Table 1.
Comparison of effective naringenin doses in various disease models.
| Therapeutics | Diseases | Treatment | Targets and Effects | Route | Experimental Model | Ref. |
|---|---|---|---|---|---|---|
| Anti-Hepatitis C virus | Hepatitis C | 2.7 mg/500 mL | Lipid profile and liver enzyme AST (decreased) | p.o. | Adult patients | [25] |
| 200 µM | Inhibition of apolipoprotein B secretion | - | In vitro, Huh7.5.1 human hepatoma cell | [26] | ||
| Antiaging | Aging-associated damage | 4–40 μM | Reduction of senescence markers (X-gal, cell cycle regulator), oxidative stress (radical oxidative species, mitochondrial metabolic activity, mitochondrial calcium buffer capacity, estrogenic signaling functions) | - | In vitro, H9c2 embryonic rat cells | [27] |
| Photoaging | 1–4 MED (45 mJ/cm2) | Anti-photoaging effects by suppression of ERK2 activity and decrease of FRA1 stability, AP-1 transactivation and MMP-1 expression | - | In vitro, HaCaT keratinocyte cell line and the BJ human fibroblast cell | [28] | |
| Senescence process | 50 mg/kg | Promotion of PI3K/Akt signaling, nuclear factor-erythroid 2-related factor 2, heme oxygenase 1, NAD(P)H-quinone oxidoreductase 1 | p.o. | In vivo, mice | [29] | |
| Anti-Alzheimer | Alzheimer | 100 mg/kg | Mitigation of lipid peroxidation and apoptosis, attenuation of impairment of learning and memory | p.o. | In vivo, Wistar rats | [30] |
| Antiasthma | Asthma | 9 mg/100 mL of the prepared fluid | Lowered subepithelial fibrosis, smooth muscle hypertrophy, and lung atelectasis | p.o. | In vivo, BALB/c mice | [31] |
| Anticancer | Breast cancer | 250 µM | Inhibition of HER2-TK activity, anti-proliferative, pro-apoptotic and anti-cancerous activity | - | In vitro, SKBR3 and MDA-MB-231 breast tumor cells | [32] |
| Liver cancer | 100–200 μM | Block in G0/G1 and G2/M phase, accumulation of p53, apoptosis induction by nuclei damage, increased ratio of Bax/Bcl-2, release of cytochrome C, and sequential activation of caspase-3 | p.o. | In vitro, human hepatocellular carcinoma HepG2 cells | [33,34] | |
| Postmenopausal breast cancer | High-fat (HF), high-fat diet with low naringenin (LN; 1% naringenin) or high-fat diet with high naringenin (HN; 3% naringenin) | Inhibition of cell growth, increases phosphorylation of AMP-activated protein kinase, down-regulation of CyclinD1 expression, and induction cell death. In vivo, delay of tumor growth (whereas no alteration of final tumor weight was observed) | p.o. |
In vitro, E0771 mammary tumor cells. In vivo, ovariectomized C57BL/6 mice injected with E0771 cells |
[17] | |
| Prostate cancer | 5–50 μM | Inhibition of proliferation and migration, induction of apoptosis and ROS production. Loss of mitochondrial membrane potential and increased ratio of Bax/Bcl-2 | - | In vitro, PC3 and LNCaP prostate cancer cells | [35] | |
| Melanoma | 25–100 μM | Antiproliferative activity, increase of subG0/G1, S and G2/M phase cell proportion, decrease of cell proportion in G0/G1 phases | - | In vitro, B16F10 melanoma cells | [36] | |
| Gliomas-brain cancer | 211 µM | Cytotoxicity | - | In vitro, human glioblastoma U-118 MG cells | [37] | |
| Breast cancer | 200 mg/kg | Decreased secretion of TGF-β1 and accumulation of intracellular TGF-β1. Inhibition of TGF-β1 transport from the trans-Golgi network, and PKC activity | - | In vivo, Balb/c mice inoculated with breast carcinoma 4T1-Luc2 cells | [38] | |
| Anti-Chikungunya virus | Chikungunya infection | 6.818 µM | Inhibition of CHIKV intracellular replication | - | In vitro, CHIKV infected hamster kidney cells (BHK-21) | [24] |
