Phytowaste as nutraceuticals in boosting public health

A total of 198 articles were found during the initial search, 38 articles were removed because they appeared as duplicates, in the course of title and abstract screening 30 articles were removed as they were not very relevant to the focus of the review leaving a total of 130 for further review, 2 more articles were not available in English. Further review of the full text of the remaining articles to ascertain the suitability of the article for relevant data extraction. The appraisal and use of the inclusion and exclusion criteria resulted in the exclusion of 32 more articles. At the end 96 articles were left and used in this systematic review. The articles provide the therapeutic effects of several peels and fruits. Figure 1 shows the study selection flow diagram.

Peel extracts have several mechanisms of action by which they act, most peel extracts act as antioxidant mainly by scavenging radicals directly in a dose-dependent manner [10]. Flavonoids act as chain-breaking antioxidants in their scavenging mechanism or recycle other chain-breaking antioxidants such as α-tocopherol by donating a hydrogen atom to the tocopheryl radical while some flavonoids prevent the formation of free radical by chelating divalent metal ions [9]. A study by Kim et al., (2005) [11] revealed that Citrus reticulate peels extract displayed potent tumor-suppressing activity in SNU-C4 human colon cancer cells, such extracts include quercetin and quercetin-3-O-beta-D-glucopyranoside, with its anticancer effect is believed to be through the up-regulation of the proapoptotic gene Bax and apoptotic gene caspase-3 or downregulation of the antiapoptotic gene bcl-2. According to Narayana et al., (2001) [12] these extracts also possess lipid-lowering and anti-atherosclerotic properties, which act as effective cardiovascular protection through its ability to oxidatively modify low-density lipoproteins (LDL) via a scavenger receptor in atherosclerosis pathogenicity, which then leads to the formation of foam cells. These antioxidant activities can be enhanced by transition metals and important pro-oxidants like iron and copper. Hesperidin and naringin (bioflavonoids) present in peels play an antidiabetic role by increasing serum insulin, hepatic glycogen content and hepatic glucokinase activity, while decreasing serum glucose concentrations, glucose-6-phosphatase and phospho-enol pyruvate activity in mice [13].

The biomolecules of the peel extracts play major role in thyroid stimulatory activity by influencing thyroid hormone metabolism. A study by Divi and Doerge (1996) [14] showed the antithyroidal role of the phenolic compound naringin which is mediated through thyroid peroxidase (TPO) inhibition, a key enzyme in the biosynthesis of thyroid hormone. Similarly, the high dopamine content of Musa paradisiaca peel extract inhibits TPO [15, 16] Auraptene in citrus peel elicit anti-inflammatory effects via reducing the expression of NF-κB, tumor necrosis factor alpha (TNF-α) and IL-1β [17]. These extracts also inhibited the activation of hepatic stellate cells (HSCs) by down-regulating the expression of TGF-β1 and α-SMA. Auraptene treatment increased the bile flow and biliary bile acid output while decreasing hepatic uptake of bile acids, consequently alleviate 17α-ethinylestradiol (EE)-induced cholestasis, associated with induction of efflux transporters (Bsep and Mrp2) and downregulation of Ntcp. Hence, auraptene reduce bile acid synthesis through repressing Cyp7a1 and Cyp8b1 but increase bile acid metabolism through an induction in the gene expression of Sult2a1 [18].

The precipitation of membrane proteins resulting in microbial cell lysis is the reported mechanism of antimicrobial activity of pomegranate peel phenolics [19]. Therapeutic interventions with extract of passion fruit peel as adjunctive therapy in asthmatic patients is reported to be via the antioxidant flavonoids properties [20]. Figure 2 described the mechanism of actions of the peel and it resultant therapeutic effects.

Banana peel extracts (M. paradisiaca L.) increase superoxide dismutase (SOD) and glutathione levels but reduce hydroperoxides, peroxidation products (MDA), conjugated dienes and the enzymatic activities of catalase (CAT) in fatty acids rich diet fed experimental rats [21]. Duda-Chodak and Tarko [2] reported essential diversities of bioactive compound among the peels and seeds of domestic and imported fruits. The peels had higher ability to scavenge free radicals and higher polyphenols concentration than the seeds [2]. Fresh and dried peels of Satsuma mandarin have potent protective activity against Musa cavendishii the generation of linoleic acid hydroperoxide, which were often due to their high tannin contents [22]. S. mandarin peels contain considerable ascorbic acid and have a beneficial effect on blood circulation, as well as bronchial and asthmatic conditions.

