Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a doule-blinded, placebo-controlled cross-over study.

Br J Nutr. Gates MA, Tworoger SS, Hecht JL, De Vivo I, Rosner B, Hankinson SE. A prospective study of dietary flavonoid intake and incidence of epithelial ovarian cancer. Int J Cancer. Giuliani C, Noguchi Y, Harii N, Napolitano G, Tatone D, Bucci I, Piantelli M, Monaco F, Kohn LD. The flavonoid quercetin regulates growth and gene expression in rat FRTL-5 thyroid cells.

Guardia T, Rotelli AE, Juarez AO, Pelzer LE. Anti-inflammatory properties of plant flavonoids. Effects of rutin, quercetin, and hesperidin on adjuvant arthritis in rat. Hanninen, Kaartinen K, Rauma AL, Nenonen M, Torronen R, Hakkinen AS, Adlercreutz H, Laakso J. Antioxidants in vegan diet and rheumatic disorders.

Harwood M, Danielewska-Nikiel B, Borzelleca JF, Flamm GW, Williams GM, Lines TC. Food Chem Toxicol. Kleemann R, Verschuren L, Morrison M, et al. Anti-inflammatory, anti-proliferative and anti-atherosclerotic effects of quercetin in human in vitro and in vivo models.

Knekt P, Isotupa S, Rissanen H, Heliovaara M, Jarvinen R, Hakkinen S et al. Quercetin intake and the incidence of cerebrovascular disease.

Eur J Clin Nut. Kurowska EM, Spence JD, Jordan J, Wetmore S, Freeman DJ, Piche LA, Serratore P. HDL-cholesterol-raising effect of orange juice in subjects with hypercholesterolemia. Lam TK, Rotunno M, Lubin JH, et al. Dietary quercetin, quercetin-gene interaction, metabolic gene expression in lung tissue and lung cancer risk.

Lamson DW, Brignall MS. Antioxidants and cancer III: quercetin. Alt Med Rev. Li N, Sun C, Zhou B, et al. Low concentration of quercetin antagonizeds the cytotoxic effects of anti-neoplastic drugs in ovarian cancer. PLoS One. Longanga OA, Vercruysse A, Foriers A.

Contribution to the ethnobotanical, phytochemical and pharmacological studies of traditionally used medicinal plants in the treatment of dysentery and diarrhoea in Lomela area, Democratic Republic of Congo DRC.

Mackraj I, Govender T, Ramesar S. The antihypertensive effects of quercetin in a salt-sensitive model of hypertension. J Cardiovasc Pharmacol. Maso V, Calgarotto AK, Franchi GC, et al. Multitarget effects of quercetin in leukemia. Cancer Prev Res Phila. Otshudi AL, Foriers A, Vercruysse A, Van Zeebroeck A, Lauwers S.

In vitro antimicorbial activity of six medicinal plants traditionally used for the treatment of dysentery and diarrhoea in Democratic Republic of Congo DRC. Owen RW, Giacosa A, Hull WE, Haubner R, Spiegelhalder B, Bartsch H.

Eur J Cancer. Owen RW, Mier W, Giacosa A, Hull WE, Spiegelhalder B, Bartsch H. Identification of lignans as major components in the phenolic fraction of olive oil.

Clin Chem. Ramos S. Effects of dietary flavonoids on apoptotic pathways related to cancer chemoprevention. J Nutr Biochem.

Epub Feb Ruiz PA, Braune A, Holzlwimmer G, Quintanilla-Fend L, Haller D. Quercetin inhibits TNF-induced NF-kappaB transcription factor recruitment to proinflammatory gene promoters in murine intestinal epithelial cells.

Shoskes D, Nickel J. Urologic Clinics of North America. Saunders Company. Staedler D, Idrizi E, Kenzaoui BH, Juillerat-Jeanneret L. Drug combinations with quercetin: doxorubicin plus quercetin in human breast cancer cells.

Cancer Chemother Pharmacol. Taepongsorat L, Tangpraprutgul P, Kitana N, Malaivijitnond S. Stimulating effects of quercetin on sperm quality and reproductive organs in adult male rats. Asian J Androl. Date limit:. Enter the date in the correct format.

