P U B L I C A T I O N S CODON ISSN 1120-1770 online, DOI 10.15586/ijfs.v33i2.2009 63 functionality that could be used as ingredients for food, food supplements or active bioactive compounds in pharmaceutical products (Rombaut et al., 2014). In food industry, citrus by-products and their val- ue-added compounds, including polyphenols, vitamins, microelements and fiber are utilized as natural addi- tives with the following properties: antimicrobials, anti- oxidants, colorants and flavoring agents (Mahato et al., 2019). These wastes have gained increasing interest for further exploitation on the production of food additives, supplements with high nutritional value and pharmaceu- tical products. The recent data were collected from several scientific databases (PubMed, Science Direct, SciFinder, Scopus, Elsevier, SpringerLink, ReserchGate and Google Scholar) from 2015 to 2020 using the following keywords: cit- rus, citrus by-products, juice, seed, peels, leaves, and P U B L I C A T I O N S CODON Citrus species: Modern functional food and nutraceutical-based product ingredient Mariarosaria Leporini1, Rosa Tundis1, Vincenzo Sicari2, Monica Rosa Loizzo1* 1Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy; 2Department of Agraria, “Mediterranea” University of Reggio Calabria, Cittadella Universitaria, Località Feo di Vito 89124 Reggio Calabria (RC), Italy *Corresponding Author: Monica Rosa Loizzo, Department of Pharmacy, Health and Nutrition Science, University of Calabria, via P. Bucci, Edificio Polifunzionale, 87036 Rende (CS), Italy. Email: monica_rosa.loizzo@unical.it Received: 25 January 2021; Accepted: 22 April 2021; Published: 27 May 2021 © 2021 Codon Publications OPEN ACCESS REVIEW Abstract Citrus is the most cultivated fruit crop in the world and occupies a place of considerable importance in the coun- try’s economy. Almost 33% of the citrus fruits are processed for juice production; however, a great amount of wastes, including peels, segment membranes, and seeds are also produced. Indeed, citrus fruits consist of 45% juice, 26% pulp, 27% peels, and 2% seeds. Pruning, a cultural practice involving the removal of tree branches and limbs, was applied to improve fruit’s quality. A large amount of leaves are produced through pruning. These agri- food matrices contain a wide range of bioactive phytochemicals compared to fruits. The present review covers the past 5 years of research carried out in chemistry, health properties, and applications in food and nutraceutical industries of all portions of citrus fruit and its major bioactive compounds. Additionally, patents are also included. Keywords: bioactive compounds, by-products, citrus, health properties, juice, peels, pulp, seeds Introduction Citrus is the most cultivated fruit tree in the world and occupies a place of considerable importance in coun- try’s economy. The citrus fruits are processed for juice production (45%), and a great amount of waste, includ- ing peels (27%), pulp (26%) and seeds (2%), is produced (Mahato et al., 2018). Food waste is defined as the by-product obtained from various industrial, agricultural and other activities of food sector. Especially, food-processing industries produce large quantities of by-products, which are difficult to dis- pose of as they have a high demand for biological oxygen. Indeed, waste disposal has high costs and, also a potential negative impact on the environment (Kumar et al., 2017). These agri-food matrices contain a wide range of bio- active phytochemicals with different structures and Italian Journal of Food Science, 2021; 33 (2): 63–107 mailto:monica_rosa.loizzo@unical.it 64 Italian Journal of Food Science, 2021; 33 (2) M. Leporini et al. The antioxidant ability of fresh squeezed Citrus limon L. Burm. cv. Femminello comune juice was analyzed by Loizzo et al. (2019), founding the IC50 values of 40.3 and 46.5 g/mL in DPPH and ABTS test, respectively, and 49.7 mg Fe (II)/g in the ferric-reducing ability power (FRAP) test. More recently, the antioxidant ability of two Citrus sinensis cultivars (Sanguinelli and Salustiana) was demonstrated by applying ABTS, DPPH, and ORAC assays (Ordóñez-Díaz et al., 2020). Citrus sinensis cv. Sanguinelli extracts were 40% more active than Citrus sinensis Salustiana samples. Recently, Ali et al. (2020) reported that animals treated with 0.75% hydrogen peroxide in drinking water with daily drenching with 1 mL lemon juice, exhibited enhancement in hemoglobin concentration, red blood cells count, white blood cells count, and total proteins, and reduction in the level of aspartate aminotransferase and alanine aminotransferase. These findings clearly con- firmed the protective and antioxidant features of lemon juice on hematological and biochemical parameters of the oxidatively stressed female mice. Metabolic syndrome Metabolic syndrome (MS) is a clustering characterized by abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides (TG), low serum, and high-density lipoprotein (HDL) that directly increase the risk of cardiovascular disease, type 2 diabetes mellitus (T2DM), and all-cause mortality (Kaur et al., 2014). Recently, the beneficial effects of Citrus bergamia juice were evaluated using an experimental animal model of MS and cardiovascular risk (De Leo et al., 2020). Results demonstrated that daily oral treatment reduced TG levels, cardiovascular risk, and showed protective effects on hepatic steatosis, probably due to the reduction of oxi- dative stress and inflammation. Previously, Impellizzeri et al. (2015) tested the in vivo anti-inflammatory activity of bergamot juice extract. Mice treated with this extract were more resistant to induction of colitis and reduction in the expression of important inflammatory mediators, tumor necrosis factor-alpha (TNF-α) and interleukin-1 β (IL-1β), was observed. The effects of a bergamot phytocomplex (Patent No. EP3116520A1) was investigated by Di Folco et al. (2018). Each tablet provided 200-mg bergamot juice dry extract, 120-mg phytosterols, 80-mg artichoke leaf extract, and 20-mg vitamin citrus. After 6 months of administra- tion, patients in the intervention group showed a signifi- cant reduction in fasting blood glucose compared to the simple dietary intervention alone. essential oils. This work is structured by dividing the text in Citrus portion and discussions on the phytochemical profile and biological activities of each. Additionally, pat- ents are also included. The information collected would be useful for research on citrus species and for food and nutraceutical industries interested in using ingredients with health potential. Juice Antioxidant activity Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are involved in the pathogenesis of many human diseases, and antioxidants play a crucial role in restoring the physiological oxidative balance and mod- ulating biological pathways and membrane functions (Smeriglio et al., 2018). The citrus genus is recognized for its protective effects against free radical-induced damage. Barberis et al. (2020) analyzed the antioxidant potential of fresh squeezed pompia, lemon (cv. Lisbon) and orange juices (cv. Hamlin, Sanguinello, and Moro). Among these, Pompia juice had a marked effect against ROS, and a mod- erate capacity to reduce ROS damages on cell membrane. On the contrary, orange juices resulted much less effec- tive. The in vitro antioxidant potential (Table 1) of fresh squeezed citrus × clementina juices, collected from dif- ferent areas of Calabria, was recently evaluated (Leporini et al., 2020a). Results revealed that juice obtained from fruits collected in Corigliano Calabro exhibited the high- est radical activity, with the concentration giving 50% inhibition (IC50) values of 81.13 and 27.82 mg/mL for 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) tests, respectively. The same juice exhibited the highest protection of lipid peroxidation. These results are similar to the previous study conducted by Loizzo et al. (2018) that reported the antioxidant activity of fresh squeezed citrus × clementina juices from fruits collected in flood plains, hills, and coastal plains of Sibari (Calabria, Italy). The following trend of radical potency was found: flood plain > coastal plain > hill. Haraoui et al. (2020) compared the antioxidant activity of fresh squeezed juices derived from different citrus fruit varieties. All investigated samples possessed radical scavenging activity with IC50 values comparable to posi- tive control ascorbic acid and butylated hydroxytoluene (BHT). Among them, Citrus maxima and Citrus auran- tium juices showed the highest DPPH radical scavenging activity (IC50 = 0.42 and 0.44 mg/mL, respectively). The same trend was observed in β-carotene bleaching test with percentage exceeding to 80.55%, followed by Citrus sinensis cv. Sanguinelli and Citrus limon. Italian Journal of Food Science, 2021; 33 (2) 65 Citrus species: modern functional food and nutraceutical-based product ingredient Table 1. Biological effects of Citrus juices. Juice Biological activity Mechanism TPC, TFC, TCC, and/or main abundant identified compounds References In vitro Citrus aurantifolia Antioxidant Radical scavenging Ferric-reducing power TPC = 52 mg GAE/L; TFC = 29.5 mg QE/L Oboh et al., 2015b Antibacterial S. aureus, S. epidermis, M. luteus, E. faecalis, B. subtillis, P. aeruginosa, K. pneumonia S. thypii, and C. diphtheriae inhibition NR NR NR Abdallah, 2020 Fadillah et al., 2020 Azhara et al., 2020 Citrus aurantium Antioxidant Radical scavenging TPC = 295.37 mg GAE/g; FC = 26.08 mg QE/g TPC = 0.58 mg GAE /mL; TFC = 0.43 mg RE/mL; Neohesperidin = 144.85 mg/mL; Naringin = 79.19 mg/mL; Hesperidin = 4.68 mg/mL. Haraoui et al., 2020 Chen et al., 2020 Antibacterial S. aureus inhibition Haraoui et al. 2020 Citrus grandis Antioxidant Radical scavenging TPC = 0.49–1.27 mg GAE /mL; TFC = 0.35–1.17 mg RE/mL; Naringin = 40.82–419.28 mg/mL; Neohesperidin = 37.52–42.54 mg/mL; Hesperidin = 3.14–12.17 mg/mL; Diosmin = 14.79–21.38 mg/mL; Tangeretin = 3.09–3.64mg/mL. Chen et al., 2020 Citrus hystrix Antibacterial S. aureus inhibition NR Kusumawardhani et al., 2020 Citrus limon Antioxidant Radical scavenging TPC = 151.7 mg GAE/L; TFC = 30.8 mg QE/L; Eriocitrin = 16.7 mg/100 mL; Hesperidin = 14.1 mg/100 mL. Loizzo et al., 2019 Metabolic syndrome Inhibition of α-amylase and β-glucosidase enzymes Loizzo et al., 2019 Antibacterial S. aureus, S. epidermis, M. luteus, E. faecalis and B. subtillis inhibition. TPC = 231.16 mg GAE/g; TFC = 25.04 mg QE/g. Haraoui et al. 2020 Neuroprotective AChE and BChE inhibition Diosmetin 6,8-di-C-glucoside = 5.35 mg/100 mL; Hesperetin 7-O-rutinoside = 3.11 mg/100 mL. Gironés-Vilaplana et al., 2015 Citrus maxima Antioxidant Radical scavenging TPC = 350.05 mg GAE/g; TFC = 55.38 mg QE/g. Haraoui et al., 2020 Antibacterial S. aureus, S. epidermis, M. luteus, E. faecalis and B. subtillis inhibition. Haraoui et al. 2020 Citrus medica Antioxidant Radical scavenging TPC = 0.30–1.37 mg GAE /mL; TFC = 0.19–0.68 mg RE/mL; Hesperidin = 42.13 mg/mL; Eriocitrin = 28.46 mg/mL; Narirutin = 28.46 mg/mL; Didymin = 12.50 mg/mL; Tangeretin = 3.76 mgmL. Chen et al., 2020 Citrus paradisi Antioxidant Radical scavenging TPC = 153.08 mg/mL; TFC = 390.21 mg/mL; Naringin = 287.15 mg/mL; Narirutin = 37.07 mg/mL; Naringenin = 31.25 mg/mL; Poncirin = 17.32 mg/mL; Neohesperidin = 13.48 mg/mL. Sicari et al., 2018 (continues) 66 Italian Journal of Food Science, 2021; 33 (2) M. Leporini et al. Table 1. Continued Juice Biological activity Mechanism TPC, TFC, TCC, and/or main abundant identified compounds References Citrus reticulata Antioxidant Radical scavenging TPC = 0.30–1.37 mg GAE /mL; TFC = 0.19–0.68 mg RE/mL; Hesperidin = 50.53–141.85 mg/mL; Naringin = 26.57–78.39 mg/mL; Neohesperidin = 69.19 mg/mL; Didymin = 1.73–10.33 mgmL; Eriocitrin = 27.17–78.39 mg/mL; Tangeretin = 3.43–4.32 mg/mL. Chen et al., 2020 Citrus sinensis Antioxidant Radical scavenging TPC = 0.47–0.67 mg GAE /mL; TFC = 0.23–0.92 mg RE/mL; Hesperidin = 94.98–173.11 mg/mL; Eriocitrin = 28.38–46.95 mg/mL; Narirutin = 28.38–46.95 mg/mL; Didymin = 1.73–10.33 mg/mL; Tangeretin = 3.52–3.67 μg/mL. Chen et al., 2020 Citrus × clementina Antioxidant Radical scavenging Ferric-reducing power Inhibition of lipid peroxidation TPC = 17.58–54.65 mg CAE/100 mL; TFC = 18.16–51.48 mg QE/100 mL; TCC = 18.23–53.54 mg β-carotene E/100 mL; Neohesperidin = 80.26–110 mg/ 100 mL; Hesperidin = 40–81.08 mg/100 mL; Naritutin = 6.25–8.50 mg/100 mL. TPC = 29.74–44.20 mg GAE/100 mL; TCC = 42.89–75.45 mg β-carotene E/100 mL; Neohesperidin = 72.96–116.50 mg/100 mL; Hesperidin = 55.24–69.52 mg/100 mL; Didymin = 3.65–5.65 mg/100 mL Leporini et al., 2020a Loizzo et al., 2018 Metabolic syndrome Inhibition of α-amylase, β-glucosidase and lipase enzymes Leporini et al., 2020a Loizzo et al., 2018 Antibacterial M. luteus and B. subtillis inhibition TPC = 75.60 mg GAE/g; TFC = 20.51 mg QE/g Haraoui et al. 2020 In vivo Citrus aurantifolia Metabolic syndrome Reduction in plasma TC, TG, and LDL-c levels and increase in plasma HDL-cholesterol levels. Oboh et al., 2015b Citrus bergamia Metabolic syndrome Reduction TG levels, cardiovascular risk, oxidative stress and inflammation, protective effects on hepatic steatosis. Neohesperidin 182.3 mg/mL; Neoeriocitrin = 165.0 mg/mL; Naringin =160.1 mg/mL Not reported De Leo et al., 2020 Impellizzeri et al., 2015 Citrus lemon Antioxidant Reduction in ROS levels Hesperidin = 77.1 mg/L; Isorhamnetin 3-O-rutinoside = 44.9 mg/L; Rhoifolin = 31.4 mg/L; Eriocitrin = 29.9 mg/L; Diosmin = 25.7 mg/L. Barberis et al., 2020 Citrus sinensis Antioxidant ROS scavenger Hesperidin = 422.8 mg/L; Naringin = 132.6 mg/L; Narirutin = 100.1 mg/L Barberis et al., 2020 Metabolic syndrome Reduction in body mass index 1 tablet/die [day] containing 400 mg of Morosil® Cardile et al., 2015 NR: not reported; TPC: total phenolics content; TFC: total flavonoids content; TCC: total carotenoids content; ROS: Reactive Oxygen Species. Italian Journal of Food Science, 2021; 33 (2) 67 Citrus species: modern functional food and nutraceutical-based product ingredient Abdallah (2020) suggested Citrus aurantifolia as nat- ural antibacterial agent against S. aureus, S. epidermis, Pseudomonas aeruginosa, and Klebsiella pneumonia. Low antibacterial activity was found for Citrus sinensis. Prebiotic effects The prebiotic effect of orange juice could be due to its positive effect on the intestinal microbiota and metabolic biomarkers of young women (aged 28.5 years) (Lima et al., 2019). Indeed, daily intake of orange juice (300 mL/ day for 2 months) did not change women’s body com- position, but improved blood biochemical parameters, such as low-density lipoprotein (LDL)-cholesterol, glu- cose, and insulin sensitivity. Additionally, orange juice positively modulated the composition and metabolic activity of microbiota, increasing the population of Bifidobacterium spp. and Lactobacillus spp and reduc- tion of Enterobacteria. Reduction in ammonium (NH4 +) and increase in the production of short-chain fatty acids were also demonstrated. More recently, this prebiotic effect in healthy female volunteers after intervention with 300-mL/day orange juice for 60 days was confirmed (Fidélix et al., 2020). Orange juice stimulated the growth of Lactobacillus spp. in the intestinal microbiota and improved glucose metabolism due to the probiotic effect of these bacteria. Daily supplementation of juices of two oranges (cv. Cara Cara and cv. Bahia) with different flavanone content for 7 days in healthy volunteers resulted in increase in the abundance of Lachnospiraceae and Ruminococcaceae that represented the two most abundant phylum Firmicutes’ families present in the gut environment (Brasili et al., 2019). Interestingly, after intake of Cara Cara juice positive correlations were found between Lachnospiraceae and butyrate, as well as between the most abundant short-chain fatty acids present in the colon, including acetate, butyrate, and propionate (Brasili et al., 2019). Pulp Antioxidant activity The radical scavenging ability of eight citrus pulp meth- anol extracts, namely Citrus sinensis cv. Hamlin, cv. red blood, cv. succuri, Citrus limetta mosambi, Citrus reticulata tangerine, Citrus paradise macfed, Citrus aurantium L., and Citrus jambhiri lush (Table 2), were investigated (Rehman et al., 2020a). Among these, Citrus sinensis cv. succuri had the highest values (65.3%). Costanzo et al. (2020) compared the antioxidant poten- tial of powdered Citrus reticulata, Citrus japonica, and The edible portion of hybrid Tacle®, a crossbreeding of Citrus × clementina and Tarocco tetraploids, was able to influence anthropometric values and lipid and glucose metabolism in a rat model having obesity and MS. For this reason, it could be included in dietary supplements for the management of metabolic disorders (Casacchia et al., 2019). A promising anti-obesity potential of fresh squeezed Citrus × clementina juices against lipase enzymes with IC50 values in the range of 179.32–197.69 mg/mL was recently confirmed (Leporini et al., 2020a). Moro juice (Citrus sinensis) extract (Morosil®, 400 mg/die [day]) was able to induce a significant reduction in body mass index (BMI) after 4 weeks of treatment (Cardile et al., 2015). One important therapeutic approach for suppress- ing postprandial hyperglycemia is to reduce or bring down dietary carbohydrate digestion and absorption. The inhibition of carbohydrate-hydrolyzing enzymes, α-glucosidase and α-amylase, in the digestive tract also determined reduction in the rate of glucose absorption and consequently blunting the post-prandial plasma glu- cose rise (Tundis et al., 2010). The fresh squeezed Citrus lemon exhibited a promising hypoglycemic inhibitory potential with the IC50 values of 31.1 and 35.3 mg/mL against α-amylase and α-glucosidase enzymes, respec- tively (Loizzo et al., 2019) whereas values in the range of 67.19–103.43 μg/mL against α-glucosidase were found for fresh squeezed Citrus × clementina juices from differ- ent areas of collection (Leporini et al., 2020a). The hypo- glycemic ability of Poncirus trifoliata juice, related to the genus citrus, was investigated against α-amylase and α-glucosidase enzymes (Tundis et al., 2016), with the IC50 values of 138.14 and 81.27 μg/mL, respectively. 