Someya et al., [23] identified the abundance of gallocatechin in the banana peel M. cavendishii peel and the major component responsible for the antioxidant activity against lipid auto-oxidation. Dietary supplementation of feed with 5% banana peel improved the antioxidant capacity, regulated the expressions of certain cytokine-related genes and enhanced GPx [24]. Rutin, quercetin, catechin, quercitrin, kaempferol, chlorogenic and ellagic acids are phenolic compounds extracted from unripe plantain peels, these are reported to inhibit Fe²⁺-induced lipid peroxidation linked with erectile dysfunction [25]. Such chelating and antioxidant properties were also reported by [26] for melon peel in different concentrations (0.5 to 2.5 mg/mL) with 46% hydromethanolic, 49% hydroethanolic and 61% for the aqueous extract efficacy.

Rambutan peel phenolic extract has high antioxidant and antiglycation activities in vitro and in vivo [27]. Pomegranate (P. granatum) peel is a rich source of flavonoids, phenolic compounds, glycosides, saponins, alkaloids and tannins. Others include nutrients like; proteins, carbohydrates and minerals like sodium, calcium, magnesium, potassium, phosphorus iron and vitamin C [28]. These are potential resources that confer on Pomegranate blood thinning, cardiovascular protective, anti-artherosclerotic, antilipidemic, antimutagenic and antioxidant properties [6].

The phytochemical, antioxidant activity and mineral composition of soursop (Annona muricata) peel and seed have been investigated [29, 30]. The peel and seed extract showed the scavenging abilities of soursop, in the peel, tannins, glycosides, steroids, alkaloids, phenols, resins, flavonoids, phlobatanins, carbohydrates and balsams were present while saponins, steroids, flavonoids, terpenoids, volatile oils, phlobatannins, carbohydrates and balsams were present in the seed. These constituents contribute to their cardiovascular protective effects [31]. Burčová et al., [32] reported that Sea buckthorn contains antioxidants like α-, β-, γ- and δ-tocopherols with higher amounts of α-tocopherols and palmitoleic acid (also present in human skin) in peels. While the seed contains β-tocopherol and unsaturated biologically active fatty acids. α-, β-, or γ-tocopherols that are less effective when compared with the delta component.

Mango peel is rich in Vitamin C and Vitamin E, peroxidase, protease, oxidase, xylanase, polyphenol and amylase activities. Ripe peel extract has more lipid peroxidation potentials compared with unripe mango peel, which has a higher lipoxygenase inhibitory activity [33]. Pineapple (Ananas comosus) peel contains antioxidants in threonine, 3-methylglutaric acid, valine, and α-linolenic acid, whereas epicatechin was responsible for the α-glucosidase inhibitory activity [34]. Two varieties of Avocado (Persea americana Mill.) ‘Hass’ and ‘Fuerte’, peels and seeds have been shown to possess phenolic composition and in vitro antioxidant activity [35] (Table 1).

Wound healing involves processes like inflammation, proliferation, migration of different cell types, especially fibroblasts and restoration of a functional barrier in nearly all types of tissue damage in a complex but dynamic way, resulting in the contraction and closure of the wound [40]. These Fibroblasts produce collagens, elastin, and proteoglycans, which are very important in wound healing. These process involves the formation or triggering of Reactive oxygen species (ROS), which are essential in cell signaling and immune responses leading to the complete healing [41, 42].

Banana skin is often used as a temporary barrier to skin breakage, and its powder added to chitosan results in a decrease in swelling, which is a process involved with the inflammatory process of pain perception and wound healing. These banana peels are also thought to increase water resistance, a functional attribute of normal skin, due to interaction between negatively charged compounds in banana peel powder such as carboxylic acids and positively charged groups on the chitosan backbone chain. Addition of banana peel constituents such as lignin decreases the level of swelling in wound dressing [43], while also acting as an antiseptic in its modulation of immune system [44]. A study by Padilla-Camberos et al [45] showed that M. paradisiaca peel extract has the capacity of wound healing due to the presence of tannins, alkaloids, saponins and phenols as principal constituents conferring antioxidant capacity, these wound healing efficacies are often dependent on the extraction process.

Atzingen et al. [46] reported an increase in the number of polymorphonuclear cells and concentration of collagen fibers, a reduced wound contraction and vascular proliferation, following the use of 4% M. sapientum L. peel gel for the treatment of the lesions by excision model. M. sapientum Linn. Var. Compressa peel extract exhibits an anti-hemmorrhagic effect on Sparague rats tested using modified bleeding time [47]. It exhibits significant anti-hemmorhagic effect at different level of concentrations. The 50% concentration of M. sapientum Linn. Var. Compressa exhibits the shortest mean bleeding time results and it was also the most statistically significant.

Phenol-rich methanolic extract of dried pomegranate peel caused a complete wound healing on the skin of Wistar rats [48]. This effect is further supported by histopathological and biochemical observations following orally infusions of pomegranate seed extract in rabbits [49, 50].

