Naringenin benefit and review, clinical trials
Feb 15 2016 by
Ray Sahelian, M.D.

Naringenin is one of the most abundant citrus bioflavonoids. A high-vegetable diet with various fruits and vegetables daily including on average one glass of orange juice, one-half orange and one-half mandarin provides 130 mg of hesperetin and 30 mg of naringenin. This plant substance has been shown to inhibit in vitro growth of in human cancer cells.

Naringenin has anti-oxidant and anti-tumor activity. It may play a role in cancer prevention or perhaps treatment, heart disease prevention, hypertension, improving circulation, and Alzheimer's disease.

Eyesight Rx with Naringenin

Unlike some vision products that provide nutrients and herbs for long term healthy vision support, and prevention of visual impairment, but don't seem to have much of an immediate effect on visual acuity, Eyesight Rx was formulated with a number of herbs to provide a quick and noticeable vision improvement within hours or days of use.

Reports from Eyesight Rx users indicate enhanced clarity of vision, colors being brighter, better focus, and overall improvement in close and distance vision.

Vitamin C Ascorbic acid
Citrus bioflavonoids (eriocitrin, hesperidin, flavonols, flavones, flavonoids, naringenin, and quercetin)
Mixed carotenoids (alpha carotene, astaxanthin, beta carotene, cryptoxanthin,
Lutein, Lycopene, Zeaxanthin)
Bilberry extract (Vaccinium myrtillus)
Eyebright extract (Euphrasia officianales)
Jujube extract (Zizyphus jujube)
Ginkgo biloba herbal extract
Suma extract (Pfaffia paniculata)
Mucuna pruriens extract (Cowhage)
Cinnamon (Cinnamomum zeylanicum)
Lycium berry extract (Lycium Barbarum) - also known as Goji Berry or wolfberry
Alpha Lipoic acid antioxidant

Role in atherosclerosis or hardening of the arteries, heart failure help
Naringenin decreases progression of atherosclerosis by improving dyslipidemia in high-fat-fed low-density lipoprotein receptor-null mice.
Arterioscler Thromb Vasc Biol. 2010; Mulvihill EE, Assini JM, Sutherland BG, DiMattia AS, Khami M, Koppes JB. Vascular Biology Group, Robarts Research Institute, The University of Western Ontario, ON, Canada.
Naringenin is a citrus flavonoid that potently inhibits the assembly and secretion of apolipoprotein B100-containing lipoproteins in cultured hepatocytes and improves the dyslipidemia and insulin resistance in a mouse model of the metabolic syndrome. In the present study, we used low-density lipoprotein receptor-null mice fed a high-fat diet (Western, TD96125) to test the hypothesis that naringenin prevents atherosclerosis. These in vivo studies demonstrate that the citrus flavonoid naringenin ameliorates the dyslipidemia in Western-fed low-density lipoprotein receptor-null mice, leading to decreased atherosclerosis; and suggests a potential therapeutic strategy for the hyperlipidemia and increased risk of atherosclerosis associated with insulin resistance.

Exp Ther Med. 2015. Naringenin attenuates pressure overload-induced cardiac hypertrophy. Cardiac hypertrophy is characterized by abnormal enlargement of cardiomyocytes and disproportionate accumulation of extracellular interstitial fibrosis, which are major predictors of the development of coronary artery disease and heart failure. Naringenin is a bitter principle component of grapefruit that has numerous pharmacological effects, including anti-inflammatory, hypolipidemic, antithrombotic and antiatherogenic properties. In order to investigate whether naringenin is able to exert a protective effect against cardiac hypertrophy induced by pressure overload, aortic banding (AB) was performed to induce cardiac hypertrophy in mice, and naringenin was administered for 7 weeks. The heart protective effect exerted by naringenin may be associated with the inhibition of PI3K/Akt, ERK and JNK signaling pathways.

Blood sugar and diabetes
Chem Biol Interact. March 2014. Naringenin inhibits α-glucosidase activity: A promising strategy for the regulation of postprandial hyperglycemia in high fat diet fed streptozotocin induced diabetic rats.

