Ischemic stroke,which is characterized by hypoxia and ischemia,triggers a cascade of injury responses,including neurotoxicity,inflammation,oxidative stress,disruption of the blood-brain barrier,and neuronal death.In t...Ischemic stroke,which is characterized by hypoxia and ischemia,triggers a cascade of injury responses,including neurotoxicity,inflammation,oxidative stress,disruption of the blood-brain barrier,and neuronal death.In this context,tryptophan metabolites and enzymes,which are synthesized through the kynurenine and 5-hydroxytryptamine pathways,play dual roles.The delicate balance between neurotoxic and neuroprotective substances is a crucial factor influencing the progression of ischemic stroke.Neuroprotective metabolites,such as kynurenic acid,exert their effects through various mechanisms,including competitive blockade of N-methyl-D-aspartate receptors,modulation ofα7 nicotinic acetylcholine receptors,and scavenging of reactive oxygen species.In contrast,neurotoxic substances such as quinolinic acid can hinder the development of vascular glucose transporter proteins,induce neurotoxicity mediated by reactive oxygen species,and disrupt mitochondrial function.Additionally,the enzymes involved in tryptophan metabolism play major roles in these processes.Indoleamine 2,3-dioxygenase in the kynurenine pathway and tryptophan hydroxylase in the 5-hydroxytryptamine pathway influence neuroinflammation and brain homeostasis.Consequently,the metabolites generated through tryptophan metabolism have substantial effects on the development and progression of ischemic stroke.Stroke treatment aims to restore the balance of various metabolite levels;however,precise regulation of tryptophan metabolism within the central nervous system remains a major challenge for the treatment of ischemic stroke.Therefore,this review aimed to elucidate the complex interactions between tryptophan metabolites and enzymes in ischemic stroke and develop targeted therapies that can restore the delicate balance between neurotoxicity and neuroprotection.展开更多
Dysregulation of neurotransmitter metabolism in the central nervous system contributes to mood disorders such as depression, anxiety, and post–traumatic stress disorder. Monoamines and amino acids are important types...Dysregulation of neurotransmitter metabolism in the central nervous system contributes to mood disorders such as depression, anxiety, and post–traumatic stress disorder. Monoamines and amino acids are important types of neurotransmitters. Our previous results have shown that disco-interacting protein 2 homolog A(Dip2a) knockout mice exhibit brain development disorders and abnormal amino acid metabolism in serum. This suggests that DIP2A is involved in the metabolism of amino acid–associated neurotransmitters. Therefore, we performed targeted neurotransmitter metabolomics analysis and found that Dip2a deficiency caused abnormal metabolism of tryptophan and thyroxine in the basolateral amygdala and medial prefrontal cortex. In addition, acute restraint stress induced a decrease in 5-hydroxytryptamine in the basolateral amygdala. Additionally, Dip2a was abundantly expressed in excitatory neurons of the basolateral amygdala, and deletion of Dip2a in these neurons resulted in hopelessness-like behavior in the tail suspension test. Altogether, these findings demonstrate that DIP2A in the basolateral amygdala may be involved in the regulation of stress susceptibility. This provides critical evidence implicating a role of DIP2A in affective disorders.展开更多
BACKGROUND The tryptophan-kynurenine(TRP-KYN)pathway may be implicated in the pathophysiology of cognitive impairment and pain severity in major depressive disorder(MDD);however,few studies have explored the intricaci...BACKGROUND The tryptophan-kynurenine(TRP-KYN)pathway may be implicated in the pathophysiology of cognitive impairment and pain severity in major depressive disorder(MDD);however,few studies have explored the intricacies of their interaction.AIM To investigate the relationship between the TRP-KYN pathway and cognitive function in MDD patients with and without painful physical symptoms(PPS).METHODS Seventy patients with MDD were recruited,including 33 and 37 with and without PSS,respectively.The Hamilton Depression Scale,the Hamilton Anxiety Scale,and the Short-form of McGill pain questionnaire(SFMPQ)were used to assess clinical symptoms.Cognitive function was assessed by the MATRICS Consensus Cognitive Battery(MCCB)score.TRP-KYN pathway metabolites’serum levels were measured using high-performance liquid chromatography-tandem mass spectrometry.RESULTS The with PPS group exhibited significantly higher TRP-KYN ratios than did the without PPS group;in the former,the SFMPQ scores positively and negatively correlated with the TRP-KYN ratio and total MCCB score,respectively.Regression analysis indicated that body mass index and SFMPQ scores were significantly associated with the TRP-KYN ratio,predicting 30%of the variance.CONCLUSION The TRP-KYN ratio is a potential biomarker for identifying patients with depression accompanied by pain symptoms,and targeting it may represent a novel therapeutic strategy for managing pain in these individuals.Further elucidation of the biological mechanisms underlying cognitive impairment in MDD patients with PPS is warranted.展开更多
OBJECTIVE:To investigate the effect of central amino acid metabolic profiles on acupuncture analgesia.METHODS:BALB/c mice were injected with Complete Freund's Adjuvant(CFA)and acupuncture was applied at Zusanli(ST...OBJECTIVE:To investigate the effect of central amino acid metabolic profiles on acupuncture analgesia.METHODS:BALB/c mice were injected with Complete Freund's Adjuvant(CFA)and acupuncture was applied at Zusanli(ST36)for 7 d after modeling.Paw withdrawal thermal latency(PWTL)and paw withdrawal mechanical threshold(PWMT)were tested during the experiment.The level of prostaglandin E2(PGE2)was measured by enzyme-linked immunosorbent assay(ELISA).Using liquid chromatography-mass spectrometry(LC-MS/MS)based on the multiple reaction monitoring(MRM)-targeted metabolomic approach,neurotransmitter in the brain and spinal cord as well as were detected,further tryptophan metabolites in spinal cord were detected,and the data was analyzed using multiquant software.RESULTS:Acupuncture significantly improved the PWTL and PWMT on the modeling side of CFA mice,and simultaneously,decreased the PGE2 level.Based on targeted neurotransmitter analysis,acupuncture increased the expression of phenylethylamine and decreased N-acetyl serotonin in the brain,while significantly up-regulated serotonin,and down-regulated the levels of homovanillic acid,5-hydroxy-L-tryptophan and 3,4-Dihydroxyphenylethylene Glyco in the spinal cord.Further investigation targeted tryptophan metabolism found that acupuncture considerably decreased the content of tryptophan and L-kynurenine,but increased serotonin.CONCLUSIONS:This study aims to assess changes in central neurotransmitters of CFA mice treated with acupuncture,revealing that abnormalities in central neurotransmitter metabolism may be a potential biochemical basis for pain.More importantly,our preliminary study suggests the potential role of tryptophan and its metabolites in acupuncture analgesia,which may provide new insight and direction for the pain management interface of neurometabolism.展开更多
The neurotransmitter 5-hydroxytryptamine(5-HT),primarily produced by intestinal enterochromaffin(EC)cells,relies on tryptophan hydroxylase 1(TPH1)for synthesis.Research suggested Bifidobacterium breve CCFM1025’s pote...The neurotransmitter 5-hydroxytryptamine(5-HT),primarily produced by intestinal enterochromaffin(EC)cells,relies on tryptophan hydroxylase 1(TPH1)for synthesis.Research suggested Bifidobacterium breve CCFM1025’s potential in regulating Tph1 gene expression,maintaining 5-HT levels in stressed mice,but its precise mechanisms were unclear.This study used metabolomic techniques to assess probiotic fermentation products,revealing acetate as the crucial element in Bb-CCFM1025’s regulation of gut 5-HT synthesis.Further exploration correlated acetate with Tph1 transcription in intestinal organoids.Transcriptomic methods and quantitative reverse transcription polymerase chain reaction validation demonstrated how acetate facilitated 5-HT synthesis and secretion.It unveiled that acetate orchestrates signaling pathways(phosphoinositide 3-kinase-protein kinase B(PI3K-AKT),phospholipase C-phosphorylated extracellular signal-regulated kinase(PLC-pERK),and PLC-1,4,5-trisphosphate(IP3)-Ca^(2+))within EC,enabling 5-HT production.These findings elucidate the biochemical mechanisms behind specific probiotics’effects,aiding in the targeted selection of similar beneficial strains.This study offers theoretical support for choosing probiotics with analogous functionalities based on their physiological impacts.展开更多