Pomegranate peel extract promotes wound healing by increasing the migration of fibroblast, accelerating the second stage of the healing, and decreasing the number of immune cells in the vicinity of the wound and injury, and its effects are attributed to its phytochemical constituents, which include; saponins, sterols, triterpenes, alkaloids, flavonoids, tannins and cardiac glycosides [51].

The fruit peel extract of Cucurbita moschata Duchesne, due to its high content of mucilage, antioxidant and moisturizing effect could act as a burn healing agent [52]. Other pumpkin peel effects on wound healing include its immunomodulatory effects, natural killer cells activity, proliferation of lymphocytes and promotion of CD4+ and CD8+ cells [53].

Other flavonoid rich fruits like Grape seed extract GSE proanthocyanidins, a procyanidolic oligomer according to play an important part in accelerating skin wound healing process [54‐56] (Table 2).

Bioactive components of peel and seed extracts have great medical potentials in the treatment and management of diabetes. Attenuating the antagonizing the damaging effects of ROS through antioxidant functions is a generally agreeable mechanism. Such a mechanism may occur directly or indirectly by increasing the activity of certain antioxidant enzymes, such as Paraoxonase (PON1), Superoxide dismutase (SOD), and catalase (CAT) [58]. As far back as 1998 avocado was used in the treatments of diabetes in adult male rabbits [59]. observed aqueous seed extract of avocado reduced hyperglycemia after an oral glucose overdose. Aqueous extracts of avocado seeds (300 or 600 mg/kg body weight) administered for 21 days to Alloxan-induced diabetic rats, it revealed reduction in blood glucose by about 78–73%. Hence, the drug-induced pancreatic islet cells deterioration was inhibited by the extract.

Passion fruit (Passiflora edulis f. flavicarpa Deg.) peel flour has pectin as one of its components, and is rich in soluble fiber [60, 61]. used yellow passion fruit peel flour supplement as adjuvant therapy decreased blood glucose and insulin resistance in type 2 diabetic animals and patients. The study further reported that the extracts protected the end organs by restoring the anti-oxidants enzyme, increasing superoxide dismutase level (SOD) and decreasing catalase (CAT) and Thiobarbituric Acid Reactive Substances (TBARS) level in visceral organs. Induced hyperglycemic condition was also ameliorated by M. indica and Citrullus vulgaris peel extracts was reported to decrease serum glucose and increase in insulin concentrations in induced hyperglycemic conditions, through mechanisms involving the reduction in the oxidative stress, and directly related to insulin secretion and β-cell apoptosis [62].

Peel extracts from Citrus sinensis and P. granatum with high total polyphenols content have been associated with antidiabetic and antiperoxidative effects [63]. reported maximum glucose lowering and antiperoxidative activities at 25 mg/kg for C. sinensis and 200 mg/kg for P. granatum peel extracts, this doses also resulted in higher insulin levels [64]. The methanolic seed extract of pomegranate significantly decreased the level of blood glucose by 47% and 42% respectively, after 12 h on streptozotocin-induced diabetes rats [64, 65]. Mcfarlin et al., [66] reported that consumption of pomegranate seed oil (PSO) decreased weight gain and reduced the risk for type 2 diabetes in wild type CD-1 mice by improving insulin sensitivity in a period of high-fat feeding. PSO is rich in linolenic acid and leptin an adipose tissue-derived hormone, important for the regulation of both energy intake and energy expenditure and lower levels of adiponectin, it is also involved in fatty acid catabolism and glucose regulation.

The pharmacological evaluation of rambutan peel phenolic extract has confirmed the high antioxidant and antiglycation activities with amelioration in fasting blood glucose level of the diabetic mice [27]. Rambutan peel phenolic extract reduced in a dose-dependent manner, the total cholesterol, triglyceride, creatinine and lipid peroxidation in diabetic mice. It also increased superoxide dismutase and glutathione peroxidase in diabetic mice (Table 3).

The antimicrobial mechanisms of phenolic compounds involve the inhibition of enzymes such as glycosyltransferases leading to bacterial death due to membrane protein precipitation [68]. Malvidin, petunidin and cyanidin are anthocyanin compounds with strong antimicrobial activities and potentials found in Syzygium cumini (black plum) fruit peel [69]. S. cumini fruit peel extract was observed to have equal potency against both Gram-negative and Gram-positive bacteria, and are comparable with antibiotics like methacillin and penicillin. Lemon peel (Citrus limon) oil exhibited high antibacterial activity against Gram positive bacteria (Staphylococcus aureus, Mycobacterium smegmatis, Bacillus cereus, Micrococcus luteus, Listeria monocytogenes) and Gram-negative bacteria (Proteus vulgaris, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae) and antifungal activity against Kluyveromyces fragilis, Candida albicans, Rhodotorula rubra, Hanseniaspora guilliermondii and Debaryomyces hansenii yeasts [70]. Essential oil obtained from citrus peel showed remarkable antibacterial activities against Cutibacterium acnes which provides a potential therapy for treatment of acne [71]. The antimicrobial activities of essential oil of lemon peel showed high antimicrobial activities with all microorganisms such as Bacillus subtilis, S. aureus, Bacillus pumilus, C. albicans and E. coli species except P. aeruginosa [72].

