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Protective Effects of Citrus Flavanoid Naringenin

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“Orange juice contains naringenin which is effective against melanoma, and guavas contain apigenin, also effective. A diet consisting of milk, orange juice, guavas, cheese, and some eggs, liver, and oysters, with aspirin would be protective against the spread of the tumor.” -Ray Peat, PhD

Free Radic Res. 2013 Oct;47(10):793-803. doi: 10.3109/10715762.2013.823643. Epub 2013 Aug 8.
Ameliorative effect of naringenin on hyperglycemia-mediated inflammation in hepatic and pancreatic tissues of Wistar rats with streptozotocin- nicotinamide-induced experimental diabetes mellitus.
Annadurai T, Thomas PA, Geraldine P.
In diabetes mellitus (DM), sustained hyperglycemia results in the generation of reactive oxygen species, ultimately leading to increased oxidative stress and inflammation in vital tissues. In the present study, possible ameliorative effects of naringenin on hyperglycemia-mediated inflammation in experimental streptozocin (STZ)-nicotinamide-induced DM were sought. DM was induced experimentally in overnight-fasted Wistar rats (150-180 g) by intra-peritoneal injection of STZ (50 mg/kg.b.w) and of nicotinamide (110 mg/kg.b.w); control rats (n = 6) received only vehicle (0.5 ml of 0.1 M of cold citrate buffer; pH 4.5). One group of diabetic rats (n = 6) was left untreated while another group of diabetic rats (n = 6) received naringenin (50 mg/kg b.w./day) orally for 21 days. At this time, hemotological indices (erythrocyte sedimentation rate [ESR], total white blood cell [WBC] count, differential WBC percentage, and platelet count) were measured. Significant alterations in expression of gene and protein biomarkers of inflammation in hepatic and pancreatic tissues were determined by measuring mRNA levels and the level of protein expressed, respectively, as was the total nitric oxide level in these tissues. Diabetic rats showed significantly higher mean ESR values, total WBC counts, differential WBC percentages, and platelet counts than those in control rats; similarly, mean mRNA levels of C-reactive protein, pro-inflammatory cytokine, nuclear factor-κB and inducible nitric oxide synthase genes and mean intensities of expression of the corresponding proteins in the hepatic and pancreatic tissue samples from diabetic rats significantly exceeded those in control rats. However, in diabetic rats treated with naringenin, the values of hematological, mRNA transcript and protein indices of inflammation were all lower than those in diabetic rats. These results suggest that naringenin possibly alleviates hyperglycemia-mediated inflammation in experimental STZ-nicotinamide-induced DM in Wistar rats.

Amino Acids. 2007 Jan;32(1):95-100. Epub 2006 May 15.
Enhancement of transglutaminase activity and polyamine depletion in B16-F10 melanoma cells by flavonoids naringenin and hesperitin correlate to reduction of the in vivo metastatic potential.
Lentini A, Forni C, Provenzano B, Beninati S.
The in vitro and in vivo effects of two flavonons, naringenin (NG) and hesperitin (HP) on the proliferation rate of highly metastatic murine B16-F10 melanoma cell were investigated. NG or HP treatment of melanoma cells produced a remarkable reduction of cell proliferation, paralleled with both the lowering of the intracellular levels of polyamine, spermidine and spermine and the enhancement of transglutaminase (TGase, EC 2.3.2.13) activity. Orally administered NG or HP in C57BL6/N mice inoculated with B16-F10 cells affected the pulmonary invasion of melanoma cells in an in vivo metastatic assay. The number of lung metastases detected by a computerized image analyzer was reduced, compared to untreated animals, by about 69% in NG-treated mice and by about 36% in HP-treated mice. Survival studies showed that 50% of the NG-treated animals died 38 +/- 3.1 days after tumor cell injection (control group: 18 +/- 1.5 days) and HP-treated mice died 27 +/- 2.3 days after cell inoculation. Taken together, these findings provide further evidences for the potential anticancer properties of dietary flavonoids as chemopreventive agents against malignant melanoma.