Background Diets with high inclusion of corn co-products such as corn fermented protein(CFP)may contain excess Leu,which has a negative impact on feed intake and growth performance of pigs due to increased catabolism ...Background Diets with high inclusion of corn co-products such as corn fermented protein(CFP)may contain excess Leu,which has a negative impact on feed intake and growth performance of pigs due to increased catabolism of Val and Ile and reduced availability of Trp in the brain for serotonin synthesis.However,we hypothesized that the negative effect of using CFP in diets for weanling pigs may be overcome if diets are fortified with crystalline sources of Val,Trp,and(or)Ile.Methods Three hundred and twenty weanling pigs were randomly allotted to one of 10 dietary treatments in a com-pletely randomized design,with 4 pigs per pen and 8 replicate pens per treatment.A corn-soybean meal diet and 2 basal diets based on corn and 10%CFP or corn and 20%CFP were formulated.Seven additional diets were formu-lated by fortifying the basal diet with 20%CFP with Ile,Trp,Val,Ile and Val,Ile and Trp,Trp and Val,or Ile,Trp and Val.A two-phase feeding program was used,with d 1 to 14 being phase 1 and d 15 to 28 being phase 2.Fecal scores were recorded every other day.Blood samples were collected on d 14 and 28 from one pig per pen.On d 14,fecal samples were collected from one pig per pen in 3 of the 10 treatments to determine volatile fatty acids,ammonium concen-tration,and microbial protein.These pigs were also euthanized and ileal tissue was collected.Results There were no effects of dietary treatments on any of the parameters evaluated in phase 1.Inclusion of 10%or 20%CFP in diets reduced(P<0.05)final body weight on d 28,and average daily gain(ADG)and average daily feed intake(ADFI)in phase 2 and for the entire experimental period.However,pigs fed the CFP diet supplemented with Val,Ile,and Trp had final body weight,ADFI,ADG and gain to feed ratio in phase 2 and for the entire experiment that was not different from pigs fed the control diet.Fecal scores in phase 2 were reduced(P<0.05)if CFP was used.Conclusions Corn fermented protein may be included by up to 20%in diets for weanling pigs without affecting growth performance,gut health,or hindgut fermentation,if diets are fortified with extra Val,Trp,and Ile.Inclusion of CFP also improved fecal consistency of pigs.展开更多
Background Tryptophan is essential for nutrition,immunity and neural activity,but cannot be synthesized endogenously.Certain natural products influence host health by modulating the gut microbiota to promote the produ...Background Tryptophan is essential for nutrition,immunity and neural activity,but cannot be synthesized endogenously.Certain natural products influence host health by modulating the gut microbiota to promote the production of tryptophan metabolites.Sanguinarine(SAN)enhances broiler immunity,however,its low bioavailability and underlying mechanisms remain unclear.This study aimed to decode the mechanisms by which sanguinarine enhances intestinal immune function in broilers.Methods Liquid chromatography-tandem mass spectrometry(LC-MS/MS)was employed to identify the main metabolites of sanguinarine in the intestine.Subsequently,equal concentrations of sanguinarine and its metabolites were separately added to the diets.The effects of sanguinarine and its metabolites on the intestinal immune function of broiler chickens were evaluated using 16S rRNA gene amplicon sequencing and tryptophan metabolomics approaches.Results We determined that dihydrosanguinarine(DHSA)is the main metabolite of sanguinarine in the intestine.Both compounds increased average daily gain and reduced feed efficiency,thereby improving growth performance.They also enhanced ileal villus height and the villus-to-crypt(V/C)ratio while decreasing crypt depth and upregulating the mRNA expression of tight junction proteins ZO-1,occludin and claudin-1.Furthermore,both compounds promoted the proliferation of intestinal Lactobacillus species,a tryptophan-metabolizing bacterium,stimulated short-chain fatty acid production,and lowered intestinal pH.They regulated tryptophan metabolism by increasing the diversity and content of indole tryptophan metabolites,activating the aryl hydrocarbon receptor(AhR)pathway,and elevating the mRNA levels of CYP1A1,CYP1B1,SLC3A1,IDO2 and TPH1.Inflammatory cytokines IL-1β and IL-6 were inhibited,while anti-inflammatory cytokines IL-10 and IL-22,serum SIgA concentration,and intestinal MUC2 expression were increased.Notably,DHSA exhibited a more pronounced effect on enhancing immune function compared to SAN.Conclusions SAN is converted to DHSA in vivo,which increases its bioavailability.DHSA regulates tryptophan metabolism by activating the AhR pathway and modulating immune-related factors through changes in the gut microbiota.Notably,DHSA significantly increases the abundance of Lactobacillus,a key tryptophan-metabolizing bacterium,thereby enhancing intestinal immune function and improving broiler growth performance.展开更多
BACKGROUND Prediabetes mellitus(PDM)is receiving increasing attention as a precursor to type 2 diabetes mellitus.Lifestyle and traditional Chinese medicine(TCM)inter-ventions are effective for PDM prevention and treat...BACKGROUND Prediabetes mellitus(PDM)is receiving increasing attention as a precursor to type 2 diabetes mellitus.Lifestyle and traditional Chinese medicine(TCM)inter-ventions are effective for PDM prevention and treatment.Therefore,we con-ducted a preliminary investigation and an exploratory randomised controlled trial to assess the effects of a combined lifestyle and TCM intervention on PDM indicators.AIM To study the effectiveness of Xiaokeqing granules(XQG)and lifestyle inter-ventions in PDM participants while using metabolomics to identify potential markers.METHODS Forty PDM participants with yin deficiency syndrome with excessive heat were recruited and randomly allocated to the control(Con)group or the XQG group(20 per group).The Con group underwent lifestyle interventions,whereas the XQG group underwent lifestyle and XQG interventions.The follow-up duration was 2 months.Fasting blood glucose,2-hour postprandial glucose(2hPG),gly-cated haemoglobin A1c,fasting insulin,homeostasis model assessment-insulin resistance levels,and serum metabolomics characteristics were compared via liquid chromatography-tandem mass spectrometry analysis.RESULTS There were significant differences in 2hPG between the two groups(P<0.05)in the intention-to-treat analysis and per-protocol analysis.The intervention method used in this study was safe(P>0.05).Groenlandicine,kaempferol,isomangiferin,etc.,are the XQG constituents absorbed in the blood.N-Nervonoyl methionine and 5-hydroxy-L-tryptophan are core potential metabolomic biomarkers for the effectiveness of XQG and lifestyle interventions.HTR1A,HTR2C,SLC6A4,etc.,are the core targets of XQG and lifestyle interventions,as well as the reason for their clinical efficacy.Possible mechanistic pathways include tryptophan metabolism,pantothenate and certificate of analysis biosynthesis,lysine degradation and biosynthesis of cofactors.CONCLUSION This pilot study provides evidence that a combined XQG and lifestyle intervention can improve 2hPG in par-ticipants with PDM.The mechanism of action is related to multiple constituents,targets and pathways.展开更多
Obesity is a major focus of researchers due to its increasing prevalence and relationship with other diseases,such as cancer and cardiovascular diseases.Probiotics are active microorganisms and have been proven to all...Obesity is a major focus of researchers due to its increasing prevalence and relationship with other diseases,such as cancer and cardiovascular diseases.Probiotics are active microorganisms and have been proven to alleviate obesity by modulating the microbiota.In this study,we found that oral administration of Bifidobacterium adolescentis CCFM8630 to obese mice inhibited high-fat diet(HFD)-induced changes in body weight and adipose tissue and alleviated hepatic oxidative stress.Furthermore,B.adolescentis CCFM8630 treatment primarily affected the relative abundances of the phyla Proteobacteria and Actinobacteria,and thereby decreased the production of lipopolysaccharide(LPS)and the occurrence of LPS related diseases.A high fiber intake increased the abundance of Lactobacillus and the concentrations of short chain fatty acids in obese mice,but these changes were reversed by B.adolescentis CCFM8630 treatment.In addition,targeted metabolomic analysis and microbiota relationship analysis revealed that B.adolescentis CCFM8630 treatment modified the microbiota of obese mice by promoting the conversion of tryptophan(Trp)to xanthurenic acid,kynurenic acid,tryptamine,indole-3-acetic acid,and indole-3-carboxaldehyde;facilitated the expression of interleukin-17A and the aryl hydrocarbon receptor to generate interleukin-22 in the colon;and upregulated the expression of tight junction proteins,thereby strengthening intestinal barriers.In summary,our findings suggest that the intake of B.adolescentis CCFM8630 may alleviate obesity by modulating the gut microbiota and related Trp metabolism.展开更多