The antimicrobial activity of various extracts from pomegranate fruit peels against some food-borne pathogens using both in vitro (agar diffusion) and in situ (food) methods have been studied⁷³. Phytochemical analysis revealed the presence of active inhibitors in peels, including phenolics and flavonoids. The 80% methanolic extract of peels (water–methanol extract) was a potent inhibitor for S. aureus, Listeria monocytogenes, E. coli and Yersinia enterocolitica. The minimum inhibitory concentration (MIC) of water–methanol extract of pomegranate fruit peel against Salmonella enteritidis was the highest (4 mg/ml) [73].

A combination of chitosan with banana peel fillers has a synergistic interaction with a broad antimicrobial spectrum against Gram-positive and Gram-negative bacteria even against strains of yeast culture that show the ability of biofilm formation [43]. The results show that the chitosan sanitary membrane as a banana peel has a synergistic action with the highest activity of 10% wt.

The in vitro and in vivo anthelmintic activity of citrus peels against Ascaridia galli, has been investigated [74]. Oil emulsions from orange was recently patented for the treatment of gastrointestinal nematodes in ruminants [75]. Limonene an active principle in citrus peels with anthelmintic activity in ruminants is reported to provide effective control against Haemonchus contortus in sheep [76].

The chloroformic and ethanolic seed extracts from P. americana seeds showed giardicidal and amoebicidal activities. The chloroformic extract inhibited the growth of M. tuberculosis multidrug resistance (MDR) SIN 4 isolate and three out of four mono resistant reference strains of Mycobacterium tuberculosis H37Rv, showed MIC = 50 μg/ml. The extract was also active at MIC values < 50 μg/ml against M. fortuitum M. smegmatis M. avium, and M. abscessus non-tuberculosis Mycobacterium strains [77].

Friedman and co-workers demonstrated that multiple potato peels prepared from commercial potatoes contain potato phenolic compounds; chlorogenic acid, caffeic acid, glycoalkaloids α-chaconine and α-solanine and quercetin [78]. They are also used for their antiprotozoal activity against pathogenic trichomonad strains that infect humans, farm animals, and felines. These activities varied by both potato variety and trichomonad organism. Russet potato peel samples had the highest activity against all strains of the evaluated peels (Table 4).

Oxidation of Low-density lipoproteins (LDL) generates harmful species, and contribute to the atherosclerotic process [80]. Aqueous seed extract of P. americana reduced the blood pressure in hypertensive rats at a dose of 500 mg/kg body weight with by reduction in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) levels in the plasma, kidney, liver and heart [81]. Similarly, there was significant reduction in the levels of total cholesterol and LDL-C in CD-1 adult male mice using Avocado seed flour of P. americana mill supplementation [82]. The cardioprotective effects of Pomegranate peel (100 mg/kg) in a rat model is via a reduction in creatine kinase-MB, lactate dehydrogenase, lipid peroxidation levels and glutathione, suggesting its usefulness against cardiac attack or arrest [83, 84]. Pomegranate peel powder has also been used as a dietary fiber source for the treatment of hypercholesterolemia and atherosclerosis.

P. granatum (Pomegranate) peel extract decreased lipid peroxidation in cardiac, hepatic and renal tissues, it also facilitated the scavenging ability of superoxide anion and hydrogen peroxide [63]. Wei et al., investigated the preventive efficacy of extracts of pomegranate peels and seeds on liver fibrosis induced by carbon tetrachloride (CCl₄) in rats [85]. The extract treatment attenuated CCl₄–induced increase in the levels of TGF-β1, hyaluronic acid laminin, hydroxyproline and procollagen type III. They also restored the decreased superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activities and inhibited the formation of lipid peroxidized products in the rats exposed to CCl₄. Pomegranate peel extract has been shown to have mild antihepatotoxic effect against paracetamol induced hepatotoxicity but greatly potentiated the protective of N-acetyl cysteine NAC on paracetamol induced liver toxicity [86]. Treatment with P. granatum (pomegranate) peel and seed oil extracts pre, during and post diethylnitrosamine administration improved liver functions, decreased the levels of DNA fragmentation, MDA, caspase-3 and GSR activities, with elevation in levels of GSH, SOD, GST and t-GPx activities. This indicates that these extracts reduced the oxidative stress and apoptosis induced by diethylnitrosamine. Some workers have reported the antioxidant functions of P. granatum peel and Vitis vinifera seeds extracts against diethylnitrosamine (DEN)-induced oxidative stress and hepatocellular damage in Wistar rats [87, 88]. In HepG2 cell lines, the extracts possess antioxidant potential. Both extracts contain alpha-tocopherol-beta-D-mannoside, a vitamin E derivative which might play a major role in its antioxidant potential and increased level of vitamin E [87, 88].

