Naringenin suppresses NLRP3 inflammasome activation via the mRNA-208a signaling pathway in isoproterenol-induced myocardial infarction

Objective:To investigate the cardioprotective effect of naringenin against isoproterenol(ISO)-induced cardiotoxicity in rats.Methods:Rats were divided into five groups:the normal group,the ISO group(85 mg/kg b.w.);the ISO+naringenin(50 mg/kg b.w.)group,the ISO+naringenin(100 mg/kg b.w.)group and the ISO+propranolol(10 mg/kg b.w.)group.Plasma creatine kinase-MB(CK-MB),cardiac troponin T,lactate dehydrogenase,brain natriuretic peptide(BNP),and IL-10,as well as cardiac transforming growth factor-β1(TGF-β1),vascular endothelial growth factor(VEGF)and malondialdehyde(MDA)were examined.In addition,NLRP3 and mRNA-208a expressions were evaluated by RT-PCR analysis.Histopathological examination was also performed to assess cardiac damages.Results:Naringenin treatment significantly decreased plasma lactate dehydrogenase,CK-MB,cardiac troponin T,BNP,and IL-10,as well as cardiac TGF-β1,VEGF,and MDA while increasing p-Akt and superoxide dismutase in ISO-administered rats.It also reduced NLRP3 and mRNA-208a gene expression levels.Furthermore,naringenin improved ISO-induced cardiac damage.Conclusions:Naringenin attenuates myocardial dysfunction in ISO-treated rats by decreasing oxidative stress and increasing cardiac endogenous antioxidant system,which may be modulated partly by improvement of NLRP3 and mRNA-208a gene expression.

Naringenin inhibits lipid accumulation by activating the AMPK pathway in vivo and in vitro

The aim of this study was to explore the lipid-lowering effect of naringenin and the underlying mechanism in high-fat-diet-fed SD rats and 3T3-L1 cells.In this study,SD rats were divided into the normal chow diet group(NCD),high fat diet group(HFD),three treatment groups feeding high-fat diet with naringenin(100,200,400 mg/kg)for 12 weeks.Results indicated that naringenin treatment decreased total cholesterol(TC),triglyceride(TG)and the non-high-density lipoprotein cholesterol(non-HDL-C)levels in serum.Naringenin also alleviated hepatic steatosis and reduced the adipocyte size in the epididymis in high-fat-diet-induced SD rats.In addition,naringenin(25−75μg/mL)decrease TG and TC levels in 3T3 mature adipocytes.The molecular mechanism of naringenin in the treatment of obesity were predicted by using network pharmacology.Real-time PCR analysis results showed that naringenin regulated the expression of lipid metabolism genes.Meanwhile,naringenin increased the AMPK(AMP-activated protein kinase)activity and the expression of AMPK phosphorylated protein in 3T3 mature adipocytes.And the inhibitory effect of naringenin on lipid accumulation in 3T3 adipocytes was abolished by Compound C.Molecular docking results indicated that naringenin could bind to AMPK protein.These results indicated naringenin reduced lipid accumulation through AMPK pathway.

Cytotoxic, genotoxic and apoptotic effects of naringenin-oxime relative to naringenin on normal and cancer cell lines

Objective: To assess and compare the cytotoxic, genotoxic, apoptotic and reactive oxygen species(ROS) generating effects of naringenin(NG) and its new derived compound naringenin-oxime(NG-Ox) on MCF-7, HT-29, PC-12 cancer and L-929 normal cell lines.Methods: The cells were incubated with different doses of NG-Ox and NG(50–1 000 mmol/L) for 24 h. The cell viability was assessed based on ATP cell viability assay.Intracellular accumulation of ROS was determined using the fluorescent probes 2070-dichlorodihydrofluorescin diacetate. Genotoxic effects were evaluated by alkaline single cell gel electrophoresis assay(comet assay) and, the apoptotic effect was evaluated by acridine orange staining at below the IC50 levels.Results: Both NG-Ox and NG exhibited cytotoxic, genotoxic and apoptotic effects and resulted in increased ROS values in a dose-dependent manner. The effects were more pronounced on cancer cell lines. The cytotoxic, genotoxic and apoptotic effects of NG-Ox were higher than that of NG in all cell lines. Significant correlations were observed between cell viability, DNA damage, apoptosis and ROS, in all cell lines exposed to either NG-Ox or NG.Conclusions: This study showed that both NG-Ox and NG possess cytotoxic, genotoxic and apoptotic activities through the production of ROS on cells, NG-Ox being the more effective one. Therefore, derived compound of NG might be used as antiproliferative agents for the treatment of cancer.

