[go: up one dir, main page]
More Web Proxy on the site http://driver.im/ Skip to main content
PMC home page
Pharmaceuticals logoLink to Pharmaceuticals
. 2019 Jan 10;12(1):11. doi: 10.3390/ph12010011

The Therapeutic Potential of Naringenin: A Review of Clinical Trials

Bahare Salehi 1, Patrick Valere Tsouh Fokou 2, Mehdi Sharifi-Rad 3,*, Paolo Zucca 4,*, Raffaele Pezzani 5,6,*, Natália Martins 7,8,*, Javad Sharifi-Rad 9,10,*
PMCID: PMC6469163  PMID: 30634637

Abstract

Naringenin is a flavonoid belonging to flavanones subclass. It is widely distributed in several Citrus fruits, bergamot, tomatoes and other fruits, being also found in its glycosides form (mainly naringin). Several biological activities have been ascribed to this phytochemical, among them antioxidant, antitumor, antiviral, antibacterial, anti-inflammatory, antiadipogenic and cardioprotective effects. Nonetheless, most of the data reported have been obtained from in vitro or in vivo studies. Although some clinical studies have also been performed, the main focus is on naringenin bioavailability and cardioprotective action. In addition, these studies were done in compromised patients (i.e., hypercholesterolemic and overweight), with a dosage ranging between 600 and 800 μM/day, whereas the effect on healthy volunteers is still debatable. In fact, naringenin ability to improve endothelial function has been well-established. Indeed, the currently available data are very promising, but further research on pharmacokinetic and pharmacodynamic aspects is encouraged to improve both available production and delivery methods and to achieve feasible naringenin-based clinical formulations.

Keywords: nutraceutics, phytochemicals, chemopreventive, cardiovascular diseases, flavonoids, citrus, flavanones

1. Introduction

Naringenin is one of the most important naturally-occurring flavonoid, predominantly found in some edible fruits, like Citrus species and tomatoes [1,2,3], and figs belonging to smyrna-type Ficus carica [4]. Chemically named as 2,3-dihydro-5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one (Figure 1), naringenin shows a molecular weight of 272.26 (C15H12O5).

Figure 1.

Figure 1

Open in a new tab

Naringenin biosynthesis.

This widely distributed molecule is insoluble in water and soluble in organic solvents, like alcohol. Within the flavonoids class, naringenin is a flavanone that derives from naringin or narirutin (its glycone precursor) hydrolysis [5]. In fact, naringenin occupies a central position as primary C15 intermediate in the flavonoid biosynthesis pathway [6]. Naringenin biosynthesis has been investigated in Medicago, parsley and other plants. Overall, the metabolic pathway constitutes of a six step process, successively catalyzed by phenylalanine ammonia lyase (PAL), cinnamate 4-hydroxylase and its associated cytochrome P450 reductase, para-coumarate-CoA ligase, chalcone synthase (the key enzyme for the synthesis of naringenin) and chalcone isomerase [7]. Of note, naringenin is obtained by the condensation of para-coumaroyl-CoA with three units of malonyl-CoA. In addition, naringenin biosynthesis starter unit is para-coumaroyl-CoA, which in dicotyledonous plants derives from phenylalanine upon PAL deamination. The latter is thereafter hydroxylated at C4 by a cinnamate-4-hydroxylase and activated by a CoA-dependent ligase, through the universal phenylpropanoid pathway leading to flavonoids and stilbenes [8]. Moreover, monocotyledonous plants may also use tyrosine as substrate, directly producing p-coumaric acid without the need of cinnamate-4-hydroxylase enzyme activity [9,10].

To overcome the limited flavonoids production, in general, and naringenin, in particular, many attempts have been made to produce naringenin from metabolic engineering of specific pathways in microbial systems, such as Escherichia coli and Saccharomyces cerevisiae [7,10,11,12,13,14]. The highest naringenin titers obtained through biotransformation were reached using E. coli [7]. In addition, S. cerevisiae engineered to produce naringenin, solely from glucose using specific naringenin biosynthesis genes from Arabidopsis thaliana, led to flux optimization towards the naringenin pathway, providing a metabolic chassis for large amounts of naringenin production and biological functions exploration [7,11]. Growing evidence from both in vitro and in vivo animal studies have reinforced various naringenin pharmacological effects, including as hepatoprotective, anti-atherogenic, anti-inflammatory, anti-mutagenic, anticancer, antimicrobial agent, even suggesting its application in cardiovascular, gastrointestinal, neurological, metabolic, rheumatological, infectious and malignant diseases control and management [15,16,17,18]. Based on these aspects, the present review has a specific focus on clinical trials assessing naringenin consumptions’ health benefits, whereas the reported reviews are more related to other aspects (in vitro studies, over-production approaches, or specifically on oxidative stress only).

2. Preclinical Pharmacological Activities of Naringenin

Naringenin is endowed with broad biological effects on human health (Table 1), which includes a decrease in lipid peroxidation biomarkers and protein carbonylation, promotes carbohydrate metabolism, increases antioxidant defenses, scavenges reactive oxygen species, modulates immune system activity, and also exerts anti-atherogenic and anti-inflammatory effects [19,20]. It has also been reported to have a great ability to modulate signaling pathways related to fatty acids metabolism, which favors fatty acids oxidation, impairs lipid accumulation in liver and thereby prevents fatty liver [3], besides efficiently impairing plasma lipids and lipoproteins accumulation [21]. In addition, naringenin potentiates intracellular signaling responses to low insulin doses by sensitizing hepatocytes to insulin [19], besides being able to traverse the blood–brain barrier and to exert diverse neuronal effects, through its ability to interact with protein kinase C signaling pathways [19].

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]
Open in a new tab

MED, minimal erythema dose.

On the other hand, anti-cancer, anti-proliferative and anticarcinogenic effects have also been ascribed to this metabolite [22], mostly linked to its ability to repair DNA. In fact, cells exposition to 80 mM/L naringenin, during 24 h, led to 24% DNA hydroxyl damages reduction [20]. Moreover, antiviral effects have been reported. Naringenin shows a dose-dependent inhibitory effect against dengue virus [23], prevents intracellular replication of chikungunya virus [24], and inhibits assembly and long-term production of infectious hepatitis C virus particles in a dose-dependent manner [19]. Unfortunately, this bioflavonoid is poorly absorbed by oral ingestion, with only 15% of ingested naringenin absorbed in the human gastrointestinal tract [20], which has triggered several studies on its bioavailability.