Limosilac to bacillus reuteri QS01 is potential probiotic isolated from the intestinal microbiota of healthy women in early pregnancy.In the current study,we examined whether QS01 can prevent gestational diabetes mell...Limosilac to bacillus reuteri QS01 is potential probiotic isolated from the intestinal microbiota of healthy women in early pregnancy.In the current study,we examined whether QS01 can prevent gestational diabetes mellitus(GDM) in an enhanced mouse model of the condition.Female C57BL/6J mouse offspring(F1 generation) born to dams fed a control(CON) or low-protein diet(GDM group) during gestation and lactation were used.Pregnant F1 mice fed a standard diet were randomly assigned to 5 groups:CON,GDM,and GDM mice treated with metformin,QS01 or Lacticaseibacillus rhamnosus HN001.An oral glucose tolerance test was performed before sacrifice at gestational day 17.Glucose tolerance was significantly ameliorated by all 3 treatments.QS01 supplementation fortified the intestinal mucosal barrier and inhibited the escalation of plasma inflammatory cytokines.QS01 treatment altered the cecal microbiota composition and function.Plasma and cecal metabolite profiles were modulated by QS01,prominently demonstrating significant upregulation of indole lactate and L-tryptophan in plasma and 5-hydroxy-tryptophan in the cecum,positively correlated with gut Lactobacillus abundance.In summary,QS01 plays a role in preventing GDM by remodeling the intestinal microbiota,reinforcing the intestinal mucosal barrier and alleviating chronic inflammation.展开更多
Background:Fructose may induce non-alcoholic fatty acids(NAFLD)due to the gut-liver axis interactions.The mechanism of fructose impairing colon barrier is unrevealed.Methods:Normal and dextran sulfate sodium(DSS)-indu...Background:Fructose may induce non-alcoholic fatty acids(NAFLD)due to the gut-liver axis interactions.The mechanism of fructose impairing colon barrier is unrevealed.Methods:Normal and dextran sulfate sodium(DSS)-induced Sprague-Dawley rats fed by 35%fructose diets were used to evaluate colon barrier functions.Microbiome and metabolome were applied to screen potential biomarker bacteria and metabolites induced by fructose.HT-29 cells were applied to validate metabolite biomarker indoleacrylic acid(IAA)and indole-3-carboxaldehyde(I3A)function in colon barrier which impaired by fructose.Results:Fructose induced colon barrier dysfunction,aggravated colon impairment in DSS-induced rats.With fructose intake,the colon length shortened,goblet numbers declined,inflammation infiltration induced,inflammatory cytokines increased,and apoptosis signals upregulated in colon tissue.Moreover,fructose induced dysbiosis of microbiota and their metabolites.Adlercreutzia and Holdemania were screened out as potential bacteria biomarkers,IAA and I3A as tryptophan metabolites were selected as metabolite biomarkers inhibited by fructose.IAA and I3A treatment alleviated the impairment induced by fructose by increasing trans epithelial electric resistance value,tight junction proteins,and Aryl hydrocarbon receptor(Ah R)activity in HT-29 cell.Conclusion:Fructose stimulated inflammation,apoptosis,gut bacteria alteration,and induced the reduction of IAA and I3A.Since fructose inhibited production of IAA and I3A,Ah R remained inactivated and consequently induced colon barrier dysfunction.展开更多
Impaired healing of diabetic wounds is one of the most important complications of diabetes,often leading to lower limb amputations and incurring significant economic and psychosocial costs.Unfortunately,there are curr...Impaired healing of diabetic wounds is one of the most important complications of diabetes,often leading to lower limb amputations and incurring significant economic and psychosocial costs.Unfortunately,there are currently no effective prevention or treatment strategies available.Recent research has reported that an imbalance in the gut microbiota,known as dysbiosis,was linked to the onset of type 2 diabetes,as well as the development and progression of diabetic complications.Indeed,the gut microbiota has emerged as a promising therapeutic approach for treating type 2 diabetes and related diseases.However,there is few of literatures specifically discussing the relationship between gut microbiota and diabetic wounds.This review aims to explore the potential role of the gut microbiota,especially probiotics,and its associated byproducts such as short chain fatty acids,bile acids,hydrogen sulfide,and tryptophan metabolites on wound healing to provide fresh insights and novel perspectives for the treatment of chronic wounds in diabetes.展开更多
The review by Bangolo et al highlights the role of the gut microbiome in cancerassociated anemia(CAA).However,the impact of microbiome-derived metabolites is underexplored.In this letter,we focus on short-chain fatty ...The review by Bangolo et al highlights the role of the gut microbiome in cancerassociated anemia(CAA).However,the impact of microbiome-derived metabolites is underexplored.In this letter,we focus on short-chain fatty acids,tryptophan metabolites,and polyamines as key mediators linking dysbiosis to impaired erythropoiesis and iron homeostasis.We also propose a research framework that integrates multi-omics analysis and gnotobiotic models.Finally,we discuss the clinical potential of metabolite-based diagnostics and microbiome-targeted therapies in managing CAA.展开更多
Metabolic reprogramming is a critical process in the activation and function of immune cells,wherein changes in metabolites and enzymes regulate the phenotype and function of immune cells by modulating en-ergy metabol...Metabolic reprogramming is a critical process in the activation and function of immune cells,wherein changes in metabolites and enzymes regulate the phenotype and function of immune cells by modulating en-ergy metabolic pathways and signaling cascades.1 In the realm of cancer immunotherapy,metabolic interventions in immune cells have demon-strated potential to enhance therapeutic efficacy.For instance,Minogue et al.2 found that glutaric acid from tryptophan metabolism can mod-ulate the antitumor T cell response by affecting pyruvate metabolism and𝛼-ketoglutarate-dependent dioxygenases.The adjustment of glutaric acid levels in CD8^(+)T cells has been shown to promote central memory T cell development,reduce exhaustion markers,and enhance cell death.展开更多
The gene encoded for tryptophan decarboxylase (TDC), which is the key enzyme in terpenoil indole alkaloids pathway, was targeted to different subcellular compartments and stably expressed in transgenic tobacco (Nicoti...The gene encoded for tryptophan decarboxylase (TDC), which is the key enzyme in terpenoil indole alkaloids pathway, was targeted to different subcellular compartments and stably expressed in transgenic tobacco (Nicotiana tabacum L.) plants at the levels detected by Western blot and tryptamine accumulation analysis. It was shown that the TDC was located in subcellular compartments, the chloroplasts and cytosol. The recombinant TDC targeted to chloroplasts and cytosol in tobacco plants was effectively expressed as soluble protein by Western blot analysis and enzymatic assay. The level of tryptamine accumulation in chloroplast was higher than that in cytosol and very low in vacuole and endoplasmic reticulum (ER) to be hardly detected by Western blot analysis. It was indicated that the highest amount of tryptamine was in chloroplasts, lower in endoplasmic reticula and the lowest in vacuoles as compared to those in wild type plants. The TDC targeted to different subcellular compartments of tobacco plants and its expression level were studied by different nucleotide sequences coding signal peptides at 5'-end of tdc gene in order to know the effects of the TDC in compartmentation on its functionality.展开更多
Irritable bowel syndrome(IBS) is an extremely prevalent but poorly understood gastrointestinal disorder. Consequently, there are no clear diagnostic markers to help diagnose the disorder and treatment options are limi...Irritable bowel syndrome(IBS) is an extremely prevalent but poorly understood gastrointestinal disorder. Consequently, there are no clear diagnostic markers to help diagnose the disorder and treatment options are limited to management of the symptoms. The concept of a dysregulated gut-brain axis has been adopted as a suitable model for the disorder. The gut microbiome may play an important role in the onset and exacerbation of symptoms in the disorder and has been extensively studied in this context. Although a causal role cannot yet be inferred from the clinical studies which have attempted to characterise the gut microbiota in IBS, they do confirm alterations in both community stability and diversity. Moreover, it has been reliably demonstrated that manipulation of the microbiota can influence the key symptoms, including abdominal pain and bowel habit, and other prominent features of IBS. A variety of strategies have been taken to study these interactions, including probiotics, antibiotics, faecal transplantations and the use of germ-free animals. There are clear mechanisms through which the microbiota can produce these effects, both humoral and neural. Taken together, these findings firmly establish the microbiota as a critical node in the gut-brain axis and one which is amenable to therapeutic interventions.展开更多
