Hyperuricemia(HUA)is a metabolic disease characterized by high levels of uric acid(UA)in the blood and varying degrees of kidney damage.Desirable nanoliposomes should simultaneously exhibit efficient biocompatibility ...Hyperuricemia(HUA)is a metabolic disease characterized by high levels of uric acid(UA)in the blood and varying degrees of kidney damage.Desirable nanoliposomes should simultaneously exhibit efficient biocompatibility and effective drug delivery.However,they both usually require special structural properties.Herein,we propose a strategy to prepare nanoliposomes with varying rigidity by replacing cholesterol(CH)with phytosterol esters(PE).The results showed that the particle size of PE naringenin nanoliposomes(PE-NAR)was 179.5 nm,and the encapsulation efficiency(EE)was 79.93%.In atomic force microscopy(AFM)tests,PE-NAR showed a 1-fold increase in rigidity compared to CH naringenin nanoliposomes(CH-NAR).By observing the effects of naringenin nanoliposomes(NAR-NLs)on the physiological and biochemical indicators in HUA mice,we explore its impact on kidney damage and inflammatory pathways in HUA mice.The results show that NAR-NLs significantly inhibit UA levels and improve kidney damage.Compared to oral naringenin,NAR-NLs generally enhance the in vivo antioxidant effects of naringenin.Furthermore,high-rigidity PE-NAR downregulated the renal inflammatory factor interleukin-1β(IL-1β)to 6.67%,demonstrating the highest inhibitory effect.Further experiments have demonstrated that naringenin exerts a protective effect in kidney injury by inhibiting the activation of NOD like receptor protein 3(NLRP3)inflammasome and reducing oxidative stress within the body.In summary,by adjusting the rigidity of the nanoliposomes,the oral administration of naringenin can effectively improve the alleviation of HUA.展开更多
Objective:To synthesize nanoformulated naringenin(NF-n)and evaluate its anti-angiogenic and anticancer activities.Methods:NF-n was synthesized using the solvent evaporation method and characterized by dynamic light sc...Objective:To synthesize nanoformulated naringenin(NF-n)and evaluate its anti-angiogenic and anticancer activities.Methods:NF-n was synthesized using the solvent evaporation method and characterized by dynamic light scattering,Fourier transform infrared spectroscopy,and scanning electron microscopy.Molecular docking studies were performed to assess NF-n’s binding affinity to vascular endothelial growth factor(VEGF).In vitro assays using HUVEC and MCF-7 cell lines were conducted to evaluate cytotoxicity and cell migration inhibition.The mRNA expression levels of angiogenesis-and inflammation-related markers(nestin,NRP-1,NRP-2,CD93,IL-1β,TNF-α,NF-κB,and Bcl-2)were quantified via RT-PCR.The anti-angiogenic effect of NF-n was further investigated using the chick chorioallantoic membrane assay.Results:Molecular docking revealed effective binding of naringenin to VEGF.NF-n demonstrated significantly reduced particle size and improved physicochemical properties.In in vitro studies,NF-n reduced cell viability and inhibited migration in both HUVEC and MCF-7 cells.RT-PCR analysis showed that NF-n significantly downregulated pro-angiogenic and inflammatory markers.Furthermore,NF-n significantly decreased blood vessel density,total branching points,and vessel length in heparin-induced chick chorioallantoic membrane.Conclusions:NF-n exhibits anti-angiogenic and anticancer properties,positioning it as a promising candidate for therapeutic application in cancer and other pathological conditions involving abnormal angiogenesis.Further preclinical studies are recommended to explore its translational potential.展开更多
Alzheimer’s disease(AD)is one of the most common forms of neurodegenerative dementia.The etiology of AD is multifactorial,and its complex pathophysiology involves tau and amyloid-βdeposition,increased oxidative stre...Alzheimer’s disease(AD)is one of the most common forms of neurodegenerative dementia.The etiology of AD is multifactorial,and its complex pathophysiology involves tau and amyloid-βdeposition,increased oxidative stress,neuroinflammation,metabolic disorders,and massive neuronal loss.Due to its complex pathology,no effective cure for AD has been found to date.Therefore,there is an unmet clinical need for the development of new drugs against AD.Natural products are known to be good sources