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Source Information August , Volume 34 Issue 6 Pages , p. BDNF-Quercetin nanogels significantly increased the corresponding positive cells. At the same time, these impairments of pyramidal cells were also found in the prefrontal cortex of CUMS rats Figure S6 , and BDNF-Quercetin nanogels showed the same therapeutic effects as in the hippocampus.

CUMS-induced cell apoptosis and proliferation in the hippocampus of rats. a TUNEL staining. b The nerve cells by TUNEL staining. c Ki67 staining. d Number of cell proliferation by Ki67 staining. Apoptosis is an essential mechanism of CUMS-induced depression [ 48 ].

As an anti-apoptotic endogenous membrane protein, B cell lymphoma-2 Bcl-2 prevents cells from entering the apoptotic program. B-cell lymphoma extra-large Bcl-xL , like Bcl-2, is another antiapoptotic factor supporting neuronal survival but not promoting axon regeneration.

BCL2-associated X Bax was a pro-apoptotic protein promoting cells to enter apoptosis. The study findings indicated that CUMS increased Bax mRNA expression in the hippocampal and prefrontal cortex tissues Figure S7 a, b and selectively decreased hippocampal Bcl-xL mRNA levels Figure S7 c, d without changing Bcl-2 mRNA expression Figure S7 e, f.

BDNF-quercetin nanogels exerted antidepressant effects on CUMS rats, mainly through anti-stress, anti-inflammation, and neuroprotection. BDNF-quercetin nanogels can restore HPA axis function, inhibit neuron cell apoptosis, and promote neuron cell regeneration. To elucidate the impact of BDNF-Quercetin nanogels on CUMS rats, a comprehensive, integrated omics approach was used to investigate potential antidepressant mechanisms.

Gene expression of total mRNA isolated from rat hippocampus was assessed using RNA sequencing. The transcriptomic volcano map revealed that compared to CUMS group, genes were differentially expressed in the BDNF-quercetin nanogels group, with significantly up-regulated genes and significantly down-regulated genes Fig.

The most enriched GO terms in Fig. Gene set enrichment analysis GSEA was next performed using the KEGG Kyoto Encyclopedia of Genes and Genomes database, revealing significant enrichment including TGF-β and PI3K-Akt signaling pathway, glutamatergic synapse, alanine, aspartate, and glutamate metabolism Fig.

Additionally, GO terms associated with antioxidant activity were identified in Table S4. Oxidative phosphorylation was further found in KEGG pathway enrichment analysis.

In line with previous studies on depression, it was found that there are glutamate receptor-related terms, PI3K-Akt, glutamatergic synapse, and glutamate metabolism signaling pathways.

These transcriptomic findings suggested that BDNF-Quercetin nanogels not only induced antioxidant activities via oxidative phosphorylation but also exerted antidepressant effects on CUMS rats by improving the glutamatergic system and PI3K-Akt signaling pathway.

A metabolomic analysis was then performed to investigate the changes in hippocampal metabolites. Partial least square analysis PLS-DA in Fig. Further analysis in Fig. The metabolic pathways associated with the antidepressant effects primarily encompassed the following biochemical process: 1 biotin metabolism; 2 citrate cycle; 3 tryptophan metabolism; 4 Alanine, aspartate, and glutamate metabolism; 5 thiamine metabolism Fig.

Taken together, transcriptomic and metabonomic data showed that the glutamatergic system and PI3K-Akt signaling pathway were the primary antidepressant mechanism of BDNF-Quercetin nanogels in CUMS rats. Western blot experiments were performed to verify related protein expression. Protein expression of the glutamatergic system was demonstrated in Fig.

These results presented that chronic stress significantly reduced the GRIA3 the receptor of AMPA protein content and increased the GRIN2B the receptor of NMDA protein content in the hippocampus of rats.

Moreover, BDNF-Quercetin nanogels regulated the PI3K-Akt signaling pathway by improving the abnormal expression of BDNF, TrkB, GSK3β, and p-mTOR after CUMS Fig. These results showed that exogenously supplemented BDNF might bind to its receptor TrkB and further activate the PI3K-Akt signaling pathway, thereby regulating the expression of abnormal GSK3β and p-mTOR proteins.

In summary, the protective effects of quercetin nanogels on BDNF were achieved by antioxidant activities associated with oxidative phosphorylation. By integrating omics prediction and protein expression verification, the results showed that BDNF-Quercetin nanogels exerted antidepressant effects on CUMS rats by modulating the glutamatergic system and PI3K-Akt signaling pathway.

