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Quercetin Attenuates Atherosclerosis via Modulating Apelin Signaling Pathway Based on Plasma Metabolomics

Chinese Journal of Integrative Medicine 2023年第12期29卷 1121-1132页

作者： LIU Li-qun ZHANG Peng QI Ying-zi LI Hui JIANG Yue-hua YANG Chuan-hua The First Clinical Medical College Shandong University of Traditional Chinese MedicineJinan(250355)China College of Integrated Chinese and Western Medicine Binzhou Medical UniversityYantaiShandong Province(264000)China Health College Shandong University of Traditional Chinese MedicineJinan(250355)China Department of Pharmacy Ruijin HospitalSchool of MedicineShanghai Jiaotong UniversityShanghai(200050)China Central Laboratory Affiliated Hospital of Shandong University of Traditional Chinese MedicineJinan(250014)China Department of Cardiovascular Affiliated Hospital of Shandong University of Traditional Chinese MedicineJinan(250014)China

Objective:To interpret the pharmacology of Quercetin in treatment of atherosclerosis(AS).Methods:Fourteen apolipoprotein E-deficient(ApoE^(-/-))mice were divided into 2 groups by a random number table:an AS model(ApoE^(-/-))group and a Quercetin treatment group(7 in each).Seven age-matched C57 mice were used as controls(n=7).Quercetin[20 mg/(kg·d)]was administered to the Quercetin group intragastrically for 8 weeks for pharmacodynamic evaluation.Besides morphological observation,the distribution of CD11b,F4/80,sirtuin 1(Sirt1)and P21 was assayed by immunohistochemistry and immunofluorescence to evaluate macrophage infiltration and tissue senescence.Ultra-performance liquid chromatography/tandem mass spectrometry(UPLC-MSC/MS)was performed to study the pharmacology of Quercetin against AS.Then,simultaneous administration of an apelin receptor antagonist(ML221)with Quercetin was conducted to verify the possible targets of Quercetin.Key proteins in apelin signaling pathway,such as angiotensin domain type 1 receptor-associated proteins(APJ),AMP-activated protein kinase(AMPK),peroxisome proliferator-activated receptor-γcoactivator-1α(PGC-1α),tissue plasminogen activator(TPA),uncoupling protein 1(UCP1)and angiotensinⅡreceptor 1(AT1R),were assayed by Western blot.Results:Quercetin administration decreased lipid deposition in arterial lumen and improved the morphology of ApoE^(-/-)aortas in vivo.Quercetin decreased the densities of CD11b,F4/80 and P21 in the aorta and increased the level of serum apelin and the densities of APJ and Sirt1 in the aorta in ApoE^(-/-)mice(all PQuercetin affected mainly glycerophospholipids and fatty acyls.Bioinformatics analysis suggested that the apelin signaling pathway was one of the main pathways.Quercetin treatment increased the protein expressions of APJ,AMPK,PGC-1α,TPA and UCP1,while decreased the AT1R level(all PQuercetin was aba

关键词： Quercetin atherosclerosis plasma metabonomics apelin signaling pathway

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A combination therapy for androgenic alopecia based on Quercetin and zinc/copper dual-doped mesoporous silica nanocomposite microneedle patch

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Bioactive Materials 2023年第6期24卷 81-95页

作者： Zhaowenbin Zhang Wenbo Li Di Chang Ziqin Wei Endian Wang Jing Yu Yuze Xu Yumei Que Yanxin Chen Chen Fan Bing Ma Yanling Zhou Zhiguang Huan Chen Yang Feng Guo Jiang Chang State Key Laboratory of High-Performance Ceramics and Superfine Microstructure Shanghai Institute of CeramicsChinese Academy of SciencesShanghai200050PR China Wenzhou Institute University of Chinese Academy of SciencesZhejiang325000PR China Center of Materials Science and Optoelectronics Engineering University of Chinese Academy of SciencesBeijing100049PR China Department of Plastic Surgery Shanghai Jiaotong University Affiliated Sixth People’s HospitalShanghai200025PR China Fudan University Shanghai200433PR China

A nanocomposite microneedle(ZCQ/MN)patch containing copper/zinc dual-doped mesoporous silica nanoparticles loaded with Quercetin(ZCQ)was developed as a combination therapy for androgenic alopecia(AGA).The degradable microneedle gradually dissolves after penetration into the skin and releases the ZCQ nanoparticles.ZCQ nanoparticles release Quercetin(Qu),copper(Cu^(2+))and zinc ions(Zn^(2+))subcutaneously to synergistically promote hair follicle regeneration.The mechanism of promoting hair follicle regeneration mainly includes the regulation of the main pathophysiological phenomena of AGA such as inhibition of dihydrotestosterone,inhibition of inflammation,promotion of angiogenesis and activation of hair follicle stem cells by the combination of Cu^(2+)and Zn^(2+)ions and Qu.This study demonstrates that the systematic intervention targeting different pathophysiological links of AGA by the combination of organic drug and bioactive metal ions is an effective treatment strategy for hair loss,which provides a theoretical basis for development of biomaterial based anti-hair loss therapy.