Naringenin在碘酸钠诱导的视网膜色素上皮细胞变性和激光诱导的脉络膜新生血管鼠模型中的作用(英文)

目的:研究naringenin滴眼对碘酸钠诱导的大鼠视网膜色素上皮(retinal pigment epithelium,RPE)变性以及对激光诱导的脉络膜新生血管(choroidal neovascularization,CNV)的作用。方法:10g/Lnaringenin滴眼液预先处理1wk(3次/d),1wk后予35mg/kg碘酸钠舌下静脉注射诱导大鼠RPE变性,在2wk和4wk末,视网膜电图(electroretinogram,ERG)测量C波。另预处理1wk(3次/d),在2wk和4wk末用荧光素血管造影(fluorescein angiography,FA)和荧光显微镜测量CNV面积。结果:碘酸钠注射后2wk,碘酸钠组ERG的C波下降至对照组的53%(P<0.01)。而naringenin+碘酸钠组则无明显变化。4wk后,碘酸钠组下降至对照组的37%(P<0.01),而naringenin+碘酸钠组下降至对照组的57%(P<0.01)。与碘酸钠组比较,naringenin+碘酸钠组控制了66%的C波下降(P<0.05)。35mg/kgnaringenin组FA测量的CNV面积2,4wk末分别是对照组的53%和49%(P<0.01)。4wk后naringenin组荧光显微镜测量的CNV面积是对照组的47%(P<0.01)。结论:10g/Lnaringenin可以显著保护碘酸钠诱导的RPE变性,也能减小CNV的形成。

Protective effect of naringenin on acetic acid-induced ulcerative colitis in rats