Auraptene (coumarin present in the peels of citrus fruits, such as grapefruit) treatment is known to alleviate 17α-ethinylestradiol (EE) -induced cholestasis by increasing the bile flow and biliary bile acid output [18]. Similar hepatoprotection by auraptene against thioacetamide (TAA)-induced hepatic fibrosis in mice have been reported [17]. Auraptene was found to be remarkably protective against liver injury induced by TAA in mice and maintained the homeostasis of bile acid via regulation of farnesoid X receptor (FXR) target genes including Bsep, Mrp2, Ntcp, Cyp7a1 and Cyp8b1 [17].

Parmar and Kar reported a dose specific antiperoxidative property of the M. indica, C. melo and C. vulgaris fruit peels in rat’s liver, the major target organ of a drug, the maximum antiperoxidative effect was observed with 200 mg /kg of M. indica, while for C. melo and C. vulgaris was at 100 mg/kg, which suggested that these doses are not only safe but might have high therapeutic potential [62]. Dried Citrus unshiu peel, also known as Chinpi, is used as an alternative remedy to improve allergy, inflammation and hepatopathy [89]. Supplementation with 2 g Grape seed extract/day for 6 months improved glomerular filtration rate (GFR) and proteinuria, enhanced the anti-oxidant status while attenuating the lipoperoxidation and carbonylation. Grape seed extract GSE reduced inflammation by decreasing C-reactive protein, triglyceridemia and counteracted anemia and thrombocytopenia [90].

Farrag et al. Reported the protective effect of Nigella sativa seeds against Lead-induced hepatorenal damage in rats [91]. The lead caused significant elevation in aspartate aminotransferase (AST), Urea, creatine, total cholesterol and triglycerides in serum, decrease in serum total protein and albumin, histopathological observation showed an indication of severe damage to the liver and kidney, N. sativa extract remarkably improved both the biochemical and histopathological conditions of the rats by decreasing AST, Urea, creatine, total cholesterol and triglycerides levels in serum, as such averting the progression of disease in stage 3 and 4 patients of chronic kidney disease [92]. Treatment of induced bromobenzene hepatorenal injury with black seed oil could attenuate hepatorenal injury, alleviate the increase of GSH, SDH, LDH, G-6- Pase, serum protein, NO, Na + −K + -ATPase, phospholipids levels and attenuate MDA, SOD, AST, ALT and ALP [93]. Pre-administration of Apple peel polyphenolic extract at 250 and 500 mg/kg·bw in mice before of CCl₄ injection show strong in vivo protective effects, decrease in serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase activities, hepatic malondialdehyde level, and enhance antioxidant superoxide dismutase and glutathione peroxidase activities [94].

Urtica dioica seeds show great ameliorative potential and antioxidant capacity in aflatoxin induced hepatorenal injury, and alleviated organ induced degenerative changes in broilers affected by aflatoxicosis [95]. This antihepatotoxicity marked by decreased AST, ALT and gamma glutamil transpeptidase (GGT) levels and hepatic lipid peroxidation and elevated the antioxidants levels as evident by histological observation [96].

Date seed Phoenix dactylifera L. var. Khalas extract displayed marked protective potential against CCl₄-induced liver and kidney injury at 100 mg/kg/rat. The extract reduced the elevated alkaline phosphatase (ALP), c-glutamyl transferase (GGT), serum levels of alanine aminotransferase and aspartate aminotransferase (ALT and AST), malondialdehyde (MDA) formation, total cholesterol (TC), bilirubin, creatinine, low-density lipoprotein cholesterol (LDL-C) and calcium, while increasing the attenuated serum levels of high-density lipoprotein cholesterol (HDL-C) and total protein (TP) in a dose dependent manner [97].

Kolaviron, a biflavonoid from Garcinia kola seeds, reversed the anti-TB drugs-induced oxidative stress in the liver and kidney of rats. Kolaviron significantly reduced the biochemical indices and oxidative stress markers [98]. Kolaviron suppressed superoxide anion radical production, exerts potent anti-inflammatory action that inhibits production of tumor necrosis factor alpha (TNF-a), and activation of NF-kB (Table 5).