3. Bioavailability of Naringenin

Naringenin bioavailability has been properly studied in previous works, suggesting an extensive pre-systemic gut flora metabolism, leading to a wide pattern of degradation products (i.e., phenolic acids) [79,80]. In a recent study, ultra-fast liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry (UFLC-Q-TOF-MS/MS) was used to assess the urinary excretion of flavonoids in Chinese 23–30 years old volunteers, after 250 mL orange juice consumption (containing 31 μM naringenin). An overall 22% recovery was detected in 4 to 12 h, evidencing a phase II metabolism (especially sulfation and glucuronidation) of the aglycone after intestinal hydrolysis [81].

Bioavailability training effect was also investigated in male endurance athletes (clinicaltrails.gov NCT02627547) [82]. In this trial, 500 mL of orange juice (containing 76 μM naringenin) was ingested before and after 7 days of physical training cessation, and the urinary excretion of phenolic metabolites analyzed. As main findings, the authors stated that the bioavailability in endurance athletes was lower when compared with less trained individuals. However, short activity cessation slightly enhanced metabolites excretion [82]. In the same line, it was also shown that the urinary metabolites excretion does not differ after fresh oranges or pasteurized orange juice consumption, even if the latter contains about half of total flavanones amount [83].

Naringenin and hesperidin bioavailability were also investigated (trial NCT03032861) to deepen knowledge on orange juice prebiotic effect [84]. In this study, a marked increase in short-chain fatty acids and commensal bacteria were stated, with a concomitant decrease in ammonium levels, even in face of a decrease in total bacteria richness values.

4. Naringenin in Clinical Trials

Although there is a huge amount of data on in vitro biological effects of naringenin [85], only few clinical studies have been carried out [16], mainly because of the reduced data on pharmacokinetic aspects, metabolic fate and chemical instability of this compound [86]. Moreover, high isolation and purification costs further affect clinical trials feasibility.

Up to now, only 10 clinical studies were registered at clinicaltrials.gov database using “naringenin” or “naringin” (its glycoside) as keywords. Curiously, only one of these studies (NCT03582553, early phase I, still on recruiting) focused on naringenin administration isolated from Citrus sinensis extract (ranging from 150 to 900 mg). The main goal of this study was to check naringenin safety, tolerability and bioavailability, besides its effects on glucose metabolism. Data provided suggest how naringenin pharmacokinetics are still needing further investigation. Indeed, some of these studies investigated naringenin as a complex food supplement (i.e., whole orange juice), constituted by several polyphenols (including obviously naringenin), making difficult to assess the single phytochemicals contribution.

4.1. Role of Naringenin in Cardiovascular Diseases

The role of flavanones (including naringenin) on cardiovascular diseases has been well-studied [87], although most of the data have been collected in epidemiological and prospective studies. An inverse correlation has been stated between high flavanones consumption and cardiovascular risk [88,89,90,91], being a beneficial effect particularly related to naringenin consumption, given its great abundance in the tested samples [91]. In fact, most of the clinical studies have been carried out using naringin (a naringenin glycoside).

In a double-blind cross-over study, 12 patients with stage I hypertension received alternatively 500 mL/day of a fruit juice containing 593 μM naringin or a juice with lower content (143 μM naringin) for 5 weeks. Systolic blood pressure decreased in both groups, but no significant differences were found, while diastolic blood pressure was more effectively reduced in high-dose naringin group [92].

Dyslipidemic patients treated with a commercial bergamot-derived extract (containing about 95 μM naringin/capsule) evidenced plasmatic lipids reduction, while improved lipoprotein profile after 6 months [93]. The same glycoside was also able to decrease total plasma cholesterol levels and to enhance antioxidant defenses in hypercholesterolemic subjects [94]. Jung and colleagues prescribed 400 mg naringin/capsule/day, and after 8 weeks they also reported a decrease in LDL-cholesterol levels and an increase in some antioxidant enzymes activity (i.e., superoxide dismutase and catalase). A somewhat similar result was obtained in 237 hyperlipemic volunteers during a 30-day program, using a bergamot extract containing several flavonoids (including naringin). This plant extract preparation was able to decrease triglycerides, total and LDL cholesterol levels [95]. Quite surprisingly, in the study of Jung and colleagues, phytochemicals supplementation did not affect cholesterol levels in the healthy control group [94], but differently, in a randomized placebo-controlled trial including 194 moderately hypercholesterolemic patients [96], a daily dose of 1300 μM pure hesperidin or 862 μM pure naringin over 4 weeks, did not affect total or LDL cholesterol levels, this last result being in contrast to the work of Jung and collaborators. In fact, the authors suggested that the mean baseline LDL-cholesterol concentration in their study could not have contributed to the absence of LDL cholesterol effects and concluded that naringin (and hesperidin) did not have cholesterol-lowering effects when consumed as capsules. Certainly, this divergence should be further deepened; however, it appears that naringenin or naringin beneficial effects are closely related to patients with increased cardiovascular risk.

On the other hand, a clinical trial (NCT00539916) analyzed the effect of 600 mL/day orange juice consumption on 25 mild hypercholesterolemic male volunteers for 4 weeks [97]. The authors found some improvements in antioxidant profile and a tendency towards endothelial dysfunction decrease and slight increase in plasma apolipoprotein A-1 concentration. Similar results were also stated using whole orange juice in patients under hepatitis C antiviral therapy: Increase in antioxidant defenses, and decrease in inflammation and blood serum cholesterol levels [25]. The same research group achieved analogous effects on healthy volunteers, highlighting marked improvements in LDL-cholesterol and apolipoprotein B levels, and metabolic syndrome risk markers [98]. Another clinical trial (NCT03527277), although still in recruiting phase, is focused on whole orange juice effects in cardiovascular diseases- and type-2 diabetes-related metabolic markers, to be compared with sugar-sweetened beverages.

4.2. Role of Naringenin in Endothelial Function

Flow-mediated dilatation (FMD) of brachial artery at 0 to 7 h was used to assess the effect of 240 mL of orange flavanone beverages (about 15 mg naringenin) in a clinical trial involving 30–65 years healthy men [99]. Postprandial endothelial dysfunction was reduced, probably through a specific flavanone’s metabolites action on nitric oxide. Additionally, in a very interesting trial (NCT01272167), the long-term effect of 340 mL of grapefruit juice/day, containing about 480 μM naringenin glycoside, was investigated on endothelial function [67]. From the 48 healthy menopausal women recruited, arterial stiffness beneficial effects were found 6 months after treatment (carotid-femoral pulse wave velocity was significantly reduced).

4.3. Role of Naringenin in Weight Control

A commercial polyphenolic extract from several Citrus fruits (Sinetrol-XPur), containing about 20% of naringenin, was tested in 95 healthy overweight volunteers (BMI ranging from 26 to 29.9 kg/m2) [100]. The main overweight-related endpoints were improved after 12-weeks randomized protocol (including waist and hip circumference, abdominal fat, body weight). Moreover, inflammatory and oxidative stress markers were all decreased [100].