AIM:To evaluate the ameliorative effect of naringenin(NG)during ulcerative colitis(UC)in rats.METHODS:Rats were treated with three different doses(25,50 and 100 mg/kg per day)of NG and a single dose of mesalazine(MES,300 mg/kg per day)for seven days prior to ulcerative colitis induction by4%acetic acid(AA).Twenty four hours after AA rectal administration,animals were scarified and the colonic tissues were dissected.Colonic mucus content was estimated using Alcian blue dye binding technique.In colon tissues,levels of total glutathione sulphadryls(T-GSH),non-protein sulphadryls(NP-SH)and thiobarbituric acid reactive substances(TBARS)were evaluated.The activities of the antioxidant enzymes,catalase(CAT)and superoxide dismutase(SOD)were measured.Concentrations of nucleic acids(DNA and RNA)and total protein were also estimated in colon tissues.Colonic levels of tumor necrosis factor-(TNF-),interleukin-1(IL-1),interleukin-6(IL-6),prostaglandin E2(PGE2)and nitric oxide(NO)were estimated.In cross section of colitis tissue the histopathological changes were observed.RESULTS:Colonic mucus content was decreased in AA compared to controls(587.09±65.59 mg/kg vs941.78±68.41 mg/kg,P<0.001).AA administration markedly reduced T-GSH(5.25±0.37 nmol/L vs 3.04±0.24 nmol/L,P<0.01),NP-SH(3.16±0.04 nmol/L vs 2.16±0.30 nmol/L,P<0.01),CAT(6.77±0.40 U/mg vs 3.04±0.2 U/mg,P<0.01)and SOD(3.10±0.11U/mg vs 1.77±0.18 U/mg,P<0.01)while TBARS,TNF-,IL-1,IL-6,PGE2 and NO levels(15.09±3.84nmol/L vs 59.90±16.34 nmol/L,P<0.01;113.56±1.91 pg/mg vs 134.24±4.77 pg/mg,P<0.01;209.20±36.38 pg/mg vs 422.19±31.47 pg/mg,P<0.01;250.83±25.09 pg/mg vs 638.58±115.9 pg/mg,P<0.01;248.19±36.98 pg/mg vs 541.74±58.34 pg/mg,P<0.01 and 81.26±2.98 mmol/g vs 101.90±10.73 mmol/g,P<0.001)were increased in colon of rats with UC compared controls respectively.Naringenin supplementation,significantly and dose dependently increased the colonic mucus content.The elevated TBARS levels were significantly decreased(39.35±5.86nmol/L,P<0.05;26.74±3.17 nmol/L,P<0.01 nmol/L and 17.74±2.69 nmol/L,P<0.01)compared to AA(59.90±16.34 nmol/L)group while the decreased levels of T-GSH and NP-SH and activities of CAT and SOD found increased by NG treatments in dose dependent manner.The decreased values of nucleic acids and total protein in AA group were also significantly(P<0.01)increased in all three NG supplemented groupsrespectively.NG pretreatment inhibited the TNF-levels(123.76±3.76 pg/mg,122.62±3.41 pg/mg and121.51±2.61 pg/mg vs 134.24±4.78 pg/mg,P<0.05)compared to AA group,respectively.Interleukins,IL-1 and IL-6 levels were also decreased in NG50+AA(314.37±16.31 pg/mg and 292.58±23.68 pg/mg,P<0.05)and NG100+AA(416.72±49.62 pg/mg and 407.96±43.87 pg/mg,P<0.05)when compared to AA(352.46±8.58 pg/mg and 638.58±115.98pg/mg)group.Similar decrease(P<0.05)was seen in PGE2and NO values when compared to AA group.The group pretreated with MES,as a reference drug,showed significant(P<0.01)protection against the changes induced in colon tissue by AA administration respectively.CONCLUSION:In present study,NG produced antioxidant and anti-inflammatory effects demonstrating protective effect in inflammatory bowel disease.

Beneficial effects of naringenin in liver diseases: Molecular mechanisms

Liver diseases are caused by different etiological agents, mainly alcohol consumption, viruses, drug intoxication or malnutrition. Frequently, liver diseases are initiated by oxidative stress and inflammation that lead to the excessive production of extracellular matrix(ECM), followed by a progression to fibrosis, cirrhosis and hepatocellular carcinoma(HCC). It has been reported that some natural products display hepatoprotective properties. Naringenin is a flavonoid with antioxidant, antifibrogenic, anti-inflammatory and anticancer properties that is capable of preventing liver damage caused by different agents. The main protective effects of naringenin in liver diseases are the inhibition of oxidative stress, transforming growth factor(TGF-β) pathway and the prevention of the transdifferentiation of hepatic stellate cells(HSC), leading to decreased collagen synthesis. Other effects include the inhibition of the mitogen activated protein kinase(MAPK), toll-like receptor(TLR) and TGF-β non-canonical pathways, the inhibition of which further results in a strong reduction in ECM synthesis and deposition. In addition, naringenin has shown beneficial effects on nonalcoholic fatty liver disease(NAFLD) through the regulation of lipid metabolism, modulating the synthesis and oxidation of lipids and cholesterol. Moreover, naringenin protects from HCC, since it inhibits growth factors such as TGF-β and vascular endothelial growth factor(VEGF), inducing apoptosis and regulating MAPK pathways. Naringenin is safe and acts by targeting multiple proteins. However, it possesses low bioavailability and high intestinal metabolism. In this regard, formulations, such as nanoparticles or liposomes, have been developed to improve naringenin bioavailability. We conclude that naringenin should be considered in the future as an important candidate in the treatment of different liver diseases.