关键词： Microneedle Zn^(2+)and Cu^(2+)dual-doping Nanocomposites Quercetin Androgenic alopecia

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Protocatechuic acid and Quercetin attenuate ETEC-caused IPEC-1 cell inflammation and injury associated with inhibition of necroptosis and pyroptosis signaling pathways

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Journal of Animal Science and Biotechnology 2023年第4期14卷 1551-1568页

作者： Kan Xiao Mohan Zhou Qingqing Lv Pengwei He Xu Qin Dan Wang Jiangchao Zhao Yulan Liu Hubei Key Laboratory of Animal Nutrition and Feed Science Wuhan Polytechnic UniversityWuhan 430023People’s Republic of China Department of Animal Science Division of AgricultureUniversity of ArkansasFayettevilleAR 72701USA

Background:Necroptosis and pyroptosis are newly identified forms of programmed cell death,which play a vital role in development of many gastrointestinal disorders.Although plant polyphenols have been reported to protect intestinal health,it is still unclear whether there is a beneficial role of plant polyphenols in modulating necroptosis and pyroptosis in intestinal porcine epithelial cell line(IPEC-1)infected with enterotoxigenic Escherichia coli(ETEC)K88.This research was conducted to explore whether plant polyphenols including protocatechuic acid(PCA)and Quercetin(Que),attenuated inflammation and injury of IPEC-1 caused by ETEC K88 through regulating necroptosis and pyroptosis signaling pathways.Methods:IPEC-1 cells were treated with PCA(40μmol/L)or Que(10μmol/L)in the presence or absence of ETEC K88.Results:PCA and Que decreased ETEC K88 adhesion and endotoxin level(P<0.05)in cell supernatant.PCA and Que increased cell number(P<0.001)and decreased lactate dehydrogenases(LDH)activity(P<0.05)in cell supernatant after ETEC infection.PCA and Que improved transepithelial electrical resistance(TEER)(P<0.001)and reduced fluorescein isothiocyanate-labeled dextran(FD4)flux(P<0.001),and enhanced membrane protein abundance of occludin,claudin-1 and ZO-1(P<0.05),and rescued distribution of these tight junction proteins(P<0.05)after ETEC infection.PCA and Que also declined cell necrosis ratio(P<0.05).PCA and Que reduced mRNA abundance and concentration of tumor necrosis factor-α(TNF-α),interleukin(IL)-6 and IL-8(P<0.001),and down-regulated gene expression of toll-like receptors 4(TLR4)and its downstream signals(P<0.001)after ETEC infection.PCA and Que down-regulated protein abundance of total receptor interacting protein kinase 1(t-RIP1),phosphorylated-RIP1(p-RIP1),p-RIP1/t-RIP1,t-RIP3,p-RIP3,mixed lineage kinase domain-like protein(MLKL),p-MLKL,dynamin-related protein 1(DRP1),phosphoglycerate mutase 5(PGAM5)and high mobility group box 1(HMGB1)(P<0.05)after ETEC infection.Moreover,PCA and Que reduced protein abundance of

关键词： Cell damage ETEC K88 Intestinal inflammation Necroptosis Protocatechuic acid Pyroptosis Quercetin

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Network Pharmacology and in vitro Experimental Veriflcation on Intervention of Quercetin, Present in Chinese Medicine Yishen Qutong Granules, on Esophageal Cancer

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Chinese Journal of Integrative Medicine 2023年第3期29卷 233-243页

作者： LI Jie CHANG Jin-yuan JIANG Zheng-long YIN Yu-kun CHEN Jia-yang JIN Wei LI Hao FENG Li National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing(100021)China Dongzhimen Hospital Beijing University of Chinese MedicineBeijing(100029)China