Naringenin study
Naringenin attenuates cisplatin nephrotoxicity in rats.
Life Sci. 2005.
The effect of naringenin, a naturally occurring citrus flavanone, on the acute nephrotoxicity produced by cisplatin (7 mg/kg, i.v.) was investigated in the rat. Oral administration of NAR (20 mg/kg/day) for 10 days, starting 5 days before cisplatin single i.v. injection, produced significant protection of renal function. Naringenin reduced the extent of cisplatin-induced nephrotoxicity, as evidenced by significant reduction in serum urea and creatinine concentrations, decreased polyuria, reduction in body weight loss, marked reduction in urinary fractional sodium excretion and glutathione S-transferase (GST) activity, and increased creatinine clearance. Cisplatin-induced alterations in renal cortex lipid peroxides and GST activity were markedly improved by Naringenin. Cisplatin-induced alterations in renal cortex antioxidant defense system were greatly prevented by Naringenin. In cisplatin-Naringenin combined treatment group, antioxidant enzymes namely superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) were significantly increased to 54.5, 30.3 and 35.6%, respectively compared to cisplatin treated group. Platinum renal content was not affected by Naringenin treatment. The results provide further insight into the mechanisms of cisplatin-induced nephrotoxicity and confirm the antioxidant potential of Naringenin.

Inhibitory effects of naringenin on tumor growth in human cancer cell lines and sarcoma S-180-implanted mice.
Biol Pharm Bull. 2005.
We have investigated the effect of naringenin on tumor growth in various human cancer cell lines and sarcoma S-180-implanted mice. NGEN showed cytotoxicity in cell lines derived from cancer of the breast (MCF-7, MDA-MB-231), stomach (KATOIII, MKN-7), liver (HepG2, Hep3B, Huh7), cervix (Hela, Hela-TG), pancreas (PK-1), and colon (Caco-2) as well as leukemia (HL-60, NALM-6, Jurkat, U937). Naringenin -induced cytotoxicity was low in Caco-2 and high in leukemia cells compared to other cell lines. It inhibited tumor growth in sarcoma S-180-implanted mice, following intraperitoneal or peroral injection once a day for 5 d. Naringin (NG) also inhibited tumor growth by peroral injection but not intraperitoneal injection. Naringenin, one of the most abundant flavonoids in citrus fruits, may have a potentially useful inhibitory effect on tumor growth.

Structure-activity relationship (SAR) between some natural flavonoids and ocular blood flow in the rabbit.
J Ocul Pharmacol Ther. 2004.
Flavonoids with two to five hydroxy groups, with or without sugar, and/or methoxy groups were studied on their effects to affect ocular blood flow. Colored microsphere technique was used to determine the ocular blood flow in rabbit eyes. RESULTS: Flavonoids with three free hydroxy (OH) groups seemed to produce the optimal effects in increasing ocular blood flow (naringenin and hesperitin, Pfalts and Bauer, Waterbury, CT). Whether the OH groups are below three (naringenin, hesperitin, Pfalts and Bauer, Waterbury, CT) or above four (Quercetin, Pfalts and Bauer, Waterbury, CT), they produced no effects on the ocular blood flow. When OH groups are four (rutin, Aldrich, Milwaukee, WI), it produced mixed effects on ocular blood flow. The attachment of rutinose and/or methoxy group in the structure did not affect the ocular blood flow one way or the other. The ocular blood flow is increased significantly by the number of OH group in the molecule, with three the best to increase the ocular blood flow.

Naringenin from Citrus junos has an inhibitory effect on acetylcholinesterase and a mitigating effect on amnesia.
Dement Geriatr Cogn Disord. 2004.
This study was performed to identify safe and more effective acetylcholinesterase (AChE) inhibitors in the treatment of Alzheimer's disease. The total methanol extract of Citrus junos had a significant inhibitory effect on AChE in vitro. By sequential fractionation of C.junos, the active component was finally identified as naringenin. Naringenin inhibited AChE activity in a dose-dependent manner. In this study, we also evaluated the anti-amnesic activity of naringenin, a major flavanone constituent isolated from C. junos, in vivo using ICR mice with amnesia induced by scopolamine (1 mg/kg body weight). Naringenin, when administered to mice at 4.5 mg/kg body weight, significantly ameliorated scopolamine-induced amnesia as measured in both the passive avoidance and the Y-maze test. These results suggest that naringenin may be a useful chemopreventive agent against Alzheimer's disease.