Chem Biodivers. 2011 Jun;8(6):1152-62. doi: 10.1002/cbdv.201000311.
In vitro cytotoxic activity of extracts and isolated constituents of Salvia leriifolia Benth. against a panel of human cancer cell lines.
Tundis R, Loizzo MR, Menichini F, Bonesi M, Colica C, Menichini F.
In the course of recent efforts to identify new potential antiproliferative active principles, Salvia leriifolia extracts and isolated constituents were evaluated for their cytotoxic activity against a panel of human cancer cell lines, including renal adenocarcinoma (ACHN), amelanotic melanoma (C32), colorectal adenocarcinoma (Caco-2), lung large cell carcinoma (COR-L23), malignant melanoma (A375), lung carcinoma (A549), and hepatocellular carcinoma (Huh-7D12) cells. The hexane and CH(2) Cl(2) extracts showed the strongest cytotoxic activity against the C32 cell line with IC(50) values of 11.2 and 13.6 μg/ml, respectively, and the AcOEt extract was the most active extract against the COR-L23 cell line (IC(50) of 20.9 μg/ml). Buchariol, a sesquiterpene obtained by biofractionation of the CH(2) Cl(2) extract, exhibited a higher activity than the positive control vinblastine against the C32 and A549 cell lines (IC(50) values of 2.1 and 12.6 μM, resp.). Interesting results were also obtained for naringenin, a flavonoid isolated from the AcOEt extract, which exhibited a strong cytotoxic activity against the C32, LNCaP, and COR-L23 cell lines (IC(50) values of 2.2, 7.7, and 33.4 μM, resp.), compared to vinblastine (IC(50) values of 3.3, 32.2, 50.0 μM, resp.). None of the tested compounds affected the proliferation of skin fibroblasts (142BR), suggesting a selective activity against tumor cells.

Biosci Biotechnol Biochem. 2006 Jun;70(6):1499-501.
Stimulation of melanogenesis by the citrus flavonoid naringenin in mouse B16 melanoma cells.
Ohguchi K, Akao Y, Nozawa Y.
Naringenin is a naturally occurring citrus flavanone. In this study, we examined the effect of naringenin on melanogenesis in mouse B16 melanoma cells. Melanin contents and tyrosinase activities were strongly increased by naringenin. Naringenin was found to cause marked increases in the expression levels of melanogenic enzymes.

J Med Food. 2010 Aug;13(4):976-84. doi: 10.1089/jmf.2009.1251.
Protective effect of naringin, a citrus flavonoid, against colchicine-induced cognitive dysfunction and oxidative damage in rats.
Kumar A, Dogra S, Prakash A.
Alzheimer’s disease is a neurodegenerative disorder. Central administration of colchicine is well known to cause cognitive impairment and oxidative damage, which simulates sporadic dementia of the Alzheimer type in humans. The present study has been designed to investigate the protective effects of naringin against the colchicine-induced cognitive impairment and oxidative damage in rats. Colchicine (15 microg/5 microL), administered intracerebroventricularly, resulted in poor memory retention in both the Morris water maze and elevated plus maze task paradigms and caused marked oxidative damage. It also caused a significant decrease in acetylcholinesterase activity. Naringin (40 and 80 mg/kg, p.o.) treatment was given daily for a period of 25 days beginning 4 days prior to colchicine administration. Chronic treatment with naringin caused significant improvement in the cognitive performance and attenuated oxidative damage, as evidenced by lowering of malondialdehyde level and nitrite concentration and restoration of superoxide dismutase, catalase, glutathione S-transferase, and reduced glutathione levels, and acetylcholinesterase activity compared to control. The present study highlights the therapeutic potential of naringin against colchicine-induced cognitive impairment and associated oxidative damage.

