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A common mRNA modification is 5-methylcytosine (m5C), whose role in gene-transcript processing and cancer remains unclear. Here, we identify serine/arginine-rich splicing factor 2 (SRSF2) as a reader of m5C and impaired SRSF2 m5C binding as a potential contributor to leukemogenesis. Structurally, we identify residues involved in m5C recognition and the impact of the prevalent leukemia-associated mutation SRSF2P95H. We show that SRSF2 binding and m5C colocalize within transcripts. Furthermore, knocking down the m5C writer NSUN2 decreases mRNA m5C, reduces SRSF2 binding, and alters RNA splicing. We also show that the SRSF2P95H mutation impairs the ability of the protein to read m5C-marked mRNA, notably reducing its binding to key leukemia-related transcripts in leukemic cells. In leukemia patients, low NSUN2 expression leads to mRNA m5C hypomethylation and, combined with SRSF2P95H, predicts poor outcomes. Altogether, we highlight an unrecognized mechanistic link between epitranscriptomics and a key oncogenesis driver.
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Leucemia , Síndromes Mielodisplásicos , Neoplasias , Metilación de ARN , Factores de Empalme Serina-Arginina , Humanos , Leucemia/genética , Síndromes Mielodisplásicos/genética , Neoplasias/genética , ARN Mensajero/genética , Proteínas de Unión al ARN/genética , Factores de Empalme Serina-Arginina/genética , Metilación de ARN/genéticaRESUMEN
Glioma cells hijack developmental programs to control cell state. Here, we uncover a glioma cell state-specific metabolic liability that can be therapeutically targeted. To model cell conditions at brain tumor inception, we generated genetically engineered murine gliomas, with deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling astrocyte differentiation during brain development. N1IC tumors harbored quiescent astrocyte-like transformed cell populations while p53 tumors were predominantly comprised of proliferating progenitor-like cell states. Further, N1IC transformed cells exhibited increased mitochondrial lipid peroxidation, high ROS production and depletion of reduced glutathione. This altered mitochondrial phenotype rendered the astrocyte-like, quiescent populations more sensitive to pharmacologic or genetic inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Treatment of patient-derived early-passage cell lines and glioma slice cultures generated from surgical samples with a GPX4 inhibitor induced selective depletion of quiescent astrocyte-like glioma cell populations with similar metabolic profiles. Collectively, these findings reveal a specific therapeutic vulnerability to ferroptosis linked to mitochondrial redox imbalance in a subpopulation of quiescent astrocyte-like glioma cells resistant to standard forms of treatment.
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The maternal-to-zygotic transition (MZT) is a conserved and fundamental process during which the maternal environment is converted to an environment of embryonic-driven development through dramatic reprogramming. However, how maternally supplied transcripts are dynamically regulated during MZT remains largely unknown. Herein, through genome-wide profiling of RNA 5-methylcytosine (m5C) modification in zebrafish early embryos, we found that m5C-modified maternal mRNAs display higher stability than non-m5C-modified mRNAs during MZT. We discovered that Y-box binding protein 1 (Ybx1) preferentially recognizes m5C-modified mRNAs through π-π interactions with a key residue, Trp45, in Ybx1's cold shock domain (CSD), which plays essential roles in maternal mRNA stability and early embryogenesis of zebrafish. Together with the mRNA stabilizer Pabpc1a, Ybx1 promotes the stability of its target mRNAs in an m5C-dependent manner. Our study demonstrates an unexpected mechanism of RNA m5C-regulated maternal mRNA stabilization during zebrafish MZT, highlighting the critical role of m5C mRNA modification in early development.
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5-Metilcitosina/metabolismo , Embrión no Mamífero/embriología , Desarrollo Embrionario/fisiología , Estabilidad del ARN/fisiología , ARN Mensajero Almacenado/metabolismo , Pez Cebra/embriología , Animales , Células HeLa , Humanos , Ratones , ARN Mensajero Almacenado/genética , Pez Cebra/genéticaRESUMEN
A visible-light-induced radical-radical cross-coupling reaction between 1,3,4-oxadiazoles and hydroxamic acid derivatives has been realized under base- and metal-free conditions. The protocol was characterized by broad substrate scope, excellent functional group tolerance, and simple operation procedures. By using this protocol, a variety of biologically important 5-aryl-1,3,4-oxadiazole-2-methylamines were obtained in good yields with excellent chemoselectivity.