Cancer is one of the most leading cause of death in developed and developing countries. Early detection and implementation of appropriate preventive measures to reduce the cancer burden remain the mainstay in cancer management. The hallmark of a promising anticancer therapeutic agent is its ability to inhibit selectively proliferation of malignant but not normal cells. Lemon peel possess the strong antioxidant activity, mandarin peel exhibited moderate cytotoxic activity against HL-60 cells, whereas grapefruit and lemon peels were ineffective anti-leukemia in his study of fruits’ phytochemical content, antioxidant, anticancer, antiproliferation, and antigenotoxic activities [100]. Citrus peels possessed immunostimulation activity via augmentation of proliferation of mouse splenocytes (T-lymphocytes) and exerted non-cytotoxic, and antigenotoxic activities through remarkable reduction of chromosomal aberrations induced by cisplatin in mouse splenocytes. Diab, showed a weak to moderate antitumor activity of the tested citrus peels in HL-60 cells, the extracts increased the cell viability and stimulation index of mouse splenocytes [100].

Citrus peels have non-volatiles (mainly polymethoxy flavones) and volatiles (essential oils, limonoids) as their bioactive/anticancer constituents. Other workers have explored the anti-tumor effects of gold lotion an extract of multiple varieties of citrus peels containing abundant flavonoids and a large percentage of polymethoxyflavones in a human prostate tumor xenograft mouse model [101]. Intraperitoneal injection and oral administration of gold lotion reduced both the volumes (78%–94% inhibition) and weights (57%–100% inhibition) of the tumors without any observed toxicity. The extract caused an induction of apoptosis in prostate tumors, down-regulation of metastasis (matrix metallopeptidase-2, MMP-2 and MMP-9), the protein levels of inflammatory enzymes (inducible nitric oxide synthase, iNOS and cyclooxygenase-2, COX-2), angiogenesis (vascular endothelial growth factor, VEGF) and proliferative molecules.

C. reticulata peels extract and oil showed significant activity against Dalton’s Lymphoma Ascites (DLA) cell line. C. reticulata peel water extracts induced cell cycle arrest of DLA in G0/G1 phase followed by nuclear condensation, formation of apoptotic bodies membrane blebbing and DNA damage leading to apoptosis. In in vivo experiments, C. reticulata peel extract pre-treated mice were significantly (50%) protected from DLA compared to post-treated mice (33%)^. Some citrus peels such as grapefruit (Citrus paradisii), orange (C. sinensis) and shaddock (Citrus maxima) are rich in phenolic compounds such as quercetin, caffeic acid, kaempferol, catechin and naringin [102, 103]. Orange peel extracts had the strongest inhibition of metalloproteinase and proteasome activities MMP in primary human colonic tumor Caco-2 and the metastatic cell lines LoVo cells, while shaddock had the least. Shaddock peel extracts also had the least MMP inhibition in LoVo/ADR lysates. Grapefruit had the least proteasome inhibition in Caco-2 and LoVo lysates.

Mango peel extract was found to have an antioxidant activity and, in a dose,-dependent manner significantly inhibit the proliferation of HeLa human cervical carcinoma cells. Ali et al. confirmed apoptotic signaling induced by mango peel extract was characterized by down-regulation of Bcl-2 and increased Bax/Bcl-2 ratio [36]. Mango peel extract treatment triggered the proteolytic activation of caspases-3, − 8, and − 9 and the degradation of poly Adenosine Diphosphate (ADP) ribose polymerase in HeLa cells [36].

Pomegranate peel is an affordable promising chemopreventive product and a promising herbal drug remedy used in the treatment of prostate cancer by inducing prostate cancer apoptosis mediated by mitochondrial intrinsic pathways [104, 105]. Pomegranate peel inhibit nuclear factor kappa B (NF-kB)-dependent reporter gene expression associated with proliferation, invasion, and motility in aggressive breast cancer phenotypes [106, 107]. Further investigation indicated that Pomegranate (P. granatum) peel increased the expression ratio of Bax/Bcl2 and activation of apoptosis executor caspase 3 and has the potential to inhibit migration and invasion, two critical steps in prostate cancer metastasis, downregulation of MMP2/MMP9 and upregulation of Tissue inhibitor of metalloproteinases 2 (TIMP2). Pomegranate peel exhibited inhibitory activity in human urinary bladder urothelial carcinoma T24 and J82 cells [99]. The study observed that the oral consumption of ethylacetate layer (2, 5, 10 and 100 mg/kg) of pomegranate peel could decrease the volume and weight of T24 tumors and caused the apoptosis in the xenografted tumors [99, 108]. established the chemopreventive activity of pomegranate seed oil against both tumor incidence and multiplicity. The evaluation of the potency of P. granatum L. Fruit Peel on breast cancer cells, has shown that P. granatum peel reduces cell proliferation and induces apoptosis on MCF-7 breast Cancer cells, with significant increases in the apoptotic cell numbers at 100, 200, and 300 lg/mL P. granatum peel concentrations [109]. In addition, expression of the pro-apoptotic gene Bax was increased, and that of the anti-apoptotic gene Bcl-2 was decreased after 200 and 300 lg/mL [109].