J Agric Food Chem. 2008 Aug 13;56(15):6185-205. doi: 10.1021/jf8006568. Epub 2008 Jul 2.
Update on uses and properties of citrus flavonoids: new findings in anticancer, cardiovascular, and anti-inflammatory activity.
Significantly, much of the activity of Citrus flavonoids appears to impact blood and microvascular endothelial cells, and it is not surprising that the two main areas of research on the biological actions of Citrus flavonoids have been inflammation and cancer. Epidemiological and animal studies point to a possible protective effect of flavonoids against cardiovascular diseases and some types of cancer. Although flavonoids have been studied for about 50 years, the cellular mechanisms involved in their biological action are still not completely known. Many of the pharmacological properties of Citrus flavonoids can be linked to the abilities of these compounds to inhibit enzymes involved in cell activation. Attempts to control cancer involve a variety of means, including the use of suppressing, blocking, and transforming agents. Suppressing agents prevent the formation of new cancers from procarcinogens, and blocking agents prevent carcinogenic compounds from reaching critical initiation sites, while transformation agents act to facilitate the metabolism of carcinogenic components into less toxic materials or prevent their biological actions. Flavonoids can act as all three types of agent. Many epidemiological studies have shown that regular flavonoid intake is associated with a reduced risk of cardiovascular diseases. In coronary heart disease, the protective effects of flavonoids include mainly antithrombotic, anti-ischemic, anti-oxidant, and vasorelaxant. It is suggested that flavonoids decrease the risk of coronary heart disease by three major actions: improving coronary vasodilatation, decreasing the ability of platelets in the blood to clot, and preventing low-density lipoproteins (LDLs) from oxidizing. The anti-inflammatory properties of the Citrus flavonoids have also been studied. Several key studies have shown that the anti-inflammatory properties of Citrus flavonoids are due to its inhibition of the synthesis and biological activities of different pro-inflammatory mediators, mainly the arachidonic acid derivatives, prostaglandins E 2, F 2, and thromboxane A 2. The anti-oxidant and anti-inflammatory properties of Citrus flavonoids can play a key role in their activity against several degenerative diseases and particularly brain diseases. The most abundant Citrus flavonoids are flavanones, such as hesperidin, naringin, or neohesperidin. However, generally, the flavones, such as diosmin, apigenin, or luteolin, exhibit higher biological activity, even though they occur in much lower concentrations. Diosmin and rutin have a demonstrated activity as a venotonic agent and are present in several pharmaceutical products. Apigenin and their glucosides have been shown a good anti-inflammatory activity without the side effects of other anti-inflammatory products. In this paper, we discuss the relation between each structural factor of Citrus flavonoids and the anticancer, anti-inflammatory, and cardiovascular protection activity of Citrus flavonoids and their role in degenerative diseases.

Toxicology. 2009 Feb 4;256(1-2):128-34. doi: 10.1016/j.tox.2008.11.012. Epub 2008 Nov 21.
Naringenin protects against cadmium-induced oxidative renal dysfunction in rats.
Renugadevi J, Prabu SM.
Cadmium (Cd) is an environmental and industrial pollutant that affects various organs in human and experimental animals. Naringenin is a naturally occurring plant bioflavonoid found in citrus fruits, which has been reported to have a wide range of pharmacological properties. A body of evidence has accumulated implicating the free radical generation with subsequent oxidative stress in the biochemical and molecular mechanisms of cadmium toxicity. Since kidney is the critical target organ of chronic Cd toxicity, we carried out this study to investigate the effects of naringenin on Cd-induced toxicity in the kidney of rats. In experimental rats, oral administration of cadmium chloride (5mg/(kgday)) for 4 weeks significantly induced the renal damage which was evident from the increased levels of serum urea, uric acid, creatinine with a significant (p<0.05) decrease in creatinine clearance. Cadmium also significantly decreased the levels of urea, uric acid and creatinine in urine. A markedly increased levels of lipid peroxidation markers (thiobarbituric acid reactive substances and lipid hydroperoxides) and protein carbonyl contents with significant (p<0.05) decrease in non-enzymatic antioxidants (total sulfhydryl groups, reduced glutathione, vitamin C and vitamin E) and enzymatic antioxidants (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione S-transferase (GST)) as well as glutathione metabolizing enzymes (glutathione reductase (GR) and glutathione-6-phosphate dehydrogenase (G6PD)) were also observed in cadmium-treated rats. Co-administration of naringenin (25 and 50mg/(kgday)) along with Cd resulted in a reversal of Cd-induced biochemical changes in kidney accompanied by a significant decrease in lipid peroxidation and an increase in the level of renal antioxidant defense system. The histopathological studies in the kidney of rats also showed that naringenin (50mg/(kgday)) markedly reduced the toxicity of Cd and preserved the normal histological architecture of the renal tissue. The present study suggest that the nephroprotective potential of naringenin in Cd toxicity might be due to its antioxidant and metal chelating properties, which could be useful for achieving optimum effects in Cd-induced renal damage.