2.3. Antibacterial activity The development of antibiotic resistance by pathogenic microorganisms necessitated the quest for alternative drug therapy. Medicinal plants are traditionally recog- nized as conventional medicines, and numerous stud- ies have confirmed their antibacterial activity (Gavarić et  al., 2015). Haraoui et al. (2020) investigated the bac- teriostatic action of citrus variety juices. Fresh squeezed citrus limon juice exhibited inhibition zone of 27.66 mm on Micrococcus luteus, followed by Citrus aurantium with an area of 24.66 mm against Staphylococcus aureus. Interesting results were observed also for Citrus maxima and citrus × clementina with inhibition zones of 23.00 and 17.66 mm, respectively, against M. luteus. The lime fresh squeezed juice as antibacterial agent was confirmed against Salmonella thypii (Fadillah et al., 2020) and Corynebacterium diphtheriae (Azhara et al., 2020). Growth of S. aureus was inhibited by fresh squeezed Citrus hystrix juice (Kusumawardhani et al., 2020). 68 Italian Journal of Food Science, 2021; 33 (2) M. Leporini et al. Ta bl e 2. . C itr us p ul p an d bi ol og ic al p ot en tia l. P ul p E xt ra ct B io lo gi ca l ac tiv ity M ec ha ni sm TP C , T FC , T C C , a nd /o r m ai n ab un da nt id en tifi ed c om po un ds R ef er en ce s C itr us au ra nt ifo lia 50 % E th an ol M et ha no l 10 % (K O H , sa po ni fic at io n) A nt io xi da nt Li po ph ili c an tio xi da nt c ap ac ity H es pe rid in = 2 3– 33 8 m g/ 10 0 g FW ; N ar in gi n = 0– 27 1 m g/ 10 0 g FW ; N eo he sp er id in = 51 –1 58 m g/ 10 0 g FW . Lu te ol in = 0 .0 2– 0. 21 m g/ 10 0 g FW ; (a ll- E )- Ze ax an th in = 0 .0 2– 0. 03 F W . E rn aw ita e t a l., 2 01 7 E rn aw ita e t a l., 2 01 6 M et ab ol ic sy nd ro m e In hi bi tio n of α -a m yl as e an d β- gl uc os id as e en zy m es E rn aw ita e t a l., 2 01 7 E th an ol , m et ha no l, an d ac et on e A nt ib ac te ria l K . p ne um on ia e, S . a ur eu s in hi bi tio n E . c ol i, K le bs ie lla , P se ud om on as , S al m on el la in hi bi tio n N R E rn aw ita e t a l., 2 01 7 B hu iy an e t a l., 2 01 9 C itr us a ur an tiu m E th an ol A nt io xi da nt R ad ic al s ca ve ng in g TP C = 1 0. 45 m g G A E /g D W ; TF C = 7 .1 4 m g R E /g D W ; N eo he sp er id in = 5 17 .1 0 m g/ 10 0 g D W ; N ar in gi n = 32 6. 44 m g/ 10 0 g D W ; D io sm in = 1 89 .1 6 m g/ 10 0 g D W ; H es pe rid in = 5 3. 05 m g/ 10 0 g D W . C he n et a l., 2 02 0 C itr us b er ga m ia E th an ol A nt io xi da nt R ad ic al s ca ve ng in g TP C = 2 08 .0 2 m g G A E /g F W . Fr at ia nn i e t a l., 2 01 9 A nt ib ac te ria l E . c ol i, L. m on oc yt og en es , P. a er ug in os a, S . a ur eu s, a nd P. c ar ot ov or um . i nh ib iti on Fr at ia nn i e t a l., 2 01 9 C itr us g ra nd is E th an ol A nt io xi da nt R ad ic al s ca ve ng in g TP C = 4 .5 2– 7. 65 m g G A E /g D W ; TF C = 3 .6 7– 8. 25 m g R E /g D W ; N ar in gi n = 19 9. 95 –7 77 .6 5 m g/ 10 0 g D W ; N eo he sp er id in = 3 4. 29 –5 2. 20 m g/ 10 0 g D W ; H es pe rid in = 2 .7 3– 13 .0 0 m g/ 10 0 g D W ; D io sm in = 2 5. 52 –6 2. 6 m g/ 10 0 g D W ; E rio ci tri n = 15 .9 5– 19 .7 7 m g/ 10 0 g D W . C he n et a l., 2 02 0 C itr us h ys tri x 50 % E th an ol M et ha no l 10 % (K O H , sa po ni fic at io n) A nt io xi da nt Li po ph ili c an tio xi da nt c ap ac ity H es pe rid in = 7 4 m g/ 10 0 g FW ; N eo he sp er id in = 7 5 m g/ 10 0 g FW . Lu te ol in = 0 .2 1 m g/ 10 0 g FW ; (a ll- E )- α -C ar ot en e = 0. 04 m g/ 10 0 g FW ; (a ll- E )- Ze ax an th in = 0 .0 2 m g/ 10 0 g FW . E rn aw ita e t a l., 2 01 7 E rn aw ita e t a l., 2 01 6 M et ab ol ic sy nd ro m e In hi bi tio n of α -a m yl as e an d β- gl uc os id as e en zy m es E rn aw ita e t a l., 2 01 7 A nt ib ac te ria l K . p ne um on ia e, a nd S . a ur eu s in hi bi tio n E rn aw ita e t a l., 2 01 7 C itr us ja po ni ca 80 % M et ha no l A nt io xi da nt R ad ic al s ca ve ng in g N R C os ta nz o et a l., 2 02 0 Italian Journal of Food Science, 2021; 33 (2) 69 Citrus species: modern functional food and nutraceutical-based product ingredient C itr us li m on E th an ol , m et ha no l, an d ac et on e A nt ib ac te ria l S . a ur eu s, E . c ol i, K le bs ie lla , P se ud om on as , S al m on el l i nh ib iti on N R B hu iy an e t a l., 2 01 9 C itr us m ac ro pt er a E th an ol , m et ha no l, an d ac et on e A nt ib ac te ria l K . p ne um on ia e, a nd S al m on el la in hi bi tio n N R B hu iy an e t a l., 2 01 9 C itr us m ed ic a E th an ol A nt io xi da nt R ad ic al s ca ve ng in g TP C = 1 48 .0 2 m g G A E /g F W . Fr at ia nn i e t a l., 2 01 9 A nt ib ac te ria l E . c ol i, L. m on oc yt og en es , P. a er ug in os a, S . a ur eu s, a nd P. c ar ot ov or um in hi bi tio n TP C = 3 .8 9– 8. 07 m g G A E /g F W ; TF C = 1 .8 9– 5. 08 m g R E /g F W ; N ar in gi n = 10 .6 3 m g/ 10 0 g FW ; N eo he sp er id in = 2 2. 96 m g/ 10 0 g FW ; H es pe rid in = 1 8. 55 –1 36 .3 9 m g/ 10 0 g FW ; D io sm in = 1 7. 36 –2 1. 64 m g/ 10 0 g FW ; E rio ci tri n = 23 .7 6– 24 .1 1 m g/ 10 0 g FW ; N ar iru tin = 2 6. 85 m g/ 10 0 g FW . C he n et a l., 2 02 0 Fr at ia nn i e t a l., 2 01 9 C itr us n ob ili s M et ha no l 10 % (K O H , sa po ni fic at io n) A nt io xi da nt Li po ph ili c an tio xi da nt c ap ac ity (9 Z) -V io la xa nt hi n = 2. 76 m g/ 10 0 g FW ; (a ll- E )- V io la xa nt hi n = 1. 93 m g/ 10 0 g FW ; (a ll- E )- A nt he ra xa nt hi n = 0. 64 m g/ 10 0 g FW . E rn aw ita e t a l., 2 01 6 50 % E th an ol M et ab ol ic sy nd ro m e In hi bi tio n of α -a m yl as e an d β- gl uc os id as e en zy m es E rn aw ita e t a l., 2 01 7 A nt ib ac te ria l K . p ne um on ia e, a nd S . a ur eu s in hi bi tio n E rn aw ita e t a l., 2 01 7 B en ze ne , e th an ol , an d m et ha no l B . c er us , S . a ur eu s, S . e pi de rm id is , P. v ul ga ris , S . t yp hi m ur iu m , P . ae ru gi no sa , C . a lb ic an s an d T. v iri de in hi bi tio n N R S ha rm a an d Ty ag i, 20 19 C itr us r et ic ul at a E th an ol 80 % E th an ol A nt io xi da nt R ad ic al s ca ve ng in g Fe rr ic -r ed uc in g po w er TP C = 4 .2 5– 8. 55 m g G A E /g D W ; TF C = 5 .2 1– 10 .9 0 m g R E /g D W ; N ar in gi n = 7. 68 –1 60 .0 3 m g/ 10 0 g; D W N eo he sp er id in = 1 9. 86 –2 87 .4 m g/ 10 0 g D W ; H es pe rid in = 1 3. 83 –4 15 .5 9 m g/ 10 0 g D W ; N ar in gi n = 7. 68 –1 60 .0 3 m g/ 10 0 g D W ; E rio ci tri n = 23 .9 2– 45 .5 0 m g/ 10 0 g D W ; N ar iru tin = 2 3. 91 –1 20 .0 3 m g/ 10 0 g D W ; Ta ng er et in = 1 .6 8– 3. 84 m g/ 10 0 g D W ; TP C = 1 27 .3 3 m g G A E /g e xt ra ct ; TF C = 0 .8 7 m g Q E /g e xt ra ct . C he n et a l., 2 02 0 B en ta ha r e t a l., 2 02 0 (c on tin ue s) 70 Italian Journal of Food Science, 2021; 33 (2) M. Leporini et al. Ta bl e 2. . C on tin ue d P ul p E xt ra ct B io lo gi ca l ac tiv ity M ec ha ni sm TP C , T FC , T C C , a nd /o r m ai n ab un da nt id en tifi ed c om po un ds R ef er en ce s C itr us s in en si s E th an ol 80 % E th an ol 50 % E th an ol A nt io xi da nt M et ab ol ic sy nd ro m e R ad ic al s ca ve ng in g Fe rr ic -r ed uc in g po w er In hi bi tio n of α -a m yl as e TP C = 4 .9 8– 9. 49 m g G A E /g D W ; TF C = 5 .3 2– 9. 81 m g R E /g D W ; H es pe rid in = 1 03 .1 4– 38 5. 37 m g/ 10 0 g D W ; E rio ci tri n = 13 .8 5– 24 .5 5 m g/ 10 0 g D W ; N ar iru tin = 4 1. 62 –1 53 .4 8 m g/ 10 0 g D W ; D id ym in = 4 .1 9– 13 .1 5 m g/ 10 0 g D W ; TP C = 1 59 .6 6 m g G A E /g e xt ra ct ; TF C = 0 .8 5 m g Q E /g e xt ra ct . TP C = 2 07 .6 9 m g C A E /g F W ; TF C = 8 5. 9 m g Q E /g F W C he n et a l., 2 02 0 B en ta ha r e t a l., 2 02 0 C as ac ch ia e t a l., 2 01 9 B en ze ne , e th an ol , an d m et ha no l A nt ib ac te ria l B . c er us , S . a ur eu s, S . e pi de rm id is , P . vu lg ar is , S . t yp hi m ur iu m , P. a er ug in os a, C . a lb ic an s an d T. v iri de in hi bi tio n S ha rm a an d Ty ag i, 20 19 C itr us × cl em en tin a 80 % M et ha no l 50 % E th an ol A nt io xi da nt R ad ic al s ca ve ng in g Li pi d pe ro xi da tio n in hi bi tio n N R TP C = 9 0. 01 m g C A E /g ; F W TF C = 4 1. 30 m g Q E /g F W . β- cr yp to xa nt hi n = 23 2. 4 µM P hy to en e = 62 .7 µ M 9- Z- V io la xa nt hi n = 60 .5 µ M A nt he ra xa nt hi n = 39 .0 µ M H es pe rid in = 3 .3 µ M N ar in ge ni n- 7- O -g lu co si de = 1 .4 µ M N ar iru tin = 1 .0 µ M C os ta nz o et a l., 2 02 0 C as ac ch ia e t a l., 2 01 9 C ill a et a l., 2 01 8 50 % E th an ol M et ab ol ic sy nd ro m e In hi bi tio n of α -a m yl as e an d lip as e en zy m e C as ac ch ia e t a l., 2 01 9 N R : n ot re po rt ed ; T P C : t ot al p he no lic s co nt en t; TF C : t ot al fl av on oi ds c on te nt ; T C C : t ot al c ar ot en oi ds c on te nt . Italian Journal of Food Science, 2021; 33 (2) 71 Citrus species: modern functional food and nutraceutical-based product ingredient the HDL-cholesterol level was found to improve (Arumugam et al., 2019). The lipase inhibitor activity of citrus pulp extracts was reported by Casacchia et al. (2019), founding the IC50 val- ues of 86.30, 105.90, and 67.20 mg/mL, respectively, for Citrus clementina, Citrus sinensis, and their hybrid called Tacle®. Antibacterial activity Citrus bergamia, Citrus medica, and Citrus medica cv. Salò pulp extracts were described as antibacterial agents against Escherichia coli, Listeria monocytogenes, Pseudomonas aeruginosa, S. aureus, and Pectobacterium carotovorum (Fratianni et al., 2019). The antibacterial activity of various citrus pulp extracts was also reported by Ernawita et al. (2017). Among them, jeruk makin and jeruk nipis showed the highest inhibitor capac- ity against Klebsiella pneumoniae (IC50 = 3.3 and 4.1 mg/mL) and S. aureus (IC50 = 2.6 and 3.1 mg/mL). In addition, Citrus limon, Citrus aurantifolia, and Citrus macroptera pulp extracts were screened for antimi- crobial activity against S. aureus, E. coli, Klebsiella sp., Pseudomonas sp., and Salmonella sp. (Bhuiyan et al., 2019). Citrus macroptera, a taxonomic synonym of Citrus hystrix (kaffir lime) known for its antioxidant, nutritious, and  therapeutic uses (Paul et al., 2017) eth- anol extracts exhibited the highest zone of inhibition (14 mm) against Klebsiella sp. while Citrus aurantifolia methanol extract showed the highest zone of inhibition (8 mm) against Salmonella sp. Citrus seed Antioxidant potential Bitter orange, blonde orange, sweet orange, lemon, and mandarin seed ultrasound methanol extracts (Table  3) were investigated for their antioxidant ability but no differences were found in the radical scavenging activ- ity (Falcinelli et al., 2020). Conversely, Costanzo et al. (2020) demonstrated that powered Citrus reticulata seed extract tissue showed the highest antioxidant capacity (55.6 mmol TE/mg FW) compared to Citrus japonica seed extract tissue (3.2 mmol TE/mg FW). The radical scavenging ability of eight citrus seed extracts were inves- tigated (Rehman et al., 2020a). Among them, Citrus jambhiri lush, Citrus sinensis cv. red blood, and Citrus reticulata tangerine possessed the highest activity (54.3, 53.6, and 53.3%, respectively). Previously, the following ranking of radical scavenging effect was demonstrated: lemon seeds extract > orange seeds extract > mandarin seeds extract (İnan et al., 2018). citrus × clementina tissue. In the citrus × clementina pulp extracts, the total antioxidant capacity (TAC) was found to be three-fold higher (7.1 mmol TE/mg fresh weight [FW]) compared to Citrus reticulata (2.6 mmol TE/mg FW) and six-fold higher compared to Citrus japonica (1.2 mmol TE/mg FW). Similarly, Citrus sinen- sis and Citrus reticulata fruits possessed good antioxi- dant activity studied by the hydroxyl radical scavenging activity and reducing power capacity methods (Bentahar et al., 2020). Fratianni et al. (2019) indicated that Citrus bergamia and Citrus medica cv. Salò homogenized  pulp extracts exhibited the highest antioxidant potential compared to Citrus medica. Previously, the in vitro lipophilic antioxidant capacity of seven citrus pulp extracts was reported (Ernawita et al., 2017). Among them, jeruk makin (Citrus aurantium) showed the highest antiox- idant capacity (19.5  µmol TE/100 g), followed by jeruk calung pulp extracts (Citrus aurantium) and jeruk nipis (Citrus aurantiifolia) (10.7 and 10.6 µmol α-TE/100 g, respectively). Previously, in vivo studies have reported that Citrus macroptera ethanol pulp extract possessed a significant lipid-lowering activity and a significant dim- inution of lipid peroxidation in liver and kidney tissues was observed (Paul et  al., 2015). The protective effect against oxidative stress of pulp bio-accessible fractions of oranges from Navel and Cara oranges cultivars as well as clementine was also demonstrated (Cilla et al., 2018). These fractions act by pre-serving cell viability, correct cell cycle progression, mitochondrial membrane poten- tial, and diminishing ROS level and lipid peroxidation. Recently, the effect of dried orange pulp on antioxidants level in the plasma was evaluated (Allam Sabbah et al., 2020). Results demonstrated that the value of total anti- oxidant capacity, as a biomarker of oxidative stress, was gradually increased (ranged from 0.420 to 0.433 mm/L) by increasing the level of dried orange pulp supplemen- tation (25, 50, and 75%). Additionally, a reduction of total lipids values was observed. Metabolic syndrome The α-amylase inhibition activity of seven citrus pulp extracts was analyzed by Ernawita et al. (2017). Makin and jeruk nipis pulp extracts exhibited the lowest IC50 values (18.8 and 19.4 mg/mL, respectively), while calung extract possessed less activity (IC50 = 56.2 mg/mL). Oral administration of Citrus hystrix and Citrus max- ima pulp extracts (5, 50, 300, and 2,000 mg/kg body weight (BW) in streptozotocin (STZ)-induced dia- betic rats for 14 days was able to reduce blood glu- cose, TG level, and serum cholesterol. Additionally, 72 Italian Journal of Food Science, 2021; 33 (2) M. Leporini et al. Table 3. Bioactivity of Citrus seed. Seed Extract Biological activity Mechanism TPC, TFC, TCC, and/or main abundant identified compounds References Citrus aurantium Methanol Antioxidant Radical scavenging TPC = 2.5 GAE/g DW Falcinelli et al., 2020 Anti-inflammatory Anti-edematogenic effects Antibacterial Proteus and Pseudomonas inhibition NR Aladekoyi et al., 2016 Citrus aurantium Methanol Antioxidant Radical scavenging TPC = 107 mg/100 g; TFC = 20.8 mg/100 g. Rehman et al., 2020c Citrus jambhiri Methanol Antioxidant Radical scavenging TCC = –25 mg/g FW Costanzo et al., 2020 Citrus jambhiri Methanol Antioxidant Radical scavenging TPC = 129 mg/100 g; TFC = 22.8 mg/100 g. Rehman et al., 2020c Citrus junos Anti-inflammatory Inhibition of NO production Not reported Ko et al., 2020 Citrus limon Methanol Antioxidant Radical scavenging Restoration of antioxidant defense system TPC = 1.2 GAE/g DW TPC = 152.70–212.30 mg GAE/kg Falcinelli et al., 2020 İnan et al., 2017 Metabolic syndrome Reduction of glucose and lipid levels NR Demir and Celik, 2019 Antibacterial Klebsiella, Proteus and Pseudomonas inhibition NR Aladekoyi et al., 2016 Citrus