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

Food Science and Human Wellness 2023年第4期12卷 1174-1183页

作者： Xiaoyu Cai Songxue Wang Huali Wang Suwen Liu Guishan Liu Huibin Chen Ji Kang Hao Wang State Key Laboratory of Food Nutrition and Safety College of Food Science and EngineeringTianjin University of Science and TechnologyTianjin 300457China China National Center for Food Safety Risk Assessment Beijing 100022China College of Food Science and Technology Hebei Normal University of Science and TechnologyQinhuangdao 066004China School of Food and Wine Ningxia UniversityYinchuan 750021China College of Life Sciences Fujian Normal UniversityFuzhou 350117China

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.

关键词： naringenin Lipid accumulation Molecular docking

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

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Asian Pacific Journal of Tropical Biomedicine 2023年第10期13卷 443-450页

作者： Ayman Eldourghamy Toka Hossam Mohammed Abdalla Hussein Amal Abdel-Aziz Samir A.El-masry Environmental Biotechnology Department Genetic Engineering and Biotechnology Research InstituteSadat UniversityEgypt Department of Medical Labs Faculty of Applied Medical Sciences TechnologyOctober 6 UniversityEgypt Department of Biotechnology Faculty of Applied Health Sciences TechnologyOctober 6 UniversityEgypt Molecular Biology Department Genetic Engineering and Biotechnology Research InstituteSadat UniversityEgypt

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.

关键词： naringenin Isoproterenol Myocardial infarction Antioxidants NLRP3 mRNA-208a

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naringenin nanocrystals for improving antirheumatoid arthritis activity

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Asian Journal of Pharmaceutical Sciences 2021年第6期16卷 816-825页

作者： Guangshuai Zhang Guangyuan Sun Haishan Guan Mo Li Yanhua Liu Baocheng Tian Zhonggui He Qiang Fu Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyang 110016China Liaoning Institute for Drug Control Shenyang 110016China School of Pharmacy Ningxia Medical UniversityYinchuan 750004China School of Pharmacy Binzhou Medical UniversityYantai 264003China Sihuan Pharmaceutical Holdings Group Ltd. Beijing 100013China

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.

关键词： naringenin Nanocrystals Anti-inflammation Rheumatoid arthritis efficacy

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

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Nano Research 2023年第1期16卷 925-937页

作者： Mengran Guo Zhongshan He Zhaohui Jin Lingjing Huang Jingmei Yuan Shugang Qin Xinchun Wang Lili Cao Xiangrong Song Department of Critical Care Medicine Department of Anesthesiology and Translational Neuroscience CenterDepartment of Clinical PharmacyFrontiers Science Center for Disease-related Molecular NetworkState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu 610000China First Affiliated Hospital of the Medical College Shihezi UniversityShihezi 832008China College of Medicine Chengdu UniversityChengdu 610000China

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.

关键词： atherosclerosis macrophages Peyer’s patches oral delivery folic acid naringenin

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

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World Journal of Gastroenterology 2017年第24期23卷 4354-4368页

作者： Erika Hernández-Aquino Natanael Zarco Sael Casas-Grajales Erika Ramos-Tovar Rosa E Flores-Beltrán Jonathan Arauz Mineko Shibayama Liliana Favari Víctor Tsutsumi José Segovia Pablo Muriel Laboratory of Experimental Hepatology Department of PharmacologyCinvestav-IPNApartado Postal 14-740Mexico City Department of Physiology Biophysics and NeurosciencesCinvestav-IPNApartado Postal 14-740Mexico City Department of Pharmacology School of MedicineAutonomous University of Baja CaliforniaMexicaliApartado Postal 21100 Department of Infectomics and Molecular Pathogenesis Cinvestav-IPNApartado Postal 14-740Mexico City

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,C

关键词：纤维变性转变生长因素 -- naringenin pSmad3 Smad3 JNK 原子因素 kappa 碳四氯化物

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naringenin protects against isoniazid- and rifampicininduced apoptosis in hepatic injury

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World Journal of Gastroenterology 2016年第44期22卷 9775-9783页

作者： Chao Wang Rui-Qin Fan Yan-Xiang Zhang Hao Nie Kan Li Department of Laboratory Medicine Medical School Yangtze University Clinical and Molecular Immunology Research Center Yangtze University Department of Hepatic Disease the Second Hospital of Jingzhou