Basic Clin Pharmacol Toxicol. 2006 May;98(5):456-61.
Influence of naringenin on oxytetracycline mediated oxidative damage in rat liver.
Pari L, Gnanasoundari M.
Naringenin is a naturally occurring citrus flavanone, which has been reported to have a wide range of pharmacological properties. The present work was carried out to evaluate the effect of naringenin on antioxidant and lipid peroxidation status in liver of oxytetracycline-intoxicated rats. Intraperitonial administration of oxytetracycline 200 mg/kg for 15 days resulted a significant elevation in serum hepatospecific markers such as aspartate transaminase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase, and bilirubin and the levels of lipid peroxidation markers (thiobarbituric acid reactive substances (TBARS) and lipid hydroperoxides) in liver. Oxytetracycline also caused a significant reduction in the activities of superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione (GSH), vitamin C and vitamin E in liver. Oral administration of naringenin (50 mg/kg b.w.t.) with oxytetracycline significantly decreased the activities of serum aspartate transaminase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase and the levels of bilirubin along with significant decrease in the levels of lipid peroxidation markers in the liver. In addition, naringenin significantly increased the activities of superoxide dismutase, catalase and GSH peroxidase as well as the level of GSH, vitamin C and vitamin E in liver of the oxytetracycline-treated rats. Our results demonstrate that naringenin exhibited antioxidant property and decrease the lipid peroxidation against oxytetracycline-induced oxidative stress in liver.

Exp Toxicol Pathol. 2010 Mar;62(2):171-81. doi: 10.1016/j.etp.2009.03.010. Epub 2009 May 5.
Cadmium-induced hepatotoxicity in rats and the protective effect of naringenin.
Renugadevi J, Prabu SM.
This experiment pertains to the protective role of naringenin against cadmium (Cd)-induced oxidative stress in the liver of rats. Cadmium is a major environmental pollutant and is known for its wide toxic manifestations. Naringenin is a naturally occurring citrus flavonone which has been reported to have a wide range of pharmacological properties. In the present investigation cadmium (5mg/kg) was administered orally for 4 weeks to induce hepatotoxicity. Liver damage induced by cadmium was clearly shown by the increased activities of serum hepatic marker enzymes namely aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), gamma glutamyl transferase (GGT) and serum total bilirubin (TB) along with the increased level of lipid peroxidation indices (thiobarbituric acid reactive substances (TBARS) and lipid hydroperoxides) and protein carbonyl contents in liver. The toxic effect of cadmium was also indicated by significantly decreased levels of enzymatic antioxidants (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione S-transferase (GST)) and non-enzymatic antioxidants (reduced glutathione (GSH), vitamin C and vitamin E). Administration of naringenin at a dose of (50mg/kg) significantly reversed the activities of serum hepatic marker enzymes to their near-normal levels when compared to Cd-treated rats. In addition, naringenin significantly reduced lipid peroxidation and restored the levels of antioxidant defense in the liver. The histopathological studies in the liver of rats also showed that naringenin (50mg/kg) markedly reduced the toxicity of cadmium and preserved the normal histological architecture of the tissue. The present study suggested that naringenin may be beneficial in ameliorating the cadmium-induced oxidative damage in the liver of rats.