Stohs and coworkers also reported the naringin use as an adjuvant (600 mg) in weight management due to the well-known thermogenic effect of Citrus aurantium (bitter orange) extract (whose main active chemical compound is protoalkaloid p-synephrine) [101]. This double-blinded, randomized, placebo-controlled clinical trial (NCT01423019), involving 10 subjects per treatment group, showed that naringin is able to synergistically increase metabolic rate, without enhancing blood pressure and heart rates.

4.4. Role of Naringenin as Anti-HCV Activity

Naringenin has also been proposed as a novel therapeutic agent for hepatitis C virus (HCV) infection treatment. Indeed, this flavanone has been described to reduce HCV secretion in infected cells by 80%, at a concentration below to the toxic value in primary human hepatocytes and in mice [26]. Accordingly, in a phase I clinical trial already registered, 1 g naringenin supplementation (NCT01091077) was applied to examine its ability to hinder HCV infection and on very-low-density lipoproteins (vLDL) secretion lowering (usually acting as HCV carrier). Nevertheless, up to now, no published results are available. Based on the above described data, it emerges that, as no study has investigated naringenin chemopreventive potential on human cancer so far, this issue could be exploited in the near future.

However, might act by interfering with bioassays through several mechanisms and are termed Pan Assay INterference compoundS (PAINS) [102,103], which may affect the obtained bioassays results’ credibility and, thus, should be carefully analyzed [104].

5. Conclusions

Despite the huge amount of data on naringenin in vitro biological effects, few studies are available on its use as a therapeutic molecule. However, some specific effects were established under pure compounds supplementation, as well as in several studies using complex polyphenolic mixtures containing naringenin. The most promising activity seems to be related to cardiovascular disease protection, especially in already compromised patients. Nevertheless, these few data should be urgently expanded to better understand the naringenin mechanism of action on pathological or physiological conditions. However, a scarce number of clinical studies have been conducted so far, compromising its commercial exploitation. Further clinical studies are needed to better address naringenin safety, efficacy, delivery and bioavailability in humans.

Acknowledgments

N.M. would like to thank the Portuguese Foundation for Science and Technology (FCT–Portugal) for the Strategic project ref. UID/BIM/04293/2013 and “NORTE2020—Programa Operacional Regional do Norte” (NORTE-01-0145-FEDER-000012).