Multiple factors are involved in the etiology of cardiovascular disease(CVD). Pathological changes occur in a variety of cell types long before symptoms become apparent and diagnosis is made. Dysregulation of physiolo...Multiple factors are involved in the etiology of cardiovascular disease(CVD). Pathological changes occur in a variety of cell types long before symptoms become apparent and diagnosis is made. Dysregulation of physiological functions are associated with the activation of immune cells,leading to local and finally systemic inflammation that is characterized by production of high levels of reactive oxygen species(ROS). Patients suffering from inflammatory diseases often present with diminished levels of antioxidants either due to insufficient dietary intake or,and even more likely,due to increased demand in situations of overwhelming ROS production by activated immune effector cells like macrophages. Antioxidants are suggested to beneficially interfere with diseases-related oxidative stress,however the interplay of endogenous and exogenous antioxidants with the overall redox system is complex. Moreover,molecular mechanisms underlying oxidative stress in CVD are not fully elucidated. Metabolic dybalances are suggested to play a major role in disease onset and progression. Several central signalingpathways involved in the regulation of immunological,metabolic and endothelial function are regulated in a redox-sensitive manner. During cellular immune response,interferon γ-dependent pathways are activated such as tryptophan breakdown by the enzyme indoleamine 2,3-dioxygenase(IDO) in monocyte-derived macrophages,fibroblasts,endothelial and epithelial cells. Neopterin,a marker of oxidative stress and immune activation is produced by GTP-cyclohydrolase Ⅰ in macrophages and dendritic cells. Nitric oxide synthase(NOS) is induced in several cell types to generate nitric oxide(NO). NO,despite its low reactivity,is a potent antioxidant involved in the regulation of the vasomotor tone and of immunomodulatory signaling pathways. NO inhibits the expression and function of IDO. Function of NOS requires the cofactor tetrahydrobiopterin(BH4),which is produced in humans primarily by fibroblasts and endothelial cells. Highly toxic peroxynitrite(ONOO-) is formed solely in the presence of superoxide anion(O2-). Neopterin and kynurenine to tryptophan ratio(Kyn/Trp),as an estimate of IDO enzyme activity,are robust markers of immune activation in vitro and in vivo. Both these diagnostic parameters are able to predict cardiovascular and overall mortality in patients at risk. Likewise,a significant association exists between increase of neopterin concentrations and Kyn/Trp ratio values and the lowering of plasma levels of vitamin-C,-E and-B. Vitamin-B deficiency is usually accompanied by increased plasma homoycsteine. Additional determination of NO metabolites,BH4 and plasma antioxidants in patients with CVD and related clinical settings can be helpful to improve the understanding of redox-regulation in health and disease and might provide a rationale for potential antioxidant therapies in CVD.展开更多
AIM: To evaluate how Helicobacter pylori(H. pylori) is able to evade the immune response and whether it enhances systemic immune tolerance against colorectal cancer.METHODS: This prospective randomized study involved ...AIM: To evaluate how Helicobacter pylori(H. pylori) is able to evade the immune response and whether it enhances systemic immune tolerance against colorectal cancer.METHODS: This prospective randomized study involved 97 consecutive colorectal cancer patients and 108 cancer-free patients with extra-digestive diseases. Colorectal cancer and cancer-free patients were assigned into subgroups according to H. pylori Ig G seropositivity. Exposure to H. pylori was determined by Ig G seropositivity which was detected by enzyme linked immunoassay(ELISA). Serum neopterin levels were measured by ELISA. Serum tryptophan, kynurenine, and urinary biopterin concentrations were measured by high performance liquid chromatography. Serum nitrite levels were detected spectrophotometrically. Serum indoleamine 2,3-dioxygenase activity was estimated by the kynurenine to tryptophan ratio and by assessing the correlation between serum neopterin concentrations and the kynurenine to tryptophan ratio. The frequencies of increased serum kynurenine to tryptophan ratio of H. pylori seronegative and seropositive colorectal cancer subgroups were estimated by comparing them with the average kynurenine to tryptophan ratio of H. pylori seronegative tumor-free patients.RESULTS: Compared with respective controls, in both H. pylori seronegative and seropositive colorectal cancer patients, while serum tryptophan levels were decreased(controls vs patients; seronegative: 20.37 ± 0.89 μmol/L vs 15.71 ± 1.16 μmol/L, P < 0.05; seropositive: 20.71 ± 0.81 μmol/L vs 14.97 ± 0.79 μmol/L, P < 0.01) the kynurenine to tryptophan ratio was significantly increased(controls vs patients; seronegative: 52.85± 11.85 μmol/mmol vs 78.91 ± 8.68 μmol/mmol, P < 0.01, seropositive: 47.31 ± 5.93 μmol/mmol vs 109.65 ± 11.50 μmol/mmol, P < 0.01). Neopterin concentrations in cancer patients were significantly elevated compared with controls(P < 0.05). There was a significant correlation between serum neopterin levels and kynurenine/tryptophan in control and colorectal cancer patients groups(r s = 0.494, P = 0.0001 and r s= 0.293, P = 0.004, respectively). Serum nitrite levels of H. pylori seropositive cancer cases were significantly decreased compared with seropositive controls(controls vs patients; 26.04 ± 2.39 μmol/L vs 20.41 ± 1.48 μmol/L, P < 0.05) The decrease in the nitrite levels of H. pylori seropositive cancer patients may be attributed to excessive formation of peroxynitrite and other reactive nitrogen species.CONCLUSION: A significantly high kynurenine/tryptophan suggested that H. pylori may support the immune tolerance leading to cancer development, even without an apparent upper gastrointestinal tract disease.展开更多
Jasmonic acid （JA） is a fatty acid-derived signaling molecule that regulates a broad range of plant defense responses against herbivores and some microbial pathogens. Molecular genetic studies have established that ...Jasmonic acid （JA） is a fatty acid-derived signaling molecule that regulates a broad range of plant defense responses against herbivores and some microbial pathogens. Molecular genetic studies have established that JA also performs a critical role in several aspects of plant development. Here, we describe the characterization of the Arabidopsis mutantjasmonic acid-hypersensitivel-1 （jah1-1）, which is defective in several aspects of JA responses. Although the mutant exhibits increased sensitivity to JA in root growth inhibition, it shows decreased expression of JA-inducible defense genes and reduced resistance to the necrotrophic fungus Botrytis cinerea. Gene cloning studies indicate that these defects are caused by a mutation in the cytochrome P450 protein CYP82C2. We provide evidence showing that the compromised resistance of thejah1-1 mutant to B. cinerea is accompanied by decreased expression of JA-induced defense genes and reduced accumulation of JA-induced indole glucosinolates （IGs）. Conversely, the enhanced resistance to B. cinerea in CYP82C2-overexpressing plants is accompanied by increased expression of JA-induced defense genes and elevated levels of JA-induced IGs. We demonstrate that CYP82C2 affects JA-induced accumulation of the IG biosynthetic precursor tryptophan （Trp）, but not the JA-induced IAA or pathogen-induced camalexin. Together, our results support a hypothesis that CYP82C2 may act in the metabolism of Trp-derived secondary metabolites under conditions in which JA levels are elevated. Thejah1-1 mutant should thus be important in future studies toward understanding the mechanisms underlying the complexity of JA-mediated differential responses, which are important for plants to adapt their growth to the ever-changing environments.展开更多
Indoleamine 2, 3-dioxygenase (IDO) is a rate-limiting enzyme for the tryptophan catabolism. In human and murine cells, IDO inhibits antigen-specific T cell proliferation in vitro and suppresses T cell responses to fet...Indoleamine 2, 3-dioxygenase (IDO) is a rate-limiting enzyme for the tryptophan catabolism. In human and murine cells, IDO inhibits antigen-specific T cell proliferation in vitro and suppresses T cell responses to fetal alloantigens during murine pregnancy. In mice, IDO expression is an inducible feature of specific subsets of dendritic cells (DCs), and is important for T cell regulatory properties. However, the effect of IDO and tryptophan deprivation on DC func- tions remains unknown. We report here that when tryptophan utilization was prevented by a pharmacological inhibitor of IDO, 1-methyl tryptophan (1MT), DC activation induced by pathogenic stimulus lipopolysaccharide (LPS) or inflam- matory cytokine TNF-α was inhibited both phenotypically and functionally. Such an effect was less remarkable when DC was stimulated by a physiological stimulus, CD40 ligand. Tryptophan deprivation during DC activation also regu- lated the expression of CCR5 and CXCR4, as well as DC responsiveness to chemokines. These results suggest that tryptophan usage in the microenvironment is essential for DC maturation, and may also play a role in the regulation of DC migratory behaviors.展开更多
基金supported by Shanghai Shenkang Center Demonstration Research Ward Construction,No.SHDC2022CRW010(to MF)Shanghai Shenkang Center Medical Enterprise Integration and Innovation Collaborative Special Project,No.SHDC2022CRT018(to MF)+4 种基金Shanghai Health System Key Supported Discipline-Rehabilitation Medicine,No.2023ZDFC0301(to JT)Science and Technology Development Project of Shanghai University of Traditional Chinese Medicine,No.23KFL009(to JT)Shanghai Postdoctoral Excellence Program,No.2022515(to CY)Yangfan Special Project of Shanghai Science and Technology Innovation Action Plan,No.23YF1447600(to CY)China Postdoctoral Science Foundation,No.2023M732338(to CY).
