Aerobic exercise facilitates synaptic plasticity,thereby improving cognitive functions such as learning and memory.The 5-hydroxytryptamine system has been indicated in these processes.5-Hydroxytryptamine type 3 recept...Aerobic exercise facilitates synaptic plasticity,thereby improving cognitive functions such as learning and memory.The 5-hydroxytryptamine system has been indicated in these processes.5-Hydroxytryptamine type 3 receptors are necessary for exercise-induced hippocampal neurogenesis.Some antipsychotic drugs with 5-hydroxytryptamine type 3 receptor antagonistic properties may impede the amelioration of cognitive impairment and hippocampal plasticity induced by exercise.However,the mechanisms underlying the facilitation of synaptic plasticity by aerobic exercise have not yet been elucidated.In this study,we found that 5-hydroxytryptamine type 3 receptors played an important role in aerobic exercise-mediated improvement of hippocampal-dependent spatial and exploratory memory in mice.While 5-hydroxytryptamine type 3 receptors did not affect baseline neurogenesis in the hippocampal dentate gyrus,5-hydroxytryptamine type 3 receptors were required for aerobic exercise-induced neurogenesis and astrocyte proliferation in this region.In addition,5-hydroxytryptamine type 3 receptors were crucial for maintaining long-term potentiation in the CA1,dentate gyrus,and CA3 regions of the hippocampus.The long-term potentiation changes induced by aerobic exercise in sub-regions of the hippocampus were heterogeneous:5-hydroxytryptamine type 3 receptors were essential for aerobic exercise to enhance long-term potentiation in the CA3,but not the CA1 or dentate gyrus,regions of the hippocampus.Furthermore,aerobic exercise up-regulated 5-hydroxytryptamine type 3 receptor expression and increased brain-derived neurotrophic factor release in the hippocampus in a 5-hydroxytryptamine type 3 receptor-dependent manner.These results suggest that aerobic exercise increases hippocampal dentate gyrus neurogenesis and astrocyte proliferation via the up-regulation of 5-hydroxytryptamine type 3 receptors,leading to more brain-derived neurotrophic factor production and release from these cells,which results in long-term potentiation facilitation in the hippocampal CA3 region and help improve memory.Our findings provide insight into the mechanisms by which physical activity enhances memory and may have implications for improving memory through modulating 5-hydroxytryptamine type 3 receptor.展开更多
BACKGROUND C-X-C chemokine receptor type 5(CXCR5)^(+)CD8^(+)T cells represent a unique immune subset with dual roles,functioning as cytotoxic cells in persistent viral infections while promoting B cell responses.Despi...BACKGROUND C-X-C chemokine receptor type 5(CXCR5)^(+)CD8^(+)T cells represent a unique immune subset with dual roles,functioning as cytotoxic cells in persistent viral infections while promoting B cell responses.Despite their importance,the specific role of CXCR5^(+)CD8^(+)T cells in chronic hepatitis B(CHB),particularly during interferon-alpha(IFN-α)treatment,is not fully understood.This study aims to elucidate the relationship between CXCR5^(+)CD8^(+)T cells and sustained serologic response(SR)in patients undergoing 48 weeks of pegylated IFN-α(peg-IFN-α)treatment for CHB.AIM To elucidate the relationship between CXCR5^(+)CD8^(+)T cells and sustained SR in patients undergoing 48 weeks of peg-IFN-αtreatment for CHB.METHODS This study enrolled 60 patients with hepatitis Be antigen(HBeAg)-positive CHB undergoing 48 weeks of peg-IFN-αtreatment.Participants were assessed for eligibility based on criteria such as persistent HBsAg-positive status for at least six months,HBeAb-negative,hepatitis B virus DNA levels exceeding 2×10^(4) copies/mL,and alanine aminotransferase(ALT)levels between 2 and 10 times the upper limit of normal.Blood samples were collected at baseline and at weeks 12,24,48,and a 24-week treatment-free follow-up(week 72)to measure serum interleukin(IL)-21 concentration via ELISA and to analyze CXCR5 and programmed death-ligand 1(PD-L1)expression on CD8^(+)T cells by flow cytometry,CXCR5 is a chemokine