BACKGROUND Colorectal cancer(CRC)has a high incidence and mortality.Recent studies have shown that indole derivatives involved in gut microbiota metabolism can impact the tumorigenesis,progression,and metastasis of CR...BACKGROUND Colorectal cancer(CRC)has a high incidence and mortality.Recent studies have shown that indole derivatives involved in gut microbiota metabolism can impact the tumorigenesis,progression,and metastasis of CRC.AIM To investigate the effect of indole-3-acetaldehyde(IAAD)on CRC.METHODS The effect of IAAD was evaluated in a syngeneic mouse model of CRC and CRC cell lines(HCT116 and DLD-1).Cell proliferation was assessed by Ki-67 fluorescence staining and cytotoxicity tests.Cell apoptosis was analysed by flow cytometry after staining with Annexin V-fluorescein isothiocyanate and propidium iodide.Invasiveness was investigated using the transwell assay.Western blotting and real-time fluorescence quantitative polymerase chain reaction were performed to evaluate the expression of epithelial-mesenchymal transition related genes and aryl hydrocarbon receptor(AhR)downstream genes.The PharmMapper,SEA,and SWISS databases were used to screen for potential target proteins of IAAD,and the core proteins were identified through the String database.RESULTS IAAD reduced tumorigenesis in a syngeneic mouse model.In CRC cell lines HCT116 and DLD1,IAAD exhibited cytotoxicity starting at 24 h of treatment,while it reduced Ki67 expression in the nucleus.The results of flow cytometry showed that IAAD induced apoptosis in HCT116 cells but had no effect on DLD1 cells,which may be related to the activation of AhR.IAAD can also increase the invasiveness and epithelial-mesenchymal transition of HCT116 and DLD1 cells.At low concentrations(<12.5μmol/L),IAAD only exhibited cytotoxic effects without promoting cell invasion.In addition,predictions based on online databases,protein-protein interaction analysis,and molecular docking showed that IAAD can bind to matrix metalloproteinase-9(MMP9),angiotensin converting enzyme(ACE),poly(ADP-ribose)polymerase-1(PARP1),matrix metalloproteinase-2(MMP2),and myeloperoxidase(MPO).CONCLUSION Indole-3-aldehyde can induce cell apoptosis and inhibit cell proliferation to prevent the occurrence of CRC;however,at high concentrations(≥25μmol/L),it can also promote epithelial-mesenchymal transition and invasion in CRC cells.IAAD activates AhR and directly binds MMP9,ACE,PARP1,MMP2,and MPO,which partly reveals why it has a bidirectional effect.展开更多
Background Pectin is a heteropolysaccharide that acts as an intestinal immunomodulator,promoting intestinal development and regulating intestinal flora in the gut.However,the relevant mechanisms remain obscure.In this...Background Pectin is a heteropolysaccharide that acts as an intestinal immunomodulator,promoting intestinal development and regulating intestinal flora in the gut.However,the relevant mechanisms remain obscure.In this study,pigs were fed a corn-soybean meal-based diet supplemented with either 5%microcrystalline cellulose(MCC)or 5%pectin for 3 weeks,to investigate the metabolites and anti-inflammatory properties of the jejunum.Result The results showed that dietary pectin supplementation improved intestinal integrity(Claudin-1,Occludin)and inflammatory response[interleukin(IL)-10],and the expression of proinflammatory cytokines(IL-1β,IL-6,IL-8,TNF-α)was down-regulated in the jejunum.Moreover,pectin supplementation altered the jejunal microbiome and tryptophan-related metabolites in piglets.Pectin specifically increased the abundance of Lactococcus,Enterococcus,and the microbiota-derived metabolites(skatole(ST),3-indoleacetic acid(IAA),3-indolepropionic acid(IPA),5-hydroxyindole-3-acetic acid(HIAA),and tryptamine(Tpm)),which activated the aryl hydrocarbon receptor(AhR)pathway.AhR activation modulates IL-22 and its downstream pathways.Correlation analysis revealed the potential relationship between metabolites and intestinal morphology,intestinal gene expression,and cytokine levels.Conclusion In conclusion,these results indicated that pectin inhibits the inflammatory response by enhancing the AhR-IL22-signal transducer and activator of transcription 3 signaling pathway,which is activated through tryptophan metabolites.展开更多