文摘Ischemic stroke,which is characterized by hypoxia and ischemia,triggers a cascade of injury responses,including neurotoxicity,inflammation,oxidative stress,disruption of the blood-brain barrier,and neuronal death.In this context,tryptophan metabolites and enzymes,which are synthesized through the kynurenine and 5-hydroxytryptamine pathways,play dual roles.The delicate balance between neurotoxic and neuroprotective substances is a crucial factor influencing the progression of ischemic stroke.Neuroprotective metabolites,such as kynurenic acid,exert their effects through various mechanisms,including competitive blockade of N-methyl-D-aspartate receptors,modulation ofα7 nicotinic acetylcholine receptors,and scavenging of reactive oxygen species.In contrast,neurotoxic substances such as quinolinic acid can hinder the development of vascular glucose transporter proteins,induce neurotoxicity mediated by reactive oxygen species,and disrupt mitochondrial function.Additionally,the enzymes involved in tryptophan metabolism play major roles in these processes.Indoleamine 2,3-dioxygenase in the kynurenine pathway and tryptophan hydroxylase in the 5-hydroxytryptamine pathway influence neuroinflammation and brain homeostasis.Consequently,the metabolites generated through tryptophan metabolism have substantial effects on the development and progression of ischemic stroke.Stroke treatment aims to restore the balance of various metabolite levels;however,precise regulation of tryptophan metabolism within the central nervous system remains a major challenge for the treatment of ischemic stroke.Therefore,this review aimed to elucidate the complex interactions between tryptophan metabolites and enzymes in ischemic stroke and develop targeted therapies that can restore the delicate balance between neurotoxicity and neuroprotection.
基金supported by the STI 2030—Major Projects 2021ZD0204000,No.2021ZD0204003 (to XZ)the National Natural Science Foundation of China,Nos.32170973 (to XZ),32071018 (to ZH)。
文摘Dysregulation of neurotransmitter metabolism in the central nervous system contributes to mood disorders such as depression, anxiety, and post–traumatic stress disorder. Monoamines and amino acids are important types of neurotransmitters. Our previous results have shown that disco-interacting protein 2 homolog A(Dip2a) knockout mice exhibit brain development disorders and abnormal amino acid metabolism in serum. This suggests that DIP2A is involved in the metabolism of amino acid–associated neurotransmitters. Therefore, we performed targeted neurotransmitter metabolomics analysis and found that Dip2a deficiency caused abnormal metabolism of tryptophan and thyroxine in the basolateral amygdala and medial prefrontal cortex. In addition, acute restraint stress induced a decrease in 5-hydroxytryptamine in the basolateral amygdala. Additionally, Dip2a was abundantly expressed in excitatory neurons of the basolateral amygdala, and deletion of Dip2a in these neurons resulted in hopelessness-like behavior in the tail suspension test. Altogether, these findings demonstrate that DIP2A in the basolateral amygdala may be involved in the regulation of stress susceptibility. This provides critical evidence implicating a role of DIP2A in affective disorders.
基金Supported by Grants from Beijing Municipal Science and Technology Commission,No.Z191100006619020Beijing Municipal Administration of Hospitals Incubating Program,2023,No.PX2023070Beijing Municipal Administration of Hospitals Incubating Program,2024,No.PX2024072.
文摘BACKGROUND The tryptophan-kynurenine(TRP-KYN)pathway may be implicated in the pathophysiology of cognitive impairment and pain severity in major depressive disorder(MDD);however,few studies have explored the intricacies of their interaction.AIM To investigate the relationship between the TRP-KYN pathway and cognitive function in MDD patients with and without painful physical symptoms(PPS).METHODS Seventy patients with MDD were recruited,including 33 and 37 with and without PSS,respectively.The Hamilton Depression Scale,the Hamilton Anxiety Scale,and the Short-form of McGill pain questionnaire(SFMPQ)were used to assess clinical symptoms.Cognitive function was assessed by the MATRICS Consensus Cognitive Battery(MCCB)score.TRP-KYN pathway metabolites’serum levels were measured using high-performance liquid chromatography-tandem mass spectrometry.RESULTS The with PPS group exhibited significantly higher TRP-KYN ratios than did the without PPS group;in the former,the SFMPQ scores positively and negatively correlated with the TRP-KYN ratio and total MCCB score,respectively.Regression analysis indicated that body mass index and SFMPQ scores were significantly associated with the TRP-KYN ratio,predicting 30%of the variance.CONCLUSION The TRP-KYN ratio is a potential biomarker for identifying patients with depression accompanied by pain symptoms,and targeting it may represent a novel therapeutic strategy for managing pain in these individuals.Further elucidation of the biological mechanisms underlying cognitive impairment in MDD patients with PPS is warranted.
基金Supported by National Natural Science Foundation of China:Study on Acupuncture Alleviate Rheumatoid Arthritis Effect and Mechanism via miR-155 Reduce Monocyte Chemokine and Chemokine Receptor Expression (No. 82004473)Natural Science Foundation of Jiangsu Province:Study on the Role and Mechanism of Aryl Hydrocarbon Receptor-mediated Acupuncture in Regulating Immune Homeostasis of the Gut-joint Axis in Rheumatoid Arthritis (No. BK20230453)
文摘OBJECTIVE:To investigate the effect of central amino acid metabolic profiles on acupuncture analgesia.METHODS:BALB/c mice were injected with Complete Freund's Adjuvant(CFA)and acupuncture was applied at Zusanli(ST36)for 7 d after modeling.Paw withdrawal thermal latency(PWTL)and paw withdrawal mechanical threshold(PWMT)were tested during the experiment.The level of prostaglandin E2(PGE2)was measured by enzyme-linked immunosorbent assay(ELISA).Using liquid chromatography-mass spectrometry(LC-MS/MS)based on the multiple reaction monitoring(MRM)-targeted metabolomic approach,neurotransmitter in the brain and spinal cord as well as were detected,further tryptophan metabolites in spinal cord were detected,and the data was analyzed using multiquant software.RESULTS:Acupuncture significantly improved the PWTL and PWMT on the modeling side of CFA mice,and simultaneously,decreased the PGE2 level.Based on targeted neurotransmitter analysis,acupuncture increased the expression of phenylethylamine and decreased N-acetyl serotonin in the brain,while significantly up-regulated serotonin,and down-regulated the levels of homovanillic acid,5-hydroxy-L-tryptophan and 3,4-Dihydroxyphenylethylene Glyco in the spinal cord.Further investigation targeted tryptophan metabolism found that acupuncture considerably decreased the content of tryptophan and L-kynurenine,but increased serotonin.CONCLUSIONS:This study aims to assess changes in central neurotransmitters of CFA mice treated with acupuncture,revealing that abnormalities in central neurotransmitter metabolism may be a potential biochemical basis for pain.More importantly,our preliminary study suggests the potential role of tryptophan and its metabolites in acupuncture analgesia,which may provide new insight and direction for the pain management interface of neurometabolism.
基金supported by the National Natural Science Foundation of China(32201988)Natural Science Foundation of Jiangsu Province(BK20210456)+3 种基金Special Fund for Science and Technology Program of Jiangsu Province(BM2022019)the National Key R&D Program of China(2023YFC2506004)the Fundamental Research Funds for the Central Universities(JUSRP123047)the Program of Collaborative Innovation Centre of Food Safety and Quality Control in Jiangsu Province.