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Cuticle proteins (CPs) are the vital components of the cuticle and chitin lining covering the digestive tract of crustaceans. In this study, four new CP genes (designated as EsCP3, EsCP4, EsCP5, and EsCP8) were initially cloned and identified from the Chinese mitten crab Eriocheir sinensis. EsCP3/4/5/8 included 375, 411, 381, and 570 bp open reading frame encoding 124, 136, 126, and 189 amino acid proteins, respectively. Except for EsCP8, EsCP3/4/5 all contained a Chitin_bind_4 domain. EsCP3/4/5/8 were clustered into different groups in the phylogenetic tree. Quantitative real-time PCR results indicated that four EsCP genes have different patterns of tissue distribution. Changes in the expression levels of these four EsCP genes were observed in the intestine of crabs under Vibrio parahaemolyticus challenge. RNA interference assay showed that the knockdown of EsCPs in the intestine could inhibit the expression of antimicrobial peptides (AMPs), including crustins and anti-lipopolysaccharide factors. In addition, the knockdown of EsRelish in the intestine decreased the expression levels of these four EsCP genes. These results indicated that EsCPs were involved in regulating the expression of AMPs, and EsCPs were regulated by EsRelish.
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The regulatory role of N(6)-methyladenosine (m(6)A) and its nuclear binding protein YTHDC1 in pre-mRNA splicing remains an enigma. Here we show that YTHDC1 promotes exon inclusion in targeted mRNAs through recruiting pre-mRNA splicing factor SRSF3 (SRp20) while blocking SRSF10 (SRp38) mRNA binding. Transcriptome assay with PAR-CLIP-seq analysis revealed that YTHDC1-regulated exon-inclusion patterns were similar to those of SRSF3 but opposite of SRSF10. In vitro pull-down assay illustrated a competitive binding of SRSF3 and SRSF10 to YTHDC1. Moreover, YTHDC1 facilitates SRSF3 but represses SRSF10 in their nuclear speckle localization, RNA-binding affinity, and associated splicing events, dysregulation of which, as the result of YTHDC1 depletion, can be restored by reconstitution with wild-type, but not m(6)A-binding-defective, YTHDC1. Our findings provide the direct evidence that m(6)A reader YTHDC1 regulates mRNA splicing through recruiting and modulating pre-mRNA splicing factors for their access to the binding regions of targeted mRNAs.
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Proteínas de Ciclo Celular/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Empalme del ARN , Proteínas de Unión al ARN/metabolismo , Proteínas Represoras/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Sitios de Unión , Exones , Células HeLa , Humanos , Factores de Empalme de ARN , ARN Mensajero/metabolismo , Factores de Empalme Serina-ArgininaRESUMEN
Ovarian cancer (OC) is a malignancy associated with poor prognosis and has been linked to regulatory T cells (Tregs) in the immune microenvironment. Nevertheless, the association between Tregs-related genes (TRGs) and OC prognosis remains incompletely understood. The xCell algorithm was used to analyze Tregs scores across multiple cohorts. Weighted gene co-expression network analysis (WGCNA) was utilized to identify potential TRGs and molecular subtypes. Furthermore, we used nine machine learning algorithms to create risk models with prognostic indicators for patients. Reverse transcription-quantitative polymerase chain reaction and immunofluorescence staining were used to demonstrate the immunosuppressive ability of Tregs and the expression of key TRGs in clinical samples. Our study found that higher Tregs scores were significantly correlated with poorer overall survival. Recurrent patients exhibited increased Tregs infiltration and reduced CD8+ T cell. Moreover, molecular subtyping using seven key TRGs revealed that subtype B exhibited higher enrichment of multiple oncogenic pathways and had a worse prognosis. Notably, subtype B exhibited high Tregs levels, suggesting immune suppression. In addition, we validated machine learning-derived prognostic models across multiple platform cohorts to better distinguish patient survival and predict immunotherapy efficacy. Finally, the differential expression of key TRGs was validated using clinical samples. Our study provides novel insights into the role of Tregs in the immune microenvironment of OC. We identified potential therapeutic targets derived from Tregs (CD24, FHL2, GPM6A, HOXD8, NAP1L5, REN, and TOX3) for personalized treatment and created a machining learning-based prognostic model for OC patients, which could be useful in clinical practice.