| Anticonvulsant | Epilepsy | 50–100 mg/kg | Inhibited production of TNFα and IL-1β, delaying the onset of seizures, and inhibiting activation of the mammalian target of rapamycin complex 1 | p.o. | In vivo, male C57BL/6 mice injected with kainic acid | [39] |
| Anti-dengue virus | Dengue | 250 μM | Prevention of infection | - | In vitro, dengue virus infected human-derived Huh7.5 hepatoma cell | [23] |
| Antidiabetic | Diabetic neuropathy | 25–50 mg/kg | Attenuation of diabetic-induced changes in serum glucose, insulin and pro-inflammatory cytokines (TNF-alpha, IL-1beta, and IL-6). Attenuation of oxidative stress biomarkers. Decrease of insulin growth factor and nerve growth factor | p.o. | In vivo, streptozotocin-induced diabetic rats | [40] |
| Diabetic retinopathy | 50 mg/kg | Amelioration of oxidative stress, neurotrophic factors (brain derived neurotrophic factor (BDNF)), tropomyosin related kinase B (TrkB) and synaptophysin), and apoptosis regulatory proteins (Bcl-2, Bax, and caspase-3) | p.o. | In vivo, streptozotocin-induced diabetic rats | [41] | |
| Diabetes | 0.05% | Improved glucose transporters (GLUTs 1, 3), and insulin receptor substrate 1 (IRS 1) levels | p.o. | In vivo, streptozotocin-induced diabetic rats | [42] | |
| Vascular endothelial dysfunction | 50–100 mg/kg | Lowered levels of blood glucose, serum lipid, malonaldehyde, ICAM-1 and insulin resistance index, increased SOD activity and improved impaired glucose tolerance | p.o. | In vivo, streptozotocin-induced diabetic rats | [43] | |
| Diabetic renal impairment | 5–10 mg/kg | Decrease in malondialdehyde levels, and affected superoxide dismutase, catalase and glutathione enzyme activities. Reduction in apoptosis activity, TGF-β1, and IL-1 expression | p.o. | In vivo, streptozotocin-induced diabetic rats | [44] | |
| Diabetes complications | 50 mg/kg | Decreased lipid peroxidation level in liver and kidney tissue | p.o. | In vivo, alloxan-induced diabetic mice | [45] | |
| Anti-Edwardsiellosis | Edwardsiellosis | 200–400 µM | Down-regulation of Edwardsiella tarda infections | - | In vitro, Goldfish scale fibroblast (GAKS) cells | [46] |
| Anti-hyperlipidemic | Alcohol abuse, alcohol intolerance, alcohol dependence and other alcohol related disabilities | 50 mg/kg | Decreased levels of plasma and tissue total cholesterol, triglycerides, free fatty acids, HMG CoA reductase and collagen content | p.o. | In vivo, male Wistar rats | [21] |
| Anti-inflammatory | Arthritic inflammation | 5–20 mg/kg | Down-regulation of TNF-α, and NF-κB mRNA. Increased Nrf-2/HO-1s | p.o. | In vivo, Wistar rats | [47] |
| Cognitive effect-memory impairment | 25–100 mg/kg | Decreased expression of caspase-3, Bad, Bax, NF-κB, tumor necrosis factor-α, interleukin (IL)-6 and IL-1β | p.o. | In vivo, newborn Sprague-Dawley rats | [48] | |
| Endometriosis | 5–100 µM | Antiproliferative and proapoptotic effect (Bax and Bak increased, activated MAPK and inactivated PI3K). Depolarization of mitochondrial membrane potential Activation of eIF2α and IRE1α, GADD153 and GRP78 proteins | - | In vitro, VK2/E6E7, vaginal mucosa derived epithelial endometriosis cells, and End1/E6E7, endocervix epithelial derived endometriotic cells | [49] | |
| Endotoxaemia | 10 mg/kg | Suppression of TNF-α, IL-6, TLR4, inducible NO synthase (iNOS), cyclo-oxygenase-2 (COX2) and NADPH oxidase-2 (NOX2), NF-κB and mitogen-activated protein kinase (MAPK) | p.o. |
In vivo, BALB/c mice In vitro, peritoneal macrophages obtained from the rats |
[50] | |