Antidepressant mechanism of BDNF-Quercetin nanogels in the thermosensitive gel on the CUMS rats. a Volcano map. b GO enrichment analysis.

c KEGG pathway enrichment analysis of BDNF-quercetin nanogels vs. CUMS model. d Partial least squares-discriminant analysis PLS-DA. e VIP analysis. f Major metabolic pathways that BDNF-Quercetin nanogels improve CUMS rats. g-h Expression of GRIA3, BDNF, TrkB, P-mTOR, GRIN2B, and GSK3β in the hippocampus of rats.

In conclusion, quercetin nanogels were successfully prepared and characterized. Quercetin nanogels showed protective effects against protein damage, exhibited antioxidant activities without affecting cell viability, proliferation, and immune response, and increased in vitro inflammatory cytokine levels.

The intranasally administered quercetin nanogels rapidly distributed in the brain within 30 min and improved the bioavailability of quercetin nearly fold at a lower dose.

The BDNF-quercetin nanogels in the thermosensitive gel exhibited excellent thermosensitivity and co-delivered quercetin and BDNF slowly and sustainably. As a protein drug carrier, quercetin nanogels exerted antidepressant effects on reserpine-induced rats and alleviated the depletion of monoamine neurotransmitters.

BDNF-quercetin nanogels effectively reversed despair behavior in mice, alleviated weight loss and anhedonia in rats, ameliorated dramatic pyramidal cell damage in hippocampal CA1 and CA3 subregions and inflammatory cytokine levels, and ameliorated CUMS-induced cell apoptosis and proliferation in rat hippocampus.

Further omics analysis and protein verification revealed that the treatment of BDNF-Quercetin nanogels on depressive disorder was mainly related to the glutamatergic system, PI3K-Akt, and BDNF-TrkB signaling pathway. These results showed that the brain delivery of BDNF- Quercetin nanogels via intranasal administration has a significant potential for the combination treatment of depressive disorder.

Chemicals and Materials and animals are described in Additional file 1 : S1 Chemicals and Materials and S2 Animals, respectively. BDNF-Quercetin nanogels were prepared using the previous study with slight modifications [ 49 ].

Preparation and characterization of BDNF-Quercetin nanogels are described in Additional file 1 : S3 Preparation and characterization of BDNF-Quercetin nanogels. In vitro release of quercetin nanogels was investigated in 0.

In vitro release of BDNF-Quercetin nanogels was investigated in 0. Quercetin nanogels and BDNF-Quercetin nanogels were placed in a dialysis bag molecular weight of 10, and suspended in 40 mL of release medium at 34 °C on a shaker at 50 rpm.

Each release sample was taken at appropriate intervals and added by fresh release medium. The analysis was conducted three times for each batch.

Antioxidant activities of quercetin nanogels : The protective effects of quercetin on protein were determined using the method of Coomassie brilliant blue. The methods are described in the Additional file 1 : S4 Antioxidant activities of quercetin nanogels.

BDNF-Quercetin nanogels in the thermosensitive gel were obtained using two steps. One step was that BDNF-Quercetin nanogels were dissolved in normal saline at room temperature, cooling to 4 °C.

The gelation temperature was observed through changes in the modulus [ 50 ]. In vitro release of BDNF-Quercetin nanogels in the thermosensitive gel was explored using PBS to mimic intranasal release behavior.

Each release sample was taken at appropriate intervals and added to fresh PBS. The residual weight was weighed and compared with the initial weight to calculate the weight loss rate.

Each batch was analyzed in triplicate. RAW Cell biology evaluation and immune response were performed in Additional file 1 : S5 Cell biology evaluation and immune response. For brain distribution studies, the Sprague-Dawley SD rats, intranasally administered to RBITC-labeled quercetin nanogels in the thermosensitive gel, were investigated after being sacrificed for 0.

In a pharmacokinetic study, SD rats were randomly divided into intranasal quercetin nanogels in the thermosensitive gel and oral administration quercetin solution at the dose of 0. The hippocampi were collected, detected, and analyzed as described in Additional file 1 : S6 Pharmacokinetic study.

Open field test OFT , forced swim test FST , tail suspension test TST , and reserpine-induced depression model are described in Additional file 1 : S7 Open field test OFT and forced swim test FST , tail suspension test TST , and reserpine-induced depression model.