J Physiol Biochem. 2012 Sep;68(3):307-18. doi: 10.1007/s13105-011-0142-y. Epub 2012 Jan 11.
Antihyperglycemic and antioxidant effects of a flavanone, naringenin, in streptozotocin-nicotinamide-induced experimental diabetic rats.
Annadurai T, Muralidharan AR, Joseph T, Hsu MJ, Thomas PA, Geraldine P.
In the present study, the putative antihyperglycemic and antioxidant effects of a flavanone, naringenin, were evaluated in comparison with those of glyclazide, a standard drug for therapy of diabetes mellitus. Diabetes was induced experimentally in 12-h-fasted rats by intraperitoneal injections of first streptozotocin (50 mg/kg b.w.) and then of nicotinamide (110 mg/kg b.w.) after a 15-min interval. Untreated diabetic rats revealed the following in comparison with normal rats: significantly higher mean levels of blood glucose and glycosylated hemoglobin, significantly lower mean levels of serum insulin, significantly lower mean activities of pancreatic antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase), significantly lower mean levels of plasma non-enzymatic antioxidants (reduced glutathione, vitamin C , vitamin E), significantly elevated mean levels of pancreatic malondialdehyde (MDA) and significantly elevated mean activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH). Following oral administration of naringenin (50 mg/kg b.w./day) to diabetic rats for 21 days, the following observations were made in comparison with untreated diabetic rats: significantly lower mean levels of fasting blood glucose and glycosylated hemoglobin, significantly elevated serum insulin levels, significantly higher mean activities of pancreatic enzymatic antioxidants, significantly higher mean levels of plasma non-enzymatic antioxidants, lower mean pancreatic tissue levels of MDA and lower mean activities of ALT, AST, ALP and LDH in serum. The values obtained in the naringenin-treated animals approximated those observed in glyclazide-treated animals. Histopathological studies appeared to suggest a protective effect of naringenin on the pancreatic tissue in diabetic rats. These results suggest that naringenin exhibits antihyperglycemic and antioxidant effects in experimental diabetic rats.

Curr Opin Lipidol. 2013 Feb;24(1):34-40. doi: 10.1097/MOL.0b013e32835c07fd.
Citrus flavonoids and lipid metabolism.
Assini JM, Mulvihill EE, Huff MW.
PURPOSE OF REVIEW:
Citrus flavonoids are polyphenolic compounds with powerful biological properties. This review aims to summarize recent advances towards understanding the ability of citrus flavonoids to regulate lipid metabolism and other metabolic parameters relevant to the metabolic syndrome, type 2 diabetes and cardiovascular disease.
RECENT FINDINGS:
Citrus flavonoids, including naringenin, hesperidin, nobiletin and tangeretin, have emerged as promising therapeutic agents for the treatment of metabolic dysregulation. Epidemiological studies report that intake of citrus flavonoid-containing foods attenuates cardiovascular diseases. Experimental and a limited number of clinical studies reveal lipid-lowering, insulin-sensitizing, antihypertensive and anti-inflammatory properties. In animal models, citrus flavonoid supplements prevent hepatic steatosis, dyslipidemia and insulin sensitivity primarily through inhibition of hepatic fatty acid synthesis and increased fatty acid oxidation. Citrus flavonoids blunt the inflammatory response in metabolically important tissues including liver, adipose tissue, kidney and the aorta. The mechanisms underlying flavonoid-induced metabolic regulation have not been completely established. In mouse models, citrus flavonoids show marked suppression of atherogenesis through improved metabolic parameters and also through direct impact on the vessel wall.
SUMMARY:
These recent studies suggest an important role of citrus flavonoids in the treatment of dyslipidemia, insulin resistance, hepatic steatosis, obesity and atherosclerosis. The favorable outcomes are achieved through multiple mechanisms. Human studies focussed on dose, bioavailability, efficacy and safety are required to propel the use of these promising therapeutic agents into the clinical arena.