of compounds with pharmacological activity and have potential for the development of new therapeutic agents.Naringin,a naturally occurring flavanone glycoside,is predominantly found in citrus fruits and Chinese medicinal herbs.Mounting evidence shows that naringin and its aglycone,naringenin,have direct neuroprotective effects on AD,such as anti-amyloidogenic,antioxidant,anti-acetylcholinesterase,and anti-neuroinflammatory effects,as well as metal chelation.Furthermore,they are known to improve disordered glucose/lipid metabolism,which is a high risk factor for AD.In this review,we summarize the latest data on the impact of naringin and naringenin on the molecular mechanisms involved in AD pathophysiology.Additionally,we provide an overview of the current clinical applications of naringin and naringenin.The novel delivery systems for naringin and naringenin,which can address their widespread pharmacokinetic limitations,are also discussed.The literature indicates that naringin and naringenin could be multilevel,multitargeted,and multifaceted for preventing and treating AD.展开更多
Glycidol is a common lipid-derived foodborne toxicant mainly presents in refined oils and related foodstuffs.Vascular endothelial cells may be potential targets of the deleterious effects associated with glycidol expo...Glycidol is a common lipid-derived foodborne toxicant mainly presents in refined oils and related foodstuffs.Vascular endothelial cells may be potential targets of the deleterious effects associated with glycidol exposure.In human umbilical vein endothelial cells(HUVECs),we found that glycidol treatment promoted endothelialto-mesenchymal transition(EndMT)at a lower concentration(0.5 mmol/L),while induced apoptosis and inflammation at a higher concentration(1 mmol/L).These harmful effects were achieved by the activation of NF-κB/MAPK signaling pathway and were mediated by reactive oxygen species(ROS).In addition,the protective potential of 6-C-(E-2-fluorostyryl)naringenin(6-CEFN)against glycidol was evaluated and compared with naringenin.HUVECs pre-treated with 6-CEFN,but not naringenin,displayed resistance to endothelial dysfunction caused by glycidol.展开更多
Objective To investigate the protective effects of naringenin(NRG)against dexamethasone(DEX)-induced osteoporosis(OP)in rats.Methods Molecular docking of NRG was done with AutoDock Vina 1.2.0 software.Forty-eight fema...Objective To investigate the protective effects of naringenin(NRG)against dexamethasone(DEX)-induced osteoporosis(OP)in rats.Methods Molecular docking of NRG was done with AutoDock Vina 1.2.0 software.Forty-eight female Wistar rats were randomly divided into six groups(n=8 each):normal control(NC),DEX(7 mg/kg,i.m.),NRG-low(NRG-L;25 mg/kg,i.g.),NRG-medium(NRG-M;50 mg/kg,i.g.),NRG-high(NRG-H;100 mg/kg,i.g.),and alendronate(ALN;0.25 mg/d,i.g.)groups.OP was induced by administering DEX once a week for five weeks in all groups except NC group.Begining in the third week after the initial DEX administration,the rats in NRG-L,NRG-M,NRG-H,and ALN groups received the corresponding treatments daily for three weeks,while NC and DEX groups received no additional treatment.Serum samples were collected at the end of the experiment for biochemical,bone turnover,antioxidant,lipid profile,and inflammatory cytokine analyses.Femur bones underwent physical parameter testing and histopathological examination.Results The molecular docking results illustrated that NRG docked with calcitonin(CT),lowdensity lipoprotein(LDL),bone morphogenetic protein(BMP),vascular endothelial growth factor(VEGF)receptor,forkhead transcription factors,and osteoprogenitor cells showed good binding energy.In rats administered with 25,50,and 100 mg/kg NRG,there was a significant enhancement in serum biochemical indices,characterized by a reduction in tartrate-resistant acid phosphatase(TRAP),parathyroid hormone(PTH),and an elevation in osteocalcin(OC)and CT levels(P<0.05,P<0.01,and P<0.001,respectively).Despite no significant changes in thickness,weight,and length(P>0.05),there was a marked increase in bone mineral density(BMD)(P<0.01,P<0.001,and P<0.001,respectively).Antioxidant enzyme markers showed significant upregulation,with higher glutathione,superoxide dismutase,and catalase,and a concurrent decrease in malondialdehyde(MDA)(P<0.05,P<0.01,and P<0.001,respectively).The lipid profile also