The chronic unpredictable mild stress CUMS model was used to investigate the antidepressant effect of BDNF-Quercetin nanogels in the thermosensitive gel and its mechanism. The protocol was approved by the Animal Ethics Committee of Tianjin University of Traditional Chinese Medicine TCME The experiments are reported by the Animal Research: Reporting in Vivo Experiments ARRIVE guidelines.

The SD rats were divided into control and CUMS groups treated with drugs. CUMS involved exposure to various mild stressors. After administration, the locomotor activity was evaluated by the OFT, consisting of the number of rearings and total distance.

The rat heparinized plasma was collected by centrifugation at × g for 10 min after the behavioral despair test. The inflammatory levels TNF-α and IL-6 and HPA axis function CRH, ACTH, corticosterone, and testosterone were measured by ELISA Assay Kit. The CA1 and CA3 regions in the hippocampus were observed and photographed by a light microscope OLYMPUS, Japan.

At the same time, the mRNA expression of the apoptosis gene was performed in a Bio-Rad C Bio-Rad, Pleasanton, CA, USA. The real-time RT-PCR primers of GAPDH, Bcl-2, Bax, and Bcl-xL were demonstrated in Table S3. To measure pyramidal neuron proliferation in the hippocampus, the slides were incubated with an anti-MKI67 polyclonal antibody overnight at 4 °C, then a secondary antibody anti-rabbit IgG.

The number of positive cells was counted using a Nikon Eclipse Ti-U inverted fluorescent microscope Nikon, Japan.

The antidepressant mechanism of BDNF-Quercetin nanogels was explored by combining RNA sequencing, metabolomic analysis, and Western blot analysis. Transcriptome sequencing was accomplished by Beijing Novogene Technology Co.

Ltd, as presented in Additional file 1 : S8 The procedure of RNA sequencing. Metabolite levels in the hippocampal tissues were determined using our previous methods in Additional file 1 : S9 Determination of hippocampal tissues in metabolite levels.

The protein expressions of GRIA3, GRIN2B, BDNF, TrkB, GSK3β, and p-mTOR were determined by western blotting according to Additional file 1 : S10 Western blotting detection.

Statistical analyses were calculated by the Origin Pro software Origin Lab, Northampton, MA. Li W, Ali T, Zheng C, He K, Liu Z, Shah FA, Li N, Yu Z-J, Li S. Mol Psychiatry. Article CAS PubMed Google Scholar. Carniel BP, da Rocha NS.

Brain-derived neurotrophic factor BDNF and inflammatory markers: perspectives for the management of depression. Prog Neuropsychopharmacol Biol Psychiatry. Article PubMed Google Scholar. Woodburn SC, Asrat HS, Flurer JK, Schwierling HC, Bollinger JL, Vollmer LL, Wohleb ES. Depletion of microglial BDNF increases susceptibility to the behavioral and synaptic effects of chronic unpredictable stress.

Brain Behav Immun. Huang F, Chen T, Chang J, Zhang C, Liao F, Wu L, Wang W, Yin Z. A conductive dual-network hydrogel composed of oxidized dextran and hyaluronic-hydrazide as BDNF delivery systems for potential spinal cord injury repair.

Int J Biol Macromol. Ma X, Gao F, Su W, Ran Y, Bilalijiang T, Tuolhen Y, Tian G, Ye L, Feng Z, Xi J. Multifunctional injectable hydrogel promotes functional recovery after Stroke by modulating microglial polarization, angiogenesis and neuroplasticity. Chem Eng J. Article CAS Google Scholar. Park SB, Cho H-J, Moon SR, Choi KJ, Jung WH, Kim KY, Koh B.

Gold nanoparticle-assisted delivery of brain-derived neurotrophic factor to cerebral organoids. Nano Res. Kraus A, Huertas M, Ellis L, Boudinot P, Levraud J-P, Salinas I.

Intranasal delivery of SARS-CoV-2 spike protein is sufficient to cause olfactory damage, inflammation and olfactory dysfunction in zebrafish. Article CAS PubMed PubMed Central Google Scholar. Zhang L, Deng L, Ma C, Zhang H, Dang Y. Brain-derived neurotrophic factor delivered Intranasally relieves post-traumatic stress disorder symptoms caused by a single prolonged stress in rats.