Several studies have shown that the immune system is highly regulated by tryptophan metabolism,which serves as an immunomodulatory factor.The indoleamine 2,3-dioxygenase 1(IDO1),as an intracellular enzyme that partici...Several studies have shown that the immune system is highly regulated by tryptophan metabolism,which serves as an immunomodulatory factor.The indoleamine 2,3-dioxygenase 1(IDO1),as an intracellular enzyme that participates in metabolism of the essential amino acid tryptophan in the kynurenine pathway,is an independent prognostic marker for pancreatic cancer(PC).First,overexpression of IDO1 inhibits the maturation of dendritic cells and T-cell proliferation in the liver and spleen.Second,the high expression of kynurenine induces and activates the aryl hydrocarbon receptor,resulting in upregulated programmed cell death protein 1 expression.Third,the induction of IDO1 can lead to loss of the T helper 17 cell/regulatory T cell balance,mediated by the proximal tryptophan catabolite from IDO metabolism.In our study,we found that overexpression of IDO1 upregulated CD8+T cells and reduced natural killer T cells in pancreatic carcinoma in mice.Hence,it may be essential to pay more attention to tryptophan metabolism in patients,especially those who are tolerant to immunotherapy for PC.展开更多
Serotonin deficiency in major depressive disorder(MDD)has formed the basis of antidepressant drug development and was originally attributed to induction of the major tryptophan(Trp)-degrading enzyme,liver Trp 2,3-diox...Serotonin deficiency in major depressive disorder(MDD)has formed the basis of antidepressant drug development and was originally attributed to induction of the major tryptophan(Trp)-degrading enzyme,liver Trp 2,3-dioxygenase(TDO),by cortisol,leading to decreased Trp availability to the brain for serotonin synthesis.Subsequently,the serotonin deficiency was proposed to involve induction of the extrahepatic Trp-degrading enzyme indoleamine 2,3-dioxygenase(IDO)by proinflammatory cytokines,with inflammation being the underlying cause.Recent evidence,however,challenges this latter concept,as not all MDD patients are immune-activated and,when present,inflammation is mild and/or transient.A wide range of antidepressant drugs inhibit the activity of liver TDO and bind specifically to the enzyme,but not to IDO.IDO induction is not a major event in MDD,but,when it occurs,its metabolic consequences may be masked and overridden by upregulation of kynurenine monooxygenase(KMO),the gateway to production of modulators of immune and neuronal functions.KMO appears to be activated in MDD by certain proinflammatory cytokines and antidepressants with anti-inflammatory properties may block this activation.We demonstrate the ability of the antidepressant ketamine to dock(bind)to KMO.The pathophysiology of MDD may be underpinned by both the serotonin deficiency and glutamatergic activation mediated respectively by TDO induction and N-methyl-D-aspartate receptor activation.Inhibition of TDO and KMO should be the focus of MDD pharmacotherapy.展开更多
基金Supported by Zhejiang Provincial Natural Science Foundation of China,No.LTGD23C040008,No.LBY23H200006,and No.LQ22H030004.
文摘BACKGROUND Colorectal cancer(CRC)has a high incidence and mortality.Recent studies have shown that indole derivatives involved in gut microbiota metabolism can impact the tumorigenesis,progression,and metastasis of CRC.AIM To investigate the effect of indole-3-acetaldehyde(IAAD)on CRC.METHODS The effect of IAAD was evaluated in a syngeneic mouse model of CRC and CRC cell lines(HCT116 and DLD-1).Cell proliferation was assessed by Ki-67 fluorescence staining and cytotoxicity tests.Cell apoptosis was analysed by flow cytometry after staining with Annexin V-fluorescein isothiocyanate and propidium iodide.Invasiveness was investigated using the transwell assay.Western blotting and real-time fluorescence quantitative polymerase chain reaction were performed to evaluate the expression of epithelial-mesenchymal transition related genes and aryl hydrocarbon receptor(AhR)downstream genes.The PharmMapper,SEA,and SWISS databases were used to screen for potential target proteins of IAAD,and the core proteins were identified through the String database.RESULTS IAAD reduced tumorigenesis in a syngeneic mouse model.In CRC cell lines HCT116 and DLD1,IAAD exhibited cytotoxicity starting at 24 h of treatment,while it reduced Ki67 expression in the nucleus.The results of flow cytometry showed that IAAD induced apoptosis in HCT116 cells but had no effect on DLD1 cells,which may be related to the activation of AhR.IAAD can also increase the invasiveness and epithelial-mesenchymal transition of HCT116 and DLD1 cells.At low concentrations(<12.5μmol/L),IAAD only exhibited cytotoxic effects without promoting cell invasion.In addition,predictions based on online databases,protein-protein interaction analysis,and molecular docking showed that IAAD can bind to matrix metalloproteinase-9(MMP9),angiotensin converting enzyme(ACE),poly(ADP-ribose)polymerase-1(PARP1),matrix metalloproteinase-2(MMP2),and myeloperoxidase(MPO).CONCLUSION Indole-3-aldehyde can induce cell apoptosis and inhibit cell proliferation to prevent the occurrence of CRC;however,at high concentrations(≥25μmol/L),it can also promote epithelial-mesenchymal transition and invasion in CRC cells.IAAD activates AhR and directly binds MMP9,ACE,PARP1,MMP2,and MPO,which partly reveals why it has a bidirectional effect.