Naringenin prevents experimental liver fibrosis by blocking TGFβ-Smad3 and JNK-Smad3 pathways

AIM To study the molecular mechanisms involved in the hepatoprotective effects of naringenin(NAR)on carbon tetrachloride(CCl4)-induced liver fibrosis.METHODS Thirty-two male Wistar rats(120-150 g)were randomly divided into four groups:(1)a control group(n=8)that received 0.7%carboxy methyl-cellulose(NAR vehicle)1 m L/daily p.o.;(2)a CCl4 group(n=8)that received 400 mg of CCl4/kg body weight i.p.3 times a week for 8 wk;(3)a CCl4+NAR(n=8)group that received 400 mg of CCl4/kg body weight i.p.3times a week for 8 wk and 100 mg of NAR/kg body weight daily for 8 wk p.o.;and(4)an NAR group(n=8)that received 100 mg of NAR/kg body weight daily for 8 wk p.o.After the experimental period,animals were sacrificed under ketamine and xylazine anesthesia.Liver damage markers such as alanine aminotransferase(ALT),alkaline phosphatase(AP),γ-glutamyl transpeptidase(γ-GTP),reduced glutathione(GSH),glycogen content,lipid peroxidation(LPO)and collagen content were measured.The enzymatic activity of glutathione peroxidase(GPx)was assessed.Liver histopathology was performed utilizing Masson’s trichrome and hematoxylin-eosin stains.Zymography assays for MMP-9 and MMP-2 were carried out.Hepatic TGF-β,α-SMA,CTGF,Col-I,MMP-13,NF-κB,IL-1,IL-10,Smad7,Smad3,p Smad3 and p JNK proteins were detected via western blot.RESULTS NAR administration prevented increases in ALT,AP,γ-GTP,and GPx enzymatic activity;depletion of GSH and glycogen;and increases in LPO and collagen produced by chronic CCl4 intoxication(P<0.05).Liver histopathology showed a decrease in collagen deposition when rats received NAR in addition to CCl4.Although zymography assays showed that CCl4 produced an increase in MMP-9 and MMP-2gelatinase activity;interestingly,NAR administration was associated with normal MMP-9 and MMP-2 activity(P<0.05).The anti-inflammatory,antinecrotic and antifibrotic effects of NAR may be attributed to its ability to prevent NF-κB activation and the subsequent production of IL-1 and IL-10(P<0.05).NAR completely prevented the increase in TGF-β,α-SMA,CTGF,Col-1,and MMP-13 proteins compared with the CCl4-treated group(P<0.05).NAR prevented Smad3phosphorylation in the linker region by JNK since this flavonoid blocked this kinase(P<0.05).CONCLUSION NAR prevents CCl4 induced liver inflammation,necrosis and fibrosis,due to its antioxidant capacity as a free radical inhibitor and by inhibiting the NF-κB,TGF-β-Smad3 and JNK-Smad3 pathways.

Targeting MAPK pathways by naringenin modulates microglia M1 / M2 polarization in lipopolysaccharide-stimulated cultures

OBJECTIVE Neuroinflammation is considered to be an important and inevitable pathological process associated with all types of damages to the central nervous system.The hallmark of neuroinflammation is the microglia activation.In response to different micro-environmental disturbances,microglia could polarize into either an M1 pro-inflammatory phenotype,exacerbating neurotoxicity,or an M2 anti-inflammatory phenotype,exerting neuroprotection.Therefore,shifting the polarization of microglia toward the M2 phenotype could possess a more viable strategy for the neuroinflammatory disorders treatment.Naringenin(NAR) is natural y a grapefruit flavonoid and possesses various kinds of pharmacological activities,such as anti-inflammatory and neuroprotective activities.In the present study,we aimed to investigate the potential effects of NAR on microglial M1/M2 polarization and further reveal the underlying mechanisms of actions.METHODS BV-2 cells were pretreated with NAR(100 μmol·L^(-1)) for 1 h and then incubated with LPS(1 mg·L^(-1)) for 24 h.The effects of NAR on LPS-induced microglia activation,microglial M1/M2 polarization and MAPK pathways were detected.In addition,BV-2 cells were incubated with or without anisomycin(ANI,a selective agonist of JNK) to evaluate the role of JNK on microglia activation and microglia M1/M2 polarization.RESULTS First,NAR inhibited LPS-induced microglial activation.Then,NAR shifted the M1 pro-inflammatory microglia phenotype to the M2 anti-inflammatory M2 microglia state as demonstrated by the decreased expression of M1 markers,ie,inducible tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β)and the elevated expression of M2 markers(ie,arginase 1,IL-4 and IL-10).In addition,the effects of NAR on microglial polarization was dependent on MAPK signaling,particularly JNK inactivation,as evidenced by the fact that the selective activator of JNK abolished NAR-promoted M2 polarization and further NAR-inhibited microglial activation.CONCLUSION NAR promotes microglia M1/M2 polarization,thus conferring anti-neuroinflammatory effects via the inhibition of MAPK signaling activation.These findings might provide new alternative avenues for neuroinflammation-related disorders treatment.