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Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/genética , Perfilación de la Expresión Génica , Terapia de Inmunosupresión , Linfocitos T Reguladores , Microambiente Tumoral/genéticaRESUMEN
Wheat plants are ubiquitously simultaneously exposed to salinity and limited iron availability caused by soil saline-alkalisation. Through this study, we found that both low Fe and NaCl severely inhibited the growth of seminal roots in wheat seedlings; however, sufficient Fe caused greater growth cessation of seminal roots than low Fe under salt stress. Low Fe improved the root meristematic division activity, not altering the mature cell sizes compared with sufficient Fe under salt stress. Foliar Fe spray and split-root experiments showed that low Fe-alleviating the salinity-induced growth cessation of seminal roots was dependent on local low Fe signals in the roots. Ionomics combined with TEM/X-ray few differences in the root Na+ uptake and vacuolar Na+ sequestration between two Fe levels under salt stress. Phytohormone profiling and metabolomics revealed salinity-induced overaccumulation of ACC/ethylene and tryptophan/auxin in the roots under sufficient Fe than under low Fe. Differential gene expression, pharmacological inhibitor addition and the root growth performance of transgenic wheat plants revealed that the rootward auxin efflux and was responsible for the low Fe-mediated amelioration of the salinity-induced growth cessation of seminal roots. Our findings will provide novel insights into the modulation of crop root growth under salt stress.
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Plantones , Triticum , Plantones/metabolismo , Triticum/genética , Salinidad , Plantas Modificadas Genéticamente , Hierro/metabolismo , Ácidos Indolacéticos/metabolismo , Raíces de Plantas/metabolismoRESUMEN
Amide and lactam frameworks were synthesized via an efficient two-step strategy. In this protocol, pyridotriazoles were first treated with isocyanates to form the corresponding amides, which were found to be sufficiently reactive to undergo subsequent intramolecular N-H insertion in the absence of any additional reagents or catalysts.
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We report the first example of B(C6F5)3-catalyzed O-H insertion reaction of sulfoxonium ylides and carboxylic acids, achieving efficient construction of diester moieties under metal-free condition. This protocol is characterized by broad substrate tolerance, particularly for various phenylacetic acids, and good compatibility with water/air condition, which is superior to most other methods.
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A new one-pot synthesis of imidazo[1,2-a]pyridine-fused 1,3-benzodiazepine derivatives via a sequential GBB-3CR/Pd(II)-catalyzed azide-isocyanide coupling/cyclization process was developed. The Groebke-Blackburn-Bienaymé three-component reactions (GBB-3CR) of 2-aminopyridine, 2-azidobenzaldehydes, and isocyanides in the presence of a catalytic amount of p-toluenesulfonic acid gave azide intermediates without separation. The reaction was followed by using another molecule of isocyanides to produce imidazo[1,2-a]pyridine-fused 1,3-benzodiazepine derivatives in good yields by the Pd(II)-catalyzed azide-isocyanide coupling/cyclization reaction. The synthetic approach produces novel nitrogen-fused polycyclic heterocycles under mild reaction conditions. The preliminary biological evaluation demonstrated that compound 6a inhibited glioma cells efficiently, suggesting potentially broad applications of the approach for synthesis and medicinal chemistry.
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The neurotrophin brain-derived neurotrophic factor (BDNF), which acts as a transducer, is responsible for improving cerebral stroke, neuropathic pain, and depression. Exercise can alter extracellular nucleotide levels and purinergic receptors in central nervous system (CNS) structures. This inevitably activates or inhibits the expression of BDNF via purinergic receptors, particularly the P2X receptor (P2XR), to alleviate pathological progression. In addition, the significant involvement of sensitive P2X4R in mediating increased BDNF and p38-MAPK for intracerebral hemorrhage and pain hypersensitivity has been reported. Moreover, archetypal P2X7R blockade induces mouse antidepressant-like behavior and analgesia by BDNF release. This review summarizes BDNF-mediated neural effects via purinergic receptors, speculates that P2X4R and P2X7R could be priming molecules in exercise-mediated changes in BDNF, and provides strategies for the protective mechanism of exercise in neurogenic disease.