limetta Methanol Antioxidant Radical scavenging TPC = 99.1 mg/100 g; TFC = 19.37 mg/100 g. Rehman et al., 2020c Citrus maxima Ethanol Antibacterial S. aureus, E. coli, and B. subtilis inhibition TFC = 1602.740 mg/kg. Sahlan et al., 2018 Citrus paradise Ethanol Antibacterial S. aureus, E. coli, S. typhimurium, S. enteritidis, P. aeruginosa, K. pneumoniae, Citrus utilis, and B. cereus inhibition TFC = 483.562 mg/kg. Sahlan et al., 2018 Citrus reticulata Methanol Antioxidant Radical scavenging TPC = 112 mg/100 g; TFC = 21.5 mg/100 g. Rehman et al., 2020c Methanol TPC = 2.4 GAE/g DW. TCC = –10 mg/g FW. TPC = 152.70–212.30 mg GAE/kg. Falcinelli et al., 2020 Costanzo et al., 2020 İnan et al., 2017 Citrus sinensis Methanol Antioxidant Radical scavenging TPC = 101–118 mg/100 g; TFC = 20.1–22.60 mg/100 g. Rehman et al., 2020c Citrus sinensis Methanol TPC = 1.3 GAE/g DW Falcinelli et al., 2020 n-Hexane Metabolic syndrome Reduction of fasting blood glucose, serum TG, serum cholesterol, HDL NR Chilaka et al., 2015 Ethanol Antibacterial S. aureus, Enterococcus faecalis, P. aeruginosa, E. coli and Citrus albicans inhibition NR Oikeh et al., 2020 NR: not reported; TPC: total phenolics content; TFC: total flavonoids content; TCC: total carotenoids content. Metabolic Syndrome It has been reported recently that lemon seed extract could prevent diabetic complications due to reduction in glucose and lipid profile levels and restoration of antioxi- dant defense system (Demir and Celik, 2019). Previously, a reduction of blood glucose in alloxan-induced diabetic rats was observed after treatment with emulsified  sweet orange seed oil (1000 mg/kg BW). In addition, this seed oil improved sugar and lipid profile with reduction of serum TG, cholesterol, and increased HDL-cholesterol in diabetic rats (Chilaka et al., 2015). Italian Journal of Food Science, 2021; 33 (2) 73 Citrus species: modern functional food and nutraceutical-based product ingredient Citrus peels Antioxidant effects Recently, the antioxidant potential of citrus × clementina peel extracts, collected from different areas of Calabria and obtained by using different methodologies, was studied (Leporini et al., 2020a). Results demonstrated that sample from Cetraro obtained by ultrasound extraction in ethanol possessed the highest antioxidant activity (Table 4). Interestingly, the citrus × clementina juice enriched with this extract (20% v/w) increased its antioxidant potential. Similarly, Pereira et al. (2020) reported the increase of beer antioxidant activity after addition of orange peels extract. Huang et al. (2020) compared the antioxidant ability of eight citrus peel extracts: grapefruit, pomelo, kumquat, mandarin, ponkan, tangerine, lemon, and sweet orange. The most active samples were ponkan extract in DPPH and FRAP assays (386.25 and 466.14 μmol TE/g of extract, respectively), tangerine extract in ABTS assay (689.43 μmol TE/g), and pomelo in ORAC assay (1964.0 μmol TE/g). An inhibition of 92.87% was reported for Citrus hystrix peels extract against DPPH radical (Ramli et al., 2020). Citrus sinensis and Citrus aurantium peels’ extracts were investigated as potent antioxidant agents against lipid peroxidation (Rafiq et al., 2018). Furthermore, the ber- gamot extract showed a higher ABTS radical inhibition with a value of 136.3 mmol TE/g dry weight (DW). The capacity of Citrus medica Diamante hydroalcoholic peels extract to inhibit both DPPH and ABTS radicals (IC50  = 0.81 and 3.48 mg/mL, respectively) was also demonstrated by Menichini et al. (2016). In β-carotene, this extract exhibited an IC50 value of 0.23 mg/mL. Da Silva et al. (2018) studied the antioxidant potential of pomelo peels cv. Toranja Buraram in n-hexane, ethyl acetate, acetone, ethanol, methanol, and methanol:water (80:20). The ethyl acetate and methanolic extracts presented the highest antioxidant activity in vitro by DPPH (IC50 = 298.3 and 303.8 μg/mL, respectively), ABTS assay (IC50 = 298.2 and 296.4 μg/mL, respectively), and FRAP (IC50 = 234.6 and 398.1 μg/mL, respectively). Long et al. (2021) evaluated the antioxidant effects of ethanol extract and its three subfractions—petroleum ether, ethyl acetate, and water extracts—of Citrus sinensis cv. Gannanzao peels. The ethyl acetate extract exhib- ited the best antioxidant potential compared to four extracts in all antioxidant assays with the IC50 values of 38.33 mg/mL and 8.47 mg/mL in DPPH and ABTS tests, respectively, and value of 21.54 mM Trolox equivalents (TE)/mg DW in FRAP assay. The results correspond to those reported by Guo et al. (2020) for Citrus sinensis cv. Newhall peels extract. Anti-inflammatory effects Nitric oxide (NO) is recognized as a mediator and reg- ulator in pathological reactions, especially in acute inflammatory responses (Terao, 2009). The develop- ment of substances to prevent the overproduction of NO has become a new research target to treat chronic inflammatory diseases. Ko et al. (2020) reported the anti-inflammatory effect of Citrus junos seed oil. NO production was suppressed by 53% at a concentration of 0.05% that does not show cytotoxicity. The possible anti-inflammatory and antinociceptive activity of Citrus aurantium seed oil, obtained by using Soxhlet appara- tus with n-hexane, was evaluated by using formalin-in- duced paw licking, edema, and myeloperoxidase activity assessment (Azadeh et al., 2019). The results showed that seed oil exhibited anti-inflammatory properties in the first and second phases of formalin test, anti- edematogenic effects but exerted no effects on myelop- eroxidase activity. Antibacterial potential Recently, the antibacterial activities of Citrus sinensis seed oil, obtained by Soxhlet apparatus using n-hex- ane as solvent and ethanol extract, was studied (Oikeh et al., 2020). The results showed that the non-oil extract had better antibacterial activity against S.  aureus, Enterococcus faecalis, and E. coli. On the contrary, the seed oil had better activity against Salmonella spp. Similar susceptibility was found for P. aeruginosa. Previously, it was demonstrated that Citrus sinensis seed oil obtained by Soxhlet apparatus using n-hexane as sol- vent possessed antibacterial activity against S. aureus and Candida albicans (Olabanji et al., 2016). Buket et al. (2018) also reported that the lemon, orange, and grape- fruit cold-pressed seed oil had inhibition zones ranging from 6.62 to 11.00 mm against pathogenic bacteria such as S. aureus, E. coli, S. typhimurium, Salmonella enter- itidis, P. aeruginosa, K. pneumoniae, Candida utilis, and Bacillus cereus Holl. The antimicrobial and antifun- gal activities of aqueous and ethanolic grapefruit seed extracts were confirmed against S. aureus, E. faecalis, Bacillus subtilis, E. coli, P. aeruginosa, K. pneumoniae, and C. albicans (Eryilmaz et al., 2018). The ethanolic extract of pomelo seeds also gives positive results with growth-inhibition effect on Bacillus subtilis, S. aureus, and E. coli (Sahlan et al., 2018). Oil extracted from lemon, lime, and bitter orange seeds possessed differ- ent antimicrobial potential. Similar activity was found for Staphylococcus, but only lemon seed oil has activ- ity against Klebsiella and the highest zone of inhibition against Proteus, while bitter orange has a maximum zone of inhibition (0.25 mm) against Pseudomonas (Aladekoyi et al., 2016). 74 Italian Journal of Food Science, 2021; 33 (2) M. Leporini et al. Ta bl e 4. B io lo gi ca l a ct iv ity o f C itr us p ee ls . P ee ls E xt ra ct /E ss en tia l o il B io lo gi ca l ac tiv ity M ec ha ni sm TP C , T FC , T C C , a nd /o r m ai n ab un da nt id en tifi ed c om po un ds R ef er en ce s C itr us a ur an tif ol ia 96 % E th an ol A nt ib ac te ria l A nt i-i nfl am m at or y S . t yp hi in hi bi tio n R ed uc tio n of IL -6 le ve ls N R K as im e t a l., 2 02 0 K as im e t a l., 2 02 0 70 % E th an ol In hi bi tio n of p aw e de m a. N R P al la vi e t a l., 2 01 8 C itr us a ur an tiu m E th an ol A nt io xi da nt M et ab ol ic sy nd ro m e R ad ic al s ca ve ng in g In hi bi tio n of li pi d pe ro xi da tio n TP C = 1 8. 15 m g G A E /g F W ; TF C = 1 7. 09 m g R E /g F W ; N eo he sp er id in = 1 62 0. 77 m g/ 10 0 g D W ; N ar in gi n = 87 9. 33 m g/ 10 0 g D W ; H es pe rid in = 3 5. 88 m g/ 10 0 g D W ; N ar ur itu n = 18 .7 2 m g/ 10 0 g D W . N R C he n et a l., 2 02 0 R afi q et a l., 2 01 8 80 % E th an ol R ed uc tio n of B W , l ip id d ro pl et s re gu la tin g ad ip og en es is a nd th er m og en es is . N ar in gi n = 0. 91 6 m g/ m L; N eo he sp er id in = 0 .6 57 m g/ m L P ar k et a l., 2 01 9 70 % E th an ol A nt i-i nfl am m at or y In hi bi tio n of p aw e de m a. P al la vi e t a l., 2 01 8 C itr us g ra nd is E th an ol A nt io xi da nt R ad ic al s ca ve ng in g TP C = 8 .7 9– 14 .9 3 m g G A E /g F W ; TF C = 8 .2 5– 14 .0 3 m g R E /g F W ; N ar in gi n = 69 4. 15 –1 67 6. 31 m g/ 10 0 g D W ; N eo he sp er id in = 2 8. 42 –7 3. 04 m g/ 10 0 g D W ; H es pe rid in = 7 .3 9– 33 .3 9 m g/ 10 0 g D W ; N ar ur itu n = 2. 72 –6 .3 7 m g/ 10 0 g D W ; E rio ci tri n = 20 .4 2– 34 .4 9 m g/ 10 0 g D W ; D io sm in = 6 .0 2– 1. 29 m g/ 10 0 g D W . C he n et a l., 2 02 0 70 % E th an ol A nt i-i nfl am m at or y In hi bi tio n of p aw e de m a. P al la vi e t a l., 2 01 8 C itr us li m on 70 % E th an ol A nt io xi da nt R ad ic al s ca ve ng in g TP C = 1 98 .5 2 m g G A /g e xt ra ct ; TF C = 1 83 .1 3 m g/ g ex tra ct ; H es pe rid in = 8 4. 24 m g/ g ex tra ct ; E rio ci tri n = 84 .8 0 m g/ g ex tra ct ; N ar ru tin = 1 3. 56 m g/ g ex tra ct . H ua ng e t a l., 2 02 0 C itr us m ax im a 70 % E th an ol A nt io xi da nt R ad ic al s ca ve ng in g TP C = 1 38 .9 3 m g G A /g e xt ra ct ; TF C = 4 16 .5 4 m g/ g ex tra ct ; N ar in ge ni n = 38 6. 37 m g/ g ex tra ct ; R ho ifo lin = 2 8. 54 m g/ g ex tra ct . H ua ng e t a l., 2 02 0 95 % E th an ol M et ab ol ic sy nd ro m e R ed uc tio n th e bl oo d gl uc os e le ve l, to ta l c ho le st er ol , T G , a nd L D L- C . In hi bi tio n of li pa se e nz ym e N R A ni a nd O ch u, 2 02 0 H ua ng e t a l., 2 02 0 C itr us m ed ic a D ia m an te 70 % E th an ol A nt io xi da nt R ad ic al s ca ve ng in g In hi bi tio n of li pi d pe ro xi da tio n A pi ge ni n = 62 .8 m g/ K g FW ; H es pe rit in = 3 0. 4 m g/ K g FW ; N er in ge ni n = 18 .6 m g/ K g FW ; Q ue rc et in = 1 8. 2 m g/ K g FW . M en ic hi ni e t a l., 2 01 6 Italian Journal of Food Science, 2021; 33 (2) 75 Citrus species: modern functional food and nutraceutical-based product ingredient M et ab ol ic sy nd ro m e R ed uc tio n of s er um g lu co se , ch ol es te ro l a nd T G . M en ic hi ni e t a l., 2 01 6 C itr us p ar ad is i 70 % E th an ol A nt io xi da nt R ad ic al s ca ve ng in g TP C = 1 79 .1 3 m g G A /g e xt ra ct ; TF C = 4 74 .5 5 m g/ g ex tra ct ; N ar in ge ni n = 25 2. 13 m g/ g ex tra ct ; N eo he sp er id in = 1 82 .3 2 m g/ g ex tra ct ; N ar iru tin = 1 4. 80 m g/ g ex tra ct ; H es pe rid in = 6 .5 5 m g/ g ex tra ct . H ua ng e t a l., 2 02 0 W at er , 8 0% e th an ol , a nd n- he xa ne M et ab ol ic sy nd ro m e R ed uc tio n in th e ch ol es te ro l a nd TG le ve ls N ob ile tin = 1 8. 13 µ g/ m L. Fa ye k et a l., 2 01 7 C itr us r et ic ul at a 70 % E th an ol A nt io xi da nt R ad ic al s ca ve ng in g TP C = 2 15 .1 1 m g G A /g e xt ra ct ; TF C = 1 92 .2 2 m g/ g ex tra ct ; H es pe rid in = 1 50 .9 6 m g/ g ex tra ct ; N ar iru tin = 1 6. 79 m g/ g ex tra ct ; E rio ci tri n = 11 .3 3 m g/ g ex tra ct . H ua ng e t a l., 2 02 0 E th an ol Fe rr ic -r ed uc in g po w er TP C = 1 0. 58 –2 3. 46 m g G A E /g F W ; TF C = 7 .5 7– 21 .3 7 m g R E /g F W ; N ar in gi n = 6. 31 –7 7. 99 m g/ 10 0 g D W ; N eo he sp er id in = 0 –7 45 m g/ 10 0 g D W ; H es pe rid in = 3 9. 98 –1 89 3. 73 m g/ 10 0 g D W ; N ar ur itu n = 16 .2 1– 14 5. 56 m g/ 10 0 g D W ; E rio ci tri n = 10 .3 2– 26 8. 69 m g/ 10 0 g D W ; D io sm in = 3 .2 9– 38 .7 3 m g/ 10 0 g D W . C he n et a l., 2 02 0 W at er n- bu ta ne M et ab ol ic sy nd ro m e R ed uc tio n in b od y m as s in de x, bo dy fa t p er ce nt ag e an d in w ai st ci rc um fe re nc e, T C a nd T G le ve ls . R ed uc tio n of b lo od g lu co se le ve l an d pl as m a in su lin le ve l. In hi bi tio n of li pa se e nz ym e H es pe rid in = 4 0 m g N ar in ge ni n = 28 m g Q ue rc et in = 2 6 m g R ut in = 2 5 m g N ob ile tin = 3 2. 28 % Ta ng er iti n = 22 .8 2% K am el e t a l., 2 01 9 G uo e t a l., 2 01 6 H ua ng e t a l., 2 02 0 A lk al in e ho t w at er D ic hl or om et ha ne a nd et hy l a ce ta te A nt i-i nfl am m at or y In hi bi tio n of N O In hi bi tio n of C O X 1 an d C O X 2 N ar iru tin = 0 .2 6– 4. 52 m g/ g ex tra ct ; H es pe rid in = 7 .0 2– 26 .8 1 m g/ g ex tra ct ; N ob ile tin = 0 .3 9– 7. 79 m g/ g ex tra ct ; Ta ng er et in = 0 .1 9– 3. 37 m g/ g ex tra ct . N R C he n et a l., 2 01 7 H am da n et a l., 2 02 0 C itr us s in en si s 70 % e th an ol 95 % E th an ol , p et ro le um et he r, et hy l a ce ta te , a nd w at er 95 % E th an ol , p et ro le um et he r, et hy l a ce ta te , a nd w at er A nt io xi da nt R ad ic al s ca ve ng in g Fe rr ic -r ed uc in g po w er TP C = 1 49 .4 2 m g G A /g e xt ra ct ; TF C = 1 86 .8 1 m g/ g ex tra ct ; H es pe rid in = 1 48 .6 3 m g/ g ex tra ct ; N ar iru tin = 2 1. 49 m g/ g ex tra ct ; D id ym in = 7 .1 8 m g/ g ex tra ct . TP C = 0 .1 2– 0. 49 m M G A E / m g D W ; TF C = 1 .2 9– 4. 20 m M H E / m g D W ; S in en se tin = 0 –1 21 .3 m g/ m g; H es pe rid in = 1 .5 6– 21 .2 3 µg /m g; E rio ci tri n = 0– 4. 20 m g/ m g; H ua ng e t a l., 2 02 0 Lo ng e t a l., 2 02 1 (c on tin ue s) 76 Italian Journal of Food Science, 2021; 33 (2) M. Leporini et al. Ta bl e 4. C on tin ue d P ee ls E xt ra ct /E ss en tia l o il B io lo gi ca l ac tiv ity M ec ha ni sm TP C , T FC , T C C , a nd /o r m ai n ab un da nt id en tifi ed c om po un ds R ef er en ce s N ar iru tin = 0 .9 4– 6. 27 m g/ m g; Ta ng er et in = 0 .1 8– 2. 72 m g/ m g. TP C = 1 8. 71 –9 1. 55 m g G A E /g D W ; TF C = 3 .6 2– 86 .9 1 m g Q E /g D W ; S in en se tin = 0 –3 6. 92 m g/ m g D W ; N ob ile tin = 0 –3 5. 54 m g/ m g D W ; N ar iru tin = 1 .2 7– 20 .2 1 m g/ m g D W ; H es pe rid in = 1 .6 5– 42 .5 6 m g/ m g D W . G uo e t a l., 2 02 0 0. 5 g an d 1 g of C itr us iM ® M et ha no l W at er , 8 0% e th an ol , a nd n- he xa ne 50 % E th an ol M et ab ol ic sy nd ro m e R ed uc tio n of fa t, an d in cr ea se le an m as s re du ci ng w ai st ci rc um fe re nc e. R ed uc ed b lo od g lu co se a nd pl as m a in su lin . R ed uc tio n in th e ch ol es te ro l a nd TG le ve ls . In hi bi tio n of α -a m yl as e an d lip as e en zy m es N R R ut in = 1 24 8. 3 m g/ g D W ;p -C ou m ar ic a ci d = 95 7. 4 m g/ g D W ; P ro to ca te ch ui c ac id = 3 26 .3 m g/ g D W ; Fe ru lic a ci d = 31 6. 0 m g/ g D W ; N ar in ge ni n = 22 0. 7 m g/ g D W ; Va ni lli c ac id = 1 12 .2 m g/ g D W . N ob ile tin = 7 3. 15 m g/ m L. TP C = 1 77 .1 6 m g C A E /g F W ; TF C = 6 5. 9 m g Q E /g F W ; K eg el e et a l., 2 01 9 S at hi ya ba m a et a l, 20 18 Fa ye k et a l., 2 01 7 C as ac ch ia e t a l., 2 01 9 M et ha no l a nd e th an ol A nt i-i nfl am m at or y In hi bi tio n of e de m a. N ot re po rt ed O sa ru m w en se e t a l., 20 17 B en ze ne , e th an ol , a nd m et ha no l A nt ib ac te ria l B . c er us , S . a ur eu s, S . e pi de rm id is , P . v ul ga ris , S . t yp hi m ur iu m , P . a er ug in os a, C . a lb ic an s an d T. v iri de in hi bi tio n E . c ol i a nd B . s ub til lis in hi bi tio n N R S ha rm a et T ya gi , 20 19 G uo e t a l., 2 02 0 C itr us tu m id a H D F+ 5 % p ee l p ow de r M et ab ol ic sy nd ro m e S up pr es si on B W g ai n N R S at o et a l., 2 01 9 C itr us u ns hi u M et ha no l A nt io xi da nt M et ab ol ic sy nd ro m e R ad ic al s ca ve ng in g Fe rr ic -r ed uc in g po w er In hi bi tio n of α -g lu co si da se a nd lip as e en zy m es H es pe rid in = 5 00 27 m g/ g D W ; N ar iru tin = 9 28 4 m g/ g D W ; N ob ile tin = 1 03 .8 m g/ g D W ; Ta ng er et in = 5 5. 5 m g/ g D W . K im e t a l., 2 02 0 K im e t a l., 2 02 0 Fe rm en te d dr ie d A nt i-i nfl am m at or y In hi bi tio n of L P S -in du ce d N O , iN O S , C O X -2 p ro te in , T N F- γ an d IL -6 N R K im e t a l., 2 01 9a C itr us × cl em en tin a E th an ol a nd 8 0% e th an ol A nt io xi da nt R ad ic al s ca ve ng in g Fe rr ic -r ed uc in g po w er In hi bi tio n of li pi d pe ro xi da tio n TP C = 3 .4 5– 8. 75 m g C A E /g F W ; TF C = 2 .4 7– 6. 05 m g Q E /g F W ; TC C = 9 .6 6– 39 .8 4 m g b- ca ro te ne E /g F W ; H es pe rid in = 1 55 .2 8– 10 93 .3 6 m g/ 10 0 g FW ; S in en se tin = 1 9. 56 -3 7. 99 m g/ 10 0 g FW ; Ta ng er et in = 5 .4 3– 9. 60 m g/ 10 0 g FW ; Lu te ol in = 3 .0 2– 8. 