Naringenin protects against isoniazid- and rifampicininduced apoptosis in hepatic injury

AIM To explore the protective effects and mechanisms of naringenin(NRG) on hepatic injury induced by isoniazid(INH) and rifampicin(RIF).METHODS Male mice were randomly divided into four groups and treated for 14 d as follows: normal control group was administered intragastrically with normal saline solution alone; model group was administered intragastrically with INH(100 mg/kg) and RIF(100 mg/kg); lowand high-dosage NRG pretreatment groups were administered intragastrically with different doses of NRG(50 or 100 mg/kg) 2 h before INH and RIF challenge. Mice were killed 16 h after the last dose of drug treatment to determine activity of serum transaminases. Oxidative stress was evaluated by measuring hepatic glutathione(GSH) and superoxide dismutase(SOD) and malondialdehyde(MDA) levels. Histopathological changes in hepatic tissue were observed under the optical microscope. Hepatocyte apoptosis was measured by TUNEL assay and caspase-3 activation. Expression of Bcl-2 and Bax in liver was determined by western blot.RESULTS Both low- and high-dosage NRG pretreatment obviously alleviated serum levels of alanine aminotransferase and aspartate aminotransferase, liver index, hepatic MDA content, and increased hepatic GSH content and SOD activity compared with the INH and RIF-treated group(44.71 ± 8.15 U/L, 38.22 ± 6.64 U/L vs 58.15 ± 10.54 U/L; 98.36 ± 14.78 U/L, 92.41 ± 13.59 U/L vs 133.05 ± 19.36 U/L; 5.34% ± 0.26%, 4.93% ± 0.25% vs 5.71% ± 0.28%; 2.76 ± 0.67 nmol/mgprot, 2.64 ± 0.64 nmol/mgprot vs 4.49 ± 1.12 nmol/mgprot; 5.91 ± 1.31 mg/gprot, 6.42 ± 1.42 mg/gprot vs 3.11 ± 0.73 mg/gprot; 137.31 ± 24.62 U/mgprot, 148.83 ± 26.75 U/mgprot vs 102.34 ± 19.22 U/mgprot; all P < 0.01 or 0.05). Histopathological evaluation showed obvious necrosis and inflammatory cell infiltration in liver of mice administered INH and RIF; however, mice pretreated with NRG showed minor hepatic injury. In addition, INH and RIF resulted in hepatocyte apoptosis, and NRG pretreatment dramatically suppressed INHand RIF-induced hepatocytes apoptosis. Furthermore, NRG-mediated anti-apoptotic effects seemed to be in connection with its regulation of Bax and Bcl-2 protein expression in hepatic tissue.CONCLUSION NRG might attenuate INH- and RIF-induced hepatic injury via suppression of oxidative stress and hepatocyte apoptosis.