receptor that directs immune cells to specific tissues,while PD-L1 is a protein that regulates immune responses by inhibiting T cell activity.RESULTS Patients with CHB exhibited significantly lower levels of circulating CXCR5^(+)CD8^(+)T cells compared to healthy controls(P<0.01).Notably,CXCR5^(+)CD8^(+)T cells were prominently expressed in patients who achieved sustained SR compared to non-SR(NSR).A significant correlation was observed between CXCR5 and PD-L1 expression(r=-0.189,P=0.002).However,there was no significant correlation between serum IL-21 levels and CXCR5+CD8+lymphocytes(r=-0.03,P=0.625)or serum ALT levels(r=0.026,P=0.678).CONCLUSION The enhanced expression of CXCR5^(+)CD8^(+)T cells in patients achieving HBeAg seroconversion during IFN-αtreatment suggests that these cells play a crucial role in antiviral immune responses against hepatitis B.This study highlights the potential of CXCR5^(+)CD8^(+)T cells as immune regulators in CHB,which may inform future therapeutic strategies to optimize antiviral treatments.展开更多
Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsol...Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsolved issue in pain medicine.Our previous study,using protein kinase C gamma(PKCγ)-tdTomato mice,highlights the spinal feedforward inhibitory circuit involving PKCγ neurons in gating neuropathic allodynia.However,the regulatory mechanisms governing this circuit necessitate further elucidation.We used diverse transgenic mice and advanced techniques to uncover the regulatory role of the descending serotonin(5-HT)facilitation system on spinal PKCγ neurons.Our findings revealed that 5-HT neurons from the rostral ventromedial medulla hyperpolarize spinal inhibitory interneurons via 5-HT_(2C) receptors,disinhibiting the feedforward inhibitory circuit involving PKCγ neurons and exacerbating allodynia.Inhibiting spinal 5-HT_(2C) receptors restored the feedforward inhibitory circuit,effectively preventing neuropathic allodynia.These insights offer promising therapeutic targets for neuropathic allodynia management,emphasizing the potential of spinal 5-HT_(2C) receptors as a novel avenue for intervention.展开更多
BACKGROUND The global prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)has continued to increase annually.Recent studies have indicated that inhibition of metabotropic glutamate receptor 5(...BACKGROUND The global prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)has continued to increase annually.Recent studies have indicated that inhibition of metabotropic glutamate receptor 5(mGluR5)may alleviate hepatic steatosis.However,the precise mechanism warrants further exploration.AIM To investigate the potential mechanism by which mGluR5 attenuates hepatocyte steatosis in vitro and in vivo.METHODS Free fatty acids(FFAs)-stimulated HepG2 cells were treated with the mGluR5 antagonist MPEP and the mGluR5 agonist CHPG.Oil Red O staining and a triglyceride assay kit were used to evaluate lipid content.Western blot analysis was conducted to detect the expression of the autophagy-associated proteins p62 and LC3-II,as well as the expression of the key signaling molecules AMPK and ULK1,in the treated cells.To further elucidate the contributions of autophagy and AMPK,we used chloroquine(CQ)to inhibit autophagy and compound C(CC)to inhibit AMPK activity.In parallel,wild-type mice and mGluR5 knockout(KO)mice fed a normal chow diet or a high-fat diet(HFD)were used to evaluate the effect of mGluR5 inhibition in vivo.RESULTS mGluR5 inhibition by MPEP attenuated hepatocellular steatosis and increased LC3-II and p62 protein expression.The autophagy inhibitor CQ reversed the effects of MPEP.In addition,MPEP promoted AMPK and ULK1 expression in HepG2 cells exposed to FFAs.MPEP treatment led to the nuclear translocation of transcription factor EB,which is known to promote p62 expression.This effect was negated by the AMPK inhibitor CC.mGluR5 KO mice presented reduced body weight,improved glucose tolerance and reduced hyperlipidemia when fed a HFD.Additionally,the livers of HFD-fed mGluR5 KO mice presented increases in LC3-II and p62.CONCLUSION Our results suggest that mGluR5 inhibition promoted autophagy and reduced hepatocyte steatosis through activation of the AMPK signaling pathway.These findings reveal a new functional mechanism of mGluR5 as a target in the treatment of MASLD.展开更多