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 apoptosi

关键词： naringenin Isoniazid Rifampicin Oxidative stress Apoptosis Hepatic injury

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

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Journal of Clinical and Translational Hepatology 2023年第1期11卷 26-37页

作者： Li Chen Siwei Xia Shuqi Wang Yuanyuan Zhou Feixia Wang Zhanghao Li Yang Li Desong Kong Zili Zhang Jiangjuan Shao Xuefen Xu Feng Zhang Shizhong Zheng Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica School of PharmacyNanjing University of Chinese MedicineNanjingJiangsuChina Chinese Medicine Modernization and Big Data Research Center Nanjing University of Chinese MedicineNanjingJiangsuChina

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.

关键词： Liver fibrosis cGAS naringenin Inflammation Hepatic stellate cells

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Heterologous biosynthesis of natural product naringenin by co-culture engineering

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Synthetic and Systems Biotechnology 2017年第3期2卷 236-242页

作者： Vijaydev Ganesan Zhenghong Li Xiaonan Wang Haoran Zhang Department of Chemical and Biochemical Engineering RutgersThe State University of New Jersey98 Brett RdPiscatawayNJ 08854USA

Co-culture engineering is an emerging approach for microbial biosynthesis of a variety of biochemicals.In this study,E.coli-E.coli co-cultures were developed for heterologous biosynthesis of the natural product naringenin.The co-cultures were composed of two independent E.coli strains dedicated to functional expression of different portions of the biosynthetic pathway,respectively.The co-culture biosynthesis was optimized by investigating the effect of carbon source,E.coli strain selection,timing of IPTG induction and the inoculation ratio between the co-culture strains.Compared with the monoculture strategy,the utilization of the designed co-cultures significantly improved the naringenin production,largely due to the reduction of metabolic stress,employment of proper hosts for improving pathway enzyme activities,and flexible adjustment of the relative biosynthetic strength between the coculture strains.The findings of this study extend the applicability of co-culture engineering in complex natural product biosynthesis.

关键词： Co-culture engineering naringenin Heterologous biosynthesis E.coli

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A Review on Pharmacological and Analytical Aspects of naringenin

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Chinese Journal of Integrative Medicine 2018年第7期24卷 551-560页

作者： Kanika Patel Gireesh Kumar Singh Dinesh Kumar Patel G.L.A Institute of Pharmaceutical Research MathuraIndia Department of Pharmaceutics Institute of TechnologyBanaras Hindu UniversityVaranasi-221005India

Flavonoids are a widely distributed group of phytochemicals having benzo-pyrone nucleus, and more than 4,000 different flavonoids have been described and categorized into flavonols, flavones, flavanones, isoflavones, catechins and anthocyanidins. Flavonoids occurs naturally in fruits, vegetables, nuts, and beverages such as coffee, tea, and red wine, as well as in medical herbs. Flavonoids are responsible for the different colors of plant parts and are important constituents of the human diet. Flavanoids have different pharmacological activities, such as antioxidant, anti-allergic, antibacterial, anti-inflammatory, antimutagenic and anticancer activity. naringenin belongs to the flavanones and is mainly found in fruits（grapefruit and oranges） and vegetables. Pharmacologically, it has anticancer, antimutagenic, anti-inflammatory, antioxidant, antiproliferative and antiatherogenic activities. naringenin is used for the treatments of osteoporosis, cancer and cardiovascular diseases, and showed lipid-lowering and insulin-like properties. In the present review, detailed pharmacological and analytical aspects of naringenin have been presented, which revealed the impressive pharmacological profile and the possible usefulness in the treatment of different types of diseases in the future. The information provided in this communication will act as an important source for development of effective medicines for the treatment of various disorders.

关键词： analytical techniques flavonoids naringenin pharmacological activity phytoconstituents

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

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中国药理学与毒理学杂志 2018年第9期32卷 697-698页

作者： CHEN Ce LI Dai-di WANG Guo-qing ZHANG Feng Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education Zunyi Medical University Zunyi 563000 China

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.

关键词： NLRP3 inflammasome naringenin dopaminergic neurons

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