The citrus-derived flavonoid naringenin exerts uterotrophic effects in female mice at human relevant doses.
Basic Clin Pharmacol Toxicol. 2004.
Gavage administration of the citrus flavonoid naringenin, 3',4,5,7-tetrahydroxyflavanon for 4 consecutive days, to immature female mice (postnatal day 17-20) at 4 or 100 mg/kg b.wt. significantly increased uterine weights 3 and 4 times, respectively. Analysis of uterine oestrogen receptor alpha revealed that naringenin significantly increased the cytosolic concentration of oestrogen receptor alpha, whereas in nuclei the oestrogen receptor alpha concentration was significantly decreased as compared to the solvent control. This was in contrast to the positive control 17 beta-oestradiolacetate which acted as a true oestrogen by increasing the concentration of both total and nuclear oestrogen receptor alpha. Both naringenin and 17 beta-oestradiolacetate, however, significantly, induced nuclear oestrogen receptor alpha in the liver, suggesting a tissue specific effect of naringenin on oestrogen receptor alpha distribution. In order to investigate the tissue levels at which the uterotrophic effect was observed, the distribution of an oral dose of tritiated naringenin (4 mg/kg) was investigated in 3-week-old female mice. The radioactivity content (ng naringenin equivalents/g tissue) was found to be highest in the gastrointestinal-tract, followed by the kidneys and liver. Uterus and ovaries were also found to contain relatively high and approximately equal amounts of naringenin. The concentration of naringenin in uterus and ovaries was found to be ten times higher as compared to the mammary tissue. The urinary excretion of more than 25% of the administered dose, within 8 hr after dosing indicated that naringenin is absorbed extensively in mice. The plasma concentration of 0.5 microM found in the present study is similar to the peak plasma concentration of naringenin (0.6 microM) observed in man following ingestion of 400-760 ml of orange juice (Erlund et al. 2001). This could be taken to suggests that ingestion of orange juice and other citrus fruits and juices may give rise to sufficiently high tissue levels of naringenin in man to exert a biological effect.

The variable effect on proliferation of a colon cancer cell line by the citrus fruit flavonoid Naringenin.
Colorectal Dis. 2003.
Naringenin, a naturally occurring flavonoid found in citrus fruits, is known to have anticarcinogenic properties. We have examined the effect of Naringenin on cell proliferation of an HT-29 colon cancer cell line. HT-29 colon cancer cells were cultured in 96-well tissue culture plates. Naringenin concentrations ranging from 0.02 to 2.85 mmol were added to the wells of the Test group. The Control group contained all the elements present in the Test group with the exception of Naringenin. Cell proliferation was measured by colourimetric assay using the 2% WST-1 cell proliferation kit. Significant inhibition of cell proliferation was observed in HT29 colon cancer cells exposed to Naringenin at doses greater than 0.71 mmol. These results suggest a potential role for citrus fruits as a source of chemoprotective agents for colon cancer.

Interaction between flavonoids and the blood-brain barrier: in vitro studies.
J Neurochem. 2003.
There is considerable current interest in the neuroprotective effects of flavonoids. This study focuses on the potential for dietary flavonoids, and their known physiologically relevant metabolites, to enter the brain endothelium and cross the blood-brain barrier (BBB) using well-established in vitro models (brain endothelial cell lines and ECV304 monolayers co-cultured with C6 glioma cells). We report that the citrus flavonoids, hesperetin, naringenin and their relevant in vivo metabolites, as well as the dietary anthocyanins and in vivo forms, cyanidin-3-rutinoside and pelargonidin-3-glucoside, are taken up by two brain endothelial cell lines from mouse (b.END5) and rat (RBE4). In both cell types, uptake of hesperetin and naringenin was greatest, increasing significantly with time and as a function of concentration. In support of these observations we report for the first time high apparent permeability (Papp) of the citrus flavonoids, hesperetin and naringenin, across the in vitro BBB model (apical to basolateral) relative to their more polar glucuronidated conjugates, as well as those of epicatechin and its in vivo metabolites, the dietary anthocyanins and to specific phenolic acids derived from colonic biotransformation of flavonoids. The results demonstrate that flavonoids and some metabolites are able to traverse the BBB, and that the potential for permeation is consistent with compound lipophilicity.

Comparison of antioxidant effects of naringin and probucol in cholesterol-fed rabbits.
Clin Chim Acta. 2002.
Twenty male rabbits were served a high-cholesterol (HC, 5 g/kg diet) diet or high-cholesterol diet supplemented with naringin (0.5 g/kg diet) or probucol (0.5 g/kg diet) for 8 weeks to compare the antioxidative effects of the citrus bioflavonoid (naringin) and antioxidative cholesterol-lowering drug (probucol). The plasma thiobarbituric acid-reactive substances (TBARS) concentration was not significantly different between the groups, whereas the hepatic TBARS concentration was significantly lower in the probucol group than in both normal and HC control or naringin group. Probucol and naringin supplementation led to an increase in the hepatic superoxide dismutase (SOD) and catalase (CAT) activities, and a decrease in the hepatic mitochondrial hydrogen peroxide (H(2)O(2)) content compared to the HC-control group. However, there was no difference in the cytosolic H(2)O(2) content or cytosolic glutathion peroxidase (GSH-Px) activity in the liver between the groups. Both naringin and probucol supplements significantly increased the plasma vitamin E concentration compared to the HC-control group. As regards the antioxidant enzyme gene expressions, naringin significantly increased the expression of three antioxidant enzyme mRNAs compared to the HC-control group, whereas probucol significantly increased the only SOD mRNA expression. The probucol supplement was very potent in the antioxidative defense system, whereas naringin exhibited a comparable antioxidant capacity based on increasing the gene expressions in the antioxidant enzymes, while also increasing the hepatic SOD and CAT activities, sparing plasma vitamin E, and decreasing the hepatic mitochondrial H(2)O(2) content.