Objective: To explore the potential mechanism of Yishen Qutong Granules(YSQTG) for the treatment of esophageal cancer using network pharmacology and experimental research. Methods: The effective components and molecular mechanism of YSQTG in treating esophageal cancer were expounded based on network pharmacology and molecular docking. The key compound was identified by high-performance liquid chromatography and mass spectrometry(HPLC-MS) to verify the malignant phenotype of the key compounds in the treatment of esophageal cancer. Then, the interaction proteins of key compounds were screened by pull-down assay combined with mass spectrometry. RNA-seq was used to screen the differential genes in the treatment of esophageal cancer by key compounds, and the potential mechanism of key compounds on the main therapeutic targets was verified. Results: Totally 76 effective compounds of YSQTG were found, as well as 309 related targets, and 102 drug and disease interaction targets. The drug-compound-target network of YSQTG was constructed, suggesting that Quercetin, luteolin, wogonin, kaempferol and baicalein may be the most important compounds, while Quercetin had higher degree value and degree centrality, which might be the key compound in YSQTG. The HPLC-MS results also showed the stable presence of Quercetin in YSQTG. By establishing a protein interaction network, the main therapeutic targets of YSQTG in treating esophageal cancer were Jun proto-oncogene, interleukin-6, tumor necrosis factor, and RELA proto-oncogene. The results of cell function experiments in vitro showed that Quercetin could inhibit proliferation, invasion, and clonal formation of esophageal carcinoma cells. Quercetin mainly affected the biological processes of esophageal cancer cells, such as proliferation, cell cycle, and cell metastasis. A total of 357 Quercetin interacting proteins were screened, and 531 genes were significantly changed. Further pathway enrichment analysis showed that Quercetin mainly affects the metabolic pathway, MAPK signaling

关键词： network pharmacology esophageal cancer Yishen Qutong Granule Chinese medicine Quercetin nuclear factor kappa B

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Pharmacological action of Quercetin against testicular dysfunction:A mini review

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Journal of Integrative Medicine 2022年第5期20卷 396-401页

作者： Damilare E.Rotimi Tomilola D.Olaolu Oluyomi S.Adeyemi SDG 03 Group–Good Health&Well-being Landmark UniversityOmu-Aran 251101Kwara StateNigeria Department of Biochemistry Medicinal BiochemistryNanomedicine&Toxicology LaboratoryLandmark UniversityOmu-Aran 251101Kwara StateNigeria

The testis is an immune-privileged organ susceptible to oxidative stress and inflammation,two major factors implicated in male infertility.A reduction in the concentration and activities of testicular function biomarkers has been shown to correlate with impaired hypothalamic-pituitary-testicular axis and oxidative stress.However,the use of natural products to ameliorate these oxidative stress-induced changes may be essential to improving male reproductive function.Quercetin possesses several pharmacological activities that may help to combat cellular reproduction-related assaults,such as altered sperm function and reproductive hormone dysfunction,and dysregulated testicular apoptosis,oxidative stress,and inflammation.Studies have shown that Quercetin ameliorates testicular toxicity,largely by inhibiting the generation of reactive oxygen species,with the aid of the two antioxidant pharmacophores present in its ring structure.The radical-scavenging property of Quercetin may alter signal transduction of oxidative stress-induced apoptosis,prevent inflammation,and increase sperm quality in relation to the hormonal concentration.In this review,the therapeutic potential of Quercetin in mediating male reproductive health is discussed.

关键词： Antioxidants Apoptosis Oxidative stress Quercetin Sperm Testicular function

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Antiviral,immunomodulatory,and anticoagulant effects of Quercetin and its derivatives:Potential role in prevention and management of COVID-19

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Journal of Pharmaceutical Analysis 2022年第1期12卷 29-34页

作者： Souparnika H.Manjunath Rajesh K.Thimmulappa Department of Biochemistry Jagadguru Sri Shivarathreeshwara Medical CollegeJagadguru Sri Shivarathreeshwara Academy of Higher Education&Research(JSSAHER)Mysore570015India

The coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection has caused a devastating health crisis worldwide.In this review,we have discussed that prophylactic phytochemical Quercetin supplementation in the form of foods or nutraceuticals may help manage the COVID-19 pandemic.The following evidence supports our argument.First,nuclear factor erythroid-derived 2-like 2(NRF2)agonists abrogate replication of SARS-CoV-2 in lung cells,and Quercetin is a potent NRF2 agonist.Second,Quercetin exerts antiviral activity against several zoonotic coronaviruses,including SARS-CoV-2,mainly by inhibiting the entry of virions into host cells.Third,inflammatory pathways activated by nuclear factor kappa B,inflammasome,and interleukin-6 signals elicit cytokine release syndrome that promotes acute respiratory distress syndrome in patients with COVID-19,and Quercetin inhibits these pro-inflammatory signals.Fourth,patients with COVID-19 develop thrombosis,and Quercetin mitigates coagulation abnormalities by inhibiting plasma protein disulfide isomerase.This review provides a strong rationale for testing Quercetin for the management of COVID-19.