Protective effects of naringenin eye drops on N-methylN-nitrosourea-induced photoreceptor cell death in rats

AIM:To investigate the effects of naringenin eye drops on N-methyl-N-nitrosourea (MNU)-induced photoreceptor cell death in rats.METHODS:Photoreceptor cell death was induced by single intraperitoneal injection of MNU(60 mg/kg)in rats.Both eyes of all animals were instilled with one drop of vehicle,0.5% or 1.0% naringenin eye drops three times per day from 7d before to 17d after MNU injection.Effects of naringenin on MNU-induced photoreceptor cell death were evaluated by electrophysiological and histological analysis.RESULTS:Flash electroretinography (FERG)and oscillatory potentials (OPs) recordings showed that the vehicle control group had remarkable reduction of amplitudes and prolongation of latency times.FERG and OPs responses were significantly reversed in MNUinduced rats treated with 0.5%or 1.0% naringenin eye drops compared with the vehicle control.The retinal morphological results showed that naringenin dosedependently preserved the outer nuclear layer,outer retina and total retina.CONCLUSION:These results indicate that topical treatment with naringenin eye drops prevented retinal neurons from MNU-induced structural and functional damages.

Naringenin nanocrystals for improving antirheumatoid arthritis activity

Naringenin(NAR)is recognized for its anti-inflammatory activity.However,the clinical application of NAR is limited by low bioavailability,which is attributed to its poor aqueous solubility.In this study,we aimed to improve the therapeutic efficacy of NAR by formulating it into nanocrystals(NCs)via wet milling.The obtained NARNCs exhibited superior dissolution behaviors,increased cellular uptake,and enhanced transcellular diffusion relative to those of bulk NAR.Oral administration of NARNCs also significantly improved bioavailability in rats.In addition,the NARNCs effectively improved rheumatoid arthritis treatment in collagen-induced arthritic rats by reducing inflammatory cell infiltration and synovial damage.These results indicate that NARNCs provides a promising strategy for rheumatoid arthritis treatment.

Antibacterial activity of naringenin-rich fraction of pigeon pea leaves toward Salmonella thypi

Objective: To identify bioactive compound in pigeon pea leaves(Cajanus cajan) that inhibits Salmonella thypi(S. thypi).Methods: The leaf sample was powdered and macerated with methanol and fractioned by liquid-liquid extraction using ethyl acetate. The fraction was chromatographed and the isolates were identified for major component with liquid chromatography-mass spectrometry and the antibacterial activity was tested against S. thypi by Kirby-Bauer method.Results: Subtraction 1 from the ethyl acetate fraction formed a yellowish solid with m/z 272, identified as naringenin. The naringenin-rich fraction shows fairly well inhibitory toward S. thypi in comparison with chloramphenicol.Conclusions: Naringcnin shows antibacterial activity and can be developed to treat typhoid.

Naringenin protects LPS-induced dopaminergic neurons damage through mediating NLRP3 inflammasome

OBJECTIVE To research the effect of naringenin(NAR) on LPS-induced dopaminergic neurons damage and its potential mechanism.METHODS Rats were randomly divided into the following six groups(n=10):control(0.9% NaCl),NAR alone(100 mg·kg-1),LPS(5 μg),LPS+NAR(50 mg·kg-1) and LPS+NAR(100 mg·kg-1).Rats were received a single LPS unilateral injection into the SN pars compacts,after seven daily intragastric administration of NAR,rats′ behavior was analyzed by rotarod test.Then,the expression of TH,IBA-1 and NLRP3 inflammasome were analyzed by Western blotting and immunofluorescence.In vitro experiments,BV-2 cel s were treated with different doses of NAR,and 1 h later,LPS(1 g·L^(-1)) was added to the medium for 24 h,then collect the culture medium and protein for later experiments.The production of IL-1β and IL-18 in culture medium were tested by ELISA,and the production of NO was detected by Griess reagent.The expression of IBA-1,NLRP3 and p-caspase 1 were detected by Western blotting.MN9 D cells were co-cultured with BV2 cells to mimic the animal experiments.MTT assay was used to analyzed the viability of MN9 D cells,and the expression of TH was detected by Western blotting.RESULTS NAR(100 mg · kg-1) could significantly improve the time of rats on the rotating(116.73 s vs 185.45 s,P<0.05).The result of the pathological analysis also suggested that NAR could decrease the activation of microglia as well as the expression of NLRP3 Inflammasome.In addition,NAR also could suppress the expression of pro-inflammatory factor levels,such as IL-1β(P<0.05),IL-18(P<0.05),and the protection of NAR could be inhibited by siR NA NLRP3.Moreover,an in vitro co-culture system with BV2 and MN9 D cells wasused to find the protection of NAR must via microglia,while there is no effect of NAR were directly added to MN9 D cells.CONCLUSION NAR protection of LPS-induced dopaminergic neurons damage might be through mediating NLRP3 inflammasome.