58 m g/ 10 0 g FW . Le po rin i e t a l., 2 02 0a Italian Journal of Food Science, 2021; 33 (2) 77 Citrus species: modern functional food and nutraceutical-based product ingredient 50 % E th an ol M et ab ol ic sy nd ro m e In hi bi tio n of α -a m yl as e, β- gl uc os id as e an d lip as e en zy m es TP C = 1 09 .8 6 m g C A E /g F W ; TF C = 6 1. 3 m g Q E /g F W ; Le po rin i e t a l., 2 02 0a C as ac ch ia e t a l., 2 01 9 C itr us a ur an tif ol ia E ss en tia l o il A nt io xi da nt R ad ic al s ca ve ng in g Li m on en e = 42 .3 5% γ- te rp in en e = 15 .4 4% β- pi ne ne = 1 2. 57 % Li n et a l., 2 01 9 M et ab ol ic sy nd ro m e Im pr ov e th e se ru m T C , T G , L D L- c, al an in e am in ot ra ns fe ra se , an d as pa rt at e tra ns am in as e le ve ls Li n et a l., 2 01 9 C itr us a ur an tiu m E ss en tia l o il A nt io xi da nt R ad ic al s ca ve ng in g Fe rr ic -r ed uc in g po w er In cr ea se in m R N A g en e ex pr es si on o f C u- Zn S O D , C AT , an d G P x Li m on en e = 85 .2 2% ; β- m yr ce ne = 4 .3 0; α -p in en e = 1. 28 % . Li m on en e = 81 .1 9% ; Li na lo ol = 4 .0 6% ; β- m yr ce ne = 3 .0 7. Li m on en e = 48 .7 % ; Li na lo ol = 3 2. 4% ; β- m yr ce ne = 1 .2 % . Ta ne va e t a l., 2 01 9 Fa ra hm an df ar e t a l., 20 20 H so un a et a l., 2 01 8 A nt ib ac te ria l E . c ol i, P. a er ug in os a, L . m on oc yt og en es , S . a ur eu s, B . s ub til is , C . a lb ic an s an d S. pa ra ty ph i B in hi bi tio n Li m on en e = 61 .8 5% ; γ- Te rm in en e = 9. 15 % ; O ct an al = 5 .2 8% ; α -p in en e = 3. 02 % . G uo e t a l., 2 01 8 A nt i-i nfl am m at or y R ed uc tio n of N O p ro du ct io n H so un a et a l., 2 01 8 R ed uc tio n of c el l m ig ra tio n, cy to ki ne p ro du ct io n an d pr ot ei n ex tra va sa tio n Li m on en e = 31 .1 % ; γ- te rp in en e = 10 .8 % ; β- pi ne ne = 8 .5 % ; N er al = 7 .1 % . A m or im e t a l., 2 01 6 C itr us b er ga m ia E ss en tia l o il A nt io xi da nt R ad ic al s ca ve ng in g Fe rr ic -r ed uc in g po w er C he la te p ro -o xi da nt m et al N R Lo m ba rd o et a l., 2 02 0 A nt i-i nfl am m at or y R ed uc tio n of IL -1 α , I L- 6, T N F- γ ni tri te /n itr at e an d P G E 2 Lo m ba rd o et a l., 2 02 0 C itr us li m on E ss en tia l o il A nt io xi da nt R ad ic al s ca ve ng in g Li m on en e = 61 .7 2% ; 3- C ar en e = 13 .6 7% ; α -P in en e = 13 .9 7% . G uo e t a l., 2 01 8 M et ab ol ic sy nd ro m e In hi bi tio n of α -a m yl as e an d β- gl uc os id as e en zy m es Li m on en e = 53 .0 7% ; β- pi ne ne = 9 .5 3% ; B or ne ol = 5 .5 7% : O bo h et a l., 2 01 7 A nt i-i nfl am m at or y R ed uc tio n of c el l m ig ra tio n, cy to ki ne p ro du ct io n an d pr ot ei n ex tra va sa tio n Li m on en e = 53 .9 % ; β- P in en e = 13 .1 % ; S ab in en e = 3. 4% . A m or im e t a l., 2 01 6 (c on tin ue s) 78 Italian Journal of Food Science, 2021; 33 (2) M. Leporini et al. Ta bl e 4. C on tin ue d P ee ls E xt ra ct /E ss en tia l o il B io lo gi ca l ac tiv ity M ec ha ni sm TP C , T FC , T C C , a nd /o r m ai n ab un da nt id en tifi ed c om po un ds R ef er en ce s A nt ib ac te ria l E . c ol i, Fu so ba ct er iu m ne cr op ho ru m , Tr ue pe re lla p yo ge ne s, S . a re us in ib iti on P. a er ug in os a, L . m on oc yt og en es , B . s ub til is , C . a lb ic an s an d S . p ar at yp hi B in hi bi tio n Li m on en e = 65 .5 9% β- P in en e = 15 .0 6% ; γ- Te rp in en e = 7. 93 . B ra ga e t a l., 2 02 0 G uo e t a l., 2 01 8 C itr us lu m ia E ss en tia l o il A nt io xi da nt R ad ic al s ca ve ng in g Fe rr ic -r ed uc in g po w er In hi bi tio n of li pi d pe ro xi da tio n Li m on en e = 48 .9 0% ; Li na lo ol = 1 8. 24 % . Li na ly l a nt hr an ila te = 1 0. 96 % . S m er ig lio e t a l., 2 01 8 C itr us m ed ic a E ss en tia l o il A nt io xi da nt R ad ic al s ca ve ng in g Li m on en e = 48 .9 4% ; α -p in en e = 2. 88 % ; M yr ce ne = 2 .2 9% . G uo e t a l., 2 01 8 A nt ib ac te ria l E . c ol i, P. a er ug in os a, L. m on oc yt og en es , S . a re us , B . s ub til is , C . a lb ic an s an d S . p ar at yp hi B in hi bi tio n G uo e t a l., 2 01 8 C itr us p ar ad is i E ss en tia l o il A nt io xi da nt A nt ib ac te ria l R ad ic al s ca ve ng in g E . c ol i, S . a ur eu s, P . a er ug in os a an d C itr us a lb ic an s in hi bi tio n Li m on en e = 91 .7 8% ; δ- 3- ca re ne = 2 .0 7% . D en ko va -K os to va et a l., 2 02 0 C itr us r et ic ul at a E ss en tia l o il A nt io xi da nt R ad ic al s ca ve ng in g Li m on en e = 61 .7 2% ; 3- C ar en e = 13 .6 7% ; α -P in en e = 13 .9 7% . G uo e t a l., 2 01 8 M et ab ol ic sy nd ro m e Im pr ov e th e hy pe rc ho le st er ol em ia , an d he pa tic s te at os is . R ed uc tio n in s er um to ta l c ho le st er ol , L D L- C , he pa tic T C a nd T G le ve ls . Li m on en e = 84 .8 9% ; δ- 3- ca re ne = 3 .1 4% . Li m on en e = 76 .5 8% ; γ- Te rp in en e = 12 .8 8% . β- M yr ce ne = 2 .4 5% . D en ko va -K os to va et a l., 2 02 0 K on gl on g et a l., 2 02 0 Italian Journal of Food Science, 2021; 33 (2) 79 Citrus species: modern functional food and nutraceutical-based product ingredient A nt ib ac te ria l E . c ol i, P. a er ug in os a, L. m on oc yt og en es , S . a re us , B . s ub til is , C itr us a lb ic an s an d S. p ar at yp hi B in hi bi tio n G uo e t a l., 2 01 8 C itr us s in en si s E ss en tia l o il A nt io xi da nt R ad ic al s ca ve ng in g In hi bi tio n of li pi d pe ro xi da tio n Li m on en e = 95 .1 1% ; M yr ce ne = 1 .0 7% . M ag al hã es e t a l., 20 19 M et ab ol ic sy nd ro m e In hi bi tio n of α -a m yl as e an d β- gl uc os id as e en zy m es Li m on en e = 92 .1 4% ; β- M yr ce ne = 2 .7 0% . O bo h et a l., 2 01 7 A nt ib ac te ria l E . c ol i, P. a er ug in os a, L. m on oc yt og en es , S . a re us , B . s ub til is , C . a lb ic an s an d S . p ar at yp hi B in hi bi tio n Li m on en e = 79 .2 8% ; 3- ca re ne = 7 .7 6% ; β- P in en e = 2. 28 % . G uo e t a l., 2 01 8 A nt i-i nfl am m at or y R ed uc tio n of e de m a Li m on en e = 80 .5 % ; tra ns -b -o ci m en e = 6. 5% ; Li na lo ol = 2 .7 % . Th an di sw a et a l., 20 20 C itr us u ns hi u E ss en tia l o il A nt io xi da nt R ad ic al s ca ve ng in g Li m on en e = 64 .2 1% ; g- Te rp in en e = 9. 44 % ; M yr ce ne = 8 .3 7% ; a- P in en e = 4. 98 % . G uo e t a l., 2 01 8 A nt ib ac te ria l E . c ol i, P. a er ug in os a, L . m on oc yt og en es , S . a re us , B . su bt ili s, C . a lb ic an s an d S . pa ra ty ph i B in hi bi tio n G uo e t a l., 2 01 8 C itr us × cl em en tin a E ss en tia l o il A nt io xi da nt M et ab ol ic sy nd ro m e R ad ic al s ca ve ng in g Fe rr ic -r ed uc in g po w er In hi bi tio n of li pi d pe ro xi da tio n In hi bi tio n of α -a m yl as e an d β- gl uc os id as e an d lip as e en zy m es . Li m on en e = 61 .3 1% ; Li na lo ol = 3 .2 9– 6. 64 % ; M yr ce ne = 3 .5 6– 9. 10 % . Le po rin i e t a l., 2 02 0a N R : n ot re po rt ed ; T P C : t ot al p he no lic s co nt en t; TF C : t ot al fl av on oi ds c on te nt ; T C C : t ot al c ar ot en oi ds c on te nt . 80 Italian Journal of Food Science, 2021; 33 (2) M. Leporini et al. The effectiveness of Citrus maxima peels ethanol extract was suggested recently in the management of diabetes (Ani and Ochu, 2020). Indeed, the administration of this extract (600 mg/kg BW/day) for 14 days decreased the blood glucose level (70.17%), TA (30.86%), TG (10.58%), and LDL-cholesterol (10.20%). Additionally, an increase of HDL-cholesterol (4.43%) was observed. Dietary inges- tion of Citrus tumida Hort. ex Tanaka peels powder (5% w/w) suppressed BW gain by decreasing epidydimal, per- irenal, and subcutaneous fat weights (Sato et al., 2019). A similar effect, that is a significant decrease of BW, was observed for Citrus aurantium extract (100 mg/kg/day) administered for 8 weeks. Additionally, the same treat- ment in 3T3-L1 adipocytes determined a reduction of lipid droplets regulating adipogenesis and thermogenesis via AMP-activated protein kinase alpha (AMPKα) path- way (Park et al., 2019). Kegele et al. (2019) investigated the effects of CitrusiM® (Citrus sinensis dried extract) on body composition: percentage of lean mass and per- centage of fat mass. This extract determined a significant reduction of fat, and increase in lean mass reducing waist circumference after a dose of 0.5 or 1 g/day. Similarly, the obese mice treated with supplementation of 0.25% and 0.5% of Citrus reticulata extract in food for 12 weeks exhibited a reduction of 21% and 34% in BW, respectively (Guo et al., 2016). This effect was probably due to the action of citrus phytochemicals on metabolism of glucose and fatty acids. Administration of Citrus sinensis methanol peels extract at doses of 50 and 100 mg/kg in diabetic rats reduced fasting blood glucose by 56.1% and 55.7%, respec- tively, and plasma insulin levels by 22.9% and 32.7%, respectively (Sathiyabama et al., 2018). Citrus medica Diamante hydroalcoholic peels extract was tested in db/db mouse model for leptin deficiency. This mutation confers susceptibility to obesity, insulin resistance, and T2DM. Administration of 600 mg/kg of Diamante peels extract significantly decreased the serum glucose level (Menichini et al., 2016). This extract was rich in phenolic compounds that are known to posses several actions to improve glucose tolerance as reported below. The in vivo reduction of blood glucose and plasma insulin levels was demonstrated for both Citrus reticulata and Citrus sudachi peels extract (Guo et al., 2016; Kobayashi et al., 2017). In particular, Citrus sudachi exerted its effect via reduction of TNF-α mRNA expression. Literature showed that citrus genus was able to counter- act the effect of high cholesterol level (Favela-Hernández et al., 2016). Recently, the hypocholesterolemic effects of mandarin peels’ aqueous and n-hexane extracts was demonstrated (Fayek et al., 2017). The results showed that these extracts decrease the cholesterol level by 59.3% and 56.8%, respectively. A reduction in cholesterol and TG levels was also observed with Citrus medica cv. Recently, the antioxidant activities of Citrus reticulata, Citrus paradise, and Citrus lemon peels’ essential oils were reported (Denkova-Kostova et al., 2020). The radical scavenging potential on DPPH radical revealed that the highest percentage of inhibition was found in the grape- fruit (87.5%), followed by lemon and tangeretine with values of 86.1% and 78.0%, respectively. The antioxidant potential of grapefruit, lemon, mandarin, and orange essential oils was also investigated by Raspo et al. (2020). Mandarin exhibited the highest activity in ABTS test, grapefruits exhibited the highest activity in FRAP test, and lemon exhibited the highest activity in DPPH test. Citrus lumia essential oil showed a strong antioxidant activity in different assays, with the following order of potency (expressed as IC50): β-carotene (22 μg/mL) > ORAC(46 μg/mL) > DPPH (104 μg/mL) > Folin-Ciocalteu (181 μg/mL) > FRAP (202 μg/mL) > Trolox equivalent antioxidant capacity (TEAC) (233 μg/mL) (Smeriglio et al., 2018). For Citrus aurantium peels’ essential oil, an inhibition percentage of 88.1% against DPPH radical was observed (Tevena et al., 2019). A lower activity was reported for bitter orange with an inhibition percentage of 31.33% (Farahmandfar et al., 2020). Metabolic syndrome Recently, the effects of Citrus reticulata peels’ water extract (800 mg) administered to obese adolescents were analyzed (Kamel et al., 2019). In this clinical trial, the extract showed a reduction in BMI, body fat percentage, and waist circumference after 4 and 8 weeks of supple- mentation. Additionally, a reduction of total cholesterol (TC) and TG levels was observed. Huang et al. (2020) compared the in vitro anti-obesity ability of grapefruit, pomelo, kumquat, mandarin, ponkan, tangerine, lemon, and sweet orange peels’ extracts. Among them, the most active sample was sweet orange, followed by tangerine and ponkan with the IC50 values of 87.25, 109.44, and 126.62 mg/mL, respectively, against lipase enzymes. Also, for Citrus unshiu peels’ water extract, an inhibitor effect was reported for lipase activity (IC50 = 507.01 μg/mL) (Kim et al., 2016). Better results were observed for cit- rus × clementina peels extract with values in the range of 112.06–191.91 mg/mL (Leporini et al., 2020a). In partic- ular, peels extract from Cetraro, obtained by ultrasound extraction EtOH, exhibited the strongest hypolipidemic activity. Additionally, this extract increased the hypolip- idemic activity of citrus × clementina juice when added at a concentration of 20% (w/v). Oboh et al. (2017) reported that the lemon peels’ essential oil exhibited stronger inhibitory activity on α-amylase and α-glucosidase activ- ities (IC50 values of 8.16 and 7.56 µg/mL, respectively) compared to orange peels’ essential oil (IC50 values of 11.51 and 11.53 µg/mL, respectively). Italian Journal of Food Science, 2021; 33 (2) 81 Citrus species: modern functional food and nutraceutical-based product ingredient essential oil, without furanocoumarins fraction, reduced levels of IL-1β, IL-6, and TNF-α in the paw homoge- nates, nitrite/nitrate, and prostaglandin E2 (PGE2) con- tents in exudates, and possesses antioxidant properties (Lombardo et al., 2020). Antiproliferative activity Selim et al. (2019) investigated the cytotoxicity activity of Citrus reticulata peels 70% ethanolic extract against human breast carcinoma, hepatocellular liver carcinoma (HepG2), and colon carcinoma and determined the IC50 values of 34, 9.9, and 30 mg/mL, respectively. Previously, the anti-cancer effects of Citrus medica (2 morphotypes), Citrus sinensis, Citrus maxima, Citrus limon, and Citrus reticolata peels’ water extracts were studied (Nair et al., 2018). Among these, Citrus reticolata had significant activity against Dalton’s lymphoma ascites (DLA) cell-in- ducing cell cycle arrest of DLA in G0/G1 phase. Antibacterial potential The in vivo antibacterial activity of Citrus hystrix ethanol peels extract against S. typhimurium was demonstrated by Zulvikar et al. (2020). In particular, the bacterial loads of this pathogen in the ileum, liver, and spleen decreased after 24 h of administration of the extract (16 mg daily for 3 days in a mouse). Lime peels extract was used to inhibit the colonization and growth of bacteria S. typhi in Balb/c mice. Doses of 510 and 750 mg/kg BW decreased the number of S. typhi colonies; even maintenance for 20 days after the intervention showed no bacterial growth (Kasim et al., 2020). Sharma and Tyagi (2019) analyzed benzene, ethanol, and methanol peels’ extracts of Citrus nobilis and Citrus sinensis against four Gram-positive and four Gram-negative bacteria and two fungal pathogens. The minimum inhibitory concentration (MIC) values in the range of 18–40 μg/mL were found against Bacillus cerus, S. aureus, S. epidermidis, Proteus vulgaris, S. typh- imurium, P. aeruginosa, C. albicans, and Trichoderma viride for Citrus nobilis ethanolic extract, while less activity was reported for methanol and benzene extracts. The same observation was made for Citrus sinensis extracts, and, in particular, the MIC values in the range of 20–50 μg/mL were observed for ethanolic extract. The results were in accordance with Rehab et al. (2018) that reported antibacterial and antifungal effects of Citrus sinensis peels’ hot, cold, and ethanol extracts against S. aureus, E. coli, P. aerogenes, B. cereus, and C. albicans. Interestingly, the green synthesis of zinc oxide nanopar- ticles using Citrus sinensis peel extract was proposed by Gao et al. (2020) in food packaging application as nano- coatings on fresh strawberries with similar antibacterial characteristic of commercial zinc oxide nanoparticles. Diamante peels’ hydroalcoholic extract of (300 and 600 mg/kg/day) administered in Zucker diabetic rats for 4 weeks (Menichini et al., 2016). Successively, Konglong et al. (2020) demonstrated that Citrus reticulata peels’ essential oil was able to ameliorate hypercholesterolemia and hepatic steatosis. In addition, a reduction in serum TC, LDL-cholesterol, and hepatic TC and TG levels was observed after supplementation (0.5% and 0.75%). Anti-inflammatory activity Fermented dried Citrus unshiu peel extracts were inves- tigated for its anti-inflammatory activities in murine macrophages and moisturizing effects in human kerati- nocytes (Kim et al., 2019a). Results evidenced that Citrus unshiu peels extract, rich in polyphenolic compounds, was able to suppress lipopolysaccharide (LPS)-induced NO without exerting cytotoxic effects on RAW 264.7 cells. Moreover, extracts inhibited the expression of inducible Nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) protein, TNF-α, and IL-6. The inhibition of NO without compromising cell viability was also reported for Citrus reticulata peels alkaline hot water extract (IC50 1.04–2.74 mg/mL) (Chen et al., 2017). Recently, the anti-inflammatory effect of Citrus sinensis peels’ hydroalcoholic and methanol extracts was con- firmed by Osarumwense et al. (2017). Interestingly, meth- anol extract was more active than hydroalcoholic extract, and a positive control drug (Indomethacin) with an inhi- bition of 95% on carrageenan induced rat paw edema at a concentration of 40 mg/kg. Similarly, after 4 h of edema induction, the oral administration (300 and 500 mg/kg BW) of pomelo peels methanol extract determined an inhibition of paw edema by 34.47% and 38.68%, respec- tively (Ibrahim et al., 2019). The same model of paw was used by Pallavi et al. (2018), establishing that intraperi- toneal (i.p.) doses (250 and 500 mg/kg) of pomelo peels extract inhibited paw edema (17% and 48%, respectively). The mandarin dichloromethane and ethyl acetate peels’ extracts against COX-1 and COX-2 were tested (Hamdan et al., 2020). The dichloromethane extract was more active against COX-1 (IC50 = 25.5 mg/mL) than ethyl acetate extract (IC50 = 28.79 mg/mL); conversely against COX-2, the ethyl acetate extract had the highest activity (IC50 = 3.55 mg/mL). Citrus limon essential oil exhibited anti-inflammatory activity (30 or 10 mg/kg oral [p.o.]) by reducing cell migration, cytokine production, and protein extrava- sation induced by carrageenan (Amorim et al., 2016). Treatment (200 and 50 mg/kg) with sweet orange dried peels essential oil evidenced a significant reduction of edema in rats (Thandiswa et al., 2020). Citrus bergamia 82 Italian Journal of Food Science, 2021; 33 (2) M. Leporini et al. et al. (2020). All investigated samples exhibited radical scavenging activity with IC50 values in the same order of positive controls such as ascorbic acid and BHT. Among them, Citrus maxima and Citrus aurantium leaves showed the highest DPPH radical scavenging activity with the IC50 values of 0.51 and 0.57 mg/mL, respec- tively (Table 5). More recently, the antioxidant activity of methanol leaves extract and ethyl acetate fraction of Citrus pseudolimon was examined (Kumar et al., 2019). The ethyl acetate fraction displayed greater DPPH radical scavenging activity than the methanol leaves extract with the IC50 values of 278.60 and 313.20 μg/mL, respectively. The IC50 values of 476.39 and 498.26 μg/mL were also found in H2O2 scavenging assay. The methanol extract of Citrus medica leaves was also investigated for its capacity to inhibit DPPH radical (Shojaemehr et al., 2020). Similar values were observed in extracts (IC50 = 0.111 mg/mL) and ascorbic acid (IC50 = 0.109 mg/mL) used as control. The citrus × clementina leaves subjected to differ- ent extractions were investigated for their antioxidant potential (Leporini et al., 2020b). The hydroalcoholic extract obtained by using ultrasound-assisted macera- tion had the highest antioxidant DPPH, ABTS, FRAP, and β- carotene bleaching values. Previously, methanol and aqueous leave extracts of Citrus clementina, Citrus limon, Citrus hamlin, Citrus navel, Citrus aurantifolia, Citrus aurantium, and Citrus grandi were investigated for their antioxidant activity (Khettal et al., 2017). Among aqueous extracts, Citrus limon had an important DPPH radical scavenging activity (IC50 = 35.35 µg/mL), while Citrus clementina exhibited the highest ABTS radical scavenging activity (IC50 = 1,174.43 µM TE/g) and ferric- reducing potential (IC50 = 30.60 mg butyl- hydroxyanisole equivalents (BHAE)/g). Regarding methanolic extracts, Citrus clementina showed the highest antioxidant activ- ity in all assays with the IC50 values of 41.85 µg/mL, 378.63 µM TE/g DM, and 13.85 mg BHAE/g DM for DPPH, ABTS radicals scavenging activities, and ferric- reducing potential, respectively. The antioxidant poten- tial of Citrus macroptera leaf methanol extract has been recently demonstrated by Lala et al. (2020) that reported the capacity of this extract to reduce ROS, which was generated on HepG2 cell line. Previously, Bonesi et al. (2018) investigated six citrus petitgrain essential oils for their antioxidant properties. In this study, Citrus aurantium petitgrain oil demon- strated the strongest radical scavenging activity in DPPH assay with an IC50 value of 27.2 μg/mL, followed by cit- rus  × clementina oil with an IC50 value of 39.0 μg/mL, while in β-carotene bleaching test, the highest antioxidant capacity was observed with Citrus sinensis oil with the IC50 values of 176.3 and 51.3 μg/mL after 30 and 60 min of incubation, respectively. Less activity was reported for clementine essential oils by Leporini et al. (2020b). The antimicrobial potential of Citrus sinensis L. and Citrus limonia Osbeck methanol, ethyl acetate, etha- nol, and distilled water peels extracts was also evaluated by Saleem and Saeed (2020) against six Gram-positive (S.  aureus, Aeromonas hydrophila, Enterococcus fae- calis, Streptococcus pyogenes, Listeria monocytogenes, and Lactobacillus casei), six Gram-negative (P. aeru- ginosa, K.  pneumoniae, Serratia marcescens, E. coli, P.  vulgaris, and S. typhi), two microscopic filamentous fungi (Aspergillus niger and Penicillium citrinum), and two yeasts (C. albicans and Saccharomyces cerevisiae). Interestingly, the zone of inhibition is well comparable with amoxicillin, used as a positive control. In addition, the yellow lemon extract exhibited the highest antimicro- bial activity compared to orange peels, and resulted more effectively on Gram-negative bacteria as compared to Gram-positive bacteria. Strawberries treated with Citrus limon, Citrus sinensis, and Citrus reticulata essential oils showed the highest TAC and physicochemical parameters compared to untreated fruits. This effect extends the shelf- life and delays the fruit senescence (Shehata et al. 2020). The antimicrobial effects of tangerine, grapefruit, and lemon peels’ essential oils on the growth of saprophytic and pathogenic microorganisms were compared by Denkova-Kostova et al. (2020). The highest inhibitory activity was observed for grapefruit, followed by tanger- ine and lemon essential oil, with MIC values in the range of 60–60 ppm against E. coli, S. aureus, P. aeruginosa, and Citrus albicans. Similarly, grapefruit and lemon have respective MIC values of 0.35 mg/mL and 0.33 mg/mL against E. coli (Raspo et al., 2020). The antimicrobial effect of bitter orange essential oil against Gram-positive and Gram-negative selected bacterial strains was studied by Farahmandfar et al. (2020). MIC values of 20, 40, and 10 mg/mL were found, respectively, for E. coli, P. aerugi- nosa, S. aureus, and L. monocytogenes. The addition of Citrus medica essential oil to the wines (0.010%) determined reduction in microbial counts com- pared to untreated wine, and is thus proposed as bio-pre- servative. In particular, it the antimicrobial activity of enriched wine against the common spoilage bacteria and yeasts/molds such as Gluconobacter cerinus, Oenococcus oeni, Pediococcus pentosaceus, Dekkera bruxellensis, Candida zemplinina, Hanseniaspora uvarum, Pichia guilliermondii, or Zygosaccharomyces bailii was studied and inoculated (Mitropoulou et al., 2020). Leaves Antioxidant effects The antioxidant activity of leaf methanol–water extracts of 10 varieties of citrus fruits was reported by Haraoui Italian Journal of Food Science, 2021; 33 (2) 83 Citrus species: modern functional food and nutraceutical-based product ingredient Ta bl e 5. B io lo gi ca l p ro pe rt ie s of C itr us le av es Le av es E xt ra ct /E ss en tia l o il B io lo gi ca l a ct iv ity M ec ha ni sm TP C , T FC , T C C , a nd /o r m ai n ab un da nt id en tifi ed co m po un ds R ef er en ce s C itr us a ur an tif ol ia W at er a nd m et ha no l A nt io xi da nt R ad ic al s ca ve ng in g Fe rr ic -r ed uc in g po w er TP C = 5 .7 7– 10 6. 05 m g G A E /g D W ; TF C = 2 .7 2– 38 .3 6 m g Q E /g D W . K he tta l e t a l., 2 01 7 E th an ol M et ab ol ic s yn dr om e R ed uc tio n in th e to ta l s er um c ho le st er ol N R C yn di e t a l., 2 01 6 C itr us a ur an tiu m W at er a nd m et ha no l A nt io xi da nt R ad ic al s ca ve ng in g Fe rr ic -r ed uc in g po w er TP C = 7 .7 7– 69 .9 7 m g G A E /g D W ; TF C = 5 .0 8– 11 .9 9 m g Q E /g D W . K he tta l e t a l., 2 01 7 C itr us g ra nd is W at er a nd m et ha no l A nt io xi da nt R ad ic al s ca ve ng in g Fe rr ic -r ed uc in g po w er TP C = 2 .4 8– 68 .2 3 m g G A E /g D W ; TF C = 1 .0 4– 13 .0 6 m g Q E /g D W . K he tta l e t a l., 2 01 7 C itr us li m on W at er a nd m et ha no l 80 % M et ha no l A nt io xi da nt R ad ic al s ca ve ng in g Fe rr ic -r ed uc in g po w er In hi bi tio n of li pi d pe ro xi da tio n TP C = 3 .8 3– 98 .0 6 m g G A E /g D W ; TF C = 2 .8 3– 38 .7 3 m g Q E /g D W . TP C = 3 0. 51 m g G A E /g ; TF C = 1 4. 64 m g Q E /g . K he tta l e t a l., 2 01 7 H ar ao ui e t a l., 2 02 0 W at er M et ab ol ic s yn dr om e R ed uc tio n of th e B W a nd p la sm a in su lin le ve ls N R Th om as e t K am at h, 2 01 7 C itr us m ac ro pt er a M et ha no l A nt io xi da nt R ed uc tio n of R O S TP C = 2 4. 55 m g G A E /g e xt ra ct ; La la e t a l., 2 02 0 A nt i-i nfl am m at or y R ed uc tio n of e de m a TF C = 1 0. 76 m g Q E / g e xt ra ct . A nt ib ac te ria l S ta ph yl oc oc cu s sp . a nd K le bs ie lla s p. in hi bi tio n C itr us m ax im a 80 % M et ha no l A nt io xi da nt R ad ic al s ca ve ng in g Fe rr ic -r ed uc in g po w er In hi bi tio n of li pi d pe ro xi da tio n TP C = 9 1. 76 m g G A E /g ; TF C = 1 6. 98 m g Q E /g . H ar ao ui e t a l., 2 02 0 E th an ol M et ab ol ic s yn dr om e R ed uc tio n of T G , T C , H D L, L D L, V LD L se ru m le ve l a nd B W N R D in es h an d H eg de , 2 01 6 A nt ib ac te ria l M . l ut eu s, S . e pi de rm is , B . s ub til is , a nd E . f ec al is in hi bi tio n H ar ao ui e t a l., 2 02 0 C itr us m ed ic a M et ha no l A nt io xi da nt R ad ic al s ca ve ng in g TP C = 1 02 .7 m g G A E /g e xt ra ct ; S ho ja em eh r e t a l., 2 02 0 A nt ib ac te ria l B . s ub til is , B . c er eu s, S . a ur eu s, M . l ut eu s, E . f ae ca lis , P . a er ug in os a, K . p ne um on ia e, S . t yp hi a nd E . c ol i in hi bi tio n TF C = 3 .9 5 m g G A E /g e xt ra ct . C itr us p se ud ol im on M et ha no l A nt io xi da nt R ad ic al s ca ve ng in g TP C = 1 0 m g G A E /g e xt ra ct TF C = 7 .9 m g G A E /g e xt ra ct K um ar e t a l., 2 01 9 M et ab ol ic s yn dr om e In hi bi tio n of α -a m yl as e an d β- gl uc os id as e en zy m es . R ed uc tio n of b lo od g lu co se le ve l C itr us s in en si s 80 % M et ha no l A nt io xi da nt R ad ic al s ca ve ng in g Fe rr ic -r ed uc in g po w er In hi bi tio n of li pi d pe ro xi da tio n TP C = 3 5- 09 -6 2. 59 m g G A E /g ; TF C = 3 .6 7– 6. 39 m g Q E /g . H ar ao ui e t a l., 2 02 0 (c on tin ue s) 84 Italian Journal of Food Science, 2021; 33 (2) M. Leporini et al. Ta bl e 5. co nt in ue d Le av es E xt ra ct /E ss en tia l o il B io lo gi ca l a ct iv ity M ec ha ni sm TP C , T FC , T C C , a nd /o r m ai n ab un da nt id en tifi ed co m po un ds R ef er en ce s M et ab ol ic s yn dr om e In hi bi tio n of li pa se e nz ym e TP C = 2 09 .2 7 m g G A E /g F W ; TF C = 6 5. 02 m g Q E / g F W . A nt ib ac te ria l M . l ut eu s, S . e pi de rm is , B . s ub til is , a nd E . f ec al is in hi bi tio n H ar ao ui e t a l., 2 02 0 C itr us u ns hi u M et ha no l M et ab ol ic s yn dr om e In hi bi tio n of li pa se e nz ym es N R Ito h et a l., 2 01 9 C itr us × c le m en tin a 80 % M et ha no l E th an ol a nd 8 0% E th an ol A nt io xi da nt R ad ic al s ca ve ng in g Fe rr ic -r ed uc in g po w er In hi bi tio n of li pi d pe ro xi da tio n TP C = 3 1. 43 m g G A E /g ; TF C = 4 .8 4 m g Q E /g . TP C = 1 33 13 –4 5. 54 m g G A E /g F W ; TF C = 5 .5 0– 29 .1 6 m g Q E /g F W ; H es pe rid in = 1 74 .9 1– 65 6. 66 m g/ 10 0 g FW ; R ut in = 4 .2 4– 68 .5 2 m g/ 10 0 g FW ; Is oq ue rc itr in = 7 .7 3– 52 .0 1 m g/ 10 0 g FW ; S in en se tin = 7 .2 4– 35 .6 9 m g/ 10 0 g FW ; Ta ng er et in =7 .4 6– 41 .7 6 m g/ 10 0 g FW ; H ar ao ui e t a l., 2 02 0 Le po rin i e t a l., 2 02 0a M et ab ol ic s yn dr om e In hi bi tio n of α -a m yl as e, β -g lu co si da se an d lip as e en zy m es Le po rin i e t a l., 2 02 0a A nt ib ac te ria l M . l ut eu s, B . s ub til is , a nd E . f ec al is in hi bi tio n H ar ao ui e t a l., 2 02 0 C itr us a ur an tif ol ia E ss en tia l o il A nt io xi da nt R ad ic al s ca ve ng in g Li m on en e = 63 .3 5% ; G er an io l = 6 .2 3% ; C itr al = 4 .3 5% . A l-A am ri et a l., 2 01 8 M et ab ol ic s yn dr om e R ed uc tio n in fa st in g bl oo d, h ep at ic gl uc os e, T C , t ria cy lg ly ce ro l a nd L D L- c Li m on en e = 57 .8 4% ; N er al = 7 .8 1% ; Li na lo ol = 4 .7 4% . Ib ra hi m e t a l., 2 01 8 A nt ib ac te ria l S . a ur eu s, a nd P . a er ug in os a in hi bi tio n E . c ol i, S . t yp hi , a nd B . c er eu s in hi bi tio n Li m on en e = 30 .1 1% ; b- pi ne ne =1 9. 27 % ; b- O ci m en e = 3. 48 % : C hi e t a l., 2 02 0 A l-A am ri et a l., 2 01 8 C itr us a ur an tiu m E ss en tia l o il A nt io xi da nt R ad ic al s ca ve ng in g Fe rr ic -r ed uc in g po w er In hi bi tio n of li pi d pe ro xi da tio n S ab in en e= 39 .8 1% ; Li na lo ol = 1 3. 75 % ; g- Te rp in en = 7 .4 3% ; d- 3- ca re ne =6 .5 5% B on es i e t a l., 2 01 8 A nt ifu ng al C . a lb ic an s in hi bi tio n N id hi e t a l., 2 02 0 C itr us b er ga m ia E ss en tia l o il A nt io xi da nt R ad ic al s ca ve ng in g Fe rr ic -r ed uc in g po w er In hi bi tio n of li pi d pe ro xi da tio n Li na ly l a ce ta te = 7 0. 51 % ; Li na lo ol =1 0. 25 % ; G er an yl a ce ta te = 3 .0 4% . B on es i e t a l., 2 01 8 C itr us g ra nd is E ss en tia l o il A nt io xi da nt A nt ib ac te ria l R ad ic al s ca ve ng in g S . a re us , S . t yp hi , a nd B . c er eu s in hi bi tio n Li m on en e = 21 .8 7% ; α -c ar yo ph yl le ne = 6 .7 5% ; β- oc im en e = 6. 35 % . C hi e t a l., 2 02 0 Italian Journal of Food Science, 2021; 33 (2) 85 Citrus species: modern functional food and nutraceutical-based product ingredient C itr us li m on E ss en tia l o il A nt io xi da nt R ad ic al s ca ve ng in g Fe rr ic -r ed uc in g po w er In hi bi tio n of li pi d pe ro xi da tio n Li m on en e = 30 .5 7% ; G er an ia l = 1 4. 44 % ; β- pi ne ne = 1 4. 98 % : B on es i e t a l., 2 01 8 A nt ib ac te ria l Li st er ia in hi bi tio n S . a ur eu s, E . c ol i, an d B . s ub til is in hi bi tio n G er an io l = 2 98 .6 5 m g/ m L; Li m on en e= 25 6. 87 m g/ m L; G er an ia l = 9 8. 39 m g/ m L; N er al = 8 6. 81 m g/ m L. N R Fa nc el lo e t a l., 2 02 0 S ae b et a l., 2 01 6 C itr us r et ic ul at a E ss en tia l o il A nt io xi da nt R ad ic al s ca ve ng in g Fe rr ic -r ed uc in g po w er In hi bi tio n of li pi d pe ro xi da tio n S ab in en e = 39 .8 1% ; Li na lo ol = 1 3. 75 % ; γ- te rp in en e = 7. 43 % ; δ- 3- ca re ne = 6 .5 5% : B on es i e t a l., 2 01 8 A nt ib ac te ria l S . a ur eu s, E . c ol i, an d B . s ub til is in hi bi tio n N R S ae b et a l., 2 01 6 C itr us s in en si s E ss en tia l o il A nt io xi da nt R ad ic al s ca ve ng in g Fe rr ic -r ed uc in g po w er In hi bi tio n of li pi d pe ro xi da tio n Li m on en e = 13 .7 7% ; β- pi ne ne = 1 6. 93 % ; β- oc im en e = 7. 48 % . S ab in en e = 49 .6 7% ; β- oc im en e = 9. 25 % ; Li m on en e = 5. 48 % C hi e t a l., 2 02 0 B on es i e t a l., 2 01 8 A nt i-i nfl am m at or y R ed uc tio n of e de m a S ab in en e = 20 .4 % ; Te rp in en -4 -o lo = 1 3. 2% ; Li m on en e = 7. 5% ; δ- 3- ca re ne = 6 .5 5% . Th an di sw a et a l., 2 02 0 A nt ib ac te ria l S . a re us , S . t yp hi , a nd B . c er eu s in hi bi tio n C hi e t a l., 2 02 0 C itr us × c le m en tin a E ss en tia l o il A nt io xi da nt R ad ic al s ca ve ng in g Fe rr ic -r ed uc in g po w er In hi bi tio n of li pi d pe ro xi da tio n S ab in en e = 27 .8 4% ; Li na lo ol = 1 9. 76 % ; Li m on en e = 6. 44 % : B on es i e t a l., 2 01 8 M et ab ol ic s yn dr om e In hi bi tio n of α -a m yl as e, α -g lu co si da se a nd li pa se e nz ym es Li na lo ol = 1 5. 80 % ; Li m on en e = 6. 41 % ; β- O ci m en e = 6. 52 % ; δ- 3- ca re ne = 6 .3 3% . Le po rin i e t a l., 2 02 0b Le po rin i e t a l., 2 02 0b N R : n ot re po rt ed ; T P C : t ot al p he no lic s co nt en t; TF C : t ot al fl av on oi ds c on te nt ; T C C : t ot al c ar ot en oi ds c on te nt ; R O S : r ea ct iv e ox yg en s pe ci es . 