基金supported by National Natural Science Foundation of China(NSFC)(31802072)China Scholarship Council(CSC NO.202103250006)+1 种基金the Central Public-interest Scientific Institution Basal Research Fund(No.Y2022GH02&PJ01618301)State Key Laboratory of Animal Nutrition(2004DA125184G2102)。
文摘Background Pectin is a heteropolysaccharide that acts as an intestinal immunomodulator,promoting intestinal development and regulating intestinal flora in the gut.However,the relevant mechanisms remain obscure.In this study,pigs were fed a corn-soybean meal-based diet supplemented with either 5%microcrystalline cellulose(MCC)or 5%pectin for 3 weeks,to investigate the metabolites and anti-inflammatory properties of the jejunum.Result The results showed that dietary pectin supplementation improved intestinal integrity(Claudin-1,Occludin)and inflammatory response[interleukin(IL)-10],and the expression of proinflammatory cytokines(IL-1β,IL-6,IL-8,TNF-α)was down-regulated in the jejunum.Moreover,pectin supplementation altered the jejunal microbiome and tryptophan-related metabolites in piglets.Pectin specifically increased the abundance of Lactococcus,Enterococcus,and the microbiota-derived metabolites(skatole(ST),3-indoleacetic acid(IAA),3-indolepropionic acid(IPA),5-hydroxyindole-3-acetic acid(HIAA),and tryptamine(Tpm)),which activated the aryl hydrocarbon receptor(AhR)pathway.AhR activation modulates IL-22 and its downstream pathways.Correlation analysis revealed the potential relationship between metabolites and intestinal morphology,intestinal gene expression,and cytokine levels.Conclusion In conclusion,these results indicated that pectin inhibits the inflammatory response by enhancing the AhR-IL22-signal transducer and activator of transcription 3 signaling pathway,which is activated through tryptophan metabolites.
基金National Natural Science Foundation of China,No.82200695。
文摘Several studies have shown that the immune system is highly regulated by tryptophan metabolism,which serves as an immunomodulatory factor.The indoleamine 2,3-dioxygenase 1(IDO1),as an intracellular enzyme that participates in metabolism of the essential amino acid tryptophan in the kynurenine pathway,is an independent prognostic marker for pancreatic cancer(PC).First,overexpression of IDO1 inhibits the maturation of dendritic cells and T-cell proliferation in the liver and spleen.Second,the high expression of kynurenine induces and activates the aryl hydrocarbon receptor,resulting in upregulated programmed cell death protein 1 expression.Third,the induction of IDO1 can lead to loss of the T helper 17 cell/regulatory T cell balance,mediated by the proximal tryptophan catabolite from IDO metabolism.In our study,we found that overexpression of IDO1 upregulated CD8+T cells and reduced natural killer T cells in pancreatic carcinoma in mice.Hence,it may be essential to pay more attention to tryptophan metabolism in patients,especially those who are tolerant to immunotherapy for PC.
文摘Serotonin deficiency in major depressive disorder(MDD)has formed the basis of antidepressant drug development and was originally attributed to induction of the major tryptophan(Trp)-degrading enzyme,liver Trp 2,3-dioxygenase(TDO),by cortisol,leading to decreased Trp availability to the brain for serotonin synthesis.Subsequently,the serotonin deficiency was proposed to involve induction of the extrahepatic Trp-degrading enzyme indoleamine 2,3-dioxygenase(IDO)by proinflammatory cytokines,with inflammation being the underlying cause.Recent evidence,however,challenges this latter concept,as not all MDD patients are immune-activated and,when present,inflammation is mild and/or transient.A wide range of antidepressant drugs inhibit the activity of liver TDO and bind specifically to the enzyme,but not to IDO.IDO induction is not a major event in MDD,but,when it occurs,its metabolic consequences may be masked and overridden by upregulation of kynurenine monooxygenase(KMO),the gateway to production of modulators of immune and neuronal functions.KMO appears to be activated in MDD by certain proinflammatory cytokines and antidepressants with anti-inflammatory properties may block this activation.We demonstrate the ability of the antidepressant ketamine to dock(bind)to KMO.The pathophysiology of MDD may be underpinned by both the serotonin deficiency and glutamatergic activation mediated respectively by TDO induction and N-methyl-D-aspartate receptor activation.Inhibition of TDO and KMO should be the focus of MDD pharmacotherapy.