Expanding the specific surface area of substrates and carrying out precise surface engineering of imprinted nanocavities are crucial methods for enhancing the identification efficiency of molecularly imprinted polymer...Expanding the specific surface area of substrates and carrying out precise surface engineering of imprinted nanocavities are crucial methods for enhancing the identification efficiency of molecularly imprinted polymers(MIPs).To implement this synergistic strategy,bioinspired surface engineering was used to incorporate dual covalent receptors via precise post-imprinting modifications(PIMs)onto mesoporous silica nanosheets.The prepared sorbents(denoted as‘‘D-PMIPs”)were utilized to improve the specific identification of adenosine 5-monophosphate(AMP).Significantly,the mesoporous silica nanosheets possess a high surface area of approximately 498.73 m^(2)·g^(-1),which facilitates the formation of abundant specific recognition sites in the D-PMIPs.The dual covalent receptors are valuable for estab-lishing the spatial orientation and arrangement of AMP through multiple cooperative interactions.PIMs enable precise site-specific functionalization within the imprinted cavities,leading to the tailor-made formation of complementary binding sites.The maximum number of high-affinity binding sites(Nmax)of the D-PMIPs is 39.99 lmol·g^(-1),which is significantly higher than that of imprinted sorbents with a sin-gle receptor(i.e.,S-BMIPs or S-PMIPs).The kinetic data of the D-PMIPs can be effectively described by a pseudo-second-order model,indicating that the main binding mechanism involves synergistic chemisorption from boronate affinity and the pyrimidine base.This study suggests that using dual cova-lent receptors and PIMs is a reliable approach for creating imprinted sorbents with high selectivity,allow-ing for the controlled engineering of imprinted sites.展开更多
Background Ruminants and monogastric animals exhibit significant differences in gluconeogenic efficiency.In dairy cows,hepatic gluconeogenesis serves as the primary source of glucose.Metabolites modulate gluconeogenes...Background Ruminants and monogastric animals exhibit significant differences in gluconeogenic efficiency.In dairy cows,hepatic gluconeogenesis serves as the primary source of glucose.Metabolites modulate gluconeogenesis efficiency through allosteric regulation,redox state,and signal transduction pathways.However,the liver-enriched metabolites that regulate hepatic gluconeogenesis in dairy cows and their specific regulatory mechanisms remain incompletely characterized.Results Six Holstein dairy cows and six Duroc×(Landrace×Yorkshire)(DLY)crossbred pigs served as research subjects.Employing non-targeted and targeted metabolomics,we discovered that three bile acids—taurodeoxycholic acid(TDCA),taurocholic acid(TCA),and glycocholic acid(GCA)—were highly enriched in Holstein dairy cows'livers.In bovine hepatocytes,individual or combined stimulation of these bile acids significantly upregulated the expression of gluconeogenesis genes(FBP1,PCK1 and G6PC)and enhanced glucose production.In fasting mice with induced gluconeogenesis,TDCA,TCA,and GCA increased fasting blood glucose levels,and pyruvate tolerance tests further revealed their capacity to enhance hepatic gluconeogenesis,enabling more efficient glucose synthesis from pyruvate.Mechanistically,these bile acids activated Takeda G protein-coupled receptor 5(TGR5),elevated intracellular cAMP levels,and ultimately enhanced gluconeogenesis via the transcription factor cAMP-response element binding protein(CREB).Notably,a TGR5 inhibitor abrogated the stimulatory effects of TDCA,TCA,and GCA on hepatic gluconeogenesis in fasting mice.Conclusion TDCA,TCA,and GCA are key metabolites promoting hepatic gluconeogenesis in dairy cows,with TGR5 as the pivotal receptor and the cAMP/PKA/CREB pathway as the critical downstream mechanism.展开更多