文摘The neurotransmitter 5-hydroxytryptamine(5-HT),primarily produced by intestinal enterochromaffin(EC)cells,relies on tryptophan hydroxylase 1(TPH1)for synthesis.Research suggested Bifidobacterium breve CCFM1025’s potential in regulating Tph1 gene expression,maintaining 5-HT levels in stressed mice,but its precise mechanisms were unclear.This study used metabolomic techniques to assess probiotic fermentation products,revealing acetate as the crucial element in Bb-CCFM1025’s regulation of gut 5-HT synthesis.Further exploration correlated acetate with Tph1 transcription in intestinal organoids.Transcriptomic methods and quantitative reverse transcription polymerase chain reaction validation demonstrated how acetate facilitated 5-HT synthesis and secretion.It unveiled that acetate orchestrates signaling pathways(phosphoinositide 3-kinase-protein kinase B(PI3K-AKT),phospholipase C-phosphorylated extracellular signal-regulated kinase(PLC-pERK),and PLC-1,4,5-trisphosphate(IP3)-Ca^(2+))within EC,enabling 5-HT production.These findings elucidate the biochemical mechanisms behind specific probiotics’effects,aiding in the targeted selection of similar beneficial strains.This study offers theoretical support for choosing probiotics with analogous functionalities based on their physiological impacts.
基金Financial support for this research from Minnesota Corn Growers Association(Burnsville,MN,USA)Green Plains Energy(Omaha,NE,USA)is greatly appreciated.
文摘Background Diets with high inclusion of corn co-products such as corn fermented protein(CFP)may contain excess Leu,which has a negative impact on feed intake and growth performance of pigs due to increased catabolism of Val and Ile and reduced availability of Trp in the brain for serotonin synthesis.However,we hypothesized that the negative effect of using CFP in diets for weanling pigs may be overcome if diets are fortified with crystalline sources of Val,Trp,and(or)Ile.Methods Three hundred and twenty weanling pigs were randomly allotted to one of 10 dietary treatments in a com-pletely randomized design,with 4 pigs per pen and 8 replicate pens per treatment.A corn-soybean meal diet and 2 basal diets based on corn and 10%CFP or corn and 20%CFP were formulated.Seven additional diets were formu-lated by fortifying the basal diet with 20%CFP with Ile,Trp,Val,Ile and Val,Ile and Trp,Trp and Val,or Ile,Trp and Val.A two-phase feeding program was used,with d 1 to 14 being phase 1 and d 15 to 28 being phase 2.Fecal scores were recorded every other day.Blood samples were collected on d 14 and 28 from one pig per pen.On d 14,fecal samples were collected from one pig per pen in 3 of the 10 treatments to determine volatile fatty acids,ammonium concen-tration,and microbial protein.These pigs were also euthanized and ileal tissue was collected.Results There were no effects of dietary treatments on any of the parameters evaluated in phase 1.Inclusion of 10%or 20%CFP in diets reduced(P<0.05)final body weight on d 28,and average daily gain(ADG)and average daily feed intake(ADFI)in phase 2 and for the entire experimental period.However,pigs fed the CFP diet supplemented with Val,Ile,and Trp had final body weight,ADFI,ADG and gain to feed ratio in phase 2 and for the entire experiment that was not different from pigs fed the control diet.Fecal scores in phase 2 were reduced(P<0.05)if CFP was used.Conclusions Corn fermented protein may be included by up to 20%in diets for weanling pigs without affecting growth performance,gut health,or hindgut fermentation,if diets are fortified with extra Val,Trp,and Ile.Inclusion of CFP also improved fecal consistency of pigs.
基金funded by National Key R&D Program of China(2023YFD1301200)the science and technology innovation Program of Hunan Province(2021RC3091).
文摘Background Tryptophan is essential for nutrition,immunity and neural activity,but cannot be synthesized endogenously.Certain natural products influence host health by modulating the gut microbiota to promote the production of tryptophan metabolites.Sanguinarine(SAN)enhances broiler immunity,however,its low bioavailability and underlying mechanisms remain unclear.This study aimed to decode the mechanisms by which sanguinarine enhances intestinal immune function in broilers.Methods Liquid chromatography-tandem mass spectrometry(LC-MS/MS)was employed to identify the main metabolites of sanguinarine in the intestine.Subsequently,equal concentrations of sanguinarine and its metabolites were separately added to the diets.The effects of sanguinarine and its metabolites on the intestinal immune function of broiler chickens were evaluated using 16S rRNA gene amplicon sequencing and tryptophan metabolomics approaches.Results We determined that dihydrosanguinarine(DHSA)is the main metabolite of sanguinarine in the intestine.Both compounds increased average daily gain and reduced feed efficiency,thereby improving growth performance.They also enhanced ileal villus height and the villus-to-crypt(V/C)ratio while decreasing crypt depth and upregulating the mRNA expression of tight junction proteins ZO-1,occludin and claudin-1.Furthermore,both compounds promoted the proliferation of intestinal Lactobacillus species,a tryptophan-metabolizing bacterium,stimulated short-chain fatty acid production,and lowered intestinal pH.They regulated tryptophan metabolism by increasing the diversity and content of indole tryptophan metabolites,activating the aryl hydrocarbon receptor(AhR)pathway,and elevating the mRNA levels of CYP1A1,CYP1B1,SLC3A1,IDO2 and TPH1.Inflammatory cytokines IL-1β and IL-6 were inhibited,while anti-inflammatory cytokines IL-10 and IL-22,serum SIgA concentration,and intestinal MUC2 expression were increased.Notably,DHSA exhibited a more pronounced effect on enhancing immune function compared to SAN.Conclusions SAN is converted to DHSA in vivo,which increases its bioavailability.DHSA regulates tryptophan metabolism by activating the AhR pathway and modulating immune-related factors through changes in the gut microbiota.Notably,DHSA significantly increases the abundance of Lactobacillus,a key tryptophan-metabolizing bacterium,thereby enhancing intestinal immune function and improving broiler growth performance.
基金Supported by the Open Bidding for Selecting the Best Candidates for Xin’an Medicine and the Modernization of Traditional Chinese Medicine of IHM,No.2023CXMMTCM024 and No.2023CXMMTCM003the Anhui University Collaborative Innovation Project,No.GXXT-2020-025+2 种基金the Scientific Research Project of Health and Wellness in Anhui Province,No.AHWJ2023BAc10002the Anhui Province New Era Education Quality Project,No.2023gjxslt014and the Clinical and Translational Research Project of Anhui Province,No.202427b10020046.
文摘BACKGROUND Prediabetes mellitus(PDM)is receiving increasing attention as a precursor to type 2 diabetes mellitus.Lifestyle and traditional Chinese medicine(TCM)inter-ventions are effective for PDM prevention and treatment.Therefore,we con-ducted a preliminary investigation and an exploratory randomised controlled trial to assess the effects of a combined lifestyle and TCM intervention on PDM indicators.AIM To study the effectiveness of Xiaokeqing granules(XQG)and lifestyle inter-ventions in PDM participants while using metabolomics to identify potential markers.METHODS Forty PDM participants with yin deficiency syndrome with excessive heat were recruited and randomly allocated to the control(Con)group or the XQG group(20 per group).The Con group underwent lifestyle interventions,whereas the XQG group underwent lifestyle and XQG interventions.The follow-up duration was 2 months.Fasting blood glucose,2-hour postprandial glucose(2hPG),gly-cated haemoglobin A1c,fasting insulin,homeostasis model assessment-insulin resistance levels,and serum metabolomics characteristics were compared via liquid chromatography-tandem mass spectrometry analysis.RESULTS There were significant differences in 2hPG between the two groups(P<0.05)in the intention-to-treat analysis and per-protocol analysis.The intervention method used in this study was safe(P>0.05).Groenlandicine,kaempferol,isomangiferin,etc.,are the XQG constituents absorbed in the blood.N-Nervonoyl methionine and 5-hydroxy-L-tryptophan are core potential metabolomic biomarkers for the effectiveness of XQG and lifestyle interventions.HTR1A,HTR2C,SLC6A4,etc.,are the core targets of XQG and lifestyle interventions,as well as the reason for their clinical efficacy.Possible mechanistic pathways include tryptophan metabolism,pantothenate and certificate of analysis biosynthesis,lysine degradation and biosynthesis of cofactors.CONCLUSION This pilot study provides evidence that a combined XQG and lifestyle intervention can improve 2hPG in par-ticipants with PDM.The mechanism of action is related to multiple constituents,targets and pathways.
