Table 3.
Health benefits of citrus fruit bioactive compounds demonstrated using in vitro experimental models.
| Compounds | Experimental System | Disease Target | Mechanism of Action | Reference |
|---|---|---|---|---|
| Flavanone-rich mandarin juice extract (0.001–1 mg/mL) | 6-hydroxydopamine (6-OHDA)-stimulated SH-SY5Y human neuroblastoma cells |
Parkinson’s disease (PD) | ↓ROS and NO, restored SOD and CAT activity, ↓caspase 3 activity, ↑Bcl-2 mRNA, ↓p53 and Bax mRNA, restored mitochondrial membrane potential, ↓oxidative DNA damage, balanced α-synuclein, LRRK2, parkin, PINK1, and DJ-1 mRNA levels | [88] |
| Flavanones (10 µM) | Caco-2 cells stimulated with IL-1 | Bowel diseases | ↓IL-6, IL-8, and NO release | [83] |
| Hesperetin and gardenin A (5–10 µM) | PMA/ ionomycin-induced EL-4 murine T-lymphoma cell cells |
Asthma | ↓ROS and IL-5 production, ↓NFAT activity and IL-5 secretion, ↑HO-1 through ↑Nrf2, PPARγ, PI3K/AKT, or ERK/JNK signaling | [84] |
| Limonene (1–100 mg/mL) | Aβ1–42 triggered toxicity in primary cortical neurons | Alzheimer’s disease (AD) | ↓AchE, ROS production, voltage-gated K+ channel KV3.4 hyperfunction, and phosphorylated ERK | [87] |
| Limonin, nomilin, and limonexic acid (20–60 µM) | Human pancreatic Panc-28 cells | Cancer (pancreatic) | ↓Cell proliferation (IC50 values < 50 μm after 72 h), ↑cleavage of caspase-3, mitochondrial membrane potential, ↑Bax/Bcl2 expression, and p21, ↓COX-2, NF-κβ, and IL-6 | [90] |
| Limonoids (Fortunellon and nomilin; 30 µM) | HeLa cells | Cancer (Cervical) | ↑Adriamycin-dependent cell death | [89] |
| Naringenin (62.5–2000 µM) | Human A549 lung epithelial cells and primary human monocyte-derived dendritic cells | Zika virus infection | ↓Replication or assembly of viral particles | [100] |
| Naringin- and hesperidin-rich junos peel extract (0.5 mg/mL) | Human lung basal epithelial NCI-H460 cells exposed to H2O2 | Oxidative stress-induced diseases | ↓p53, cytochrome c, and Bax proteins | [80] |
| Pectin oligosaccharides (5 mg/mL) | LPS-stimulated human macrophages | Atherosclerosis | ↑Immune responses, ↓TNF-α, IL-6, IL-10, and NF-κβ mRNA, ↑cholesterol efflux via LXRα and ABCA1, and ABCG1 pathway, ↓cholesterol synthesis via ↓HMGCR |
[85] |
| Phase-II flavanone metabolites (2–100 µM) | Pancreatic β-cell MIN6 cells exposed to cholesterol | Oxidative stress-induced diseases | ↓Oxidative biomarkers (superoxide anion, H2O2, and MDA), ↓SOD and GPx, ↑insulin secretion, ↓apoptosis | [81] |
| PMF nobiletin (10–50 µM) | LPS-stimulated RAW264.7 cells | Inflammatory diseases | ↓Release of NO, ↓expression of iNOS and COX-2, ↑autophagy, activation of the IL-6/STAT3/FOXO3a signal pathway | [32] |
| β-cryptoxanthin from mandarin oranges; IC50—4.5µM (24 h treatment) | HeLa cells | Cancer (cervical) | ↓Bcl-2 mRNA, ↑Bax, caspase-3, -7, and -9 mRNA, nuclear condensation and disruption of the integrity of the mitochondrial membrane, activation of caspase-3 proteins, nuclei DNA damage, and apoptosis |
[101] |
The upregulation and downregulation are denoted by upward (↑) and downward (↓) arrows, respectively. Abbreviations are as follows: ABCA1: adenosine triphosphate-binding cassette transporter subfamily A member 1; ABCG1: adenosine triphosphate-binding cassette transporter subfamily G member 1; AChE: acetylcholinesterase; AKT: protein kinase B; Aβ1–42: amyloid β-protein; Bax: B-cell lymphoma 2 (Bcl-2)-associated X protein; Bcl2: B-cell lymphoma 2; CAT: catalase; COX-2: cyclooxygenase-2; DJ: Parkinson disease protein 1; EPO: eosinophil peroxidase; ERK: extracellular signal-regulated kinases; FOXO3a: Forkhead box O3a; GPx: glutathione peroxidase; H2O2: hydrogen peroxide; HeLa: human cervical cancer cells; HMGCR: 3-hydroxy-3-methylglutaryl-coenzyme A reductase; HO-1: Heme oxygenase-1; IL: Interleukin; iNOS: inducible nitric oxide synthase; JNK: c-Jun N-terminal kinases; LPS: lipopolysaccharide; LRRK2: leucine-rich repeat kinase 2; LXRα: liver X receptor-α; MDA: malondialdehyde; MPO: myeloperoxidase; NFAT: nuclear factor of activated T cells; NF-κβ: nuclear factor-kappa β; NO: nitric oxide; Nrf2: nuclear factor-erythroid 2 related factor 2; PI3K: phosphoinositide 3-kinase; PINK1: phosphatase and tensin homolog (PTEN)-induced putative kinase 1; PMA: phorbol 12-myristate 13-acetate; PMF: polymethoxylated flavone; PPARγ: peroxisome proliferator-activated receptor γ; ROS: reactive oxygen species; SOD: superoxide dismutase; STAT3: signal transducer and activator of transcription 3; TNF-α: tumor necrosis factor α.