Flavanone absorption after naringin, hesperidin, and citrus administration.
Clin Pharmacol Ther. 1996.
Disposition of citrus flavonoids was evaluated after single oral doses of pure compounds (500 mg naringin and 500 mg hesperidin) and after multiple doses of combined grapefruit juice and orange juice and of once-daily grapefruit. Cumulative urinary recovery indicated low bioavailability ( < 25%) of naringin and hesperidin. The aglycones naringenin and hesperitin were detected in urine and plasma. After juice administration, we detected naringenin, hesperitin, and four related flavanones, tentatively identified as monomethoxy and dimethoxy derivatives. These methoxyflavanones appear to be absorbed from juice. Absorbed citrus flavanones may undergo glucuronidation before urinary excretion.

Naringenin supplement questions
Q. Please advise me as to how effective oral supplementation of naringenin is. How much is absorbed by the GI tract?
   A. As of 2012, we are not aware of human research with naringenin supplements to determine its benefits and the absorption rate. It is quite well absorbed from foods.

Plasma concentrations of the flavonoids hesperetin, naringenin and quercetin in human subjects following their habitual diets, and diets high or low in fruit and vegetables.
Eur J Clin Nutr. 2002. To determine the fasting plasma concentrations of quercetin, hesperetin and naringenin in human subjects consuming their habitual diets, and diets either high or low in fruit and vegetables. To investigate whether plasma concentrations of flavanones can serve as biomarkers of their intake. This was a cross-over, strictly controlled dietary intervention consisting of a 2 week baseline period, and two 5 week dietary periods with a 3 week wash-out period in between. The low-vegetable diet contained few fruit and vegetables and no citrus fruit. The high-vegetable diet provided various fruits and vegetables daily including on average one glass of orange juice, one-half orange and one-half mandarin. The high-vegetable diet provided 132 mg of hesperetin and 29 mg of naringenin. The low-vegetable diet contained no flavanones. After the high-vegetable diet, hesperetin and naringenin were detectable in 54 and 22% of all samples. Quercetin was detectable in nearly all samples after all study periods. Hesperetin, naringenin and quercetin are bioavailable from the diet, but the plasma concentrations of hesperetin and naringenin are poor biomarkers of intake.

I am interested in the naringenin content in Eyesight Rx product (per capsule in mg).
   We use a bioflavonoid complex that has several substances in it and it does not say the specific amount.

I am attempting to locate a source of naringenin but have not had any success. I would prefer a purified source from a chemical company, but again, I have not been able to identify any biochemical supply house that offers this product. I would be most appreciative if you could help me out. Even a dietary supplement would be a good start. I am wanting to test its effects on human liver cancer cells. Please disregard my prior e-mail about locating a source. I just found that Sigma Aldrich sells a purified source.

We are a group of middle school students participating in the First Lego League robotics competition. As part of the competition we are researching a topic in Biomedicine and trying to find a unique solution to a key issue in the body. As part of the effort we are to identify a problem as it relates to a specific body part. Our research led us to the negative impact of the fat and sugars in fast food on the pancreas. The high sugar contents of most fast food over stimulate the pancreas causing a peak in sugar, follow by a rapid drop, leaving the individual tired and some cases hungry. This cycle over-stimulates the pancreas and the false sense of repetitive cycle causes obesity and more serious diseases such as diabetes and cancer. To break this cycle, we found that narigenin, a chemical in citrus peels, counteracts the bad effects of fat and sugar on the pancreas.
   One nutrient or substance alone is not able to counteract the deleterious effect of fats and sugars, there is no substitute for a healthy diet, there are hardly any human studies with naringenin as a pill taken orally so it is not known what kind of overall benefit or side effect it will have when taken alone as a supplement as opposed to being present and consumed in combination with other substances found naturally in fruits.

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