improved significantly,with lower cholesterol(CH),triglycerides(TG),and low-density lipoprotein(LDL)levels,and an increase in high-density lipoprotein(HDL)level(P<0.05,P<0.01,and P<0.001,respectively).Inflammatory cytokine levels were reduced,as evidenced by decreases in tumor necrosis factor(TNF),interleukin(IL)-6,and IL-1β(P<0.05,P<0.01,and P<0.001,respectively).Furthermore,histological alterations revealed obvious improvements,and the body weight of rats treated with NRG showed an increase compared with DEX group.Conclusion These findings imply that NRG exhibited a protective effect against DEX-induced OP in rats as it promotes the bone formation process by increasing the number of bone turnover markers including OC and CT,and restoring of antioxidant status,lipid metabolism,and inflammatory markers.展开更多
[Objectives]To investigate the protective mechanism of naringenin on acute myocardial ischemia-reperfusion injury(AMI-RI)in Sprague-Dawley(SD)rats.[Methods]A total of 32 SD rats with AMI-RI model construction were ran...[Objectives]To investigate the protective mechanism of naringenin on acute myocardial ischemia-reperfusion injury(AMI-RI)in Sprague-Dawley(SD)rats.[Methods]A total of 32 SD rats with AMI-RI model construction were randomly divided into AMI-RI model control group and citrus pigment A/B/C groups(n=8).The naringenin A,B,and C groups were administrated 20,40 and 80 mg/(kg•d)for 10 d.The AMI group served as the negative control and was not treated.At the conclusion of the treatment regimen,a sample of intraventricular blood was collected for the purpose of measuring lactate dehydrogenase(LDH),glutathione peroxidase(GLH-PX),nitric oxide(NO),and superoxide dismutase(SOD)levels.Additionally,myocardial tissue was identified within the ischemic region.The content of malondialdehyde(MDA)was determined by inducing nitric oxide synthase(iNOS)and endodermal nitric oxide synthase(eNOS)positive cells in the left anterior descending coronary artery.[Results]Following citrus treatment,the contents of GLH-PX and SOD in ventricular blood of the citrus B group were found to be significantly elevated,while the contents of NO and LDH in myocardial MDA and ventricle were observed to be significantly reduced.The number of eNOS-positive cells was significantly increased,while the number of iNOS-positive cells was significantly decreased.The difference was statistically significant when compared with the AMI-RI group(P<0.05).The changes observed in the above indicators in the citrus C group were more pronounced than those observed in the citrus B group.The difference between the citrus C and the B group was statistically significant(P<0.05),indicating that this effect is concentration dependent.[Conclusions]In addition to its ability to inhibit myocardial lipid peroxidation during AMI-RI by increasing SOD activity,naringenin may also affect the synthesis and release of NO by regulating eNOS and iNOS,thereby achieving protection against AMI-RI.One effect is enhanced as the dose of the drug increases.展开更多
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 ca...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.展开更多
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 lea...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.展开更多
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,...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.展开更多
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 ac...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.展开更多
To study the molecular mechanisms involved in the hepatoprotective effects of naringenin (NAR) on carbon tetrachloride (CCl<sub>4</sub>)-induced liver fibrosis. METHODSThirty-two male Wistar rats (120-150 ...To study the molecular mechanisms involved in the hepatoprotective effects of naringenin (NAR) on carbon tetrachloride (CCl<sub>4</sub>)-induced liver fibrosis. METHODSThirty-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 mL/daily p.o.; (2) a CCl<sub>4</sub> group (n = 8) that received 400 mg of CCl<sub>4</sub>/kg body weight i.p. 3 times a week for 8 wk; (3) a CCl<sub>4</sub> + NAR (n = 8) group that received 400 mg of CCl<sub>4</sub>/kg body weight i.p. 3 times 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, pSmad3 and pJNK proteins were detected via western blot. RESULTSNAR 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 CCl<sub>4</sub> intoxication (P < 0.05). Liver histopathology showed a decrease in collagen deposition when rats received NAR in addition to CCl<sub>4</sub>. Although zymography assays showed that CCl<sub>4</sub> produced an increase in MMP-9 and MMP-2 gelatinase 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 CCl<sub>4</sub>-treated group (P < 0.05). NAR prevented Smad3 phosphorylation in the linker region by JNK since this flavonoid blocked this kinase (P < 0.05). CONCLUSIONNAR prevents CCl<sub>4</sub> 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.展开更多