The pathophysiology of nonalcoholic fatty liver disease(NAFLD)was characterized by alterations in the intestinal microbiota and bile acids(BAs).Flaxseed powder(FLA)was rich in active components such asα-linolenic aci...The pathophysiology of nonalcoholic fatty liver disease(NAFLD)was characterized by alterations in the intestinal microbiota and bile acids(BAs).Flaxseed powder(FLA)was rich in active components such asα-linolenic acid,dietary fiber,and lignans,which had lipid-lowering and anti-inflammatory effects.Here,we investigated whether FLA reduced liver fat and improved inflammation by modulating the gut microbiota,enriching bacteria involved in the production of 6α-hydroxylated BAs,and activating the gut-liver-BA metabolic pathway-specific receptor Takeda G protein-coupled receptor 5(TGR5).Wild-type(WT)and TGR5 knockout mice were set up in a low-fat control group,a high-fat model group and a flaxseed powder intervention group for 12 weeks.At the end of the experiment,we examined the levels of lipids(TC,LDL-C,HDL-C,and TG),the levels of inflammatory factors(TNF-αand IL-6),the pathological changes in the liver,and the differences in the expression of key proteins(CYP7A1,TLR4,and NF-κB)in the liver of TGR5^(–/–)and WT mice.In the current study,we found that 12 weeks of FLA intervention significantly attenuated the progression of NAFLD in WT mice,whereas TGR5 knockout exacerbated the extent of disease in mice with NAFLD.TGR5 gene knockout blocked the anti-inflammatory effect of FLA,but did not block its lipid-lowering effect.The TGR5 gene may be a key protein in the anti-inflammatory pathway of FLA,rather than a key protein in the lipid-lowering pathway of FLA.FLA intervention altered the relative abundance of gut microbiota with BA metabolizing enzymes,which in turn regulated the composition of intestinal BA,particularly the proportion of the key functional BAs 6α-hydroxylated BAs,thereby activating the intestinal BA-specific receptor TGR5,which might play a role in ameliorating inflammation.FLA might be a promising functional food for the prevention of NAFLD by modulating the microbiota and BAs.展开更多
Objective:Breast cancer is the most common malignancy in women and is characterized by a high recurrence rate that severely impacts patient survival.Regulatory T cells(Tregs)in the tumor microenvironment(TME)promote i...Objective:Breast cancer is the most common malignancy in women and is characterized by a high recurrence rate that severely impacts patient survival.Regulatory T cells(Tregs)in the tumor microenvironment(TME)promote immune evasion and metastasis,increasing recurrence risk.This study determined how the epigenetic regulators,DNMT3A and METTL7A,modulate Treg infiltration via the DDR1/STAT3/CXCL5 axis and influence breast cancer recurrence and prognosis.Methods:RNA sequencing(RNA-seq)was used to identify differentially expressed genes(DEGs),followed by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment.Machine learning algorithms,including least absolute shrinkage and selection operator(LASSO),supported vector machine-recursive feature elimination(SVM-RFE)and ElasticNet identified DDR1 as a key gene.Validation included RT-qPCR,western blot,MSP,MeRIP-qPCR,and Co-IP to assess epigenetic regulation.Functional assays(CCK-8,Transwell,and Treg differentiation/chemotaxis)and xenograft models evaluated the role of DDR1 in tumor progression and recurrence.Results:DNMT3A upregulated DDR1 via DNA methylation,while METTL7A enhanced DDR1 mRNA stability via m6A modification.Co-regulation activated the DDR1/STAT3/CXCL5 axis,which boosted cancer cell proliferation,migration,and invasion.CXCL5 secretion increased Treg infiltration and accelerated tumor growth in vivo.DDR1 silencing reversed these effects,confirming that DDR1 has a pivotal role in breast cancer recurrence.Conclusion:DNMT3A and METTL7A were shown to cooperatively regulate DDR1 via DNA/m6A methylation,which drives Tregmediated immune suppression and recurrence.This study provided novel insights and therapeutic targets for breast cancer prognosis and treatment.展开更多
基金supported by the National Natural Science Foundation of China,Nos.31972914,31771175(both to YH).