| Hypertrophic scars (HS) | 25–50 µM | Inhibition of hypertrophic scars. Downregulation of TNF-α, IL-1β, IL-6 and TGF-β1 | p.o. | In vivo, female KM mice | [51] | |
| Liver diseases | 50 mg/kg | Inhibition of oxidative stress, through TGF-β pathway and prevention of the trans-differentiation of hepatic stellate cells (HSC). Pro-apoptotic effect, inhibition of MAPK, TLR, VEGF, and TGF-β, Modulation of lipids and cholesterol synthesis. | p.o. | In vivo | [33] | |
| LPS-induced endotoxemia and Con A–induced hepatitis | 100 μM 50 mg/kg 10 mg/kg |
Post-translational inhibition of TNF-α and IL-6 (no interfering with TLR signaling cascade, cytokine mRNA stability, or protein translation) | - p.o. i.p. |
In vitro, murine macrophage cell line RAW264.7 In vivo, female C57BL/6 mice In vivo, female BALB/c mice |
[52] | |
| Lung injury | 50–100 mg/kg | Down-regulation of nuclear factor-x03BA;B, inducible NO synthase, tumor necrosis factor-α, caspase-3; increased heat shock protein 70 | p.o. | In vivo, rats | [53] | |
| Neuroinflammation-spinal cord injury | 50–100 mg/kg | Repression of miR-223 | p.o. | In vivo, female Wistar rats | [54] | |
| Osteoarthritis | 40 mg/kg | Reduction in pain behavior and improvement in the tissue morphology. Inhibition of MMP-3 expression and NF-κB pathway | p.o. | In vivo, male Wistar rats | [55] | |
| Oxidative stress and lung damage | 100 mg/kg | Reduction of oxidative stress, increase of antioxidant enzymes. Down-regulation of NF-κB, and COX-2 | p.o. | In vivo, Wistar rats | [56] | |
| Pain | 16.7–150 mg/kg | Analgesic effect, through activation of NO−cGMP−PKG−ATP-sensitive potassium channel pathway. Reduction of neutrophil recruitment, tissue oxidative stress, and cytokine production (IL-33, TNF-α, and IL-1β). Downregulation of mRNA expression of gp91phox, cyclooxygenase (COX)-2, and preproendothelin-1. Upregulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) mRNA, and heme oxygenase (HO-1) mRNA expression, and NF-κB | p.o. | In vivo, male Swiss mice | [18,57] | |
| Protective effect on renal failure | 50 mg/Kg | Improvement of renal markers. Decreased lipid profile and inhibition of pro-oxidant and inflammation markers | - | In vivo, rats | [58] | |
| Skin damage-burns | 25–100 mg/kg | Inhibition of TNF-α, IL-1β, IL-6, NO, PGE2, caspase-3, LTB4 and NF-κB levels. Increased SOD, catalase, GPx and GST activities | p.o. | In vivo, male Wistar albino rats | [59] | |
| Antimicrobial | Food-borne Staphylococcus aureus | 0.92–3.68 mM) | Increased bacterial membrane permeability and changed cell morphology | - | In vitro, Staphylococcus aureus ATCC 6538 | [60] |
| Escherichia coli, Staphylococcus aureus, Candida albicans, Alternaria alternata, Fusarium linii, Aspergillus niger | OD in the range of 0–0.49 vs. 1.87 for controls | Antibacterial activity | - | In vitro, Escherichia coli ATCC10536, Staphylococcus aureus DSM799, Candida albicans DSM1386, Alternaria alternata CBS1526, Fusarium linii KB-F1, and Aspergillus niger DSM1957 | [61] | |
| Antioxidant | Skin injury | Pemphigus vulgaris (PV) serum treated HaCaT cell | Down-regulation of Dsg1, Dsg3, E-cadherin, ROS production, amelioration of the drop of mitochondrial membrane potential. Increase of the activity of SOD, GSH-Px and TAC. Decreased of NOD2, RIPK2 and NF-κB p-p65, | - | In vitro, human keratinocyte cell line HaCaT | [62] |
| Antiplatelet | Cardiovascular diseases | - | Antiplatelet activity targeting PAR-1, P2Y12 and COX-1 platelet activation pathways | - | In silico | [63] |
| Anti-stroke damage | Ischaemic stroke | 20–80 µM | Inhibition of apoptosis and oxidative stress, and regulation of the localization of Nrf2 protein | p.o. | In vivo/in vitro, cortical neuron cells isolated from neonatal Sprague-Dawley rats | [64] |