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 ...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.展开更多
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 im...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.展开更多
OBJECTIVE:To characterize naringenin(NAR) population pharmacokinetics(PPK) in Chinese women with primary osteoporosis.METHODS:Ninety-eight female patients with primary osteoporosis from the Jingshan,Beixinqiao,Jiaodao...OBJECTIVE:To characterize naringenin(NAR) population pharmacokinetics(PPK) in Chinese women with primary osteoporosis.METHODS:Ninety-eight female patients with primary osteoporosis from the Jingshan,Beixinqiao,Jiaodaokou,Chaoyangmen,and Donghuamen communities in Beijing,China,aged 40 to 80 years,received oral Qianggu capsules(250 mg).Blood samples were collected before and at 0.5,1,2,3,4,6,8,10,12,and 24 h after administration.The concentration of NAR in the blood samples was measured using high performance liquid chromatography-tandem mass spectrometry.PPK analyses were performed with nonlinear mixed-effect modeling software(version 7.1.2,PsN3.2.12).The clearance(C1),central distribution volume(V),absorption rate constant(Ka1),peripheral distribution volume(VII),and inter-compartmental clearance(CLII) were set as parameters and estimated by the base model,covariate model,and final model.Kidney-Yang deficiency[Shenyangxu(SYAX)]and liver-kidney-Yin deficiency(Ganshenyinxu) are patterns of symptoms in Traditional Chinese Medicine that were set as covariates,along with age,height,blood urea nitrogen,serum creatinine,alanine transaminase,aspartate transaminase,and hyperlipidemia.Both stepwise forward and backward procedures were accomplished to build models.The final model was evaluated by internal and external validation,visual predictive check,bootstrap,and leverage analysis.RESULTS:A one compartment open model with first order degradation was the best fitted to the concentration-time profiles following oral administration of NAR.The mean of population parameters of the final model,C1,SYAX on C1,V,Ka1,CLII,and VII,were measured to be 37.6 L/h,0.427 L,123 L/h,0.12/h,0.3056,and 1.446,respectively.Inter-individual variability was estimated and SYAX was identified as a significant covariate.CONCLUSION:The population pharmacokinetic model described in this study could effectively characterize the pharmacokinetic profile of NAR following administration of a single dose of oral Qianggu capsules in Chinese women with primary osteoporosis.Among the tested covariates,only SYAX was a significant factor.展开更多
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(6...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.展开更多
To identify bioactive compound in pigeon pea leaves (Cajanus cajan) that inhibits Salmonella thypi (S. thypi).MethodsThe leaf sample was powdered and macerated with methanol and fractioned by liquid-liquid extrac...To identify bioactive compound in pigeon pea leaves (Cajanus cajan) that inhibits Salmonella thypi (S. thypi).MethodsThe 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.ResultsSubfraction 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.ConclusionsNaringenin shows antibacterial activity and can be developed to treat typhoid.展开更多
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 grou...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.展开更多
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 ...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.展开更多
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...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.展开更多
基金funded by National Key R&D Plan of China(2024YFE0109500)the National Natural Science Foundation of China(32472367,32372249)Key Program of the Natural Science Foundation of Zhejiang Province(HZSZ25C200001).