Author Contributions

All authors contributed equally to this work. B.S., P.Z., R.P., N.M. and J.S.-R. critically reviewed the manuscript. All the authors read and approved the final manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  • 1.Mbaveng A.T., Zhao Q., Kuete V. Toxicological Survey of African Medicinal Plants. Elsevier; New York, NY, USA: 2014. Chapter 20—Harmful and protective effects of phenolic compounds from African medicinal plants; pp. 577–609. [Google Scholar]
  • 2.Jadeja R.N., Devkar R.V. Polyphenols in Human Health and Disease. Academic Press; San Diego, CA, USA: 2014. Polyphenols and flavonoids in controlling non-alcoholic steatohepatitis; pp. 615–623. [Google Scholar]
  • 3.Zobeiri M., Belwal T., Parvizi F., Naseri R., Farzaei M.H., Nabavi S.F., Sureda A., Nabavi S.M. Naringenin and its nano-formulations for fatty liver: Cellular modes of action and clinical perspective. Curr. Pharm. Biotechnol. 2018;19:196–205. doi: 10.2174/1389201019666180514170122. [DOI] [PubMed] [Google Scholar]
  • 4.Soltana H., De Rosso M., Lazreg H., Vedova A.D., Hammami M., Flamini R. LC-QTOF characterization of non-anthocyanic flavonoids in four Tunisian fig varieties. J. Mass Spectrom. JMS. 2018;53:817–823. doi: 10.1002/jms.4209. [DOI] [PubMed] [Google Scholar]
  • 5.Wilcox L.J., Borradaile N.M., Huff M.W. Antiatherogenic properties of naringenin, a citrus flavonoid. Cardiovasc. Drug Rev. 1999;17:160–178. doi: 10.1111/j.1527-3466.1999.tb00011.x. [DOI] [Google Scholar]
  • 6.De Souza Bido G., de Lourdes Lucio Ferrarese M., Marchiosi R., Ferrarese-Filho O. Naringenin inhibits the growth and stimulates the lignification of soybean root. Braz. Arch. Biol. Technol. 2010;53:533–542. doi: 10.1590/S1516-89132010000300005. [DOI] [Google Scholar]
  • 7.Koopman F., Beekwilder J., Crimi B., van Houwelingen A., Hall R.D., Bosch D., van Maris A.J., Pronk J.T., Daran J.M. De novo production of the flavonoid naringenin in engineered saccharomyces cerevisiae. Microb. Cell Fact. 2012;11:155. doi: 10.1186/1475-2859-11-155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Jeandet P., Sobarzo-Sánchez E., Clément C., Nabavi S., Habtemariam S., Nabavi S., Cordelier S. Engineering stilbene metabolic pathways in microbial cells. Biotechnol. Adv. 2018;36:2264. doi: 10.1016/j.biotechadv.2018.11.002. [DOI] [PubMed] [Google Scholar]
  • 9.Alvarez-Alvarez R., Botas A., Albillos S.M., Rumbero A., Martin J.F., Liras P. Molecular genetics of naringenin biosynthesis, a typical plant secondary metabolite produced by Streptomyces clavuligerus. Microb. Cell Fact. 2015;14:178. doi: 10.1186/s12934-015-0373-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Eichenberger M., Lehka B.J., Folly C., Fischer D., Martens S., Simon E., Naesby M. Metabolic engineering of saccharomyces cerevisiae for de novo production of dihydrochalcones with known antioxidant, antidiabetic, and sweet tasting properties. Metab. Eng. 2017;39:80–89. doi: 10.1016/j.ymben.2016.10.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Wu J., Zhou T., Du G., Zhou J., Chen J. Modular optimization of heterologous pathways for de novo synthesis of (2S)-naringenin in Escherichia coli. PLoS ONE. 2014;9:e101492. doi: 10.1371/journal.pone.0101492. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Pandey R., Parajuli P., Koffas M., Sohng J. Microbial production of natural and non-natural flavonoids: Pathway engineering, directed evolution and systems/synthetic biology. Biotechnol. Adv. 2016;34:634. doi: 10.1016/j.biotechadv.2016.02.012. [DOI] [PubMed] [Google Scholar]
  • 13.Trantas E.A., Koffas M.A., Xu P., Ververidis F. When plants produce not enough or at all: Metabolic engineering of flavonoids in microbial hosts. Front. Plant Sci. 2015;6:7. doi: 10.3389/fpls.2015.00007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Nabavi S.M., Shirooie S., Šamec D., Tomczyk M., Milella L., Russo D., Habtemariam S., Suntar I., Rastrelli L., Daglia M., et al. Flavonoid biosynthetic pathways in plants: Versatile targets for metabolic engineering. Biotechnol. Adv. 2019 doi: 10.1016/j.biotechadv.2018.11.005. in press. [DOI] [PubMed] [Google Scholar]
  • 15.Yin J., Liang Y., Wang D., Yan Z., Yin H., Wu D., Su Q. Naringenin induces laxative effects by upregulating the expression levels of c-Kit and SCF, as well as those of aquaporin 3 in mice with loperamide-induced constipation. Int. J. Mol. Med. 2018;41:649–658. doi: 10.3892/ijmm.2017.3301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Karim N., Jia Z., Zheng X., Cui S., Chen W. A recent review of citrus flavanone naringenin on metabolic diseases and its potential sources for high yield-production. Trends Food Sci. Technol. 2018;79:35–54. doi: 10.1016/j.tifs.2018.06.012. [DOI] [Google Scholar]
  • 17.Ke J.Y., Banh T., Hsiao Y.H., Cole R.M., Straka S.R., Yee L.D., Belury M.A. Citrus flavonoid naringenin reduces mammary tumor cell viability, adipose mass, and adipose inflammation in obese ovariectomized mice. Mol. Nutr. Food Res. 2017;61:1600934. doi: 10.1002/mnfr.201600934. [DOI] [PubMed] [Google Scholar]
  • 18.Pinho-Ribeiro F.A., Zarpelon A.C., Fattori V., Manchope M.F., Mizokami S.S., Casagrande R., Verri W.A., Jr. Naringenin reduces inflammatory pain in mice. Neuropharmacology. 2016;105:508–519. doi: 10.1016/j.neuropharm.2016.02.019. [DOI] [PubMed] [Google Scholar]
  • 19.Wang Q., Yang J., Zhang X.-M., Zhou L., Liao X.-L., Yang B. Practical synthesis of naringenin. J. Chem. Res. 2015;39:455–457. doi: 10.3184/174751915X14379994045537. [DOI] [Google Scholar]
  • 20.National Center for Biotechnology Information, PubChem Compound Database, cid=439246. [(accessed on 16 November 2018)]; Available online: https://pubchem.ncbi.nlm.nih.gov/compound/439246.
  • 21.Jayachitra J., Nalini N. Effect of naringenin (citrus flavanone) on lipid profile in ethanol-induced toxicity in rats. J. Food Biochem. 2012;36:502–511. doi: 10.1111/j.1745-4514.2011.00561.x. [DOI] [Google Scholar]
  • 22.Erlund I., Meririnne E., Alfthan G., Aro A. Plasma kinetics and urinary excretion of the flavanones naringenin and hesperetin in humans after ingestion of orange juice and grapefruit juice. J. Nutr. 2001;131:235–241. doi: 10.1093/jn/131.2.235. [DOI] [PubMed] [Google Scholar]