P. guajava peel and seed extracts exert anti-cancer control on both haematological and solid neoplasias [110]. P. guajava extract’s antitumour properties are tightly bound to induction of differentiation [110]. The peel causes cell differentiation as the use of ex vivo myeloid leukaemia blasts corroborated that P. guajava was able to induce cell death but did not exhibit anti-cancer effects on all malignant cells investigated, indicating selective activity against certain types of tumour.

Melon peels and seeds extract could be promising antitumor agents and exhibit several activities against different tumor cell lines [26]. Nirmala and Narendhirakannan investigated the efficacy of V. vinifera peel and seed aqueous extracts, the peel and seed demonstrated chemopreventive potential by attenuating the cumulative number of tumors while enhancing the antioxidant enzyme activities in the gold nanoparticles treated mice [111]. The down-regulated expression of mutant p53, Bcl-2 and the levels of pan-cytokeratins could have enhanced the process of apoptosis in the chemical carcinogenesis process.

A natural product isolated from the peel of M. sapientum L. (±)-19b induced cell apoptosis and exhibited potent in vitro antivascular and in vivo antitumor activities through the disruption of intracellular microtubule network, causing G2/M phase arrest and depolarization of K562 cells mitochondria [112] (Table 6).

Inflammation is a cellular reaction to injury or insult, and has been linked to the development or worsening of several non-infectious diseases. Inflammatory cells include neutrophils, macrophages and monocytes, and may inflict damage to nearby tissues in the various diseases presentations and sequel, such as emphysema, acute respiratory distress syndrome, athero- sclerosis, reperfusion injury, malignancy and rheumatoid arthritis [115].

Extracts and essential oils derived from citrus fruits exhibit in-vitro anti-inflammatory activities by inhibiting the production of pro-inflammatory cytokines [116] through blocking c-Jun NH₂-terminal kinase (JNK), extracellular signal regulated kinase (ERK) and NF-κB signaling pathways in lipopolysaccharide-activated macrophages [117] C. melo var. reticulatus peels at 50 mg/kg caused a significant reduction in both TNF-α and IL-1β levels, while C. melo var. cantalupensis peels caused the most significant reductions in PGE-2 and interleukin-6 (IL-6) levels [118]. Same was observed with essential oil from the peels of Citrus limetta as reported by Maurya and co-workers to decrease the production of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) in lipopolysaccharide-induced inflammation in macrophages in a dose-dependent manner without any cytotoxic effect [119]. In the in - vivo system primary skin irritation study in rabbits revealed that Citrus limetta fruit peels essential oil is safe for topical application on skin.

Lin et al. evaluated the effect of gold lotion a formulated product extracted from the peels of six citrus fruits (C. hassaku, C. limon, C. natsudaidai, C. miyauchi Iyo and Satsuma), on imiquimod (IMQ)-induced psoriasis-like inflammation in mice, the study indicated that oral administration of gold lotion reversed IMQ-induced psoriasis-like inflammation in BALB/c mice [113]. It also attenuated the infiltration of T cells and neutrophils and the expression of pro-inflammatory cytokines in skin lesions, and lowered the percentages of Th17 populations in the lymph nodes, impaired the IMQ-induced type I interferons mainly IFN- - α/β. Peels of C. grandis showed an anti-inflammatory effect in xylene-induced ear edema and carrageenan-induced paw edema in mice. These coumarins were responsible for the regulation and inhibition of inflammatory mediators and cytokines in lipopolysaccharide induced RAW 264.7 cells [120]. H. rhamnoides peel extract exhibited maximum edema-reducing effect and suggest that the activity is most probably based on a membrane stabilizing effect caused by the inhibition of degranulation of mast cells [121].

Ouachrif et al., explored and compared the analgesic and anti-inflammatory activities of the methanol extract obtained from fruit peels of two varieties of pomegranate Amrouz and Sefri [122]. P. granatum contains active constituents such as punicalagin, strictinin A, punicalin and granatin B which possess antinociceptive and anti-inflammatory activities [122].

In a study using pear peel extract, Carrageenan-induced mice hind paw edema and xylene-induced mice ear edema models were used to determine the anti-inflammatory activity of the peel. The methanol extract of pear peels showed an appreciable reduction in mice paw edema in a dose-dependent manner [123]. The anti-inflammatory and antinociceptive activities of essential oils from peel and seed of Campomanesia adamantium fruits in rat have been evaluated confirming that 100 mg/kg seed and peel essential oils from C. adamantium fruit inhibited inflammation, leukocyte migration and neurogenic pain and oedema [124].