文摘Hyperuricemia(HUA)is a metabolic disease characterized by high levels of uric acid(UA)in the blood and varying degrees of kidney damage.Desirable nanoliposomes should simultaneously exhibit efficient biocompatibility and effective drug delivery.However,they both usually require special structural properties.Herein,we propose a strategy to prepare nanoliposomes with varying rigidity by replacing cholesterol(CH)with phytosterol esters(PE).The results showed that the particle size of PE naringenin nanoliposomes(PE-NAR)was 179.5 nm,and the encapsulation efficiency(EE)was 79.93%.In atomic force microscopy(AFM)tests,PE-NAR showed a 1-fold increase in rigidity compared to CH naringenin nanoliposomes(CH-NAR).By observing the effects of naringenin nanoliposomes(NAR-NLs)on the physiological and biochemical indicators in HUA mice,we explore its impact on kidney damage and inflammatory pathways in HUA mice.The results show that NAR-NLs significantly inhibit UA levels and improve kidney damage.Compared to oral naringenin,NAR-NLs generally enhance the in vivo antioxidant effects of naringenin.Furthermore,high-rigidity PE-NAR downregulated the renal inflammatory factor interleukin-1β(IL-1β)to 6.67%,demonstrating the highest inhibitory effect.Further experiments have demonstrated that naringenin exerts a protective effect in kidney injury by inhibiting the activation of NOD like receptor protein 3(NLRP3)inflammasome and reducing oxidative stress within the body.In summary,by adjusting the rigidity of the nanoliposomes,the oral administration of naringenin can effectively improve the alleviation of HUA.
文摘Objective:To synthesize nanoformulated naringenin(NF-n)and evaluate its anti-angiogenic and anticancer activities.Methods:NF-n was synthesized using the solvent evaporation method and characterized by dynamic light scattering,Fourier transform infrared spectroscopy,and scanning electron microscopy.Molecular docking studies were performed to assess NF-n’s binding affinity to vascular endothelial growth factor(VEGF).In vitro assays using HUVEC and MCF-7 cell lines were conducted to evaluate cytotoxicity and cell migration inhibition.The mRNA expression levels of angiogenesis-and inflammation-related markers(nestin,NRP-1,NRP-2,CD93,IL-1β,TNF-α,NF-κB,and Bcl-2)were quantified via RT-PCR.The anti-angiogenic effect of NF-n was further investigated using the chick chorioallantoic membrane assay.Results:Molecular docking revealed effective binding of naringenin to VEGF.NF-n demonstrated significantly reduced particle size and improved physicochemical properties.In in vitro studies,NF-n reduced cell viability and inhibited migration in both HUVEC and MCF-7 cells.RT-PCR analysis showed that NF-n significantly downregulated pro-angiogenic and inflammatory markers.Furthermore,NF-n significantly decreased blood vessel density,total branching points,and vessel length in heparin-induced chick chorioallantoic membrane.Conclusions:NF-n exhibits anti-angiogenic and anticancer properties,positioning it as a promising candidate for therapeutic application in cancer and other pathological conditions involving abnormal angiogenesis.Further preclinical studies are recommended to explore its translational potential.
基金supported by the Joint Funds of the Zhejiang Provincial Natural Science Foundation of China(No.TGD23C050001)by National Natural Science Foundation of China(No.82074186).
文摘Alzheimer’s disease(AD)is one of the most common forms of neurodegenerative dementia.The etiology of AD is multifactorial,and its complex pathophysiology involves tau and amyloid-βdeposition,increased oxidative stress,neuroinflammation,metabolic disorders,and massive neuronal loss.Due to its complex pathology,no effective cure for AD has been found to date.Therefore,there is an unmet clinical need for the development of new drugs against AD.Natural products are known to be good sources of compounds with pharmacological activity and have potential for the development of new therapeutic agents.Naringin,a naturally occurring flavanone glycoside,is predominantly found in citrus fruits and Chinese medicinal herbs.Mounting evidence shows that naringin and its aglycone,naringenin,have direct neuroprotective effects on AD,such as anti-amyloidogenic,antioxidant,anti-acetylcholinesterase,and anti-neuroinflammatory effects,as well as metal chelation.Furthermore,they are known to improve disordered glucose/lipid metabolism,which is a high risk factor for AD.In this review,we summarize the latest data on the impact of naringin and naringenin on the molecular mechanisms involved in AD pathophysiology.Additionally,we provide an overview of the current clinical applications of naringin and naringenin.The novel delivery systems for naringin and naringenin,which can address their widespread pharmacokinetic limitations,are also discussed.The literature indicates that naringin and naringenin could be multilevel,multitargeted,and multifaceted for preventing and treating AD.