  • 23.Frabasile S., Koishi A.C., Kuczera D., Silveira G.F., Verri W.A., Jr., Duarte Dos Santos C.N., Bordignon J. The citrus flavanone naringenin impairs dengue virus replication in human cells. Sci. Rep. 2017;7:41864. doi: 10.1038/srep41864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Ahmadi A., Hassandarvish P., Lani R., Yadollahi P., Jokar A., Bakar S.A., Zandi K. Inhibition of chikungunya virus replication by hesperetin and naringenin. RSC Adv. 2016;6:69421–69430. doi: 10.1039/C6RA16640G. [DOI] [Google Scholar]
  • 25.Goncalves D., Lima C., Ferreira P., Costa P., Costa A., Figueiredo W., Cesar T. Orange juice as dietary source of antioxidants for patients with hepatitis c under antiviral therapy. Food Nutr. Res. 2017;61:1296675. doi: 10.1080/16546628.2017.1296675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Nahmias Y., Goldwasser J., Casali M., van Poll D., Wakita T., Chung R.T., Yarmush M.L. Apolipoprotein b-dependent hepatitis c virus secretion is inhibited by the grapefruit flavonoid naringenin. Hepatology. 2008;47:1437–1445. doi: 10.1002/hep.22197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Da Pozzo E., Costa B., Cavallini C., Testai L., Martelli A., Calderone V., Martini C. The citrus flavanone naringenin protects myocardial cells against age-associated damage. Oxidative Med. Cell. Longev. 2017;2017:9536148. doi: 10.1155/2017/9536148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Jung S.K., Ha S.J., Jung C.H., Kim Y.T., Lee H.K., Kim M.O., Lee M.H., Mottamal M., Bode A.M., Lee K.W., et al. Naringenin targets ERK2 and suppresses UVB-induced photoaging. J. Cell. Mol. Med. 2016;20:909–919. doi: 10.1111/jcmm.12780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Zhang Y., Liu B., Chen X., Zhang N., Li G., Zhang L.H., Tan L.Y. Naringenin ameliorates behavioral dysfunction and neurological deficits in a d-galactose-induced aging mouse model through activation of PI3K/AKT/NRF2 pathway. Rejuvenation Res. 2017;20:462–472. doi: 10.1089/rej.2017.1960. [DOI] [PubMed] [Google Scholar]
  • 30.Ghofrani S., Joghataei M.T., Mohseni S., Baluchnejadmojarad T., Bagheri M., Khamse S., Roghani M. Naringenin improves learning and memory in an Alzheimer’s disease rat model: Insights into the underlying mechanisms. Eur. J. Pharmacol. 2015;764:195–201. doi: 10.1016/j.ejphar.2015.07.001. [DOI] [PubMed] [Google Scholar]
  • 31.Seyedrezazadeh E., Kolahian S., Shahbazfar A.A., Ansarin K., Pour Moghaddam M., Sakhinia M., Sakhinia E., Vafa M. Effects of the flavanone combination hesperetin-naringenin, and orange and grapefruit juices, on airway inflammation and remodeling in a murine asthma model. Phytother. Res. 2015;29:591–598. doi: 10.1002/ptr.5292. [DOI] [PubMed] [Google Scholar]
  • 32.Chandrika B.B., Steephan M., Kumar T.R.S., Sabu A., Haridas M. Hesperetin and naringenin sensitize HER2 positive cancer cells to death by serving as HER2 tyrosine kinase inhibitors. Life Sci. 2016;160:47–56. doi: 10.1016/j.lfs.2016.07.007. [DOI] [PubMed] [Google Scholar]
  • 33.Hernandez-Aquino E., Muriel P. Beneficial effects of naringenin in liver diseases: Molecular mechanisms. World J. Gastroenterol. 2018;24:1679–1707. doi: 10.3748/wjg.v24.i16.1679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Arul D., Subramanian P. Naringenin (citrus flavonone) induces growth inhibition, cell cycle arrest and apoptosis in human hepatocellular carcinoma cells. Pathol. Oncol. Res. 2013;19:763–770. doi: 10.1007/s12253-013-9641-1. [DOI] [PubMed] [Google Scholar]
  • 35.Lim W., Park S., Bazer F.W., Song G. Naringenin-induced apoptotic cell death in prostate cancer cells is mediated via the PI3K/AKT and MAPK signaling pathways. J. Cell. Biochem. 2017;118:1118–1131. doi: 10.1002/jcb.25729. [DOI] [PubMed] [Google Scholar]
  • 36.Nasr Bouzaiene N., Chaabane F., Sassi A., Chekir-Ghedira L., Ghedira K. Effect of apigenin-7-glucoside, genkwanin and naringenin on tyrosinase activity and melanin synthesis in B16F10 melanoma cells. Life Sci. 2016;144:80–85. doi: 10.1016/j.lfs.2015.11.030. [DOI] [PubMed] [Google Scholar]
  • 37.Stompor M., Uram L., Podgorski R. In vitro effect of 8-prenylnaringenin and naringenin on fibroblasts and glioblastoma cells-cellular accumulation and cytotoxicity. Molecules. 2017;22:1092. doi: 10.3390/molecules22071092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Zhang F., Dong W., Zeng W., Zhang L., Zhang C., Qiu Y., Wang L., Yin X., Zhang C., Liang W. Naringenin prevents TGF-beta1 secretion from breast cancer and suppresses pulmonary metastasis by inhibiting PKC activation. Breast Cancer Res. 2016;18:38. doi: 10.1186/s13058-016-0698-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Park J., Jeong K.H., Shin W.H., Bae Y.S., Jung U.J., Kim S.R. Naringenin ameliorates kainic acid-induced morphological alterations in the dentate gyrus in a mouse model of temporal lobe epilepsy. Neuroreport. 2016;27:1182–1189. doi: 10.1097/WNR.0000000000000678. [DOI] [PubMed] [Google Scholar]
  • 40.Al-Rejaie S.S., Aleisa A.M., Abuohashish H.M., Parmar M.Y., Ola M.S., Al-Hosaini A.A., Ahmed M.M. Naringenin neutralises oxidative stress and nerve growth factor discrepancy in experimental diabetic neuropathy. Neurol. Res. 2015;37:924–933. doi: 10.1179/1743132815Y.0000000079. [DOI] [PubMed] [Google Scholar]
  • 41.Al-Dosari D.I., Ahmed M.M., Al-Rejaie S.S., Alhomida A.S., Ola M.S. Flavonoid naringenin attenuates oxidative stress, apoptosis and improves neurotrophic effects in the diabetic rat retina. Nutrients. 2017;9:1161. doi: 10.3390/nu9101161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Sandeep M.S., Nandini C.D. Influence of quercetin, naringenin and berberine on glucose transporters and insulin signalling molecules in brain of streptozotocin-induced diabetic rats. Biomed. Pharmacother. 2017;94:605–611. doi: 10.1016/j.biopha.2017.07.142. [DOI] [PubMed] [Google Scholar]
  • 43.Ren B., Qin W., Wu F., Wang S., Pan C., Wang L., Zeng B., Ma S., Liang J. Apigenin and naringenin regulate glucose and lipid metabolism, and ameliorate vascular dysfunction in type 2 diabetic rats. Eur. J. Pharmacol. 2016;773:13–23. doi: 10.1016/j.ejphar.2016.01.002. [DOI] [PubMed] [Google Scholar]