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Neuralgia , Accidente Cerebrovascular , Animales , Ratones , Antidepresivos , Factor Neurotrófico Derivado del Encéfalo , Neuroprotección , Receptores Purinérgicos P2X4 , Receptores Purinérgicos P2X7/metabolismoRESUMEN
Oxaliplatin (OXA) is a common chemotherapy drug for colorectal, gastric, and pancreatic cancers. The anticancer effect of OXA is often accompanied by neurotoxicity and acute and chronic neuropathy. The symptoms present as paresthesia and pain which adversely affect patients' quality of life. Herein, five consecutive intraperitoneal injections of OXA at a dose of 4 mg/kg were used to mimic chemotherapy. OXA administration induced mechanical allodynia, activated spinal astrocytes, and increased inflammatory response. To develop an effective therapeutic measure for OXA-induced neuropathic pain, emodin was intrathecally injected into OXA rats. Emodin developed an analgesic effect, as demonstrated by a significant increase in the paw withdrawal threshold of OXA rats. Moreover, emodin treatment reduced the pro-inflammatory cytokines (tumor necrosis factor-α and interleukin-1ß) which upregulated in OXA rats. Furthermore, autodock data showed four hydrogen bonds were formed between emodin and cyclooxygenase-2 (COX2), and emodin treatment decreased COX2 expression in OXA rats. Cell research further proved that emodin suppressed nuclear factor κB (NF-κB)-mediated inflammatory signal and reactive oxygen species level. Taken together, emodin reduced spinal COX2/NF-κB mediated inflammatory signal and oxidative stress in the spinal cord of OXA rats which consequently relieved OXA-induced neuropathic pain.
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Emodina , Neuralgia , Ratas , Animales , Oxaliplatino/efectos adversos , FN-kappa B/metabolismo , Ciclooxigenasa 2 , Emodina/efectos adversos , Calidad de Vida , Ratas Sprague-Dawley , Neuralgia/inducido químicamente , Neuralgia/tratamiento farmacológico , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológicoRESUMEN
PURPOSE: The aim of this study was to explore the predictive role of microRNAs (miRNAs) from maternal serum exosomes in early recurrent pregnancy loss (RPL) and the related mechanism in early pregnancy. METHODS: Maternal serum was collected from pregnant women with RPL history or women with ongoing pregnancy (OP); serum exosomes were extracted and identified. Differentially expressed (DE) miRNAs in exosomes were screened by RNA sequencing and further validated by qRT-PCR. Next, the predictive value of exosomal miRNA and the clinical indicators for subsequent miscarriage in RPL patients were evaluated. Additionally, we verified the regulatory relationship between miR-185-5p and vascular endothelial growth factor (VEGF) in decidual natural killer (dNK) cells by overloading or inhibiting the exosomal miR-185-5p level in trophoblast cells. RESULTS: The miRNA sequencing revealed 43 DE miRNAs between OP and RPL patients. The five most significant DE miRNAs (miR-22-3p, miR-185-5p, miR-335-3p, miR-362-5p, and miR-378a-3p) were selected for identification, and miR-185-5p was increased in RPL patients. The area under curve (AUC) of the receiver operating characteristic was 0.925 when using miR-185-5p as a biomarker for subsequent miscarriage in RPL patients. In addition, miR-185-5p in exosomes secreted from HTR-8 cells reduces VEGF expression of dNK cells. CONCLUSIONS: The current study, for the first time, successfully constructed the correlation between maternal circulating exosomal miR-185-5p expression pattern and RPL, which may be involved in the pathogenesis of RPL by downregulating the VEGFA of dNK cells and perturbing angiogenesis at the maternal-fetal interface.