基金supported by the National Key R&D Program of China(2021YFD2100103)the National Natural Science Foundation of China(32101935).
文摘Glycidol is a common lipid-derived foodborne toxicant mainly presents in refined oils and related foodstuffs.Vascular endothelial cells may be potential targets of the deleterious effects associated with glycidol exposure.In human umbilical vein endothelial cells(HUVECs),we found that glycidol treatment promoted endothelialto-mesenchymal transition(EndMT)at a lower concentration(0.5 mmol/L),while induced apoptosis and inflammation at a higher concentration(1 mmol/L).These harmful effects were achieved by the activation of NF-κB/MAPK signaling pathway and were mediated by reactive oxygen species(ROS).In addition,the protective potential of 6-C-(E-2-fluorostyryl)naringenin(6-CEFN)against glycidol was evaluated and compared with naringenin.HUVECs pre-treated with 6-CEFN,but not naringenin,displayed resistance to endothelial dysfunction caused by glycidol.
文摘Objective To investigate the protective effects of naringenin(NRG)against dexamethasone(DEX)-induced osteoporosis(OP)in rats.Methods Molecular docking of NRG was done with AutoDock Vina 1.2.0 software.Forty-eight female Wistar rats were randomly divided into six groups(n=8 each):normal control(NC),DEX(7 mg/kg,i.m.),NRG-low(NRG-L;25 mg/kg,i.g.),NRG-medium(NRG-M;50 mg/kg,i.g.),NRG-high(NRG-H;100 mg/kg,i.g.),and alendronate(ALN;0.25 mg/d,i.g.)groups.OP was induced by administering DEX once a week for five weeks in all groups except NC group.Begining in the third week after the initial DEX administration,the rats in NRG-L,NRG-M,NRG-H,and ALN groups received the corresponding treatments daily for three weeks,while NC and DEX groups received no additional treatment.Serum samples were collected at the end of the experiment for biochemical,bone turnover,antioxidant,lipid profile,and inflammatory cytokine analyses.Femur bones underwent physical parameter testing and histopathological examination.Results The molecular docking results illustrated that NRG docked with calcitonin(CT),lowdensity lipoprotein(LDL),bone morphogenetic protein(BMP),vascular endothelial growth factor(VEGF)receptor,forkhead transcription factors,and osteoprogenitor cells showed good binding energy.In rats administered with 25,50,and 100 mg/kg NRG,there was a significant enhancement in serum biochemical indices,characterized by a reduction in tartrate-resistant acid phosphatase(TRAP),parathyroid hormone(PTH),and an elevation in osteocalcin(OC)and CT levels(P<0.05,P<0.01,and P<0.001,respectively).Despite no significant changes in thickness,weight,and length(P>0.05),there was a marked increase in bone mineral density(BMD)(P<0.01,P<0.001,and P<0.001,respectively).Antioxidant enzyme markers showed significant upregulation,with higher glutathione,superoxide dismutase,and catalase,and a concurrent decrease in malondialdehyde(MDA)(P<0.05,P<0.01,and P<0.001,respectively).The lipid profile also improved significantly,with lower cholesterol(CH),triglycerides(TG),and low-density lipoprotein(LDL)levels,and an increase in high-density lipoprotein(HDL)level(P<0.05,P<0.01,and P<0.001,respectively).Inflammatory cytokine levels were reduced,as evidenced by decreases in tumor necrosis factor(TNF),interleukin(IL)-6,and IL-1β(P<0.05,P<0.01,and P<0.001,respectively).Furthermore,histological alterations revealed obvious improvements,and the body weight of rats treated with NRG showed an increase compared with DEX group.Conclusion These findings imply that NRG exhibited a protective effect against DEX-induced OP in rats as it promotes the bone formation process by increasing the number of bone turnover markers including OC and CT,and restoring of antioxidant status,lipid metabolism,and inflammatory markers.