Int J Tissue React. 1983;5(4):415-20.
The gastric anti-ulcer activity of naringenin, a specific histidine decarboxylase inhibitor.
Parmar NS.
The gastric anti-ulcer activity of a specific histidine decarboxylase inhibitor naringenin, the aglycone of naringin, a naturally occurring flavanone glycoside obtained from kino and grapefruits, has been studied on the various types of ulcers experimentally induced in rats, viz., pylorus-ligated (Shay method) and restraint ulcers, and on the gastric mucosal damage induced by aspirin, phenylbutazone or reserpine. Naringenin possessed significant anti-ulcer activity in all these models, manifesting a dose-dependent anti-ulcer effect on the pylorus-ligated and restraint ulcers. However, the ED50 value against ulcers in the pylorus-ligated rats (132 mg/kg) was significantly greater than that against ulcers in the restraint rats (42 mg/kg). Amongst all the models used, naringenin was found most effective against the restraint rats. It is suggested that a mechanism involving the inhibition of formation and release of endogenous histamine in the gastric mucosa of rats is implicated in the protective effect of naringenin.

Phytomedicine. 2011 Nov 15;18(14):1244-9. doi: 10.1016/j.phymed.2011.06.028. Epub 2011 Jul 28.
Citrus flavanone naringenin enhances melanogenesis through the activation of Wnt/β-catenin signalling in mouse melanoma cells.
Huang YC, Yang CH, Chiou YL.
Citrus fruits are the major source of flavonoids for humans, and flavanones are the main flavonoids in the Citrus species. Among the Citrus flavanones, the glycoside derivatives of naringenin, naringin and narirutin, are the most abundant in grapefruit. The present study aimed to investigate the molecular events of melanogenesis induced by naringenin in murine B16-F10 melanoma cells. Melanin content, tyrosinase activity and Western blot analysis were performed to elucidate the possible underlying mechanisms. Exposure of melanoma cells to naringenin resulted in morphological changes accompanied by the induction of melanocyte differentiation-related markers, such as melanin synthesis, tyrosinase activity, and the expression of tyrosinase and microphthalmia-associated transcription factor (MITF). We also observed an increase in the intracellular accumulation of β-catenin as well as the phosphorylation of glycogen synthase kinase-3β (GSK3β) protein after treatment with naringenin. Moreover, the activity of phosphatidylinositol 3-kinase (PI3K) was up-regulated by naringenin since the phosphorylated level of downstream Akt protein was enhanced. Based on these results, we concluded that naringenin induced melanogenesis through the Wnt-β-catenin-signalling pathway.

Phytother Res. 2011 Apr;25(4):569-76. doi: 10.1002/ptr.3302. Epub 2010 Sep 20.
Hydrolysates of citrus plants stimulate melanogenesis protecting against UV-induced dermal damage.
Chiang HM, Lin JW, Hsiao PL, Tsai SY, Wen KC.
The sun-tanning process occurs as a spontaneous response to ultraviolet (UV) irradiation. UV will induce tanning and DNA damage, processes that can lead to photoaging and skin disorders such as hyperpigmentation and cancer. The pigment melanin protects skin from UV damage; therefore, an efficient melanin-promoting suntan lotion could be highly beneficial. In this study, a process was developed to increase the content of naringenin in citrus extracts and to determine whether a higher naringenin content of citrus would induce melanogenesis. Melanin content and tyrosinase expression in mouse B16 melanoma cells were assayed after treatment with citrus plant extracts and their hydrolysates. The results indicate that hydrolysis increased the naringenin content in citrus extracts and that citrus preparations stimulated cellular melanogenesis and tyrosinase expression. It is suggested that this method is applicable to the industrial production of melanin-promoting suntan lotions with antiphotocarcinogenic properties derived from citrus rind and citrus products.