Zhou X, Deng X, Liu M, He M, Long W, Xu Z, Zhang K, Liu T, So K-F, Fu Q-L. Intranasal delivery of BDNF-loaded small extracellular vesicles for cerebral ischemia therapy. J Control Release. Long Y, Yang Q, Xiang Y, Zhang Y, Wan J, Liu S, Li N, Peng W.

Nose to brain drug delivery-a promising strategy for active components from herbal medicine for treating cerebral ischemia reperfusion. Pharmacol Res. Cristea IA, Naudet F. US Food and Drug Administration approval of esketamine and brexanolone.

Lancet Psychiatry. Kryst J, Kawalec P, Pilc A. Efficacy and safety of intranasal esketamine for the treatment of major depressive disorder.

Expert Opin Pharmacother. Quintana DS, Steen NE, Andreassen OA. The Promise of Intranasal Esketamine as a Novel and effective antidepressant. JAMA Psychiatry. Kandemir K, Tomas M, McClements DJ, Capanoglu E. Recent advances on the improvement of quercetin bioavailability.

Trends Food Sci Technol. Onugwu AL, Nwagwu CS, Onugwu OS, Echezona AC, Agbo CP, Ihim SA, Emeh P, Nnamani PO, Attama AA, Khutoryanskiy VV. Nanotechnology based drug delivery systems for the treatment of anterior segment eye Diseases. Liu W, Ma Z, Wang Y, Yang J.

Multiple nano-drug delivery systems for intervertebral disc degeneration: current status and future perspectives. Bioact Mater. PubMed Google Scholar. Chen YB, Zhang YB, Wang YL, Kaur P, Yang BG, Zhu Y, Ye L, Cui YL.

A novel inhalable quercetin-alginate nanogel as a promising therapy for acute lung injury. J Nanobiotechnol. Article Google Scholar. Correa D, Scheuber MI, Shan H, Weinmann OW, Baumgartner YA, Harten A, Wahl A-S, Skaar KL, Schwab ME. Intranasal delivery of full-length anti-Nogo-A antibody: A potential alternative route for therapeutic antibodies to central nervous system targets.

Liu Z, Tang W, Liu J, Han Y, Yan Q, Dong Y, Liu X, Yang D, Ma G, Cao H. A novel sprayable thermosensitive hydrogel coupled with zinc modified metformin promotes the healing of skin wound.

CAS PubMed Google Scholar. Madry H, Gao L, Rey-Rico A, Venkatesan JK, Muller-Brandt K, Cai X, Goebel L, Schmitt G, Speicher-Mentges S, Zurakowski D, et al.

Thermosensitive hydrogel based on PEO-PPO-PEO poloxamers for a controlled in situ release of recombinant Adeno-Associated viral vectors for effective gene therapy of cartilage defects.

Adv Mater. Donati I, Christensen BE. Alginate-metal cation interactions: macromolecular approach. Carbohydr Polym. Li X, Liu Y, Yu Y, Chen W, Liu Y, Yu H. Nanoformulations of quercetin and cellulose nanofibers as healthcare supplements with sustained antioxidant activity. Tan Y, Zi Y, Peng J, Shi C, Zheng Y, Zhong J.

Gelatin as a bioactive nanodelivery system for functional food applications. Food Chem. Kumar MN, Kalarikkal SP, Bethi CM, Singh SN, Narayanan J, Sundaram GM. An eco-friendly one-pot extraction process for curcumin and its bioenhancer, piperine, from edible plants in exosome-like nanovesicles.

Green Chem. Huang K, Zhong P, Xu B. Discrimination on potential adulteration of extra virgin olive oils consumed in China by differential scanning calorimeter combined with dimensionality reduction classification techniques. Guo S, Kim WJ, Lok J, Lee SR, Besancon E, Luo BH, Stins MF, Wang X, Dedhar S, Lo EH.

Neuroprotection via matrix-trophic coupling between cerebral endothelial cells and neurons. Xu D, Hu MJ, Wang YQ, Cui YL.

Antioxidant activities of Quercetin and its complexes for Medicinal Application. Xu D, Qiao T, Wang Y, Wang QS, Cui YL. Alginate nanogels-based thermosensitive hydrogel to improve antidepressant-like effects of albiflorin via intranasal delivery.