文摘Aerobic exercise facilitates synaptic plasticity,thereby improving cognitive functions such as learning and memory.The 5-hydroxytryptamine system has been indicated in these processes.5-Hydroxytryptamine type 3 receptors are necessary for exercise-induced hippocampal neurogenesis.Some antipsychotic drugs with 5-hydroxytryptamine type 3 receptor antagonistic properties may impede the amelioration of cognitive impairment and hippocampal plasticity induced by exercise.However,the mechanisms underlying the facilitation of synaptic plasticity by aerobic exercise have not yet been elucidated.In this study,we found that 5-hydroxytryptamine type 3 receptors played an important role in aerobic exercise-mediated improvement of hippocampal-dependent spatial and exploratory memory in mice.While 5-hydroxytryptamine type 3 receptors did not affect baseline neurogenesis in the hippocampal dentate gyrus,5-hydroxytryptamine type 3 receptors were required for aerobic exercise-induced neurogenesis and astrocyte proliferation in this region.In addition,5-hydroxytryptamine type 3 receptors were crucial for maintaining long-term potentiation in the CA1,dentate gyrus,and CA3 regions of the hippocampus.The long-term potentiation changes induced by aerobic exercise in sub-regions of the hippocampus were heterogeneous:5-hydroxytryptamine type 3 receptors were essential for aerobic exercise to enhance long-term potentiation in the CA3,but not the CA1 or dentate gyrus,regions of the hippocampus.Furthermore,aerobic exercise up-regulated 5-hydroxytryptamine type 3 receptor expression and increased brain-derived neurotrophic factor release in the hippocampus in a 5-hydroxytryptamine type 3 receptor-dependent manner.These results suggest that aerobic exercise increases hippocampal dentate gyrus neurogenesis and astrocyte proliferation via the up-regulation of 5-hydroxytryptamine type 3 receptors,leading to more brain-derived neurotrophic factor production and release from these cells,which results in long-term potentiation facilitation in the hippocampal CA3 region and help improve memory.Our findings provide insight into the mechanisms by which physical activity enhances memory and may have implications for improving memory through modulating 5-hydroxytryptamine type 3 receptor.
基金supported by the Shanxi Province Overseas Returnees Research Funding Project(No.2023-102)Shanxi Province Postgraduate Research Innovation Program(No.2023KY385,2023KY360,2022Y396)。
基金Supported by Changsha Science and Technology Program,No.kq2022397Natural Science Foundation of Hunan Province(Departmental Joint Fund),No.2023JJ60440+2 种基金Research Program of Health Commission of Hunan Province,No.202303088786Clinical Medical Research Center for Viral Hepatitis of Hunan Province,No.2023SK4009the Scientific Research Program of FuRong Laboratory,No.2023SK2108.
文摘BACKGROUND C-X-C chemokine receptor type 5(CXCR5)^(+)CD8^(+)T cells represent a unique immune subset with dual roles,functioning as cytotoxic cells in persistent viral infections while promoting B cell responses.Despite their importance,the specific role of CXCR5^(+)CD8^(+)T cells in chronic hepatitis B(CHB),particularly during interferon-alpha(IFN-α)treatment,is not fully understood.This study aims to elucidate the relationship between CXCR5^(+)CD8^(+)T cells and sustained serologic response(SR)in patients undergoing 48 weeks of pegylated IFN-α(peg-IFN-α)treatment for CHB.AIM To elucidate the relationship between CXCR5^(+)CD8^(+)T cells and sustained SR in patients undergoing 48 weeks of peg-IFN-αtreatment for CHB.METHODS This study enrolled 60 patients with hepatitis Be antigen(HBeAg)-positive CHB undergoing 48 weeks of peg-IFN-αtreatment.Participants were assessed for eligibility based on criteria such as persistent HBsAg-positive status for at least six months,HBeAb-negative,hepatitis B virus DNA levels exceeding 2×10^(4) copies/mL,and alanine aminotransferase(ALT)levels between 2 and 10 times the upper limit of normal.Blood samples were collected at baseline and at weeks 12,24,48,and a 24-week treatment-free follow-up(week 72)to measure serum interleukin(IL)-21 concentration via ELISA and to analyze CXCR5 and programmed death-ligand 1(PD-L1)expression on CD8^(+)T cells by flow cytometry,CXCR5 is a chemokine receptor that directs immune cells to specific tissues,while PD-L1 is a protein that regulates immune responses by inhibiting T cell activity.RESULTS Patients with CHB exhibited significantly lower levels of circulating CXCR5^(+)CD8^(+)T cells compared to healthy controls(P<0.01).Notably,CXCR5^(+)CD8^(+)T cells were prominently expressed in patients who achieved sustained SR compared to non-SR(NSR).A significant correlation was observed between CXCR5 and PD-L1 expression(r=-0.189,P=0.002).However,there was no significant correlation between serum IL-21 levels and CXCR5+CD8+lymphocytes(r=-0.03,P=0.625)or serum ALT levels(r=0.026,P=0.678).CONCLUSION The enhanced expression of CXCR5^(+)CD8^(+)T cells in patients achieving HBeAg seroconversion during IFN-αtreatment suggests that these cells play a crucial role in antiviral immune responses against hepatitis B.This study highlights the potential of CXCR5^(+)CD8^(+)T cells as immune regulators in CHB,which may inform future therapeutic strategies to optimize antiviral treatments.