  • 44.Roy S., Ahmed F., Banerjee S., Saha U. Naringenin ameliorates streptozotocin-induced diabetic rat renal impairment by downregulation of TGF-beta1 and IL-1 via modulation of oxidative stress correlates with decreased apoptotic events. Pharm. Biol. 2016;54:1616–1627. doi: 10.3109/13880209.2015.1110599. [DOI] [PubMed] [Google Scholar]
  • 45.Sirovina D., Orsolic N., Gregorovic G., Koncic M.Z. Naringenin ameliorates pathological changes in liver and kidney of diabetic mice: A preliminary study. Arch. Ind. Hyg. Toxicol. 2016;67:19–24. doi: 10.1515/aiht-2016-67-2708. [DOI] [PubMed] [Google Scholar]
  • 46.Shinyoshi S., Kamada Y., Matsusaki K., Chigwechokha P.K., Tepparin S., Araki K., Komatsu M., Shiozaki K. Naringenin suppresses Edwardsiella tarda infection in GAKS cells by NanA sialidase inhibition. Fish Shellfish Immunol. 2017;61:86–92. doi: 10.1016/j.fsi.2016.12.018. [DOI] [PubMed] [Google Scholar]
  • 47.Fan R., Pan T., Zhu A.L., Zhang M.H. Anti-inflammatory and anti-arthritic properties of naringenin via attenuation of NF-kappab and activation of the heme oxygenase HO-1/related factor 2 pathway. Pharmacol. Rep. 2017;69:1021–1029. doi: 10.1016/j.pharep.2017.03.020. [DOI] [PubMed] [Google Scholar]
  • 48.Hua F.Z., Ying J., Zhang J., Wang X.F., Hu Y.H., Liang Y.P., Liu Q., Xu G.H. Naringenin pre-treatment inhibits neuroapoptosis and ameliorates cognitive impairment in rats exposed to isoflurane anesthesia by regulating the PI3/AKT/PTEN signalling pathway and suppressing NF-kappab-mediated inflammation. Int. J. Mol. Med. 2016;38:1271–1280. doi: 10.3892/ijmm.2016.2715. [DOI] [PubMed] [Google Scholar]
  • 49.Park S., Lim W., Bazer F.W., Song G. Naringenin induces mitochondria-mediated apoptosis and endoplasmic reticulum stress by regulating MAPK and AKT signal transduction pathways in endometriosis cells. Mol. Hum. Reprod. 2017;23:842–854. doi: 10.1093/molehr/gax057. [DOI] [PubMed] [Google Scholar]
  • 50.Liu X., Wang N., Fan S., Zheng X., Yang Y., Zhu Y., Lu Y., Chen Q., Zhou H., Zheng J. The citrus flavonoid naringenin confers protection in a murine endotoxaemia model through AMPK-ATF3-dependent negative regulation of the TLR4 signalling pathway. Sci. Rep. 2016;6:39735. doi: 10.1038/srep39735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Shan S., Zhang Y., Wu M., Yi B., Wang J., Li Q. Naringenin attenuates fibroblast activation and inflammatory response in a mechanical stretch-induced hypertrophic scar mouse model. Mol. Med. Rep. 2017;16:4643–4649. doi: 10.3892/mmr.2017.7209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Jin L., Zeng W., Zhang F., Zhang C., Liang W. Naringenin ameliorates acute inflammation by regulating intracellular cytokine degradation. J. Immunol. 2017;199:3466–3477. doi: 10.4049/jimmunol.1602016. [DOI] [PubMed] [Google Scholar]
  • 53.Fouad A.A., Albuali W.H., Jresat I. Protective effect of naringenin against lipopolysaccharide-induced acute lung injury in rats. Pharmacology. 2016;97:224–232. doi: 10.1159/000444262. [DOI] [PubMed] [Google Scholar]
  • 54.Shi L.B., Tang P.F., Zhang W., Zhao Y.P., Zhang L.C., Zhang H. Naringenin inhibits spinal cord injury-induced activation of neutrophils through miR-223. Gene. 2016;592:128–133. doi: 10.1016/j.gene.2016.07.037. [DOI] [PubMed] [Google Scholar]
  • 55.Wang C.C., Guo L., Tian F.D., An N., Luo L., Hao R.H., Wang B., Zhou Z.H. Naringenin regulates production of matrix metalloproteinases in the knee-joint and primary cultured articular chondrocytes and alleviates pain in rat osteoarthritis model. Braz. J. Med. Biol. Res. 2017;50:e5714. doi: 10.1590/1414-431x20165714. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Ali R., Shahid A., Ali N., Hasan S.K., Majed F., Sultana S. Amelioration of benzo[a]pyrene-induced oxidative stress and pulmonary toxicity by naringenin in Wistar rats: A plausible role of COX-2 and NF-kappab. Hum. Exp. Toxicol. 2017;36:349–364. doi: 10.1177/0960327116650009. [DOI] [PubMed] [Google Scholar]
  • 57.Manchope M.F., Calixto-Campos C., Coelho-Silva L., Zarpelon A.C., Pinho-Ribeiro F.A., Georgetti S.R., Baracat M.M., Casagrande R., Verri W.A., Jr. Naringenin inhibits superoxide anion-induced inflammatory pain: Role of oxidative stress, cytokines, Nrf-2 and the NO-cGMP-PKG-KATP channel signaling pathway. PLoS ONE. 2016;11:e0153015. doi: 10.1371/journal.pone.0153015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Chtourou Y., Kamoun Z., Zarrouk W., Kebieche M., Kallel C., Gdoura R., Fetoui H. Naringenin ameliorates renal and platelet purinergic signalling alterations in high-cholesterol fed rats through the suppression of ROS and NF-kappab signaling pathways. Food Funct. 2016;7:183–193. doi: 10.1039/C5FO00871A. [DOI] [PubMed] [Google Scholar]
  • 59.Al-Roujayee A.S. Naringenin improves the healing process of thermally-induced skin damage in rats. J. Int. Med Res. 2017;45:570–582. doi: 10.1177/0300060517692483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Wang L.H., Wang M.S., Zeng X.A., Xu X.M., Brennan C.S. Membrane and genomic DNA dual-targeting of citrus flavonoid naringenin against staphylococcus aureus. Integr. Biol. 2017;9:820–829. doi: 10.1039/C7IB00095B. [DOI] [PubMed] [Google Scholar]
  • 61.Kozlowska J., Potaniec B., Zarowska B., Aniol M. Synthesis and biological activity of novel o-alkyl derivatives of naringenin and their oximes. Molecules. 2017;22:1485. doi: 10.3390/molecules22091485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Liang J., Halipu Y., Hu F., Yakeya B., Chen W., Zhang H., Kang X. Naringenin protects keratinocytes from oxidative stress injury via inhibition of the NOD2-mediated NF-kappab pathway in pemphigus vulgaris. Biomed. Pharmacother. 2017;92:796–801. doi: 10.1016/j.biopha.2017.05.112. [DOI] [PubMed] [Google Scholar]
  • 63.Stylos E., Chatziathanasiadou M.V., Tsiailanis A., Kellici T.F., Tsoumani M., Kostagianni A.D., Deligianni M., Tselepis A.D., Tzakos A.G. Tailoring naringenin conjugates with amplified and triple antiplatelet activity profile: Rational design, synthesis, human plasma stability and in vitro evaluation. Biochim. Biophys. Acta Gen. Subj. 2017;1861:2609–2618. doi: 10.1016/j.bbagen.2017.08.018. [DOI] [PubMed] [Google Scholar]
