5 were either carbohydrate digestion. It also helps in avoiding chronic overweight or obese. Overall, ~ 13 % of the world's hyperglycemia that characterize type 2 Diabetes population (11 % of men and 15 % of women) were mellitus.(15) Citrus extracts especially flavanones and obese in 2014. The world prevalence of obesity is polymethoxyflavone have been found to provide continuously increasing and has become doubled estrogen effects and therefore, useful in hormone between 1980 and 2014. Surprisingly, overweight and replacement therapy. The latter is a common therapy for obesity are linked to more number of deaths worldwide estrogen deficiency in women especially post then underweight (11). Furthermore, WHO predicted menopause which may lead further complications of that by the year 2030, the affected population might osteoporosis, coronary diseases and bone density increase to 3.3 billion (i.e., 1.7 times). This not only is reduction , disturbed blood cholesterol profile and expected to alter the quality of health and life, but also unpleasant symptoms, such as hot flashes and insomnia. increases economic burden in terms of direct and Conventional pharmacological treatments have shown indirect health care costs which includes health increased risks of cardiovascular diseases and induce monitoring, nutritional supplements and surgical breast cancer development, stroke and blood clots. (16) management. Macromolecules present in our body fluid play Orlistat (Xenical) approved by FDA is a very popular important role in crystal aggregation, especially and relatively effective drug of the present time and calcium oxalate crystallization leading to stone prescribed for long term treatment of obesity. It formation or urolithiasis. Calcium oxalate crystals are efficiently inhibits the pancreatic lipase enzyme and sparingly soluble or insoluble and tend to grow in size prevents the absorption of dietary fats. (12, 13) blocking urinary functions. In severe consequences, it However, it also causes severe gastrointestinal side- leads to kidney failure and gall bladder malfunctioning. effects. The side-effects make pharmacological Even after treatment or removal of these stones, chances approaches less attractive than therapeutic agents, of reoccurrences are many and a big challenge for which make natural remedies derived from medical experts. phytochemicals a relatively more viable alternative. Therefore, the recent studies are being focused on

Table 1. Effect of citrus waste derived phytochemical compounds on various health aspects.

Citrus fruit Fruit part Active compound(s) Effect on health Animal Model Ref. ERA'Sextract Citrus Water extract of Hesperidin, narirutin Anti-aging effect In vivo (Mice) (17) unshiu dried peels (Chinpi)

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Table 1. Effect of citrus waste derived phytochemical compounds on various health aspects.(cont..) Citrus Water extract of avoniods, Hepatoprotective In vivo (Mice) (18) sinensis (L.) dried peels polymethoxyavonoids and Osbek immunosuppressive effects Citrus Peel extract in Tannins, saponins, Antimicrobial effect In vitro (agar (19) sinensis ethanol and phenolic compounds, against dental caries well diffusion water (hot and essential oils and bacteria method) cold) avonoids Streptococcus mutans and Lactobaccillus acidophilus Lemon peel Antibacterial 8-geranyloxypsolaren; Antimicrobial effect In vitro (20) compounds 8-geranyloxypsolaren; against dental caries isolated from 5-geranyloxy-7- bacteria, viz., methanolic methoxycoumarin; Streptococcus extract using Phloroglucinol 1-β-D mutans ATCC7270, water, ethanol glucopyranoside Prevotella and n-hexane (phlorin) intermedia, Porphyromonas gingivalis 381 Syrian Peel extract limonene, γ-terpinene, Cytotoxic effect on In vitro (21) Citrus limon from β-pinene, O-cymene colorectal carcinoma L. hydrodistillation and citral cells of 3h Citrus Peel extract in Flavonoids-, Cardioprotective In vivo (Adult (22) grandis L. 80 % ethanol by narirutin, activity against male Wistar rats) Osbek Soxhlet, 8h neohesperidin cyclophosphamide (CYP) and doxorubicin (DOX) induced cardiac toxicity in rats Citrus Grapefruit Seed Flavonoids (naringin), Ameliorating effect In vivo (Adult (23) paradisi Extract (GSE) in Vit-C, Vit-E on DOX-induced male Sprague- (grapefruit) 100 % ethanol cardiomyopathy Dawley rats) Citrus Peel extract in HBE polysaccharides Inhibitory effect on In-vitro (24) spherocarpa water and (HBE-I, II, III, IV) breast cancer (Korean ethanol metastasis hallabong) followed by Sephadex G-75 gel ltration Citrus Dried peel Flavonoids (naringin, Hepatoprotective In vivo (25) unshiu extract in 70 % hesperidin) effects; Improves (Ovariectomized ethanol, lipid and bone (OVX) rats reuxed for 3h metabolism (animal model at 80°C; of post concentrated menopausal and lyophilize osteoporosis) Citrus ERA'SPeel extract in Flavanone and Modulation of blood In vivo (26) reticulata 70 % ethanol, by polymethoxyavone cholesterol and bone (Ovariectomized maceration for 5 density (OVX) rats) days; ltration and evaporation