基金supported by the National Natural Science Foundation of China(32272332,32021005,31820103010)the Fundamental Research Funds for the Central Universities(JUSRP622020,JUSRP22006,JUSRP51501)the Program of Collaborative Innovation Centre of Food Safety and Quality Control in Jiangsu Province.
文摘Obesity is a major focus of researchers due to its increasing prevalence and relationship with other diseases,such as cancer and cardiovascular diseases.Probiotics are active microorganisms and have been proven to alleviate obesity by modulating the microbiota.In this study,we found that oral administration of Bifidobacterium adolescentis CCFM8630 to obese mice inhibited high-fat diet(HFD)-induced changes in body weight and adipose tissue and alleviated hepatic oxidative stress.Furthermore,B.adolescentis CCFM8630 treatment primarily affected the relative abundances of the phyla Proteobacteria and Actinobacteria,and thereby decreased the production of lipopolysaccharide(LPS)and the occurrence of LPS related diseases.A high fiber intake increased the abundance of Lactobacillus and the concentrations of short chain fatty acids in obese mice,but these changes were reversed by B.adolescentis CCFM8630 treatment.In addition,targeted metabolomic analysis and microbiota relationship analysis revealed that B.adolescentis CCFM8630 treatment modified the microbiota of obese mice by promoting the conversion of tryptophan(Trp)to xanthurenic acid,kynurenic acid,tryptamine,indole-3-acetic acid,and indole-3-carboxaldehyde;facilitated the expression of interleukin-17A and the aryl hydrocarbon receptor to generate interleukin-22 in the colon;and upregulated the expression of tight junction proteins,thereby strengthening intestinal barriers.In summary,our findings suggest that the intake of B.adolescentis CCFM8630 may alleviate obesity by modulating the gut microbiota and related Trp metabolism.
基金supported by the grants from the Nutrition and care of Maternal and Child Research Funding program (2020BINCMCF056)。
文摘Limosilac to bacillus reuteri QS01 is potential probiotic isolated from the intestinal microbiota of healthy women in early pregnancy.In the current study,we examined whether QS01 can prevent gestational diabetes mellitus(GDM) in an enhanced mouse model of the condition.Female C57BL/6J mouse offspring(F1 generation) born to dams fed a control(CON) or low-protein diet(GDM group) during gestation and lactation were used.Pregnant F1 mice fed a standard diet were randomly assigned to 5 groups:CON,GDM,and GDM mice treated with metformin,QS01 or Lacticaseibacillus rhamnosus HN001.An oral glucose tolerance test was performed before sacrifice at gestational day 17.Glucose tolerance was significantly ameliorated by all 3 treatments.QS01 supplementation fortified the intestinal mucosal barrier and inhibited the escalation of plasma inflammatory cytokines.QS01 treatment altered the cecal microbiota composition and function.Plasma and cecal metabolite profiles were modulated by QS01,prominently demonstrating significant upregulation of indole lactate and L-tryptophan in plasma and 5-hydroxy-tryptophan in the cecum,positively correlated with gut Lactobacillus abundance.In summary,QS01 plays a role in preventing GDM by remodeling the intestinal microbiota,reinforcing the intestinal mucosal barrier and alleviating chronic inflammation.
基金supported by the Special Funds of Basic Research of Central Public Welfare Institute(JY2010 and ZX2410)。
文摘Background:Fructose may induce non-alcoholic fatty acids(NAFLD)due to the gut-liver axis interactions.The mechanism of fructose impairing colon barrier is unrevealed.Methods:Normal and dextran sulfate sodium(DSS)-induced Sprague-Dawley rats fed by 35%fructose diets were used to evaluate colon barrier functions.Microbiome and metabolome were applied to screen potential biomarker bacteria and metabolites induced by fructose.HT-29 cells were applied to validate metabolite biomarker indoleacrylic acid(IAA)and indole-3-carboxaldehyde(I3A)function in colon barrier which impaired by fructose.Results:Fructose induced colon barrier dysfunction,aggravated colon impairment in DSS-induced rats.With fructose intake,the colon length shortened,goblet numbers declined,inflammation infiltration induced,inflammatory cytokines increased,and apoptosis signals upregulated in colon tissue.Moreover,fructose induced dysbiosis of microbiota and their metabolites.Adlercreutzia and Holdemania were screened out as potential bacteria biomarkers,IAA and I3A as tryptophan metabolites were selected as metabolite biomarkers inhibited by fructose.IAA and I3A treatment alleviated the impairment induced by fructose by increasing trans epithelial electric resistance value,tight junction proteins,and Aryl hydrocarbon receptor(Ah R)activity in HT-29 cell.Conclusion:Fructose stimulated inflammation,apoptosis,gut bacteria alteration,and induced the reduction of IAA and I3A.Since fructose inhibited production of IAA and I3A,Ah R remained inactivated and consequently induced colon barrier dysfunction.
基金Supported by Sichuan Provincial Department of Science and Technology Youth Fund Project,No.2024NSFSC1609Sichuan Province Postdoctoral Special Funding Project,No.TB2023046。
文摘Impaired healing of diabetic wounds is one of the most important complications of diabetes,often leading to lower limb amputations and incurring significant economic and psychosocial costs.Unfortunately,there are currently no effective prevention or treatment strategies available.Recent research has reported that an imbalance in the gut microbiota,known as dysbiosis,was linked to the onset of type 2 diabetes,as well as the development and progression of diabetic complications.Indeed,the gut microbiota has emerged as a promising therapeutic approach for treating type 2 diabetes and related diseases.However,there is few of literatures specifically discussing the relationship between gut microbiota and diabetic wounds.This review aims to explore the potential role of the gut microbiota,especially probiotics,and its associated byproducts such as short chain fatty acids,bile acids,hydrogen sulfide,and tryptophan metabolites on wound healing to provide fresh insights and novel perspectives for the treatment of chronic wounds in diabetes.
文摘The review by Bangolo et al highlights the role of the gut microbiome in cancerassociated anemia(CAA).However,the impact of microbiome-derived metabolites is underexplored.In this letter,we focus on short-chain fatty acids,tryptophan metabolites,and polyamines as key mediators linking dysbiosis to impaired erythropoiesis and iron homeostasis.We also propose a research framework that integrates multi-omics analysis and gnotobiotic models.Finally,we discuss the clinical potential of metabolite-based diagnostics and microbiome-targeted therapies in managing CAA.
基金supported by Zhejiang Provincial Natural Science Foundation of China(grant number:LGD22H090003).
文摘Metabolic reprogramming is a critical process in the activation and function of immune cells,wherein changes in metabolites and enzymes regulate the phenotype and function of immune cells by modulating en-ergy metabolic pathways and signaling cascades.1 In the realm of cancer immunotherapy,metabolic interventions in immune cells have demon-strated potential to enhance therapeutic efficacy.For instance,Minogue et al.2 found that glutaric acid from tryptophan metabolism can mod-ulate the antitumor T cell response by affecting pyruvate metabolism and𝛼-ketoglutarate-dependent dioxygenases.The adjustment of glutaric acid levels in CD8^(+)T cells has been shown to promote central memory T cell development,reduce exhaustion markers,and enhance cell death.
文摘The gene encoded for tryptophan decarboxylase (TDC), which is the key enzyme in terpenoil indole alkaloids pathway, was targeted to different subcellular compartments and stably expressed in transgenic tobacco (Nicotiana tabacum L.) plants at the levels detected by Western blot and tryptamine accumulation analysis. It was shown that the TDC was located in subcellular compartments, the chloroplasts and cytosol. The recombinant TDC targeted to chloroplasts and cytosol in tobacco plants was effectively expressed as soluble protein by Western blot analysis and enzymatic assay. The level of tryptamine accumulation in chloroplast was higher than that in cytosol and very low in vacuole and endoplasmic reticulum (ER) to be hardly detected by Western blot analysis. It was indicated that the highest amount of tryptamine was in chloroplasts, lower in endoplasmic reticula and the lowest in vacuoles as compared to those in wild type plants. The TDC targeted to different subcellular compartments of tobacco plants and its expression level were studied by different nucleotide sequences coding signal peptides at 5'-end of tdc gene in order to know the effects of the TDC in compartmentation on its functionality.