  • 64.Wang K., Chen Z., Huang J., Huang L., Luo N., Liang X., Liang M., Xie W. Naringenin prevents ischaemic stroke damage via anti-apoptotic and anti-oxidant effects. Clin. Exp. Pharmacol. Physiol. 2017;44:862–871. doi: 10.1111/1440-1681.12775. [DOI] [PubMed] [Google Scholar]
  • 65.Liu Y., An W., Gao A. Protective effects of naringenin in cardiorenal syndrome. J. Surg. Res. 2016;203:416–423. doi: 10.1016/j.jss.2016.03.003. [DOI] [PubMed] [Google Scholar]
  • 66.Tang J.Y., Jin P., He Q., Lu L.H., Ma J.P., Gao W.L., Bai H.P., Yang J. Naringenin ameliorates hypoxia/reoxygenation-induced endoplasmic reticulum stress-mediated apoptosis in H9c2 myocardial cells: Involvement in ATF6, IRE1alpha and perk signaling activation. Mol. Cell. Biochem. 2017;424:111–122. doi: 10.1007/s11010-016-2848-1. [DOI] [PubMed] [Google Scholar]
  • 67.Habauzit V., Verny M.A., Milenkovic D., Barber-Chamoux N., Mazur A., Dubray C., Morand C. Flavanones protect from arterial stiffness in postmenopausal women consuming grapefruit juice for 6 mo: A randomized, controlled, crossover trial. Am. J. Clin. Nutr. 2015;102:66–74. doi: 10.3945/ajcn.114.104646. [DOI] [PubMed] [Google Scholar]
  • 68.Bawazeer N.A., Choudary H., Zamzami M.A., Abdulaal W.H., Zeyadi M., ALbukhari A., Middleton B., Moselhy S.S. Possible regulation of LDL-receptor by naringenin in HepG2 hepatoma cell line. Afr. J. Tradit. Complement. Altern. Med. 2017;14:278–287. doi: 10.21010/ajtcam.v14i1.30. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Meng X.M., Zhang Y., Huang X.R., Ren G.L., Li J., Lan H.Y. Treatment of renal fibrosis by rebalancing TGF-beta/Smad signaling with the combination of asiatic acid and naringenin. Oncotarget. 2015;6:36984–36997. doi: 10.18632/oncotarget.6100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Shi R., Xiao Z.T., Zheng Y.J., Zhang Y.L., Xu J.W., Huang J.H., Zhou W.L., Li P.B., Su W.W. Naringenin regulates CFTR activation and expression in airway epithelial cells. Cell. Physiol. Biochem. 2017;44:1146–1160. doi: 10.1159/000485419. [DOI] [PubMed] [Google Scholar]
  • 71.Oguido A., Hohmann M.S.N., Pinho-Ribeiro F.A., Crespigio J., Domiciano T.P., Verri W.A., Jr., Casella A.M.B. Naringenin eye drops inhibit corneal neovascularization by anti-inflammatory and antioxidant mechanisms. Investig. Ophthalmol. Vis. Sci. 2017;58:5764–5776. doi: 10.1167/iovs.16-19702. [DOI] [PubMed] [Google Scholar]
  • 72.Adana M.Y., Akang E.N., Peter A.I., Jegede A.I., Naidu E.C.S., Tiloke C., Chuturgoon A.A., Azu O.O. Naringenin attenuates highly active antiretroviral therapy-induced sperm DNA fragmentations and testicular toxicity in sprague-dawley rats. Andrology. 2018;6:166–175. doi: 10.1111/andr.12439. [DOI] [PubMed] [Google Scholar]
  • 73.Maatouk M., Elgueder D., Mustapha N., Chaaban H., Bzeouich I.M., Loannou I., Kilani S., Ghoul M., Ghedira K., Chekir-Ghedira L. Effect of heated naringenin on immunomodulatory properties and cellular antioxidant activity. Cell Stress Chaperones. 2016;21:1101–1109. doi: 10.1007/s12192-016-0734-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Lin H., Zhou Z., Zhong W., Huang P., Ma N., Zhang Y., Zhou C., Lai Y., Huang S., An H., et al. Naringenin inhibits alcoholic injury by improving lipid metabolism and reducing apoptosis in zebrafish larvae. Oncol. Rep. 2017;38:2877–2884. doi: 10.3892/or.2017.5965. [DOI] [PubMed] [Google Scholar]
  • 75.Lin H.J., Ku K.L., Lin I.H., Yeh C.C. Naringenin attenuates hepatitis b virus x protein-induced hepatic steatosis. BMC Complement. Altern. Med. 2017;17:505. doi: 10.1186/s12906-017-2019-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76.Lim W., Song G. Naringenin-induced migration of embrynoic trophectoderm cells is mediated via PI3K/AKT and ERK1/2 MAPK signaling cascades. Mol. Cell. Endocrinol. 2016;428:28–37. doi: 10.1016/j.mce.2016.03.018. [DOI] [PubMed] [Google Scholar]
  • 77.Kumar S., Tiku A.B. Biochemical and molecular mechanisms of radioprotective effects of naringenin, a phytochemical from citrus fruits. J. Agric. Food Chem. 2016;64:1676–1685. doi: 10.1021/acs.jafc.5b05067. [DOI] [PubMed] [Google Scholar]
  • 78.Ke J.Y., Cole R.M., Hamad E.M., Hsiao Y.H., Cotten B.M., Powell K.A., Belury M.A. Citrus flavonoid, naringenin, increases locomotor activity and reduces diacylglycerol accumulation in skeletal muscle of obese ovariectomized mice. Mol. Nutr. Food Res. 2016;60:313–324. doi: 10.1002/mnfr.201500379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Pereira-Caro G., Borges G., van der Hooft J., Clifford M.N., Del Rio D., Lean M.E., Roberts S.A., Kellerhals M.B., Crozier A. Orange juice (poly)phenols are highly bioavailable in humans. Am. J. Clin. Nutr. 2014;100:1378–1384. doi: 10.3945/ajcn.114.090282. [DOI] [PubMed] [Google Scholar]
  • 80.Kanaze F.I., Bounartzi M.I., Georgarakis M., Niopas I. Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects. Eur. J. Clin. Nutr. 2007;61:472–477. doi: 10.1038/sj.ejcn.1602543. [DOI] [PubMed] [Google Scholar]
  • 81.Zeng X., Su W., Bai Y., Chen T., Yan Z., Wang J., Su M., Zheng Y., Peng W., Yao H. Urinary metabolite profiling of flavonoids in Chinese volunteers after consumption of orange juice by UFLC-Q-TOF-MS/MS. J. Chromatogr. B. 2017;1061–1062:79–88. doi: 10.1016/j.jchromb.2017.07.015. [DOI] [PubMed] [Google Scholar]
  • 82.Pereira-Caro G., Polyviou T., Ludwig I.A., Nastase A.M., Moreno-Rojas J.M., Garcia A.L., Malkova D., Crozier A. Bioavailability of orange juice (poly)phenols: The impact of short-term cessation of training by male endurance athletes. Am. J. Clin. Nutr. 2017;106:791–800. doi: 10.3945/ajcn.116.149898. [DOI] [PubMed] [Google Scholar]
  • 83.Aschoff J.K., Riedl K.M., Cooperstone J.L., Hogel J., Bosy-Westphal A., Schwartz S.J., Carle R., Schweiggert R.M. Urinary excretion of citrus flavanones and their major catabolites after consumption of fresh oranges and pasteurized orange juice: A randomized cross-over study. Mol. Nutr. Food Res. 2016;60:2602–2610. doi: 10.1002/mnfr.201600315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Duque A.L.R.F., Monteiro M., Adorno M.A.T., Sakamoto I.K., Sivieri K. An exploratory study on the influence of orange juice on gut microbiota using a dynamic colonic model. Food Res. Int. 2016;84:160–169. doi: 10.1016/j.foodres.2016.03.028. [DOI] [Google Scholar]