基金supported by the National Natural Science Foundation of China(81971058,82371226,82101295,82301398)the National Funded Postdoctoral Researcher Program(GZC20233585)The Boost Plan of Xijing Hospital(XJZT24QN25,XJZT25CX22).
文摘Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsolved issue in pain medicine.Our previous study,using protein kinase C gamma(PKCγ)-tdTomato mice,highlights the spinal feedforward inhibitory circuit involving PKCγ neurons in gating neuropathic allodynia.However,the regulatory mechanisms governing this circuit necessitate further elucidation.We used diverse transgenic mice and advanced techniques to uncover the regulatory role of the descending serotonin(5-HT)facilitation system on spinal PKCγ neurons.Our findings revealed that 5-HT neurons from the rostral ventromedial medulla hyperpolarize spinal inhibitory interneurons via 5-HT_(2C) receptors,disinhibiting the feedforward inhibitory circuit involving PKCγ neurons and exacerbating allodynia.Inhibiting spinal 5-HT_(2C) receptors restored the feedforward inhibitory circuit,effectively preventing neuropathic allodynia.These insights offer promising therapeutic targets for neuropathic allodynia management,emphasizing the potential of spinal 5-HT_(2C) receptors as a novel avenue for intervention.
基金Supported by National Natural Science Foundation of China,No.81800771 and No.81300702.
文摘BACKGROUND The global prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)has continued to increase annually.Recent studies have indicated that inhibition of metabotropic glutamate receptor 5(mGluR5)may alleviate hepatic steatosis.However,the precise mechanism warrants further exploration.AIM To investigate the potential mechanism by which mGluR5 attenuates hepatocyte steatosis in vitro and in vivo.METHODS Free fatty acids(FFAs)-stimulated HepG2 cells were treated with the mGluR5 antagonist MPEP and the mGluR5 agonist CHPG.Oil Red O staining and a triglyceride assay kit were used to evaluate lipid content.Western blot analysis was conducted to detect the expression of the autophagy-associated proteins p62 and LC3-II,as well as the expression of the key signaling molecules AMPK and ULK1,in the treated cells.To further elucidate the contributions of autophagy and AMPK,we used chloroquine(CQ)to inhibit autophagy and compound C(CC)to inhibit AMPK activity.In parallel,wild-type mice and mGluR5 knockout(KO)mice fed a normal chow diet or a high-fat diet(HFD)were used to evaluate the effect of mGluR5 inhibition in vivo.RESULTS mGluR5 inhibition by MPEP attenuated hepatocellular steatosis and increased LC3-II and p62 protein expression.The autophagy inhibitor CQ reversed the effects of MPEP.In addition,MPEP promoted AMPK and ULK1 expression in HepG2 cells exposed to FFAs.MPEP treatment led to the nuclear translocation of transcription factor EB,which is known to promote p62 expression.This effect was negated by the AMPK inhibitor CC.mGluR5 KO mice presented reduced body weight,improved glucose tolerance and reduced hyperlipidemia when fed a HFD.Additionally,the livers of HFD-fed mGluR5 KO mice presented increases in LC3-II and p62.CONCLUSION Our results suggest that mGluR5 inhibition promoted autophagy and reduced hepatocyte steatosis through activation of the AMPK signaling pathway.These findings reveal a new functional mechanism of mGluR5 as a target in the treatment of MASLD.