To confirm the anti-inflammatory effects of Ursolic acid (UA), a pentacyclic triterpene acid found in apple peels (Malus domestica, Borkh, Rosaceae) was used in zymosan-induced paw edema, the injection of zymosan in the pleural cavity of mice induced a leukocyte influx and exudation 4 h after stimulation. When treated with Ursolic acid, it attenuated protein extravasation into the thoracic cavity; paw edema was reduced by 46%; tibio-femoral edema by 40%; and leukocyte influx into the synovial cavity reduced the levels of mediators related to synovial inflammation, such as KC/CXCL-1 levels by 95%, TNF-a levels by 76% and IL-1b levels by 57% [125] Ursolic acid inhibited the increased vascular permeability in these models of inflammation.

A piece of banana peel when placed on a wart, with the yellow side out, can be a natural alternative to kill off a wart and to reduce swelling and irritation after a mosquito bite by rubbing the affected area with the inside of a banana skin [126] (Table 7).

The role of G. kola seed extract as an antidote in restoring the activity of reduced acetylcholinesterase by stimulating Clarias gariepinus with the enzyme inhibitor glyphosate pesticide formulation [127]. The seed extracts normalize the secretion of acetylcholinesterase by stabilizing the concentrations of the neurotransmitter acetylcholine.

Treatment with Citrus unshiu peel extract enhanced dexamethasone-induced depressive-like behaviors and attenuated neurotoxicity effects in a concentration dependent manner in SH-SY5Y cells [89]. Repeated dexamethasone injection markedly reduced brain derived neurotrophic factor (BDNF) level, tropomyosin receptor kinase B (TrkB), and cyclic AMP-response element-binding protein (CREB), while Citrus unshiu peel extract treatment enhanced these levels in the hippocampus and cerebral cortex regions. It has also been reported that extracts of four batches of nobiletin-rich C. reticulata peels, facilitated cAMP-response element (CRE)-mediated transcription in cultured hippocampal neurons [128]. It was found that tangeretin, 6-demethoxynobiletin, 6-demethoxytangeretin, and sinensetin, contained in the extract, contributed to the CRE-mediated transcription-enhancing activity of the extract toward hippocampal neurons and facilitated PKA/ERK/CREB signaling in the culture [128]. Additionally, the extract restored MK-801-induced learning and memory impairment through the activation of ERK signaling in animal. Naringenin abundant in the peels of citrus fruits reduced anxiogenic-like behaviour impairment induced by the exposure to 50 mg of Fe-dextran/kg/day intraperitoneally for 28 days in rats. Naringenin attenuated iron-induced reactive oxygen species formation and restored the iron-induced decrease of the acetylcholinesterase expression level, mitochondrial membrane potential and mitochondrial complexes activities in the hippocampus of rats. It also restored the alteration on the activity and expression of ectonucleotidases such as adenosine triphosphate diphosphohydrolase and 5′-nucleotidase, enzymes which hydrolyze and therefore control extracellular ATP and adenosine concentrations in the synaptic cleft and iron induced cholinergic deficits in the cerebral cortex in rats [129]. Naringenin exerts protective effect against cerebral ischemic injury, attenuates bamyloid toxicity [130] induces the activation of MAP kinases, modulates glutamate uptake [131] and prevents neurodegeneration with cognitive impairment caused by the intracerebroventricular-streptozotocin in diabetic oxidative damage rat model [132].

Ripa et al [133] scrutinized the antinociceptive and central nervous system (CNS) reduction activity of the methanol extracts of seeds and peels of Nephelium longan in rats. Both extracts displayed dose dependent suppression of motor activity and exploratory behavior in the tested models in the case of CNS depressant activity.

In Alzheimer’s disease (AD) an in vitro approach demonstrated the anti-cholinesterase and antioxidant activities of an aqueous extract of avocado leaves and seeds to be beneficial in Alzheimer’s disease treatment [134]. Avocado P. americana (var. Colinred) peel extract can protect and prevent transgenic parkin Drosophila melanogaster fly against paraquat-induced oxidative stress, movement impairment and lipid peroxidation, in a model of Parkinson’s disease [135].

The anti-stress, antidepressant and memory enhancing effects of banana (M. sapientum L.) fruit peel extract in male mice have been investigated with the confirmation of significant reductions in time immobility during forced swimming test (FST) suggesting antidepressant like effects [136]. Learning and memory assessment showed a reduction in time to reach platform in both short-term and long-term memory test, this suggested increased memory function in banana peel treated animals. Liu et al. identified a compound isochromanone, (±) 7, 8-dihydroxy-3-methyl-isochromanone-4 (1), a nature product contained in banana (M. sapientum L.) peel which displayed potent antihypertensive activity in renal hypertensive rat models [137]. Isochromanone, (±) 7,8-dihydroxy-3-methyl-isochromanone-4 has moderate ACE inhibitory activity and beneficial effects in reducing blood pressure, which indicates that ACE is its potential target, or at least one of its potent targets (Table 8).