文摘[Objectives]To investigate the protective mechanism of naringenin on acute myocardial ischemia-reperfusion injury(AMI-RI)in Sprague-Dawley(SD)rats.[Methods]A total of 32 SD rats with AMI-RI model construction were randomly divided into AMI-RI model control group and citrus pigment A/B/C groups(n=8).The naringenin A,B,and C groups were administrated 20,40 and 80 mg/(kg•d)for 10 d.The AMI group served as the negative control and was not treated.At the conclusion of the treatment regimen,a sample of intraventricular blood was collected for the purpose of measuring lactate dehydrogenase(LDH),glutathione peroxidase(GLH-PX),nitric oxide(NO),and superoxide dismutase(SOD)levels.Additionally,myocardial tissue was identified within the ischemic region.The content of malondialdehyde(MDA)was determined by inducing nitric oxide synthase(iNOS)and endodermal nitric oxide synthase(eNOS)positive cells in the left anterior descending coronary artery.[Results]Following citrus treatment,the contents of GLH-PX and SOD in ventricular blood of the citrus B group were found to be significantly elevated,while the contents of NO and LDH in myocardial MDA and ventricle were observed to be significantly reduced.The number of eNOS-positive cells was significantly increased,while the number of iNOS-positive cells was significantly decreased.The difference was statistically significant when compared with the AMI-RI group(P<0.05).The changes observed in the above indicators in the citrus C group were more pronounced than those observed in the citrus B group.The difference between the citrus C and the B group was statistically significant(P<0.05),indicating that this effect is concentration dependent.[Conclusions]In addition to its ability to inhibit myocardial lipid peroxidation during AMI-RI by increasing SOD activity,naringenin may also affect the synthesis and release of NO by regulating eNOS and iNOS,thereby achieving protection against AMI-RI.One effect is enhanced as the dose of the drug increases.
文摘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.
基金Supported by National Council of Science and Technology(Conacyt)of Mexico,No.253037
文摘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.
基金Supported by The Deanship of Scientific Research at King Saud University for its funding this research through the research group project,No.RGP-VPP-266
文摘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.
基金National Natural Science Foundation of China(8146055681760658)+2 种基金Foundation for High-level Innovative Talents of Guizhou Province(20164027)Innovation Research Group Projectof Education Department of Guizhou Province(2016038)Foundation for ExcellentYoung
文摘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.
基金Supported by National Council of Science and Technology(Conacyt)of Mexico,No.253037 to Muriel P,and No.239516 to Segovia JFellowship No.358378 Hernández-Aquino E to from Conacytsupported by a grant of PRODEP(UABC-PTC-464)Mexico
文摘To study the molecular mechanisms involved in the hepatoprotective effects of naringenin (NAR) on carbon tetrachloride (CCl<sub>4</sub>)-induced liver fibrosis. METHODSThirty-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 mL/daily p.o.; (2) a CCl<sub>4</sub> group (n = 8) that received 400 mg of CCl<sub>4</sub>/kg body weight i.p. 3 times a week for 8 wk; (3) a CCl<sub>4</sub> + NAR (n = 8) group that received 400 mg of CCl<sub>4</sub>/kg body weight i.p. 3 times 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, pSmad3 and pJNK proteins were detected via western blot. RESULTSNAR 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 CCl<sub>4</sub> intoxication (P < 0.05). Liver histopathology showed a decrease in collagen deposition when rats received NAR in addition to CCl<sub>4</sub>. Although zymography assays showed that CCl<sub>4</sub> produced an increase in MMP-9 and MMP-2 gelatinase 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 CCl<sub>4</sub>-treated group (P < 0.05). NAR prevented Smad3 phosphorylation in the linker region by JNK since this flavonoid blocked this kinase (P < 0.05). CONCLUSIONNAR prevents CCl<sub>4</sub> 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.