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Table 1. Effect of citrus waste derived phytochemical compounds on various health aspects.(cont..) Citrus karna Peel extract by Flavonoids and Anti-ulcerogenic In vivo (Wistar (27) maceration in phenolic acids and antioxidant rats; Water hexane, CHCl3, activity immersion ethyl acetate and (WIS) and methanol, 24h Hypothermic restraint (HRS) stress models)

Citrus Whole fruit Flavonoids and Antiulcer activity In vivo (Mice) (4) medica Linn. aqueous extract phenolic acids by maceration

Citrus Flesh and peel Total phenolic content Antioxidant activity: In-vitro (8) auranthium extract in experiments on acetone, ethanol HepG2 (ATCC and methanol 8065) cells; for 72h at 25 Antioxidant °C; ltered, activity by evaporated and DPPH method redissolved in DMSO (dimethyl sulphoxide) to a concentration of 50 mg/ml

Citrus Aqueous peel Polyphenolic Anti diabetic In-vitro (28) limetta extract compounds (antihyperglycemic); (Antioxidant antioxidant activity activity by DPPH method)

Citrus Citrus Peel + Polyphenolic Anti-obesity effect In-vivo (Mice) (29) unshiu Diospyros kaki (especially tannins) fruit extract in carotenoids, boiling water, falvanoids, vitamins, 2h; enzyme minerals and dietary decomposition, bers 15g; enzyme viscozyme inactivation at 90 °C, 30 min; ltration and concentrated; sterlization Citrus Soxhlet Flavonoids, saponins, Antibacterial effect In-vitro (30) sinensis; extraction of steroids, terpenoids, (Mice) Citrus limon ERA'Scitrus peel in tannins, alkaloids ethyl acetate, acetone, ethanol, ether and water

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Table 1. Effect of citrus waste derived phytochemical compounds on various health aspects.(cont..) Citrus Peel extract in Tannins, alkaloids and Anti-helminthic In vivo (Mice) (31) aurentifolia methanol polyphenols effect against fractioned using Heligmosomoides ethyl acetate, bakeri (nematod) in butanol and mice aqueous methanol , Ethanolic Limonene (90%), b- Antihelminthic In vivo (32) lemon and extract of citrus pinene (0.5%), a- effect on Ascaridia (Chicken) mandarin peel suspended pinene (0.5%), galli in chickens in 0.5% DMSO sabinene (0.3%) collected from their intestines Citrus limon Peel essential terpenoids Antifungal effect on In-vitro (33) oils from cold oral candidiasis pressing (Candida albicans) fungus Citrus Extract of avonoida, Anticancer activity In-vivo (Female (34) multiple polymethoxyavones (Skin, Colon, ICR mice) varieties of (PMFs) Prostate) citrus peels (Gold Lotion or GL copmrising extracts from the peels of six citrus fruits produced in Japan) Citrus Essential oil a-terpineol (33.59%), Antituberculosis In-vitro (35) sinensis L. from g-muurolene (4.44%), effect hydrodistillation D-limonene (17.74%), linalool (9.73%), citronellol (4.88%), and isopiperitenone (3.58%), etc. Citrus Glycosides of decreased amount of Antioxidant and In-vitro (RAW (36) x GKP converted avanone rutinoside anti-inamatory 264.7 cells) ; into aglycosides forms (nerirutin and GKP (jeju activity Hallabong by enzyme hesperidin) and ) cytolase increased amount of avanone aglycoside forms (naringenin and hesperetin) Citrus Peel waste is Hesperidin and Proangiogenic In-vitro (Human (35) unshiu lyophilized, narirutin effects; improves umbilical vein ground and blood circulation endothelial suspended in 50 cells-HUVECs) mM sodium ERA'Sacetate buffer Citrus Extracted and Bioavonoid Cholesterol In vivo (Rats) (37) puried naringenin regulation