  • 85.Zaidun N.H., Thent Z.C., Latiff A.A. Combating oxidative stress disorders with citrus flavonoid: Naringenin. Life Sci. 2018;208:111–122. doi: 10.1016/j.lfs.2018.07.017. [DOI] [PubMed] [Google Scholar]
  • 86.Amawi H., Ashby C.R., Jr., Tiwari A.K. Cancer chemoprevention through dietary flavonoids: What’s limiting? Chin. J. Cancer. 2017;36:50. doi: 10.1186/s40880-017-0217-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Testai L., Calderone V. Nutraceutical value of citrus flavanones and their implications in cardiovascular disease. Nutrients. 2017;9:502. doi: 10.3390/nu9050502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88.Yamada T., Hayasaka S., Shibata Y., Ojima T., Saegusa T., Gotoh T., Ishikawa S., Nakamura Y., Kayaba K. Frequency of citrus fruit intake is associated with the incidence of cardiovascular disease: The Jichi Medical School cohort study. J. Epidemiol. 2011;21:169–175. doi: 10.2188/jea.JE20100084. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89.Knekt P., Kumpulainen J., Jarvinen R., Rissanen H., Heliovaara M., Reunanen A., Hakulinen T., Aromaa A. Flavonoid intake and risk of chronic diseases. Am. J. Clin. Nutr. 2002;76:560–568. doi: 10.1093/ajcn/76.3.560. [DOI] [PubMed] [Google Scholar]
  • 90.Cassidy A., Rimm E.B., O’Reilly E.J., Logroscino G., Kay C., Chiuve S.E., Rexrode K.M. Dietary flavonoids and risk of stroke in women. Stroke. 2012;43:946–951. doi: 10.1161/STROKEAHA.111.637835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91.Onakpoya I., O’Sullivan J., Heneghan C., Thompson M. The effect of grapefruits (Citrus paradisi) on body weight and cardiovascular risk factors: A systematic review and meta-analysis of randomized clinical trials. Crit. Rev. Food Sci. Nutr. 2017;57:602–612. doi: 10.1080/10408398.2014.901292. [DOI] [PubMed] [Google Scholar]
  • 92.Reshef N., Hayari Y., Goren C., Boaz M., Madar Z., Knobler H. Antihypertensive effect of sweetie fruit in patients with stage i hypertension. Am. J. Hypertens. 2005;18:1360–1363. doi: 10.1016/j.amjhyper.2005.05.021. [DOI] [PubMed] [Google Scholar]
  • 93.Toth P.P., Patti A.M., Nikolic D., Giglio R.V., Castellino G., Biancucci T., Geraci F., David S., Montalto G., Rizvi A., et al. Bergamot reduces plasma lipids, atherogenic small dense LDL, and subclinical atherosclerosis in subjects with moderate hypercholesterolemia: A 6 months prospective study. Front. Pharmacol. 2015;6:299. doi: 10.3389/fphar.2015.00299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94.Jung U.J., Kim H.J., Lee J.S., Lee M.K., Kim H.O., Park E.J., Kim H.K., Jeong T.S., Choi M.S. Naringin supplementation lowers plasma lipids and enhances erythrocyte antioxidant enzyme activities in hypercholesterolemic subjects. Clin. Nutr. 2003;22:561–568. doi: 10.1016/S0261-5614(03)00059-1. [DOI] [PubMed] [Google Scholar]
  • 95.Mollace V., Sacco I., Janda E., Malara C., Ventrice D., Colica C., Visalli V., Muscoli S., Ragusa S., Muscoli C., et al. Hypolipemic and hypoglycaemic activity of bergamot polyphenols: From animal models to human studies. Fitoterapia. 2011;82:309–316. doi: 10.1016/j.fitote.2010.10.014. [DOI] [PubMed] [Google Scholar]
  • 96.Demonty I., Lin Y., Zebregs Y.E., Vermeer M.A., van der Knaap H.C., Jakel M., Trautwein E.A. The citrus flavonoids hesperidin and naringin do not affect serum cholesterol in moderately hypercholesterolemic men and women. J. Nutr. 2010;140:1615–1620. doi: 10.3945/jn.110.124735. [DOI] [PubMed] [Google Scholar]
  • 97.Constans J., Bennetau-Pelissero C., Martin J.F., Rock E., Mazur A., Bedel A., Morand C., Berard A.M. Marked antioxidant effect of orange juice intake and its phytomicronutrients in a preliminary randomized cross-over trial on mild hypercholesterolemic men. Clin. Nutr. 2015;34:1093–1100. doi: 10.1016/j.clnu.2014.12.016. [DOI] [PubMed] [Google Scholar]
  • 98.Silveira J.Q., Dourado G.K., Cesar T.B. Red-fleshed sweet orange juice improves the risk factors for metabolic syndrome. Int. J. Food Sci. Nutr. 2015;66:830–836. doi: 10.3109/09637486.2015.1093610. [DOI] [PubMed] [Google Scholar]
  • 99.Rendeiro C., Dong H., Saunders C., Harkness L., Blaze M., Hou Y., Belanger R.L., Corona G., Lovegrove J.A., Spencer J.P. Flavanone-rich citrus beverages counteract the transient decline in postprandial endothelial function in humans: A randomised, controlled, double-masked, cross-over intervention study. Br. J. Nutr. 2016;116:1999–2010. doi: 10.1017/S0007114516004219. [DOI] [PubMed] [Google Scholar]
  • 100.Dallas C., Gerbi A., Elbez Y., Caillard P., Zamaria N., Cloarec M. Clinical study to assess the efficacy and safety of a citrus polyphenolic extract of red orange, grapefruit, and orange (Sinetrol-XPur) on weight management and metabolic parameters in healthy overweight individuals. Phytother. Res. 2014;28:212–218. doi: 10.1002/ptr.4981. [DOI] [PubMed] [Google Scholar]
  • 101.Stohs S.J., Preuss H.G., Keith S.C., Keith P.L., Miller H., Kaats G.R. Effects of p-synephrine alone and in combination with selected bioflavonoids on resting metabolism, blood pressure, heart rate and self-reported mood changes. Int. J. Med Sci. 2011;8:295–301. doi: 10.7150/ijms.8.295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 102.Aldrich C., Bertozzi C., Georg G.I., Kiessling L., Lindsley C., Liotta D., Merz K.M., Schepartz A., Wang S. The ecstasy and agony of assay interference compounds. ACS Cent. Sci. 2017;3:143–147. doi: 10.1021/acscentsci.7b00069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 103.Baell J.B. Feeling nature’s pains: Natural products, natural product drugs, and pan assay interference compounds (pains) J. Nat. Prod. 2016;79:616–628. doi: 10.1021/acs.jnatprod.5b00947. [DOI] [PubMed] [Google Scholar]
  • 104.Jardim A.C.G., Shimizu J.F., Rahal P., Harris M. Plant-derived antivirals against hepatitis c virus infection. Virol. J. 2018;15:34. doi: 10.1186/s12985-018-0945-3. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Pharmaceuticals are provided here courtesy of Multidisciplinary Digital Publishing Institute (MDPI)

RESOURCES