Table 4.
Health benefits of citrus fruit bioactive compounds demonstrated using the animal models.
| Bioactive and Doses | Experimental System | Disease Target | Mechanism of Action | Reference |
|---|---|---|---|---|
| Auraptene (50 mg/kg), naringin (50 mg/kg) for 14 days | STZ-induced hyperglycemia in C57BL/6 mice | Alzheimer’s disease (AD) | ↓Tau hyperphosphorylation, astroglial activation, and ↑neurogenesis in the hippocampus | [108] |
| Citrus concentrate containing 0.086 mg β-cryptoxanthin, 5.69 mg hesperidin, and 7.5 mg pectin for 8 weeks | Wistar male rats fed with high-fructose diet | Metabolic syndrome (type 2 diabetes) | ↓Plasma glucose, glycemia, insulinemia, and LDL-C, VLDL-C, and TG levels, ↑liver retinyl palmitate, and plasma β-cryptoxanthin | [103] |
| Coumarin (auraptene, 7.5–30 mg/kg for three days a week for total of 8 weeks) | TAA-induced hepatic fibrosis in male C57BL/6 mice | Hepatic fibrosis (cirrhosis and liver cancer) | ↓Bile acids in liver by increasing their efflux, ↓activation of HSCs by suppressing the expression of TGF-β1 and -SMAα and ↓expression of NF-κB, TNF-α, and IL-1β |
[116] |
| Coumarin auraptene (5–20 mg/kg) | 17α-Ethinylestradiol (synthetic estrogen) induced cholestasis in male C57BL/6 mice | Estrogen-induced cholestasis | ↑Bile acid transporters (Bsep and Mrp2) mRNA and proteins, ↑Shp and Fgf15, FXR, ↑bile acid metabolism, ↑SULT2A1, ↓Cyp7a1 and Cyp8b1 mRNA, ↓hepatic inflammation (↓TNF-α, IL-1β, and IL-6) | [117] |
| Essential oil (0.75% of the diet for 42 weeks) | Male SD rats fed with HFD | Metabolic syndrome (hyperlipidemia) | ↓TC, LDL-C, hepatic TC, TG, and hepatic lipid droplet accumulation, ↓liver FFAs, TG, and CE | [102] |
| Essential oil (limonene; daily inhalation for 1.5 and 24 h, for five days) | CUMS male Kunming mice mouse model | Depression | ↑Curiosity, body weight, sucrose preference, 5-HT, DA, NE, BNDF, TrkB, GR, ↓CRF, CORT | [106] |
| Flavanone aglycones rich ougan (cv. Suavissima) juice (20 mL/kg for 10 weeks) | HFD-fed C57BL/6J mice | Metabolic syndrome (obesity) | ↓Weight gain, ↓fat accumulation, ↓liver steatosis, ↑glucose homeostasis and insulin sensitivity, ↑BAT activity, and ↑WAT browning, ↑diversity of gut microbiota | [109] |
| Flavanones (eriocitrin and eriodictyol), 25 and 50 mg/kg | BALB/c mice with LPS-induced periodontal disease | Periodontitis | ↓Gingival IL-1β and TNF-α, ↑IL-10, ↓MPO and EPO activity, SOD, ↑CAT and GPx activities, ↓MDA | [118] |
| Flavanones (naringin, naringenin, hesperidin, and hesperetin; 100 mg/kg/day for 16 weeks) | ApoE−/− mice | Atherosclerosis | ↑Bile acid synthesis (naringin), ↑cholesterol reverse transport (hesperidin), ↓cholesterol synthesis (naringenin and hesperetin) |
[33] |
| Flavonoid-rich bitter/sour orange fruit peel extract (125–500 mg/kg for 3 days) | TNBS-induced IBD in male Sprague/Dawley (SD) rats | IBD | ↓Weight loss and diarrhea, colitis inflammatory cell infiltration, and proinflammatory cytokines (TNF-α, iNOS, COX-2), ↓serum and colon NO and MPO activity | [119] |
| Hesperetin (40 mg/kg for 45 days) | STZ-induced diabetes in male albino Wistar strain rats | Diabetes | ↓Plasma glucose, ↑plasma insulin and glycogen, ↑antioxidant system (↑SOD, CAT, GPx), ↑insulin secretion by renovating pancreatic β-cells, ↓dyslipidemia (hepatic cholesterol, FFAs, TG, and PLs), ↓serum levels of ALT, AST, and ALP, ↓renal damage (serum urea, creatinine, and uric acid) | [104] |
| Hesperetin (50 mg/kg daily for five weeks) | LPS-induced neuroinflammation C57BL/6 N mice | Alzheimer’s disease (AD) and Parkinson’s disease (PD) | ↓Inflammatory mediators (phosphorylated-NF-κβ, TNF-α, and IL-1), ROS/lipid peroxidation, ↑antioxidant protein (Nrf2 and HO-1), ↓phosphorylated-JNK, Bax, and caspase-3 protein, ↑Bcl-2, ↑synaptic integrity, cognition, and memory processes, ↑ phosphorylated-CREB, PSD-95, and Syntaxin | [107] |
| Hesperetin (50 mg/kg/day for 46 days) | STZ-induced diabetes in male Wistar rats | Diabetes-associated testicular injury | ↓Body weight loss, ↓ serum glucose, ↓MDA, ROS, protein carbonyl, DNA fragmentation, and caspase 3 activity, ↑testicular antioxidant system (↑GSH, MMP, FRAP, SOD, CAT, GPx) | [120] |
| Hesperidin (100 mg/kg for eight weeks) | Male SD rats fed an obesogenic cafeteria diet | Metabolic syndrome (obesity) | ↓TC, LDL-C, FFAs, MCP-1 | [121] |