86 Italian Journal of Food Science, 2021; 33 (2) M. Leporini et al. and Citrus sinensis cv. Jaffa leave extracts with an inhi- bition area of 20.00 mm and 16.00 mm, respectively. For Gram-negative bacteria, the best results were observed for the Citrus lemon extract with an inhibition area of 15.66 mm (P. aeruginosa) and 15.33 mm (E. coli). The antibacterial effects of different extracts obtained from Citrus medica leaves were tested. Interestingly, the inhibitory activity of methanol extract on B. cereus, E. coli, and E. aerogenes was more potent than the genta- micin used as a positive control (Shojaemehr et al., 2020). Citrus aurantium leaves essential oil demonstrated strong antifungal activity against two strains of Citrus albicans with MIC values of 0.15–0.31% (v/v) (Nidhi et  al., 2020). Interestingly, Citrus limon var pompia leaves essential oil showed specific anti-listeria activity on ricotta salata cheese (Fancello et al., 2020). Recently, De Oliveira Filho et al., (2020) proposed a chitosan films enriched with Citrus limonia leaves essential oil as an active packaging material for food preservation for its capacity to: (a)  reduce the moisture content and water vapor permeability; (b) decrease the visible light trans- mission rate values; (c) change the color of bioactive films significantly, remaining darker and yellowish; and (d) inhibit S. aureus. Similarly, the addition of lemon essential oil to chitosan coatings enhanced fermentative process during storage, with modification of strawberry fruit aroma composition notably appreciated (Perdones et al., 2015). Bioactive compounds Polyphenolic compounds are a wide group of metabolites that originate from the secondary metabolism of plants. These are considered as potent antioxidants for their capacity to increase catalase activity, trap reactive oxygen species, and to act as a metal chelator. Additionally, they determined the inhibition of chain lipid peroxidation by trapping peroxyl radical and quickly reacted with peroxy nitrite (Pisoschi and Pop, 2015). Flavonoids and phenolic acid (Figure 1) are dominant bioactive compounds found in citrus. In particular, peels are rich in flavone aglycons and polymethoxy flavones, rarely found in other plants. Polyphenols are present in both edible and nonedible parts of the fruits (Singh et al., 2020). In addition, citrus fruit is a good source of carotenoids (Figure 2) com- pounds recognized for their beneficial effects on human health (Ikoma et al., 2016). Citrus by-products represented a rich source of essen- tial oils that possessed a wide range of antioxidant, antimicrobial, and antidiabetic properties, and thus used in pharmaceutical and food industries (Bora et al., 2020). Metabolic syndrome In recent decades, numerous in vitro and in vivo studies have demonstrated the importance of genus Citrus in the prevention of T2DM. Recently, the hypoglycemic effects of citrus × clementina leaves extract has been reported by Leporini et al. (2020b), who found the IC50 values of 64.37–247.61 mg/mL in α-amylase enzyme and the IC50 values of 51.61–282.65 mg/mL against α-glucosidase. In particular, hydroalcoholic extract obtained by ultra- sound-assisted maceration from Corigliano Calabro leaves was found to be the most active. The addition of this extract to the juice increased its hypoglycemic (+37% and +25% against α-glucosidase and α-amylase, respectively) and hypolipidemic (+17% against lipase) potential. The inhibitory activity of Citrus unshiu leaf methanol extract on pancreatic lipase enzyme was reported by Itoh et al. (2019) that showed an IC50 value of 44 µg/mL. Citrus pseudolimon methanol leave extracts and ethyl acetate fraction possessed a hypoglycemic potential (Kumar et al., 2019). The ethyl acetate fraction displayed a greater inhibition against α-glucoside (84.18%) in com- parison to the methanol extract (82.94%). The IC50 val- ues of 83.66% and 78.52% for ethyl acetate and methanol extract, respectively, were found against α-amylase. In addition, the authors indicated that oral administration of methanol leaves extract (200 mg/kg) and ethyl acetate fraction (100 mg/kg) for 21 days decreased the fasting blood glucose level in diabetic rats. Aqueous extract of Citrus limon leaves was tested against STZ-induced dia- betic rats. This extract, orally administered at doses of 50 mg/kg BW and 100 mg/kg BW for 28 days, decreased BW and plasma insulin levels and increased blood glu- cose levels (Thomas and Kamath, 2017). The hypocho- lesterolemic effects of Citrus aurantifolia was reported by Cyndi et al. (2016). Indeed, the ethanol extract of leaves determined reduction in TC serum in mice, with the most significant reduction at a dosage of 3.5 g/kg BW. Similarly, the oral administration of Citrus max- ima leaves extract (200 and 400 mg/kg BW) in obese rats determined reduction in TG, TC, HDL, LDL, and very low-density lipoprotein (VLDL) serum levels and BW (Dinesh and Hegde, 2016). Antibacterial effect More recently, Haraoui et al. (2020) investigated the antibacterial activity of leaves methanol water extracts obtained from Citrus aurantium, Citrus maxima, Citrus lemon, Citrus Clementine, and Citrus sinensis cv. Sanguinelli, Thomson, Washington, Portuguese, Double Fine, and Jafa. M. luteus resulted in the most sensitive Gram-positive bacteria to the action of Citrus aurantium Italian Journal of Food Science, 2021; 33 (2) 87 Citrus species: modern functional food and nutraceutical-based product ingredient In an in vivo study, hesperidin and naringin increased the production and release of insulin from the islet cells and decreased intestinal glucose absorption (Mahmoud et al., 2015). In addition, hesperidin and hesperetin inhibited two gluconeogenesis enzymes, alanine aminotransferase and aspartate aminotransferase, indicating their effec- tiveness in treating diabetes mellitus (Zareei et al., 2017). The therapeutic potential of hesperidin has been con- firmed recently (Rehman et al., 2020b). This flava- none  improved leptin and insulin resistance, IL-6 and TNF-α more significantly compared to the reference drug Orlistat used in high fat diet (HFD)-induced obese rats. In addition, the treatment with 500-mg hesperidin significantly reduced the plasma levels of C-reactive protein and serum amyloid A in individuals with MS (Homayouni et al., 2017). Moreover, hesperidin reduced symptoms of MS and improved cardiac function in HFD- induced MS in rats (Prasatthong et al., 2021). Indeed, treatment with hesperidin (15 or 30 mg/kg) ameliorated cardiac dysfunction and hypertrophy in rats, restored the insulin signaling pathway, and IRS/Akt/GLUT4 protein expression. The consummation (500 mL) of orange juice enriched with hesperidin had positive effects on blood and pulse pressures in mildly hypertensive individuals (Valls et al., 2021). The results are in accordance with a recent study in which high blood pressure was attenuated by hes- peridin (50 mg/kg BW). Regulation in the expressions of TNF-α, COX-2, and PGE2 with improvement of oxi- dative stress by increasing glutathione reductase and decreasing malondialdehyde (MAD) was also observed (Khidr et al., 2020). Previously, the cardioprotective effect of hesperidin was investigated by Haidari et al. (2015). Administration of 600 mg/day of hesperidin decreases levels of adiponectin and HDL-cholesterol and increases E-selectin in patients with myocardial infarction. The neuroprotective activity of hesperidin was evaluated by Thenmozhi et al. (2015). In this study, administration of 100 mg/kg of hesperidin along with aluminum chlo- ride (AlCl3) injection for 60 days significantly reduced the concentration of ROS in hippocampus and cortex, the AchE activity, the protein expressions of amyloid precursor protein, the levels of both Ab1–42 and b and g secretases. Recently, Li and Schluesener (2017) demon- strated that administration of 100 mg/kg of hesperidin for 10 days significantly attenuated α-amyloid depo- sition and microglial activation in brain of transgenic mice. The combination of diosmin and hesperidin exerted analgesic and/or anti-inflammatory effects (Patent No. Flavonoids Flavonoids are secondary metabolites in plants, with a multitude of functions: They regulate the development of plants, their pigmentation, and protect them from UV-light. Furthermore, they act as defense and signal- ing between plants and microorganisms (Mathesius, 2018). Hesperidin Hesperidin is one of the main flavanone glycosides know in citrus fruits. Great attention has been focused on hes- peridin and its aglycone form, hesperetin, which plays an important role in the prevention of diseases associated with oxidative stress such as obesity, diabetes, inflam- mation, and cancer (Barreca et al., 2017). Its antioxidant mechanism was correlated to direct ROS scavenging, transition metal ion chelation, and its ability to increase cellular glutathione content. De Souza et al. (2016) com- pared the antioxidant activity of hesperidin, hesperetin, and G-hesperidin in vitro and in vivo, administrating each of these for 30 days at 1 mmol/kg body mass to Wistar male rats. The aglycone form has the greatest inhibitory activity of xanthine oxidase by increasing superoxide dismutase (SOD) activity in the liver of ani- mals. Recently, the antioxidant activity of hesperidin, and its ability to inhibit pancreatic lipase enzyme, was studied (Huang et al., 2020). Results demonstrated that hydrogen bonds and van der Waals forces played major roles in the interaction of hesperidin and lipase. The metabolic effects of hesperidin were also demon- strated by Sahnoun et al. (2017) and Zeng et al. (2018), who reported its ability to inhibit α-amylase, α-glucosi- dase, and lipase enzyme with the IC50 values of 111 and 1 μM, and 688.25 μg/mL, respectively. In a randomized double-blind controlled clinical trial design, 23 subjects with T2DM consumed 500 mg/day hesperidin supple- ment for 8 weeks. Hesperidin supplementation led to significant decrease in fasting blood glucose and glyco- sylated hemoglobin (HbA1c). A significant increase in serum insulin and decrease in TG were also observed in the hesperidin-treated group (Eghtesadi et al., 2016). Similarly, the supplementation with hesperidin (500 mg/ day for 8 weeks) in T2DM patients resulted in reduc- tion of fasting blood glucose, TC, and HbA1c, and at the same time a significant increase in serum insulin (Mohammadi et al., 2016). A dose of 100 mg or 500 mg of hesperidin for 6 weeks in subjects with hypercholes- terolemia decreased serum TG and LDL levels (Li and Schluesener, 2017). In addition, intra-gastric hesperi- din attenuates the increased level of plasma cholesterol, LDL-cholesterol VLDL-cholesterol, TG, free fatty acids, and phospholipids, and decreased levels of high- density lipoprotein-cholesterol (HDL-c) (Homayouni et al., 2017). 88 Italian Journal of Food Science, 2021; 33 (2) M. Leporini et al. (a) Structure of flavones (b) Structure of flavones (c) Structure of flavonols (C)(B)(A) (d) Chlorogenic (A), gallic (B) and caffeic acid (C) NAME R1 R2 R3 R4 R5 R6 R7 Naringenin OH H OH H H OH H Hesperetin OH H OH H OH OCH3 H Narirutin OH H O-Rut H H OH H Naringenin OH H O-Neo H H OH H Poncirin OH H O-Neo H H OCH3 H Eriocitrin OH H O-Rut H OH OH H Neoeriocitrin OH H O-Neo H OH OH H Hesperidin OH H O-Rut H OH OCH3 H Neohesperidin OH H O-Neo H OH OCH3 H Didymin OH H O-Rut H H OCH3 H NAME R1 R2 R3 R5 R5 R6 R7 Apigenin OH H OH H H OH H Luteolin OH H OH H OH OH H Sinensetin OCH3 OCH3 OCH3 H OCH3 OCH3 H Tangeretin OCH3 OCH3 OCH3 OCH3 H OCH3 H Nobiletin OCH3 OCH3 OCH3 OCH3 OCH3 OCH3 H NAME R1 Quercetin OH Kaempferol OH Rutin OCH3 R5 R6 R7 R4 R3 R2 R1 O O R5 R1 OH OH OH O OHO HO HO HO HO COOH OH OH OH OH OH OH HO O O O CO2H R6 R7 R4 R3 R2 R1 O O Figure 1. The main phenolic constituents of Citrus species. WO2015019334) as reported by López Muñozmaría et  al. (2015). This application was used for the treat- ment of different kinds of pain: moderate to severe pain, chronic pain, and/or neuropathic pain. No occurrence of adverse effects was observed. Supplementation of a mixture of Imperata cylindri- cal, Citrus unshiu markovich-hesperidin, and Evodia officinalis Dode-Evodiamine for 12 weeks significantly reduced the BW, body fat mass, and waist circumference in overweight subjects (Cho et al., 2017). Recently, it was Italian Journal of Food Science, 2021; 33 (2) 89 Citrus species: modern functional food and nutraceutical-based product ingredient R1 HO HO HO O OH OH β-cryptoxanthin β-carotene Lutein violaxanthinO R1 R2 R2 NAME Figure 2. The most abundant Citrus carotenoids. reported that hesperidin ameliorates hepatic dysfunction and dyslipidemia in male Wistar rats exposed to cad- mium chloride (Aja et al., 2020). Hesperetin Recently, hesperetin showed cellular antioxidant activ- ity with a value of 23.57 μmol of QE/100 μmol (Huang et al., 2020). Both hesperidin and hesperetin were able to reduce oxidative stress directly by scavenging intracellu- lar ROS and increase natural antioxidant defense system with particular reference to glutathione (Dhanya and Jayamurthy, 2020). In addition, these flavonoids inhib- ited the non-enzymatic glycation of proteins involved in the formation of advanced glycation end-products which have an important role in developing diabetes. Previously, Jayaraman et al. (2018) investigated the anti-hyperglycemic, antioxidant, and anti-hyperlipidemic effects of hesperetin against STZ-induced experimental rats. Supplementation with 40 mg/kg of hesperetin for 45 days determined a significant decline in plasma glucose level and a marked improvement in insulin and glycogen secretions. Hesperetin is also known to induce apoptosis in cancer cells primarily through activation of caspase-9 (Farooqi et al., 2015). This compound revealed significant cyto- toxicity for HeLa cell line, and its anticancer ability was revalidated by in silico molecular docking study, which exhibited strong interaction with E6 protein of HPV16 cervical carcinoma with significant binding energy (Prakash et al., 2020). The capacity of hesperetin to atten- uate testicular alteration in Wistar rats was also reported through inhibition of inflammation, oxidative stress, and apoptosis (Samie et al., 2018). Interestingly, Li et al. (2018; Patent No. CN108815154A) investigated the ability of hesperetin to inhibit chloride channel and propose its use for the treatment of diarrhea, heart disease, pulmonary disease, stomach, brain, and mental diseases, rhinitis, ontological disease, and eye dis- ease drug development. Hesperetin administered orally (50 mg/kg/day for 46  days) reduced ROS, DNA fragmentation, serum glu- cose, MDA levels, and caspase 3 activity. In addition, this compound potentiated testicular antioxidant system with consequent increase in glutathione levels, ferric-reduc- ing antioxidant power, catalase (CAT), SOD, and gluta- thione peroxidase (GPx) activity in diabetic rats (Samie et al., 2018). Shagirtha et al. (2017) has recently demon- strated the neuroprotective properties of hesperetin. The oral administration of this flavanone (40 mg/kg BW for 21 days) protected the brain of Wistar rats by increasing the levels of enzymatic antioxidants such as CAT, SOD, GPx, and glutathione-s-transferase (GSTs). In addition, hesperetin reduced oxidative stress, neuroinflammation, and motor dysfunction as well as amyloidogenesis and cognitive dysfunction in mice with positive effect against Parkinson’s and Alzheimer’s diseases (Khan et al., 2020). Neohesperidin The in vivo hypoglycemic and hypolipidemic effects of neohesperidin on KK-A(y) mice were studied (Jia et  al., 2015). Treatment with neohesperidin significantly 90 Italian Journal of Food Science, 2021; 33 (2) M. Leporini et al. Moreover, naringenin decreased blood glucose, serum lipid, and ameliorated glucose tolerance through down- regulating oxidative stress and inflammation in STZ- induced rats (Jia et al., 2015). Liang et al. (2015; Patent No. CN104940932A) reported the protective effects of naringenin and naringin during radiotherapy. Additionally, the use of naringenin and its derivative in preventing Alzheimer’s disease and other cognitive disorders was reported (Liao, 2018; Patent No. CN108785301A). The administration of naringenin (50 mg/kg/day) increased the serum level of insulin and consequently glu- cose uptake, improved lipid profile, TNF-α, IL-6, normal- ized level of NO, and increased SOD level (Rehman et al., 2020c). These effects were confirmed by Wu et al. (2016); they showed how this compound inhibited the expression of cytokine signaling, iNOS, COX-2, and release of NO and pro-inflammatory cytokines in microglial cells. A direct effect of this flavanone determined downregulation of genes involved in de novo lipogenesis, lipolysis, and tri- glyceride synthesis/storage. Moreover, narirutin