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Aborto Habitual , Exosomas , MicroARNs , Humanos , Femenino , Embarazo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , MicroARNs/metabolismo , Biomarcadores/metabolismo , Exosomas/genética , Aborto Habitual/genética , Aborto Habitual/metabolismoRESUMEN
OBJECTIVE: The human gut fungal community, known as the mycobiome, plays a fundamental role in the gut ecosystem and health. Here we aimed to investigate the determinants and long-term stability of gut mycobiome among middle-aged and elderly adults. We further explored the interplay between gut fungi and bacteria on metabolic health. DESIGN: The present study included 1244 participants from the Guangzhou Nutrition and Health Study. We characterised the long-term stability and determinants of the human gut mycobiome, especially long-term habitual dietary consumption. The comprehensive multiomics analyses were performed to investigate the ecological links between gut bacteria, fungi and faecal metabolome. Finally, we examined whether the interaction between gut bacteria and fungi could modulate the metabolic risk. RESULTS: The gut fungal composition was temporally stable and mainly determined by age, long-term habitual diet and host physiological states. Specifically, compared with middle-aged individuals, Blastobotrys and Agaricomycetes spp were depleted, while Malassezia was enriched in the elderly. Dairy consumption was positively associated with Saccharomyces but inversely associated with Candida. Notably, Saccharomycetales spp interacted with gut bacterial diversity to influence insulin resistance. Bidirectional mediation analyses indicated that bacterial function or faecal histidine might causally mediate an impact of Pichia on blood cholesterol. CONCLUSION: We depict the sociodemographic and dietary determinants of human gut mycobiome in middle-aged and elderly individuals, and further reveal that the gut mycobiome may be closely associated with the host metabolic health through regulating gut bacterial functions and metabolites.
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Microbioma Gastrointestinal , Micobioma , Adulto , Anciano , Bacterias , Ecosistema , Heces/microbiología , Hongos , Humanos , Persona de Mediana Edad , Micobioma/fisiologíaRESUMEN
Bone is the preferential site of metastasis for breast cancer. Invasion of cancer cells induces the destruction of bone tissue and damnification of peripheral nerves and consequently induced central sensitization which contributes to severe pain. Herein, cancer induced bone pain (CIBP) rats exhibited destruction of tibia, mechanical allodynia and spinal inflammation. Inflammatory response mainly mediated by astrocyte and microglia in central nervous system. Our immunofluorescence analysis revealed activation of spinal astrocytes and microglia in CIBP rats. Transmission electron microscopy (TEM) observations of mitochondrial outer membrane disruption and cristae damage in spinal mitochondria of CIBP rats. Proteomics analysis identified abnormal expression of proteins related to mitochondrial organization and function. Intrathecally, injection of GSK-3ß activity inhibitor TDZD-8 significantly attenuated Drp1-mediated mitochondrial fission and recovered mitochondrial function. Inhibition of GSK-3ß activity also suppressed NLRP3 inflammasome cascade and consequently decreased mechanical pain sensitivity of CIBP rats. For cell research, TDZD-8 treatment significantly reversed TNF-α induced mitochondrial membrane potential (MMP) deficiency and high mitochondrial reactive oxygen species level. Taken together, GSK-3ß inhibition by TDZD-8 decreases spinal inflammation and relieves cancer induced bone pain via reducing Drp1-mediated mitochondrial damage.
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Inflamación , Neoplasias , Animales , Huesos , Glucógeno Sintasa Quinasa 3 beta , Dolor , Ratas , Ratas Sprague-DawleyRESUMEN
Chronic pain is the predominant problem for rheumatoid arthritis patients, and negatively affects quality of life. Arthritis pain management remains largely inadequate, and developing new treatment strategies are urgently needed. Spinal inflammation and oxidative stress contribute to arthritis pain and represent ideal targets for the treatment of arthritis pain. In the present study, collagen-induced arthritis (CIA) mouse model was established by intradermally injection of type II collagen (CII) in complete Freund's adjuvant (CFA) solution, and exhibited as paw and ankle swelling, pain hypersensitivity and motor disability. In spinal cord, CIA inducement triggered spinal inflammatory reaction presenting with inflammatory cells infiltration, increased Interleukin-1ß (IL-1ß) expression, and up-regulated NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and cleaved caspase-1 levels, elevated spinal oxidative level presenting as decreased nuclear factor E2-related factor 2 (Nrf2) expression and Superoxide dismutase (SOD) activity. To explore potential therapeutic options for arthritis pain, emodin was intraperitoneally injected for 3 days on CIA mice. Emodin treatment statistically elevated mechanical pain sensitivity, suppressed spontaneous pain, recovered motor coordination, decreased spinal inflammation score and IL-1ß expression, increased spinal Nrf2 expression and SOD activity. Further, AutoDock data showed that emodin bind to Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) through two electrovalent bonds. And emodin treatment increased the phosphorylated AMPK at threonine 172. In summary, emodin treatment activates AMPK, suppresses NLRP3 inflammasome response, elevates antioxidant response, inhibits spinal inflammatory reaction and alleviates arthritis pain.