| Limonene-rich essential oil (0.0765 mL/kg for 7 days) | SD rats with estradiol benzoate and oxytocin-induced uterine contraction | Primary dysmenorrhea (PD) | ↑Antioxidant status markers (SOD,T-AOC, CAT, and GSH), ↓MDA and iNOS, and PGF2α/PGE2 | [105] |
| Naringin- and hesperidin-rich C. junos peel extract (200 mg/kg/day, 10 days | Acrolein-induced pulmonary apoptosis in male C57BL/6J mice | Pulmonary edema and COPD | ↓Cleaved caspase 3, cleaved PARP, Bax and PUMA, p53, Prx-SO3 | [80] |
| Pectin oligosaccharides (0.15–0.9 g/kg for 30 days) | Male C57BL/6 mice fed with HFD | Metabolic syndrome | ↓Serum TC, LDL-C, ↓Firmicutes ↑Bacteroidetes
↑SCFAs (acetate, propionate, and butyrate) |
[122] |
| PMF (nobilitin, tangeritin)-rich extract (30–120 mg/kg) | C57BL/6J male mice fed with HFD | Metabolic syndrome | ↓Firmicutes-to-Bacteroidetes ratio, ↓serum BCAA, ↓mTORC1 and P70S6K activation, ↓SREBPs | [35] |
| PMF (nobilitin, tangeritin, and 5-OH nobiletin)-rich aged chenpi peel extract (0.25 and 0.5% of diet weight for 11 weeks) | Male C57BL/6J mice fed with HFD | Metabolic syndrome (obesity) | ↑Fecal SCFAs (acetic acid and propionic acid), ↑healthy gut microbiota | [34] |
| PMF 5-Demethylnobiletin (12 mg per kg) | Azoxymethane/DSS-driven colorectal carcinogenesis in male CD-1 mice | Cancer (colorectal) | ↓Cell proliferation, ↑apoptosis, and ↓mRNA and protein levels of IL-1β, IL-6, and TNF-α in the colon | [36] |
| PMF- and HOPMF-rich extract (0.5% of HFD for 16 weeks) | Male C57BL/6 mice fed with HFD | Metabolic syndrome (obesity) | ↓Adipocyte size, adipose tissue weight, and alleviated the total body weight, levels of lipid droplets, and perilipin 1 protein and SREBP-1 expression, ↑gut microbiota Prevotella, ↓rc4–4 bacteria |
[111] |
The upregulation and downregulation are denoted by upward (↑) and downward (↓) arrows, respectively. Abbreviations are as follows: 5-HT: 5-hydroxytryptamine; ALP: alkaline phosphatase; ApoE: apolipoprotein E; AST: aspartate aminotransferase; BAT: brown adipose tissue; Bax: B-cell lymphoma 2 (Bcl-2)-associated X protein; BCAA: branched-chain amino acid; Bcl-2: B-cell lymphoma 2; BNDF: brain-derived neurotrophic factor; Bsep: bile salt export pump; CAT: catalase; CE: cholesterol esters; COPD: obstructive pulmonary disease; CORT: corticosterone; COX-2: cyclooxygenase-2; CREB: cAMP response element-binding protein; CRF: corticotropin-releasing factor (CRF); CUMS: chronic unpredictable mild stress; Cyp7a1: cholesterol 7α-hydroxylase; Cyp8b1: sterol-12α-hydroxylase; DA: dopamine; DSS: dextran sulfate sodium; FFA: free fatty acids; FFAs: free fatty acids; Fgf15: fibroblast growth factor 15; FRAP: ferric reducing antioxidant; FXR: farnesoid X receptor; GPx: glutathione peroxidase; GR: glucocorticoid receptor; GSH: glutathione; HFD: high-fat diet;.HO-1: Heme oxygenase; HOPMFs: hydroxy polymethoxyflavones; HSCs hepatic stellate cells; HSCs: hepatic stellate cells; IBD: inflammatory bowel disease; IL: Interleukin; iNOS: inducible nitric oxide synthase; JNK: c-Jun N-terminal kinases; LDL-C: low-density lipoprotein cholesterol (LDL-c); LPS: lipopolysaccharide; MCP-1: monocyte chemoattractant protein 1; MDA: malondialdehyde; MMP: mitochondrial membrane potential; MPO: myeloperoxidase; Mrp2: multidrug-resistance-related protein 2; mTOR: mammalian target of rapamycin; mTORC1: mammalian target of rapamycin (mTOR) complex1; NE: norepinephrine; NF-κβ: nuclear factor-kappa β; NO: nitric oxide; Nrf2: nuclear factor-erythroid 2 related factor 2; P70S6K: phospho-p70 S6 kinase; PARP: poly (ADP-ribose) polymerase; PGE2: prostaglandin E2; PGF2α: prostaglandin F2α;.PLs: phospholipids; PMF: polymethoxyflavones; Prx-SO3: oxidized peroxiredoxin; PSD-95: postsynaptic density protein-95; PUMA: p53 upregulated modulator of apoptosis; ROS: reactive oxygen species; SCFAs: short-chain fatty acids; SD: Sprague Dawley; Shp: small heterodimer partner; SMAα: α-smooth muscle actin; SOD: superoxide dismutase; SREBP-1Sterol regulatory element-binding protein 1; STZ: streptozotocin;SULT2A1: sulfotransferase family 2a member 1; TAA: thioacetamide; T-AOC: total antioxidant capacity; TC: total cholesterol; TG: triglyceride and hepatic lipid droplet accumulation; TGF-β1: transforming growth factor-β1; TNBS: trinitrobenzene sulfonic acid; TNF-α: tumor necrosis factor α; TrkB: tropomyosin receptor kinase B; VLDL-C: very-low-density lipoprotein-cholesterol; WAT: white adipose tissue.