Improved performance of naringenin herbosomes over naringenin in streptozotocin- induced diabetic rats: In vitro and in vivo evaluation

Objective:To prepare naringenin herbosome and evaluate its antidiabetic activity.Methods:Herbosomes were prepared by the solvent evaporation method.In vitro parameters like particle size,polydispersity index,zeta potential,and entrapment efficiency were estimated and in vitro diffusion study was performed.The in vivo studies were also performed in streptozotocin-induced diabetic male Sprague Dawley rats to evaluate blood glucose,total cholesterol,triglyceride,blood urea nitrogen,total protein,albumin level,aspartate aminotransferase,and alanine aminotransferase levels.Results:The optimized herbosome batch showed a particle size of 564.4 nm,a polydispersity index of 0.412,and zeta potential of−39.3 mV.The percentage entrapment of this formulation was 84.04%,with complete drug release within 8 h.Treatment of diabetic rats with naringenin herbosomes for 28 d significantly reduced the elevated level of plasma glucose as compared to plain naringenin.In biochemical parameters,the treatment showed a significant decrease in total cholesterol,triglyceride,and blood urea nitrogen;while elevated levels of aspartate aminotransferase and alanine aminotransferase were returned to normal.Pure naringenin and herbosome formulation at high dose increased the total protein whereas albumin level significantly increased in naringenin herbosomes at the highest dose but not in the pure naringenin treatment group.Conclusions:Naringenin herbosomes could improve the metabolic profile of diabetic rats,indicating enhanced antidiabetic activity of herbosome formulation.

Therapeutic Applications of Naringenin, a Flavanone Enriched in Citrus Fruits, for Disorders beyond Diabetes

In recent years,there has been an increase in epidemiological studies to highlight the health benefits of plant secondary metabolites.Flavonoids(polyphenolic plant secondary metabolites)are recently emerging as an important source for the discovery of new drugs increasing their pharmaceuticals,nutraceutical and medicinal applications.Naringenin is a flavanone,enriched in citrus fruits,tomatoes,bergamot,etc.which has been evaluated extensively for managing diabetes.However,in addition to this,naringenin had been ascribed to various important biological activities like antioxidant,antiviral,anticancer,anti-inflammatory,antiestrogenic,etc.This article aims at highlighting the therapeutic value of naringenin in managing disorders other than diabetes and its role in regulating gene expression by altering chromatin structure as histone deacetylase inhibitor.The understanding of these phenomena will increase the overall knowledge of the various health-promoting effects of citrus fruits.

Ameliorative effect of naringenin in intoxication cases recovery

The use of bioactive compounds as alternative medicine in the treatment of some intoxication cases is growing in the last years.Flavonoids are one of these bioactive compounds that are plant-based dietary nutrients.Naringenin is the most influential flavonoid wherein it is found in citrus fruits such as orange,grapefruit,and mandarin.A lot of studies showed the ability of naringenin to scavenge free radicals in different body tissues preventing oxidative stress toxicity and lipid peroxidation.Therefore,naringenin can protect many body organs and systems against toxic manifestations of many drugs and toxic agents.So,it prevents the liver,kidney,heart,testes,and neurological system from toxic effects of a wide range of toxicants.Moreover,it can also ameliorate manifestations of cytotoxicity and developmental toxicity based on its efficacy as an antioxidant.