Citrus Extracted and Bioavonoid Hepatic cholesterol In vivo (Spragne (38) puried naringenin regulation Dawley rats)

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Table 1. Effect of citrus waste derived phytochemical compounds on various health aspects.(cont..) Orange Peel and pulp Essential oils Antimicrobial In vitro (Cattle) (39) residue, activity shredded, dried and added to cattle feed Citrus Peel extract in phenolics and Anti-aging effect In vitro (40) reticulata ethanol from avonoids (Antioxidant soxhlation and and anti-enzyme maceration assay) Citrus Peel extract and bioavonoids Inhibition of stone In vivo (Rats) (41) formulations forming proteins Citrus Dried peel Auraptene Anti-inamatory In vivo (Mice) (42) kawachiensis powder effect Citrus Nobiletin Nobiletin; ANTII Enhances learning In vivo (Mice) (43) reticulate, extracted from NOBILS and memory Citrus C. depressa PERICAPRIUM unshiu, using Citrus chromatography depressa and recrystallized in actone; dried peels of C. reticulata Blanco and C. unshiu Markovich employed as ANTII NOBILS PERICAPRIUM

Citrus derived phytochemicals, notably citric acid helps The concept of consuming citrus regularly is a part of in converting the oxalates into citrates which are the everyday life in oriental countries. It is preserved relatively more soluble in water and can be passed along with peels and seeds. Cleaned citrus fruits are cut through urine. Furthermore, phytotherapy including in small pieces, added with sugar, boiled for 4-7 naringenine, hesperidin and rutin have started gaining minutes, further boiled with honey for 4-7 minutes and interest in recent years. Some of the study reports can be stored for months. It is consumed as herbal tea with hot found in the references.(44-46) Table 1 lists and water. Preserved honey tea is shown in Figure 4. elaborates some of the recent scientific studies on the Citrus is also preserved with ginger, rosemary, ginseng effects of citrus derived phytochemicals and various and other herbs for enhancing flavour and aroma as diseases, illnessERA'S and health profiles. well as nutritional benefits.

Lemon Ginger Grapefruit Lemon Cherry Lemon

28 CITRUS WASTE REUSE FOR HEALTH BENEFITS AND PHARMA-/NEUTRACEUTICAL APPLICATIONS

Lemon Raspberry Lemon Fig Lemon Blue

Figure 4. Honey citron tea. Oriental concept of preserving citrus fruits along with peels and seeds with honey and consumed as herbal tea. It is also preserved with ginger, cherry, raspberry, g, plum, resins and other herbs for additional benets, avour and aroma. Furthermore, it is also freeze dried and jellied with agar agar and consumed as snacks. CONCLUSION: extract in carrageenan induced inflammatory Increasing health awareness and quality of pain in rats. Research Journal of Medicinal healthy life has incorporated citrus as an essential part of Plants. 2009;(3);123-33. diet and cuisine. Citrus not only provides nutritional supplements but also helps reducing risks of several 2. Kirtikar KR, Basu BD. Indian Medicinal illnesses. Edible as well as non-edible parts of citrus both Plants. Dehradun; 1983;(44);115-59. are rich in various phytochemical and value added compounds. Non-edible parts or citrus wastes are reused 3. Peter EE, Peter JE, Nes BI, Asukwo GE. to obtain more than 400 commercial products which are Physiochemical properties and fungi toxicity of either utilized in nutritional supplements, curative the essential oil of Citrus medica L. against medicines, food processing, preservatives, or cosmetics- groundnut storage fungi. Turkish Journal of making, home utilities and toiletries. The ongoing Botany. 2008;(32);161-4. research on citrus waste reuse is dedicated to minimise 4. Nagaraju B, Anand SC, Ahmed N, Chandra the hazards from direct disposal and maximise the JNNS, Ahmed F, Padmavathi GV. Antiulcer recovery of valueERA'S added products. activity of aqueous extract of Citrus medica REFERENCES: Linn. fruit against ethanol-induced ulcer in 1. Sood S, Bansal S, Muthuraman A, Gill NS, Bali rats. Advances in Biological Research. M. Therapeutic potential of Citrus medica L. peel 2012;6(1);24-9. 5. Sharma K, Mahato N, Cho MH, Lee YR.

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