基金supported by the National Natural Science Foundation of China(22078132,22108103,and U22A20413)the Open Funding Project of the National Key Labora-tory of Biochemical Engineering(2021KF-02)+3 种基金China Postdoctoral Science Foundation(2021M691301)Jiangsu Key Research and Development Program(BE2022356)the Postdoctoral Fellowship Program of China Postdoctoral Science Foundation(CPSF)(GZ20230989)Jiangsu Agricultural Independent Innovation Fund Project(CX(21)3079).
文摘Expanding the specific surface area of substrates and carrying out precise surface engineering of imprinted nanocavities are crucial methods for enhancing the identification efficiency of molecularly imprinted polymers(MIPs).To implement this synergistic strategy,bioinspired surface engineering was used to incorporate dual covalent receptors via precise post-imprinting modifications(PIMs)onto mesoporous silica nanosheets.The prepared sorbents(denoted as‘‘D-PMIPs”)were utilized to improve the specific identification of adenosine 5-monophosphate(AMP).Significantly,the mesoporous silica nanosheets possess a high surface area of approximately 498.73 m^(2)·g^(-1),which facilitates the formation of abundant specific recognition sites in the D-PMIPs.The dual covalent receptors are valuable for estab-lishing the spatial orientation and arrangement of AMP through multiple cooperative interactions.PIMs enable precise site-specific functionalization within the imprinted cavities,leading to the tailor-made formation of complementary binding sites.The maximum number of high-affinity binding sites(Nmax)of the D-PMIPs is 39.99 lmol·g^(-1),which is significantly higher than that of imprinted sorbents with a sin-gle receptor(i.e.,S-BMIPs or S-PMIPs).The kinetic data of the D-PMIPs can be effectively described by a pseudo-second-order model,indicating that the main binding mechanism involves synergistic chemisorption from boronate affinity and the pyrimidine base.This study suggests that using dual cova-lent receptors and PIMs is a reliable approach for creating imprinted sorbents with high selectivity,allow-ing for the controlled engineering of imprinted sites.
基金supported by the National Science Fund for Excellent Young Scholars(grant number 32422082)the Natural Science Basic Research Plan in Shaanxi Province(grant number 2025JC-QYXQ-009)。
文摘Background Ruminants and monogastric animals exhibit significant differences in gluconeogenic efficiency.In dairy cows,hepatic gluconeogenesis serves as the primary source of glucose.Metabolites modulate gluconeogenesis efficiency through allosteric regulation,redox state,and signal transduction pathways.However,the liver-enriched metabolites that regulate hepatic gluconeogenesis in dairy cows and their specific regulatory mechanisms remain incompletely characterized.Results Six Holstein dairy cows and six Duroc×(Landrace×Yorkshire)(DLY)crossbred pigs served as research subjects.Employing non-targeted and targeted metabolomics,we discovered that three bile acids—taurodeoxycholic acid(TDCA),taurocholic acid(TCA),and glycocholic acid(GCA)—were highly enriched in Holstein dairy cows'livers.In bovine hepatocytes,individual or combined stimulation of these bile acids significantly upregulated the expression of gluconeogenesis genes(FBP1,PCK1 and G6PC)and enhanced glucose production.In fasting mice with induced gluconeogenesis,TDCA,TCA,and GCA increased fasting blood glucose levels,and pyruvate tolerance tests further revealed their capacity to enhance hepatic gluconeogenesis,enabling more efficient glucose synthesis from pyruvate.Mechanistically,these bile acids activated Takeda G protein-coupled receptor 5(TGR5),elevated intracellular cAMP levels,and ultimately enhanced gluconeogenesis via the transcription factor cAMP-response element binding protein(CREB).Notably,a TGR5 inhibitor abrogated the stimulatory effects of TDCA,TCA,and GCA on hepatic gluconeogenesis in fasting mice.Conclusion TDCA,TCA,and GCA are key metabolites promoting hepatic gluconeogenesis in dairy cows,with TGR5 as the pivotal receptor and the cAMP/PKA/CREB pathway as the critical downstream mechanism.