| Cardioprotective | Cardiorenal syndrome | 50 mM; 25–50 mg/kg | Attenuation of cardiac remodeling and cardiac dysfunction, decrease of left ventricle weight (LVW), increase of body weight (BW), decrease of LVW/BW, blood urea, type-B natriuretic peptide, aldosterone, angiotensin (Ang) II, C-reactive protein | p.o. |
In vivo, male Sprague Dawley rats In vitro, cardiac fibroblasts |
[65] |
| Hypoxia/reoxygenation (H/R) injury | 80 µM | Overexpression of Bcl-2, glucose-regulated protein 78, cleaved activating transcription factor 6 (ATF6) and phosphorylation levels of phospho-extracellular regulated protein kinases (PERK). Decrease of caspase-3, and Bax | - | In vitro, rat cardiomyocyte H9c2 cells | [66] | |
| Arterial stiffness in postmenopausal | 210 mg/day | Decreased carotid-femoral pulse wave velocity | p.o. | Patients, healthy postmenopausal women | [67] | |
| Atherosclerosis and coronary heart diseases | 200 µM | Upregulation of SREBP-1a promoter activity | - | In vitro, human hepatoma HepG2 cells | [68] | |
| Chronic kidney disease | Renal fibrosis/ obstructive nephropathy | 50 mg/kg | Inhibition of Smad3 phosphorylation and transcription | p.o. | In vivo, C57BL6 male mice | [69] |
| Expectorant | Sputum symptoms | 100 µM | Increase of CFTR expression, stimulation of chloride anion secretion | apical | In vivo, Sprague-Dawley rats | [70] |
| Eye-protective | Corneal neovascularization | 0.08–80 µg; 8 µL of 0.01–10 g/L solution | Inhibition of alkali burn-induced neutrophil (myeloperoxidase activity and recruitment of Lysm-GFP+ cells) and macrophage (N-acetyl-β-D glycosaminidase activity) recruitment. Inhibition of IL-1β., IL-6 production, Vegf, Pdgf, and Mmp14 mRNA expression | Eye drop | In vivo, male Swiss mice | [71] |
| Fertility | Infertility | 40–80 mg/kg | Attenuation of DNA fragmentation and sperm count during antiretroviral therapy | p.o. | In vivo, male Sprague-Dawley rats | [72] |
| Immunomodulatory | Immunodepression | 5.4–21.6 μg/mL | Increase of B cell proliferation, and NK activity | - | In vitro, spleen mice lymphocytes and peritoneal macrophages obtained from pathogen-free male BALB/c mice | [73] |
| Laxative | Constipation | 75–300 mg/kg | Amelioration of constipation, increased c-Kit, SCF, and aquaporin 3 | p.o. | In vivo, ICR mice | [15] |
| Hepatoprotective | Alcoholic liver disease/steatosis | 2.5–10 mg/kg | Reduction of alcohol-related gene expression (cyp2y3, cyp3a65, hmgcra, hmgcrb, fasn, fabp10α, fads2 and echs1) | - | In vivo, zebrafish larvae | [74] |
| Hepatitis B virus protein X (HBx)-induced hepatic steatosis | 30 mg/kg | Down-regulation of SREBP1c, LXRα, and PPARγ genes | p.o. |
In vivo, HBx-transgenic C57BL/6 mice In vitro, HBx-transfected human hepatoma HepG2 cells |
[75] | |
| Pregnancy | Migration mechanism(s) of peri-implantation conceptuses | 20 µM | Stimulation of pTr cells migration, through PI3K/AKT and ERK1/2 MAPK signaling pathways | - | In vitro, porcine trophectoderm (pTr) cells | [76] |
| Radioprotective | Radiation-induced DNA, chromosomal and membrane damage. | 50 mg/kg | Inhibition of NF-kB pathway, apoptotic proteins: p53, Bax, Bcl-2 | p.o. | In vivo, Swiss albino mice | [77] |
| Weight loss | Obesity: Muscle loss and metabolic syndrome in postmenopausal women. | 3% naringenin diet | Down-regulation of genes involved in de novo lipogenesis, lipolysis and triglyceride synthesis/storage | p.o. | In vivo, C57BL/6J mice | [78] |
MED, minimal erythema dose.