基金Supported by National Natural Science Foundation of China,No.31502059Education Department of Hubei Province,No.B2016039+1 种基金Medical School of Yangtze University,No.YXYQ201406Clinical and Molecular Immunology Research Center of Yangtze University
文摘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.
基金supported by the National Natural Science Foundation of China(No.82173765)the Science Foundation for Outstanding Youth of Liaoning Province(2021-YQ08)+2 种基金Ningxia Key Research and Invention Program(No.2021BEG02039)Basic Research Projects of Liaoning Provincial Department of Education(2020LFW01)Beijing Postdoctoral Work Funding Project,and the Career Development Program for Young Teachers in Shenyang Pharmaceutical University(ZQN2019003).
文摘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.
基金Supported by Grant from Significant Drug Research and Development in Important State Science and Technology Specific And Key Technique Research(Key Issues Research on Re-evaluation of Listed Herbal Hedicine,No.2009ZX09502-030)Visiting Fellow Joint Innovation Research Project of The China Academy of Chinese Medical Sciences(Exploratory Research in Population Pharmacokinetics of Bioactive Compounds of Osteopractic Total Flavone Based on Total Quantum Statistical Moment.No.ZZ070834)
文摘OBJECTIVE:To characterize naringenin(NAR) population pharmacokinetics(PPK) in Chinese women with primary osteoporosis.METHODS:Ninety-eight female patients with primary osteoporosis from the Jingshan,Beixinqiao,Jiaodaokou,Chaoyangmen,and Donghuamen communities in Beijing,China,aged 40 to 80 years,received oral Qianggu capsules(250 mg).Blood samples were collected before and at 0.5,1,2,3,4,6,8,10,12,and 24 h after administration.The concentration of NAR in the blood samples was measured using high performance liquid chromatography-tandem mass spectrometry.PPK analyses were performed with nonlinear mixed-effect modeling software(version 7.1.2,PsN3.2.12).The clearance(C1),central distribution volume(V),absorption rate constant(Ka1),peripheral distribution volume(VII),and inter-compartmental clearance(CLII) were set as parameters and estimated by the base model,covariate model,and final model.Kidney-Yang deficiency[Shenyangxu(SYAX)]and liver-kidney-Yin deficiency(Ganshenyinxu) are patterns of symptoms in Traditional Chinese Medicine that were set as covariates,along with age,height,blood urea nitrogen,serum creatinine,alanine transaminase,aspartate transaminase,and hyperlipidemia.Both stepwise forward and backward procedures were accomplished to build models.The final model was evaluated by internal and external validation,visual predictive check,bootstrap,and leverage analysis.RESULTS:A one compartment open model with first order degradation was the best fitted to the concentration-time profiles following oral administration of NAR.The mean of population parameters of the final model,C1,SYAX on C1,V,Ka1,CLII,and VII,were measured to be 37.6 L/h,0.427 L,123 L/h,0.12/h,0.3056,and 1.446,respectively.Inter-individual variability was estimated and SYAX was identified as a significant covariate.CONCLUSION:The population pharmacokinetic model described in this study could effectively characterize the pharmacokinetic profile of NAR following administration of a single dose of oral Qianggu capsules in Chinese women with primary osteoporosis.Among the tested covariates,only SYAX was a significant factor.
基金Supported by Guangdong Provincial Department of Science and Technology Grant(No.2011B031700052)
文摘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.
文摘To identify bioactive compound in pigeon pea leaves (Cajanus cajan) that inhibits Salmonella thypi (S. thypi).MethodsThe 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.ResultsSubfraction 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.ConclusionsNaringenin shows antibacterial activity and can be developed to treat typhoid.
文摘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.
基金National Natural Science Foundation of China(8146055681760658).
文摘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.
文摘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.