J Periodontal Res. 2008 Aug;43(4):400-7. doi: 10.1111/j.1600-0765.2007.01055.x.
Naringenin has anti-inflammatory properties in macrophage and ex vivo human whole-blood models.
Bodet C1, La VD, Epifano F, Grenier D.
BACKGROUND AND OBJECTIVE:
Periodontitis is a chronic inflammatory disease of bacterial etiology, affecting tooth-supporting tissues. The host inflammatory response to periodontopathogens, notably the high and continuous production of cytokines, is considered a major factor causing the local tissue destruction observed in periodontitis. The aim of the present study was to investigate the effect of naringenin, a major flavanone in grapefruits and tomatoes, on the lipopolysaccharide-induced pro-inflammatory cytokine production by host cells, using two different models.
MATERIAL AND METHODS:
The effect of naringenin was characterized using macrophages stimulated with the lipopolysaccharide of either Aggregatibacter actinomycetemcomitans or Escherichia coli and using whole blood stimulated with A. actinomycetemcomitans lipopolysaccharide, in the presence or absence of naringenin. Lipopolysaccharide-induced interleukin-1 beta, interleukin-6, interleukin-8 and tumor necrosis factor-alpha production by macrophages and whole-blood samples treated with naringenin were evaluated using an enzyme-linked immunosorbent assay. Changes in the phosphorylation states of macrophage kinases induced by A. actinomycetemcomitans lipopolysaccharide and naringenin were characterized by immunoblot screening.
RESULTS:
Our results clearly indicated that naringenin is a potent inhibitor of the pro-inflammatory cytokine response induced by lipopolysaccharide in both macrophages and in whole blood. Naringenin markedly inhibited the phosphorylation on serines 63 and 73 of Jun proto-oncogene-encoded AP-1 transcription factor in lipopolysaccharide-stimulated macrophages.
CONCLUSION:
The results from the present study suggest that naringenin holds promise as a therapeutic agent for treating inflammatory diseases such as periodontitis.

Br J Nutr. 2013 Aug;110(4):599-608. doi: 10.1017/S0007114512005594. Epub 2013 Mar 18.
Protective effect of naringenin against experimental colitis via suppression of Toll-like receptor 4/NF-κB signalling.
Dou W1, Zhang J, Sun A, Zhang E, Ding L, Mukherjee S, Wei X, Chou G, Wang ZT, Mani S.
Naringenin, one of the most abundant flavonoids in citrus, grapefruits and tomatoes, has been used as a traditional anti-inflammatory agent for centuries. However, the molecular mechanism of naringenin in intestinal inflammation remains unknown so far. The present study investigated a molecular basis for the protective effect of naringenin in dextran sulphate sodium-induced murine colitis. Pre-administration of naringenin significantly reduced the severity of colitis and resulted in down-regulation of pro-inflammatory mediators (inducible NO synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1), cyclo-oxygenase-2 (Cox2), TNF-α and IL-6 mRNA) in the colon mucosa. The decline in the production of pro-inflammatory cytokines, specifically TNF-α and IL-6, correlated with a decrease in mucosal Toll-like receptor 4 (TLR4) mRNA and protein. Phospho-NF-κB p65 protein was significantly decreased, which correlated with a similar decrease in phospho-IκBα protein. Consistent with the in vivo results, naringenin exposure blocked lipopolysaccharide-stimulated nuclear translocation of NF-κB p65 in mouse macrophage RAW264.7 cells. In addition, in vitro NF-κB reporter assays performed on human colonic HT-29 cells exposed to naringenin demonstrated a significant inhibition of TNF-α-induced NF-κB luciferase expression. Thus, for the first time, the present study indicates that targeted inhibition of the TLR4/NF-κB signalling pathway might be an important mechanism for naringenin in abrogating experimental colitis.

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