Naringenin is a Potential Immunomodulator for Inhibiting Liver Fibrosis by Inhibiting the cGAS-STING Pathway

Background and Aims:Naringenin is an anti-inflammatory flavonoid that has been studied in chronic liver disease.The mechanism specific to its antifibrosis activity needs further investigation This study was to focused on the cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)pathway in hepatic stellate cells and clarified the antifibrosis mechanism of naringenin.Methods:The relationship between the cGAS-stimulator of interferon genes(STING)pathway and liver fibrosis was analyzed using the Gene Expression Omnibus database.Histopathology,immunohistochemistry,fluorescence staining,Western blotting and polymerase chain reaction were performed to assess gene and protein expression levels associated with the cGAS pathway in clinical liver tissue samples and mouse livers.Molecular docking was performed to evaluate the relationship between naringenin and cGAS,and western blotting was performed to study the expression of inflammatory factors downstream of cGAS in vitro.Results:Clinical database analyses showed that the cGAS-STING pathway is involved in the occurrence of chronic liver disease.Naringenin ameliorated liver injury and liver fibrosis,decreased collagen deposition and cGAS expression,and inhibited inflammation in carbon tetrachloride(CCl4)-treated mice.Molecular docking found that cGAS may be a direct target of naringenin.Consistent with the in vivo results,we verified the inhibitory effect of naringenin on activated hepatic stellate cells(HSCs).By using the cGAS-specific agonist double-stranded(ds)DNA,we showed that naringenin attenuated the activation of cGAS and its inflammatory factors affected by dsDNA.We verified that naringenin inhibited the cGAS-STING pathway,thereby reducing the secretion of inflammatory factors by HSCs to ameliorate liver fibrosis.Conclusions:Interrupting the cGAS-STING pathway helped reverse the fibrosis process.Naringenin has potential as an antihepatic fibrosis drug.

Oral nanoparticles containing naringenin suppress atherosclerotic progression by targeting delivery to plaque macrophages

Atherosclerosis is the main cause of ischemic stroke and myocardial infarction diseases.Nanoparticles have shown unique benefits for atherosclerosis treatment by targeting the lesional macrophages of plaques.However,most of the nanocarriers are administered intravenously,which is inconvenient and may cause complications.Herein,we developed an oral lipid-polymer based nanoparticles(FA-LNPs)decorated with folic acid,which can not only effectively overcome intestinal mucosal-epithelial barrier by increasing the transmembrane transport through intestinal epithelial and the accumulation in Peyer’s patches but also actively target to the aortic plaque sites and accumulate in lesional macrophages.Subsequently,naringenin(Nrg),one of the antiinflammation drugs,was designed to be the oral nanomedicine(FA-LNPs/Nrg)for the first time via the encapsulation of FALNPs.FA-LNPs/Nrg presented highly anti-atherosclerotic efficacy.After the atherosclerotic ApoE−/−mice were treated by FALNPs/Nrg via oral administration for three months,the aortic lesion area,plaque area,and necrotic core area of the aortic root were significantly decreased.Meanwhile,the lipid-related blood parameters recovered to normal levels.Our study provides a promising approach to atherosclerosis treatment based on the novel oral targeting delivery system.

海洋中药厚藤中柚皮素(naringenin)衍生物合成及胆碱酯酶抑制活性研究

本文以柚皮素(naringenin)为先导化合物,采用新药设计的原理,设计合成一系列查尔酮衍生物并对其进行AChE和BuChE的抑制活性研究。市售的邻羟基苯甲醛与丙烯醛在K2CO3催化下生成苯并吡喃-3-甲醛中间体。苯并吡喃-3-甲醛与取代的苯乙酮经过Claisen-Schmidt反应得到目标化合物。采用改进的Ellmańs法测定查尔酮化合物对AChE和BuChE的抑制活性。8个化合物均显示出一定的抑制AChE和BuChE的活性,其中化合物2d显示出比较高的抑制胆碱酯酶的活性。分子对接结果表明,2d与AChE和BuChE有明显的相互作用.本实验研究表明具有香豆素的查尔酮化合物可能是发现具有潜在抗AD新先导物的一个途径。