关键词： COVID-19 Quercetin Immunomodulation Cytokine response syndrome NRF2 Antiviral

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Protective mechanism of Quercetin in alleviating sepsis-related acute respiratory distress syndrome based on network pharmacology and in vitro experiments

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World Journal of Emergency Medicine 2024年第2期15卷 111-120页

作者： Weichao Ding Wei Zhang Juan Chen Mengmeng Wang Yi Ren Jing Feng Xiaoqin Han Xiaohang Ji Shinan Nie Zhaorui Sun Department of Emergency Medicine Jinling HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjing 210002China Department of Emergency Medicine Jinling Clinical Medical College of Nanjing University of Chinese MedicineNanjing 210002China Department of Emergency Medicine the Affiliated Hospital of Xuzhou Medical UniversityXuzhou 221002China Department of Emergency Medicine Xuzhou Municipal Hospital Affiliated to Xuzhou Medical UniversityXuzhou 221000China

BACKGROUND:Sepsis-related acute respiratory distress syndrome(ARDS)has a high mortality rate,and no effective treatment is available currently.Quercetin is a natural plant product with many pharmacological activities,such as antioxidative,anti-apoptotic,and anti-inflammatory effects.This study aimed to elucidate the protective mechanism of Quercetin against sepsis-related ARDS.METHODS:In this study,network pharmacology and in vitro experiments were used to investigate the underlying mechanisms of Quercetin against sepsis-related ARDS.Core targets and signaling pathways of Quercetin against sepsis-related ARDS were screened and were verified by in vitro experiments.RESULTS:A total of 4,230 targets of Quercetin,360 disease targets of sepsis-related ARDS,and 211 intersection targets were obtained via database screening.Among the 211 intersection targets,interleukin-6(IL-6),tumor necrosis factor(TNF),albumin(ALB),AKT serine/threonine kinase 1(AKT1),and interleukin-1β(IL-1β)were identified as the core targets.A Gene Ontology(GO)enrichment analysis revealed 894 genes involved in the inflammatory response,apoptosis regulation,and response to hypoxia.Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis identified 106 pathways.After eliminating and generalizing,the hypoxia-inducible factor-1(HIF-1),TNF,nuclear factor-κB(NF-κB),and nucleotide-binding and oligomerization domain(NOD)-like receptor signaling pathways were identified.Molecular docking revealed that Quercetin had good binding activity with the core targets.Moreover,Quercetin blocked the HIF-1,TNF,NF-κB,and NODlike receptor signaling pathways in lipopolysaccharide(LPS)-induced murine alveolar macrophage(MH-S)cells.It also suppressed the inflammatory response,oxidative reactions,and cell apoptosis.CONCLUSION:Quercetin ameliorates sepsis-related ARDS by binding to its core targets and blocking the HIF-1,TNF,NF-κB,and NOD-like receptor signaling pathways to reduce inflammation,cell apoptosis,and oxidative stress.

关键词： Quercetin Sepsis-related acute respiratory distress syndrome Network pharmacology

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Quercetin-derivatives painting the yellow petals of American lotus(Nelumbo lutea)and enzymatic basis for their accumulation

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Horticultural Plant Journal 2023年第1期9卷 169-182页

作者： Qingqing Liu Dasheng Zhang Fengluan Liu Zhuoxing Liu Xiaohan Wang Yong Yang Shanshan Li Hanchun Li Daike Tian Liangsheng Wang Key Laboratory of Plant Resources/Beijing Botanical Garden Institute of BotanyChinese Academy of SciencesBeijing 100093China Shanghai Key Laboratory of Plant Functional Genomics and Resources Shanghai Chenshan Botanical GardenShanghai 201602China University of Chinese Academy of Sciences Beijing 100049China

American lotus(Nelumbo lutea)is one of the two species in Nelumbo and has only yellow flower.Identification of total flavonoids showed wild American lotus contained almost only flavonols with Quercetin 3-O-glucuronide to be the dominant pigment.The variation tendency of the total flavonol content was coincident with yellow color variation of petals during flower development.To understand the mechanism of accumulation and constituent of pigments in petals,three pivotal genes,NlFLS1,NlFLS2 and NlFLS3,which were predicted to encode flavonol synthases were isolated and characterized by analyses of basic bioinformatics,temporal and spatial expression patterns and enzymatic activity.Their temporal expression levels showed the same variation tendency,which was also consistent with the development-dependent variation of total flavonol content.Spatial expression patterns indicated the three genes should function in petals.All the three proteins were demonstrated to be bifunctional dioxygenase,possessing both flavonol synthase activity and flavanone 3-hydroxylase activity.Besides,other flavonol biosynthesis related genes were also investigated on their expression levels to give more clues on the mechanism.Substrate preferences of the three FLSs,substrate competitions between the FLSs and other flavonol biosynthesis related enzymes,and the greatly differential expression levels between F3’H(flavonoid 3-hydroxylase)and F3’5’H(flavonoid 3,5-hydroxylase)contributed to the flavonol constituent in the petals of America lotus,namely abundant Quercetin-derivatives while very few kaempferol-derivatives and myricetin-derivatives.