and did- ymin are able to inhibit lipase enzyme with the IC50 values of 58.98 and 67.30 μg/mL, respectively (Zeng et al., 2018). Didymin Didymin acted as an anticancer agent by inhibiting phthalate-mediated invasion, migration, and prolifer- ation of breast cancer cells (Hsu et al., 2016), and as a scavenger of free radicals (Lin et al., 2016). More recently, Ali et al. (2019) demonstrated that didymin was also able to inhibit α-glucosidase and α-amylase enzymes and increase glucose uptake. In addition, didymin reduced the expression of two key enzymes involved in the gluco- neogenesis such as glucose 6-phosphatase and phospho- enolpyruvate carboxy-kinase with a consequent decrease of glucose production. Recently, it was found that didy- min prevented hyperglycemia-induced ROS, production of lipid peroxidation product MAD, hyperglycemia- induced monocyte-endothelial cell adhesion, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activation. In addition, this compound inhib- ited the release of various inflammatory cytokines and chemokines (Kirtikar et al., 2018). Eriocitrin Eriocitrin is known as a strong antioxidant agent (Smeriglio et al., 2019). It has been shown that a major role is played by its two hydroxy groups that are bound to the B ring in ortho position with respect to each other (Diab et al., 2015). This flavanone (200 mg/kg) showed protective effects against inflammation and oxidative stress in C57BL/6J mice, and may therefore prevent met- abolic alterations associated with the development of cardiovascular diseases (Ferreira et al., 2016). decreased serum glucose, fasting glucose, glycosylated serum protein, and insulin resistance. Moreover, this bioactive compound significantly decreased TC, serum TG, leptin level, and inhibited lipid accumulation. Lv et al. (2015) also noted that naringin and neohesperi- din mainly inhibited amylose digestion. In addition, the neohesperidin administration (50 mg/kg/day) attenuates weight gain, low-grade inflammation, and insulin resis- tance in mice, as well as restored gut barrier damage and metabolic endotoxemia (Lu et al., 2020). A novel pharmaceutical use of neohesperidin in the preparation of drug for treating bronchial asthma or dis- eases caused by Th1/Th2 cell immune imbalance was dis- closed (Shi and Yang, 2018; Patent No. CN108478586). The efficacy of citrus flavonoids on MS resulted in the commercialization of Bergavit®, a standardized extract containing 150 mg of main active flavonoids of bergamot juice (16% of neoeriocitrin, 47% of neohesperidin, and 37% of naringin). This supplement was administrated at a fixed daily dose for 6 months in patients with moderate hypercholesterolemia. Results revealed reduction in TG, TC, and LDL-cholesterol (Toth et al., 2016). It has been demonstrated recently that the neohesperidin inhibited Angiotensin II-induced myocardial contrac- tile dysfunction, and reduced hypertension, myocardial hypertrophy, fibrosis, SOD production, and inflamma- tion (Zhang et al., 2020). Naringenin Naringin, as reported by Sahnoun et al. (2017), showed an excellent inhibition for α-amylase and α-glucosidase enzyme, with IC50 values of 8.0 μM and 0.55 μM, respec- tively. Lim et al. (2018) studied the protective effects and molecular mechanisms of naringin in diabetic mice. The results showed that this flavanone ameliorated hypergly- cemia and protected STZ-induced β-cell death by inhib- iting both intrinsic and extrinsic apoptotic pathways. These protective effects have been related to the ability of naringin to reduce ROS and pro-inflammatory cytokines accumulation. It was suggested recently that antioxidant and anti-inflammatory properties of naringenin could confer hepatoprotective effects after oral treatment with 60 mg/kg BW (Kometsi et al., 2020). In a clinical study, administration of naringin (400 mg/ capsule/day) for 8 weeks in hypercholesterolemic indi- viduals resulted in reduced concentration of plasma TC and LDL-cholesterol. Naringin exerted its effect by inhibiting gluconeogenesis and upregulation of AMPK, hence metformin-like effects. In addition, it increased glucose uptake in skeletal muscles, ameliorated pro- inflammatory reactions, and prevented metabolic dys- regulation and atherosclerosis (Nyane et al., 2017). Italian Journal of Food Science, 2021; 33 (2) 91 Citrus species: modern functional food and nutraceutical-based product ingredient (100  mg/kg/day for 6 weeks) ameliorated LPS-triggered memory deficit regarding synaptic dysfunctions and neu- ronal loss, and inhibited the microglial activation and pro-inflammatory cytokine secretion (IL-1β, COX-2, TNF-α, and iNOS). In addition, in BV-2 microglia cells, the action of this flavone decreased pro-inflammatory cytokines secretion, and channeled modulation of mito- gen-activated protein kinase (MAPKs), phosphatidylinosi- tol 3-kinase/phosphorylated protein kinase B (PI3K/Akt), and NF-κB signaling pathways. Interestingly, nobiletin promotes antioxidant and anti-inflammatory responses and elicits protection against ischemic stroke in vivo with increase in the expression of SOD and glutathione (GSH) which are responsible of antioxidant endogenous defense systems. Moreover, a reduction in the levels of NF-κB and MDA was also observed (Zhang et al., 2016). Wen-Zhe et al. (2015; Patent No. US9808477B2) detected a pharmaceutical composition for multidrug-resistant cancer treatment comprising citrus methoxyflavone (nobiletin) and chemotherapeutic drug. In addition, Chen and Wang (2015; Patent No. CN105030559A) proposed application of nobiletin in preparation of health prod- ucts or medicines for prevention and/or treatment of oral cancer. The experiments showed that these compounds possessed an obvious effect on inhibiting proliferation of human oral epidermoid carcinoma cells through the anti-proliferation effects of hesperetin, naringenin, and nobiletin on human oral epidermoid carcinoma cells. Tangeretin Both nobiletin and tangeretin ameliorated ROS produc- tion and lipid peroxidation in mutant Saccharomyces cer- evisiae deficient in glutathione synthase, SOD, or CAT (Wang et al., 2018). Similarly, a significant decrease in ROS content, with increase in the activities of SOD, CAT, and GPx through inhibition of NF-κB pathway in rats’ insuli- noma cell line (INS-1) pre-treated with tangeretin (0, 10, or 20 μM) for 12 h was also observed (Liu et al., 2019b). Recent report has elucidated the anti-obesity capacity of tangeretin via inhibition of pancreatic lipase. This com- pound inhibited the enzyme with an IC50 value of 57.31 mg/mL (Zeng et al., 2018). Moreover, tangeretin amelio- rated insulin resistance and increased glucose uptake by attenuating obesity-induced inflammation in adipose tis- sue through reduction of NO production, the expression of IL-6, IL-1β, TNF-α, iNOS, and COX-2 in 3T3-L1 adipo- cytes and macrophage cell line (Shin et al., 2017). Sahnoun et al. (2017) evaluated the inhibitory activities of tangere- tin on carbohydrate metabolism key enzymes. This penta- methoxy flavone showed the IC50 values of 141.0 μM and 14.8 μM against α-amylase and α-glucosidase, respectively. Recently, the neuroprotective effect of tangeretin against cerebral ischemia-reperfusion injury was demonstrated More recently, Kwon and Choi (2020) proposed a possi- ble eriocitrin mechanism of action. In this study, dietary supplementation with eriocitrin (0.005%) in C57BL/6N mice for 16 weeks improved adiposity by increasing adi- pocyte fatty acid oxidation, energy expenditure, mRNA expression of thermogenesis-related genes in brown adipose tissue and skeletal muscle, and decreasing the expression of lipogenesis-related genes in white adi- pose tissue. The supplementation with eriocitrin also decreased hepatic lipogenesis and prevented hyperlipid- emia whereas increased hepatic fatty acid (FA) oxidation and fecal lipid excretion. Moreover, eriocitrin supple- mentation improved insulin resistance, glucose tolerance, and decreased hepatic gluconeogenesis and pro-inflam- matory responses. Previously, Liu et al. (2019a; Patent No. CN109806272A) proposed eriocitrin as potential α-glucosidase inhibitor. Nobiletin Nobiletin is one of the most abundant polymethoxylated flavones. This compound was investigated for its capacity to improve and prevent obesity and metabolic diseases. Recently, the application of nobiletin in preparation treatment of gastric accommodation disorder remedies was reported (Li, 2019; Patent No. CN108619130B). This compound selectively relaxes stomach smooth muscles, promotes the recovery of physiological gastrointestinal motility, and calms stomach upset. As a new therapeutic agent, it has provided and presented great market pros- pects and economic value. Sahnoun et al. (2017) reported the carbohydrate hydro- lyzing enzymes inhibitory activity of nobiletin with the IC50 values of 42.0 μM and 50.0 μM against α-amylase and α-glucosidase, respectively. This flavone was also able to inhibit lipase with an IC50 value of 26.28 mg/mL (Zeng et al., 2018), with IC50 value being better than that those reported for the positive control. In db/db diabetic mice, oral administration of nobiletin (200 mg/kg BW for 10 weeks) significantly attenuated BW gain, decreased fast- ing glucose levels, improved glucose tolerance and insu- lin sensitivity, and diminished serum TG levels (He et al., 2016). Moreover, nobiletin was able to reduce the protein peroxisomal acyl-coenzyme A oxidase 1, carnitine palmi- toyltransferase-1, and ameliorated fatty acids β-oxidation via AMPK (Lone et al., 2018). In addition, treatment with this compound at 10–100 mg/kg BW for 8 weeks in obese mice accelerated lipid catabolism in adipose tissues. Recently, it was found that nobiletin improved cogni- tive deficits and the pathological features of Alzheimer’s disease, such as Aβ pathology, hyperphosphorylation of tau, and oxidative stress (Nakajima and Ohizumi, 2019). In addition, nobiletin ameliorated motor and cognitive deficits in Parkinson’s disease models. Qi et al. (2019) also demonstrated that oral administration of nobiletin 92 Italian Journal of Food Science, 2021; 33 (2) M. Leporini et al. Quercetin Quercetin has been used as a nutritional supplement and may have beneficial effects against a variety of dis- eases. Several in vitro and in vivo studies have evidenced its biological functions. Recently, Doustimotlagh et al. (2020) suggested the ability of quercetin (50 mg/kg/ day for 10 days) to cause a significant decrease in pro- tein carbonyl, hydroxyproline, and to regulate the GPx activity. Therefore, quercetin acted as an enzyme inducer by renewing the glutathione peroxidase activity and inhibiting the oxidation of proteins, and hence decreases ROS production. These results confirmed the positive role of quercetin in attenuating the liver damage and degeneration. Milanezi et al. (2019) analyzed the anti- oxidant activity of quercetin-capped gold nanoparticles. Quercetin-capped gold nanoparticles (IR50 0.37 μg/mL) exhibited greater activity than free quercetin (IR50 0.57 μg/mL) by NO free radical scavenging assay. Similarly, quercetin vesicular formulations (Eudragit- coated liposomes) were capable of ensuring optimal pro- tection against oxidative stress in human intestinal cells by reducing ROS production, as reported by Caddeo et al. (2019). Its antioxidant capacities were correlated to the presence of two antioxidant pharmacophores in the molecule that had optimal configuration for free radical scavenging. The high antioxidant potential of querce- tin was also confirmed in superoxide test with the IC50 values of 0.025 mM versus 0.243 mM, for quercetin and kaempferol, respectively. Increasing in vivo studies have proved that quercetin acted as an antioxidant because of its ability to ameliorate antioxidant defenses, decrease free radical formation, and inhibit xanthine oxidase and lipid peroxidation (Shi et al., 2019). Literatures data show that quercetin was able to reduce glucose levels when it was administered at a minimum dose of 30 mg/kg BW for 14 days (Yang and Kang, 2018). Additionally, this compound potentiated insulin secre- tion induced by glucose and glibenclamide and protected β-cells against oxidative damages (Shi et al., 2019). It was reported recently that the oral administration of quer- cetin (25 and 50 mg/kg) for 28 days remarkably reduced the level of blood glucose, HbA1c, hepatic glycogen, and restored the activity of glucose-6-phosphatase and hex- okinase in diabetic rats (Oyedemi et al., 2019). Eid et al. (2015) proposed the use of quercetin as an anti- diabetic compound, since this flavonoid could act through the stimulation of GLUT4 translocation in the skeletal muscle and the inhibition of glucose-6-phosphatase in hepatocytes. In a human study of 12-week, Lee et al. (2016) used 100 mg/day/subject of quercetin to treat obesity and showed that this compound diminished the total body fat, and decreased the BMI of overweight or obese subjects. In (Yang et al., 2020). This compound downregulated the inflammatory and pro-inflammatory cytokines and oxi- dative stress parameters in the serum and brain tissues of rats with suppression of IL-1β, TNF-α, and IL-6. Lee et al. (2018; Patent No. KR102015221B1) proposed the application of tangeretin for the prevention and treat- ment of post-traumatic stress disorder. This compound showed an excellent anti-anxiety effect, and was conse- quently included in the pharmaceutical composition of foods as an active ingredient. Moreover, tangeretin was an active ingredient for alleviating, preventing, or treat- ing renal fibrosis or cirrhosis of kidney glomerulus or albuminuria (Young-Hee and Min-Kyung, 2018; Patent No. KR101949471B1). Sinensetin The effects of sinensetin on lipid metabolism in mature 3T3-L1 adipocytes without causing cyto- toxicity were reported by Kang et al. (2015). This compound showed anti-adipogenic property by down- regulation of sterol regulatory element-binding pro- tein 1c, and lipolytic property with increase of lipase enzyme. Moreover, sinensetin inhibited insulin-stim- ulated glucose uptake by decreasing the phosphor- ylation of insulin receptor substrate, and increased the phosphorylation of AMPK and acetyl-CoA car- boxylase. It also upregulated mRNA expression of carnitine palmitoyltransferase-1a, suggesting that sinensetin enhances fatty acid β-oxidation through AMPK pathway. In addition, it was found that sin- ensetin quenched the fluorescence of α-glucosidase, and inhibited α-glucosidase and non-enzymatic gly- cation (Liu et al., 2020). Kim et al. (2019b) reported the anti-inflammatory activities of sinensetin on LPS- stimulated L6 skeletal muscle by regulating NF-κB. Recently, the application of sinensetin as an active ingre- dient for preventing, ameliorating, or treating liver can- cer or gastric cancer has been proposed (Kim and Lee, 2018; Patent No. KR20190050535A). Luteolin Sangeetha (2019) reported the antioxidant activity of luteolin and demonstrated how this polymethoxyflavone protects the pancreas and promotes insulin secretion. In addition, luteolin suppressed oxidative damage, lipid peroxidation, and increased antioxidant enzymes such as CAT and SOD (Xu et al., 2019). Antioxidant properties of luteolin are also proved in the central nervous system (CNS). The inhibition of gastric secretion and reduction of pepsin activity by luteolin was reported by Dai and Li (2018; Patent No. CN108309971B). In particular, the preparation includes 3–5 parts of luteolin and 1–2 parts of schisandrin B as active ingredients, and the dosage form of the compound preparation was preferably tab- lets, capsules, injections, and granules. Italian Journal of Food Science, 2021; 33 (2) 93 Citrus species: modern functional food and nutraceutical-based product ingredient levels of TG and VLDL, and increased the level of HDL. Additionally, rutin decreased ROS formation, advanced glycation end-product precursors, and production of inflammatory cytokines. The anti-inflammatory activ- ity of rutin was recently confirmed by Su et al. (2019). Authors evidenced the inhibition of NF-κB pathway and understatement of endoplasmic reticulum stress. Phenolic acids Phenolic acids are a diverse class of phenolic compounds made by plants. They act as agents of plant defense, and are, indeed, immensely important in plant–microbe interactions/symbiosis (Mandal et al., 2010). Chlorogenic acid Chlorogenic acid is an important bioactive dietary poly- phenol. Several studies have reported the ability of chlo- rogenic acid to act in metabolic disease through different mechanisms of action. Recently, use of chlorogenic acid in the treatment of metabolic disorders was proposed (Kodimule, 