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Artritis Experimental , Emodina , Animales , Ratones , Proteínas Quinasas Activadas por AMP/metabolismo , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide , Dolor Crónico , Emodina/uso terapéutico , Inflamación/tratamiento farmacológico , Factor 2 Relacionado con NF-E2/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Estrés Oxidativo , Superóxido Dismutasa/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
A new one-pot preparation of 4-tetrazolyl-3,4-dihydroquinazolines has been reported. The Ugi-azide reactions of 2-azidobenzaldehydes, amines, trimethylsilyl azide, and isocyanides produced azide intermediates without separation, which were treated with isocyanides to give 4-tetrazolyl-3,4-dihydroquinazoline derivatives through a sequential Palladium-catalyzed azide-isocyanide cross-coupling/cyclization reaction in moderate to good yields. The biological evaluation demonstrated that compound 6c inhibited breast cancer cells well and displayed broad applications for synthesis and medicinal chemistry.
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Cianuros , Paladio , Azidas , Catálisis , Cianuros/química , Ciclización , Estructura Molecular , Paladio/químicaRESUMEN
Glioma, as one of the most common primary intracranial tumors, is in an urgent need for specific targeting agents. Multi-branched RGD ligand is a promising alternative for liposome functionalization which combines the benefits of high affinity with αvß3 receptors and proper branching structure in response to the receptor clustering. Herein, we designed and synthesized single branched, double branched and triple branched RGD ligand (1RGD-Chol, 2RGD-Chol and 3RGD-Chol) respectively, which were then modified on the liposomes to prepare six different kinds of liposomes (including 1RGD-Lip, 2RGD-Lip, 3RGD-Lip, 2 × 1RGD-Lip, 3 × 1RGD-Lip and unmodified Lip). Subsequently, a series of assays were conducted. The results exhibited that the liposome decorated with 3RGD-Chol ligand possessed superior cellular internalization ability in C6 cells and bEnd.3 cells, suggesting the strongest ability of 3RGD-Lip to target the blood-brain barrier (BBB) and glioma cells. Besides, both the cytotoxicity and pro-apoptotic assays revealed that PTX-3RGD-Lip had the strongest ability to inhibit the survival of C6 cells. Moreover, the enrichment of liposomes at tumor site was 3RGD-Lip > 3 × 1RGD-Lip ≈ 2RGD-Lip ≈ 2 × 1RGD-Lip > 1RGD-Lip > Lip according to the in vivo imaging of C6-bearing mice, which was consistent with the result of in vitro targeting experiments. To sum up, the targeting efficiency of liposomes can be strongly promoted by improving the amount of targeting molecules, whereas the branching structure and spatial distance of RGD residues also accounted for the affinity between liposomes and αvß3 receptors. Collectively, PTX-3RGD-Lip would be a prospective strategy in glioma treatment.
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Neoplasias Encefálicas , Glioma , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos/métodos , Glioma/tratamiento farmacológico , Glioma/patología , Ligandos , Liposomas/química , Ratones , Oligopéptidos/química , Estudios ProspectivosRESUMEN
Quercetin (Que), a polyphenolic flavonoid compound with antioxidant properties has been explicated to have neuroprotective effects on neuronal injury/neurodegenerative diseases. However, low water-solubility, instability and inability to cross the blood-brain barrier (BBB) imped its application. To enhance the neuroprotective effects and improve the potential application of quercetins as a nutraceutical or medicine, we designed and synthesized two types of glycosylated quercetins--Glu-Que and 2Glu-Que through click reaction. Glu-Que and 2Glu-Que improved the water solubility and stability of quercetin, as well as alleviating H2O2-induced neurotoxicity by increasing the cell viability of PC12 cells and reducing the ROS generation. What's more, glycosylated quercetins enhanced neuroprotective effects on cerebral ischemia-reperfusion (I/R). Among the two types of glycosylated quercetin, 2Glu-Que displayed higher neuroprotective potential than Glu-Que. In conclusion, the glycosylated quercetin 2Glu-Que, with better water solubility, bioavailability and brain-targeting ability, significantly enhanced the neuroprotective effects of quercetin, making it a promising nutraceutical or candidate drug in neuroprotection.