关键词： Lotus Nelumbo Flavonoid Flavonol Quercetin

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Anti-leishmanial,immunomodulatory and anti-oxidative activity of Quercetin against cutaneous leishmaniasis caused by Leishmania major

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Asian Pacific Journal of Tropical Biomedicine 2023年第1期13卷 26-34页

作者： Ahmad Oryan Effat Bemani Somayeh Bahrami Department of Pathology School of Veterinary MedicineShiraz UniversityShirazIran Department of Parasitology Faculty of Veterinary MedicineShahid Chamran University of AhvazAhvazIran

Objective:To evaluate the in vitro and in vivo efficacy of Quercetin and its immunomodulatory and anti-oxidative activity against Leishmania major(L.major).Methods:L.major promastigotes and amastigotes were incubated with different concentrations of Quercetin to estimate EC_(50).For in vivo study,the base of tails of mice was infected with L.major.After developing ulcers in the inoculation site,mice were treated with 50 mg/kg Quercetin orally for 28 consecutive days.The wound-healing potential of Quercetin was evaluated by histopathological analysis of tissue sections stained by hematoxylin and eosin as well as Masson's trichrome.In addition,the levels of tumor necrosis factor-α,interleukin-6,malondialdehyde,and adiponectin,the ferric reducing ability of plasma,as well as superoxide dismutase and glutathione peroxidase activities were measured.Results:The EC_(50)values of Quercetin against L.major promastigotes and intracellular amastigotes were 0.27 and 0.85μM,respectively.Histopathological analysis showed that fewer inflammatory cells,more fibroblasts,and more collagen deposition were observed in tissue sections of Quercetin-treated mice.In addition,treatment with Quercetin markedly increased glutathione peroxidase activity,the ferric reducing ability of plasma and adiponectin levels while decreasing malondialdehyde,interleukin-6,and tumor necrosis factor-αlevels.Conclusions:Quercetin shows anti-leishmanial activity,immunomodulatory,anti-oxidative,and anti-inflammatory effects.Therefore,it may be further explored as an effective drug in treating leishmaniasis.

关键词： Leishmania major Cutaneous leishmaniosis Wound healing Quercetin Immunomodulator

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Quercetin modulates ovarian autophagy-related molecules and stereological parameters in a rat model of PCOS

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Asian Pacific Journal of Tropical Biomedicine 2023年第1期13卷 9-16页

作者： Asma Neisy Farhad Koohpeyma Majid Jafari Khorchani Fatemeh Karimi Fatemeh Zal Department of Biochemistry School of MedicineShiraz University of Medical SciencesShirazIran Physiology Endocrine and Metabolism Research CenterShiraz University of Medical ScienceShirazIran Department of Clinical Biochemistry Faculty of Medical SciencesTarbiat Modares UniversityTehranIran Histomorphometry and Stereology Research Center Shiraz University of Medical SciencesShirazIran

Objective:To examine the effect of Quercetin on stereological parameters and autophagy-related genes in ovaries of polycystic ovary syndrome(PCOS)rats.Methods:Fifty female Sprague-Dawley rats were randomly divided into five groups:the control group,the ethanol group,the Quercetin group(15 mg/kg/day),the PCOS group,as well as the PCOS+Quercetin group.After the induction of PCOS,Quercetin was administered orally for 30 days.Histological,stereological and real-time PCR analyses were carried out to evaluate the effect of Quercetin on PCOS rats.Results:Stereological analysis revealed that Quercetin significantly increased the number of ovarian follicles and the volume of corpus luteum and induced a significant decrease in atretic follicles in comparison to the PCOS group.In addition,Quercetin markedly increased mTOR gene expression while decreasing Beclin-1 and LC3 gene expression.Conclusions:Quercetin strongly modulates the expression of ovarian autophagy-related genes and stereological parameters in PCOS rats.Therefore,it can be considered as an ameliorative component for ovarian follicular impairments.

关键词： Quercetin Autophagy pathway mTOR Beclin-1 LC3 Ovarian follicles Polycystic ovary syndrome

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