基金supported by the National Natural Science Foundation of China(82073551).
文摘The pathophysiology of nonalcoholic fatty liver disease(NAFLD)was characterized by alterations in the intestinal microbiota and bile acids(BAs).Flaxseed powder(FLA)was rich in active components such asα-linolenic acid,dietary fiber,and lignans,which had lipid-lowering and anti-inflammatory effects.Here,we investigated whether FLA reduced liver fat and improved inflammation by modulating the gut microbiota,enriching bacteria involved in the production of 6α-hydroxylated BAs,and activating the gut-liver-BA metabolic pathway-specific receptor Takeda G protein-coupled receptor 5(TGR5).Wild-type(WT)and TGR5 knockout mice were set up in a low-fat control group,a high-fat model group and a flaxseed powder intervention group for 12 weeks.At the end of the experiment,we examined the levels of lipids(TC,LDL-C,HDL-C,and TG),the levels of inflammatory factors(TNF-αand IL-6),the pathological changes in the liver,and the differences in the expression of key proteins(CYP7A1,TLR4,and NF-κB)in the liver of TGR5^(–/–)and WT mice.In the current study,we found that 12 weeks of FLA intervention significantly attenuated the progression of NAFLD in WT mice,whereas TGR5 knockout exacerbated the extent of disease in mice with NAFLD.TGR5 gene knockout blocked the anti-inflammatory effect of FLA,but did not block its lipid-lowering effect.The TGR5 gene may be a key protein in the anti-inflammatory pathway of FLA,rather than a key protein in the lipid-lowering pathway of FLA.FLA intervention altered the relative abundance of gut microbiota with BA metabolizing enzymes,which in turn regulated the composition of intestinal BA,particularly the proportion of the key functional BAs 6α-hydroxylated BAs,thereby activating the intestinal BA-specific receptor TGR5,which might play a role in ameliorating inflammation.FLA might be a promising functional food for the prevention of NAFLD by modulating the microbiota and BAs.
基金supported by the National Natural Science Foundation of China(Grant No.82060479)Key Research and Development Program of Ningxia Hui Autonomous Region(Grant No.2021BEG03062)Ningxia Natural Science Fund Key Project(Grant No.2024AAC02080).
文摘Objective:Breast cancer is the most common malignancy in women and is characterized by a high recurrence rate that severely impacts patient survival.Regulatory T cells(Tregs)in the tumor microenvironment(TME)promote immune evasion and metastasis,increasing recurrence risk.This study determined how the epigenetic regulators,DNMT3A and METTL7A,modulate Treg infiltration via the DDR1/STAT3/CXCL5 axis and influence breast cancer recurrence and prognosis.Methods:RNA sequencing(RNA-seq)was used to identify differentially expressed genes(DEGs),followed by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment.Machine learning algorithms,including least absolute shrinkage and selection operator(LASSO),supported vector machine-recursive feature elimination(SVM-RFE)and ElasticNet identified DDR1 as a key gene.Validation included RT-qPCR,western blot,MSP,MeRIP-qPCR,and Co-IP to assess epigenetic regulation.Functional assays(CCK-8,Transwell,and Treg differentiation/chemotaxis)and xenograft models evaluated the role of DDR1 in tumor progression and recurrence.Results:DNMT3A upregulated DDR1 via DNA methylation,while METTL7A enhanced DDR1 mRNA stability via m6A modification.Co-regulation activated the DDR1/STAT3/CXCL5 axis,which boosted cancer cell proliferation,migration,and invasion.CXCL5 secretion increased Treg infiltration and accelerated tumor growth in vivo.DDR1 silencing reversed these effects,confirming that DDR1 has a pivotal role in breast cancer recurrence.Conclusion:DNMT3A and METTL7A were shown to cooperatively regulate DDR1 via DNA/m6A methylation,which drives Tregmediated immune suppression and recurrence.This study provided novel insights and therapeutic targets for breast cancer prognosis and treatment.