2018; Patent No. US20190111015A1). Chlorogenic acid supplementation in hypercholesterol- emic rats at a dose of 20 or 90 mg/kg BW for 12 weeks suppressed serum lipid levels, while a dosage of 10 mg/ kg significantly reduced total LDL-cholesterol and increased HDL-cholesterol by upregulating the expres- sion of PPAR-γ gene (Huang et al., 2015). Additionally, administration of chlorogenic acid at a dose of 80 mg/kg BW for 12 weeks decreased percentage of body fat, fast- ing plasma glucose, and HbA1c level via modulation of adiponectin receptor signaling pathways (Jin et al., 2015). Recently, Di Wang et al. (2019) reported that chlorogenic acid (100 mg/kg/day BW) taken for 4 weeks ameliorated the survival rate after myocardial infarction and demon- strated that this compound showed a protective effect on myocardial infarction by reducing inflammatory response, exerting antioxidant activity, and minimizing weight gain. Similarly, chlorogenic acid (100 or 150 mg/ day) reduced oxidative-induced damage and increased antioxidant protection in the inflamed paw skin, and reduced lipid peroxidation in serum (Mitrea et al., 2020). The effect of chlorogenic acid (100 mg/kg BW for 13 weeks) on energy balance in obese mice has been stud- ied recently (He et al., 2020). This compound reduced food intake, increased body temperature, thermal dis- sipation, brown adipose tissue activity, and improved glucose tolerance. The anti-obesity effect of chlorogenic acid was also observed in male Sprague–Dawley rats at a dose of 20 or 90 mg/kg BW for 12 weeks (Huang et al., 2015). Oboh et al. (2015a) evaluated the inhibitory effects of chlorogenic acid on α-amylase and α-glucosidase enzymes. This compound showed the IC50 values of 9.10 μg/mL and 9.24 μg/mL for α-amylase and α-glucosidase, addition, quercetin ameliorated mitochondrial functions in adipose tissue of HFD-induced obese mice by increas- ing the levels of oxidative stress-sensitive transcription factor and antioxidant enzymes (Kobori et al., 2016). Kaempferol The protective effect of kaempferol against oxidative stress in STZ-induced diabetic rats was evaluated by Al-Numair et al. (2015). Kaempferol administration (100 mg/kg BW) to diabetic rats reduced plasma glucose, insulin, and lipid peroxidation products enzymatic such as SOD, CAT, GPX, and GSTs. Another study (Alkhalidy et al., 2018) demonstrated that oral administration of kaempferol (50 mg/kg/day than corresponding human equivalent dose of 240 mg/ day for 60 kg) ameliorated blood glucose control in obese mice as well as reduced hepatic glucose produc- tion and improved insulin sensitivity. Additionally, these authors have found that kaempferol was a direct inhib- itor of pyruvate carboxylase and suppressed glucone- ogenesis in HepG2 cells. Torres-Villarreal et al. (2019) studied the kaempferol effects (60 μM for 21 days) in order to evaluate its lipolytic and anti-adipogenic poten- tial. The results of anti-obesity effects showed that kae- mpferol modulated adipogenic differentiation in 3T3-L1 cells through promoting downregulation of Cebpa gene expression and decreased lipid accumulation in mature adipocytes for its positive effects on Pnpla2 and Lipe mRNA levels. Rutin Rutin is considered a strong antioxidant agent; in fact, it acts as free radical scavenger, metal ions chelator, and reducing agent (Kaurinovic et al., 2019). In STZ-induced diabetic rats, oral administration of 50 or 100 mg/kg BW of this compound decreased fasting blood glucose as well as HbA1c levels. Moreover, chronic administration of 200 mg/kg BW of rutin reduced (30– 40%) the prevalence of diabetes in STZ-treated mice (Ghorbani, 2017). In addition, rutin treatment (50 mg/ kg) for 24 weeks arrested the biochemical disturbances of diabetic retinopathy, lowering vascular endothelial growth factor (VEGF), TNF-α, and increasing TAC in the retina (Gupta et al., 2019). This compound also acted in reducing adiposity, increasing energy expenditure, and improving glucose homeostasis in obese mice (Yuan et al., 2017). The positive effects of rutin on lipid profile was also proved (Wang et al., 2015). Glucose and lipid metabo- lism are strictly correlated. The most important clinical manifestation of this interaction is diabetic dyslipidemia characterized by high level of TG, LDL, and VLDL. Rutin, among its antidiabetic effects, decreased serum 94 Italian Journal of Food Science, 2021; 33 (2) M. Leporini et al. contains Lactobacillus sporogenes (1×107 CFU), 0.1-g inu- lin, and 0.05-g β-carotene. Results showed that this syn- biotic food had favorable effects on homeostatic model assessment of insulin resistance, insulin, TG, VLDL- cholesterol, and TC/HDL-cholesterol ratio, and NO and glutathione levels. Antioxidant immune response, and anti-inflammatory, anti-diabetic, and antitumor activi- ties of β-carotene are also reported (Torregrosa-Crespo et al., 2018). In addition, existence of a positive effect of β-carotene on insulin sensitivity in obese patients through a positive regulation of adiponectin, either directly or via its pro-vitamin, was also suggested (Ben Amara et al., 2015). Lutein (β, ε-carotene-3,30-diol) acted as a powerful antioxidant, prevented HFD-induced atherosclerosis in apoE-deficient mice by inhibiting NADPH oxidase and increasing PPAR-γ gene expression (Han et al., 2015). Additionally, it protects dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- induced apoptotic death and motor dysfunction by ame- liorating mitochondrial disruption and oxidative stress (Nataraj et al., 2016). β-Cryptoxanthin is used as a coloring agent for food products in certain countries. It is associated with the E number, E161C β-Cryptoxanthin, obtained from its common food sources. It exhibits high bioavailability, and β-cryptoxanthin-rich foods might be considered equivalent to β-carotene-rich foods as a source of ret- inol (Burri et al., 2016). Recently, Dhuique-Mayer et al. (2020) suggested that citrus × clementina juice enriched in β-cryptoxanthin (43 μg/g), hesperidin (2,850 μg/g), and pectin (376 mg/100 g) can be used for prevention of MS/T2DM. Moreover, the cancer preventive effects of β-cryptoxanthin have been described (Leoncini et al., 2016). The study included over 6,000 subjects with oral, laryngeal, and pharyngeal cancers. The treatment with β-cryptoxanthin determined a reduction of at least 18% in the rate of oral and pharyngeal cancers and a reduc- tion of 17% in the rate of laryngeal cancer. Lycopene, one of most potent oxygen-quenching reagents among carotenoids, possessed the ability to inhibit the reactions initiated by free radicals, such as peroxy radi- cals or hydroxyl radicals. Indeed, cellular enzymes gluta- thione S-transferase, superoxide dismutase, and quinone reductase were activated by lycopene with consequent protection cells against ROS (Supatra, 2019). Owing to its antioxidant potential, lycopene (a) facilitated cell-to-cell communication at sites called “gap junctions” and conse- quently prevent cancer from developing; (b) stimulated the immune system; (c) regulated the endocrine commu- nication pathways; and (d) regulated the cell reproductive cycle, preventing development of cancer (Supatra, 2019). Caseiro et al. (2020) also reported the ability of lycopene respectively. Additionally, the same authors suggested its antioxidant properties with an IC50 value of 38.83 μg/mL. Caffeic acid The antioxidant protection of caffeic acid and chloro- genic acid against oxidative stress was studied in vivo using BY4741 strain and SOD and glutathione-deficient mutants of S. cerevisiae (Prudêncio et al., 2019). In the cell viability tests, caffeic acid showed higher stress tolerance, with a 106% increase in S. cerevisiae BY4741. However, in the SOD mutant, the effect of chlorogenic acid was stron- ger than caffeic acid, with a 3.3-fold increase. Conversely, in the glutathione-deficient mutant both treatments showed a similar level of protection. Arriagada et al. (2019) proposed the use of a hybrid nano-carrier consist- ing of core-shell silica nano-spheres linked to the surface with caffeic acid. These nano-spheres characterized by a potentiated antioxidant property accept the caffeic acid alone. Gallic acid Gallic acid was able to restore vitamin C and GSH levels in the pancreas of STZ-treated rats (Kahkeshani et  al., 2019). Yang (2018; Patent No. CN108464949A) disclosed a kind of antioxidant lightening compositions and its applications. The antioxidant lightening compositions include element of orange peels (tangeretin) and gallic acid. Carotenoids Carotenoids are a group of natural tetraterpenoid pig- ments distributed widely in plants. They play essential roles: (a) in photosynthesis and photoprotection; (b) as precursors for the biosynthesis of phytohormones; and (c) as signaling molecules to mediate plant development and responses to environmental cues (Sun et al., 2018). In humans, carotenoids were recognized for their bio- logical activities associated with the reduction of risk of developing chronic diseases such as cancer, cardiovascu- lar and neurodegenerative diseases as well as metabolic disease. Additionally, these compounds acted as antioxi- dants and protected the cells against free radicals formed in the tissues. Some of these compounds are vitamin A precursors (Cardoso et al., 2017). β-Carotene (Figure 2) is an intense orange-colored pig- ment used as a food coloring agent (Milne, 2005). In nature, β-carotene is a vitamin A precursor, which is synthesized from carotenoids via the action of enzyme β-carotene 15,150-monooxygenase. The beneficial effects of β-carotene-fortified synbiotic food intake on met- abolic status were studied in T2DM patients (Asemi et al., 2016). The β-carotene-fortified synbiotic food also Italian Journal of Food Science, 2021; 33 (2) 95 Citrus species: modern functional food and nutraceutical-based product ingredient (Figure  3), and D-limonene is the most abundant ele- ment. This monocyclic terpene is consumed by humans as an ingredient of traditional foods and is listed in the Code of Federal Regulations, as Generally Recognized as a Safe (GRAS) and used as a flavoring agent (Roberto et al., 2010). The ameliorative effects of limonene on cadmium-in- duced genotoxicity in cultured human peripheral blood lymphocytes has been demonstrated recently (Verma et al., 2019). In this in vitro study, at concentrations of 20 and 100 Μm, it reduced the sister chromatid exchange frequency and peroxidation of lipids. D-limonene reduced weight gain percentage, TC, LDL, and VLDL, and increased the level of HDL-cholesterol (Khan et al., 2019). In addition, the monoterpene (400 mg/kg) increased the levels of thiobarbituric acid (TBARS), SOD, CAT, and (GSH) in the liver tissue after treatment for 28 days. These results agreed with those reported by Yu et al. (2017); the authors observed how treatment with 50 or 100 mg/kg of D-limonene increased the levels of endogenous antioxidant enzymes. The treatment with limonene (50 mg/kg) dis- played anti-inflammatory activity through decreasing TNF-α, IL-6, and IL-1β levels and increasing the level of IL-10 (De Souza et al., 2019). Additionally, this com- pound determined reduction in gastric ulcer area (93%) and myeloperoxidase activity. Increase in GPx activity was also observed. Limonene has also reported its abil- ity to protect PC12 cells against corticosterone-induced neurotoxicity by activating the AMPK pathway (Tang et al., 2019). In fact, reductions were observed in MDA to protect lipids, proteins, and DNA from oxidative dam- age, and stimulate the modulation of cell growth and the expression of connexin 43, insulin-like growth factor-1 and/or blood levels of insulin-like growth factor-binding proteins, as well as intermediate levels in the immune system and inflammatory processes. In addition, lyco- pene improved insulin sensitivity through inhibition of signal transducer and activator of transcription 3/Srebp- 1c-mediated lipid accumulation and inflammation in mice fed with HFD (Zeng et al., 2017). Terpenes Terpenes are the largest class of natural products applied in industrial sector as flavors, fragrances, and spices as well as used in perfumery and cosmetics.  In plants, these act as defense against biotic and abiotic stresses, or they are treated as signal molecules to attract insects for polli- nation (Singh and Sharma, 2015).  Ameh and Obodozie-Ofoegbu (2016) reported the utili- zation of citrus essential oil as flavorings in carbonated cola and citrus soft drinks. In particular, lemon–lime sodas contain Citrus limon, Citrus aurantifolia, and Citrus aurantium essential oils as main flavorings, while orange sodas contain Citrus aurantium oil as the main flavoring constituent. The chemical variation of each component in citrus essential oil is based on variety, season, and geographical position as well as the ripening phase of the fruit (Bora et al., 2020). The major components are monoterpenes CH3 CH3 CH3 H (a) (b) (c) (d) (e) H2C H Figure 3. Chemical structure of main monoterpenes of citrus essential oils: (a) sabinene, (b) limonene, (c) δ-3-carene, (d) linalool, (e) β-caryophyllene. 96 Italian Journal of Food Science, 2021; 33 (2) M. Leporini et al. and NO levels, NADPH oxidase activity, iNOS, COX-2, IL-6, IL-1β, TNF-α, and expressions of pro-apoptotic proteins. Another monoterpene found particularly abundant in citrus essential oil is sabinene which acts as a potential modulator of bacterial resistance. It could act in syn- ergism with antibiotics to reduce MIC values against bacterial strains of PA03 and SA358 (Matias et al., 2016). Linalool is an acyclic monoterpene tertiary alcohol (Figure 3) and is one of the most investigated aroma com- pounds. Currently, linalool and citral are mainly used as flavoring and natural preservatives due to their anti- microbial and antifungal ability. Indeed, they were used to extend the short shelf-life of seafood products and cheese because of their capacity to reduce populations of microorganisms, especially Enterobacteriaceae (Bora et al., 2020). At a concentrations of 0.1%, linalool exhib- ited antimicrobial activity against different strains such as S. aureus, E. coli, B. subtilis, and Pasteurella multocida, with major activity against Gram-positive bacteria than Gram-negative bacteria. Baldissera et al. (2017) evaluated the effect of β-caryo- phyllene on hypercholesterolemia in rats and the possible effect on hepatic antioxidant enzymes. Administration of β-Caryophyllene at a dose of 1.0 mL/kg for 3 days reduced the levels of TC, LDL-cholesterol, and TG, inhibited the HMG-CoA reductase activity, and increased the antioxidant system of ROS and TBARS lev- els. These results agree with those reported by Basha and Sankaranarayanan (2016), who investigated the effect of β-caryophyllene on hyperglycemia. Oral administration of this compound (200 mg/kg BW) for 45 days reduced the level of glucose and increased the level of insulin, with restored antioxidant status enhancing the activity of CAT, SOD, and GPx as well as inhibition of pro-in- flammatory cytokines, TNF-α and IL-6. It has been recently demonstrated that β-caryophyllene reduced PGE2 and iNOS production and COX-2 expression (Hu et al., 2017). Varga et al. (2018) have successively evi- denced that at a dose of 10 mg/kg BW, this compound improved the chronic and binge alcohol-induced liver injury and inflammation by attenuating the pro-inflam- matory phenotypic “M1” switch of Kupffer cells and diminishing the expression of E-Selectin, P-Selectin, and neutrophil infiltration. Additionally, it ameliorated the hepatic metabolic dysregulation, such as protein hyperacetylation, steatosis, and PPAR-γ – gene signaling. These protective effects were correlated to activation of type-2 cannabinoid receptor. Interaction with this recep- tor causes the expression of vascular cell adhesion mol- ecule-1 mediated by the JAK2/STAT1/IRF-1 pathway (Zhang et al., 2017). Conclusion A critical review of recent studies on the health proper- ties of different portions of citrus fruits and their major bioactive compounds was reported. It was interesting to observe that not only the edible portion but also its by-products are characterized by high biological value. A large number of in vitro and in vivo studies have sug- gested an inverse relationship between increased con- sumption of citrus fruits and lowered risk of chronic diseases correlated to their large contents in polyphe- nols responsible for a wide range of beneficial effects in humans. The extraction of this bioactive compound, its addition to food, and development of nutraceuticals have gained increasing interest. 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