基金Supported by Science Foundation Ireland,No.SFI/12/RC/2272,No.02/CE/B124,No.07/CE/B1368Health Research Board No.HRA_POR/2011/23Brain and Behaviour Research Foundation No.20771
文摘Irritable bowel syndrome(IBS) is an extremely prevalent but poorly understood gastrointestinal disorder. Consequently, there are no clear diagnostic markers to help diagnose the disorder and treatment options are limited to management of the symptoms. The concept of a dysregulated gut-brain axis has been adopted as a suitable model for the disorder. The gut microbiome may play an important role in the onset and exacerbation of symptoms in the disorder and has been extensively studied in this context. Although a causal role cannot yet be inferred from the clinical studies which have attempted to characterise the gut microbiota in IBS, they do confirm alterations in both community stability and diversity. Moreover, it has been reliably demonstrated that manipulation of the microbiota can influence the key symptoms, including abdominal pain and bowel habit, and other prominent features of IBS. A variety of strategies have been taken to study these interactions, including probiotics, antibiotics, faecal transplantations and the use of germ-free animals. There are clear mechanisms through which the microbiota can produce these effects, both humoral and neural. Taken together, these findings firmly establish the microbiota as a critical node in the gut-brain axis and one which is amenable to therapeutic interventions.
文摘Multiple factors are involved in the etiology of cardiovascular disease(CVD). Pathological changes occur in a variety of cell types long before symptoms become apparent and diagnosis is made. Dysregulation of physiological functions are associated with the activation of immune cells,leading to local and finally systemic inflammation that is characterized by production of high levels of reactive oxygen species(ROS). Patients suffering from inflammatory diseases often present with diminished levels of antioxidants either due to insufficient dietary intake or,and even more likely,due to increased demand in situations of overwhelming ROS production by activated immune effector cells like macrophages. Antioxidants are suggested to beneficially interfere with diseases-related oxidative stress,however the interplay of endogenous and exogenous antioxidants with the overall redox system is complex. Moreover,molecular mechanisms underlying oxidative stress in CVD are not fully elucidated. Metabolic dybalances are suggested to play a major role in disease onset and progression. Several central signalingpathways involved in the regulation of immunological,metabolic and endothelial function are regulated in a redox-sensitive manner. During cellular immune response,interferon γ-dependent pathways are activated such as tryptophan breakdown by the enzyme indoleamine 2,3-dioxygenase(IDO) in monocyte-derived macrophages,fibroblasts,endothelial and epithelial cells. Neopterin,a marker of oxidative stress and immune activation is produced by GTP-cyclohydrolase Ⅰ in macrophages and dendritic cells. Nitric oxide synthase(NOS) is induced in several cell types to generate nitric oxide(NO). NO,despite its low reactivity,is a potent antioxidant involved in the regulation of the vasomotor tone and of immunomodulatory signaling pathways. NO inhibits the expression and function of IDO. Function of NOS requires the cofactor tetrahydrobiopterin(BH4),which is produced in humans primarily by fibroblasts and endothelial cells. Highly toxic peroxynitrite(ONOO-) is formed solely in the presence of superoxide anion(O2-). Neopterin and kynurenine to tryptophan ratio(Kyn/Trp),as an estimate of IDO enzyme activity,are robust markers of immune activation in vitro and in vivo. Both these diagnostic parameters are able to predict cardiovascular and overall mortality in patients at risk. Likewise,a significant association exists between increase of neopterin concentrations and Kyn/Trp ratio values and the lowering of plasma levels of vitamin-C,-E and-B. Vitamin-B deficiency is usually accompanied by increased plasma homoycsteine. Additional determination of NO metabolites,BH4 and plasma antioxidants in patients with CVD and related clinical settings can be helpful to improve the understanding of redox-regulation in health and disease and might provide a rationale for potential antioxidant therapies in CVD.
文摘AIM: To evaluate how Helicobacter pylori(H. pylori) is able to evade the immune response and whether it enhances systemic immune tolerance against colorectal cancer.METHODS: This prospective randomized study involved 97 consecutive colorectal cancer patients and 108 cancer-free patients with extra-digestive diseases. Colorectal cancer and cancer-free patients were assigned into subgroups according to H. pylori Ig G seropositivity. Exposure to H. pylori was determined by Ig G seropositivity which was detected by enzyme linked immunoassay(ELISA). Serum neopterin levels were measured by ELISA. Serum tryptophan, kynurenine, and urinary biopterin concentrations were measured by high performance liquid chromatography. Serum nitrite levels were detected spectrophotometrically. Serum indoleamine 2,3-dioxygenase activity was estimated by the kynurenine to tryptophan ratio and by assessing the correlation between serum neopterin concentrations and the kynurenine to tryptophan ratio. The frequencies of increased serum kynurenine to tryptophan ratio of H. pylori seronegative and seropositive colorectal cancer subgroups were estimated by comparing them with the average kynurenine to tryptophan ratio of H. pylori seronegative tumor-free patients.RESULTS: Compared with respective controls, in both H. pylori seronegative and seropositive colorectal cancer patients, while serum tryptophan levels were decreased(controls vs patients; seronegative: 20.37 ± 0.89 μmol/L vs 15.71 ± 1.16 μmol/L, P < 0.05; seropositive: 20.71 ± 0.81 μmol/L vs 14.97 ± 0.79 μmol/L, P < 0.01) the kynurenine to tryptophan ratio was significantly increased(controls vs patients; seronegative: 52.85± 11.85 μmol/mmol vs 78.91 ± 8.68 μmol/mmol, P < 0.01, seropositive: 47.31 ± 5.93 μmol/mmol vs 109.65 ± 11.50 μmol/mmol, P < 0.01). Neopterin concentrations in cancer patients were significantly elevated compared with controls(P < 0.05). There was a significant correlation between serum neopterin levels and kynurenine/tryptophan in control and colorectal cancer patients groups(r s = 0.494, P = 0.0001 and r s= 0.293, P = 0.004, respectively). Serum nitrite levels of H. pylori seropositive cancer cases were significantly decreased compared with seropositive controls(controls vs patients; 26.04 ± 2.39 μmol/L vs 20.41 ± 1.48 μmol/L, P < 0.05) The decrease in the nitrite levels of H. pylori seropositive cancer patients may be attributed to excessive formation of peroxynitrite and other reactive nitrogen species.CONCLUSION: A significantly high kynurenine/tryptophan suggested that H. pylori may support the immune tolerance leading to cancer development, even without an apparent upper gastrointestinal tract disease.
基金We gratefully acknowledge Dr Jianru Zuo （Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, China） for providing T-DNA mutagenized population of Arabidopsis, Dr Salome Prat （Institut de Biologia Molecular de Barcelona, Spain） for providing homozygous atmyc2-2 mutant （T-DNA insertion line SALK_083483） seeds and Dr Jane Glazebrook for assisting with camalexin measurements. This work was supported by grants from the Chinese Academy of Sciences （KSCX2- YW-N-045, KSCX2-YW-N-015）, the Ministry of Agriculture of China （2008ZX08009-003-001） and the Ministry of Science and Technology of China （2007CB948201, 2006AA10A116）. Work in the laboratory of Jerry D Cohen was supported by grants from the US National Science Foundation （MCB-0725149 and DBI- PGRP-0606666） and the USDA, National Research Initiative （2005-35318-16197）.
文摘Jasmonic acid （JA） is a fatty acid-derived signaling molecule that regulates a broad range of plant defense responses against herbivores and some microbial pathogens. Molecular genetic studies have established that JA also performs a critical role in several aspects of plant development. Here, we describe the characterization of the Arabidopsis mutantjasmonic acid-hypersensitivel-1 （jah1-1）, which is defective in several aspects of JA responses. Although the mutant exhibits increased sensitivity to JA in root growth inhibition, it shows decreased expression of JA-inducible defense genes and reduced resistance to the necrotrophic fungus Botrytis cinerea. Gene cloning studies indicate that these defects are caused by a mutation in the cytochrome P450 protein CYP82C2. We provide evidence showing that the compromised resistance of thejah1-1 mutant to B. cinerea is accompanied by decreased expression of JA-induced defense genes and reduced accumulation of JA-induced indole glucosinolates （IGs）. Conversely, the enhanced resistance to B. cinerea in CYP82C2-overexpressing plants is accompanied by increased expression of JA-induced defense genes and elevated levels of JA-induced IGs. We demonstrate that CYP82C2 affects JA-induced accumulation of the IG biosynthetic precursor tryptophan （Trp）, but not the JA-induced IAA or pathogen-induced camalexin. Together, our results support a hypothesis that CYP82C2 may act in the metabolism of Trp-derived secondary metabolites under conditions in which JA levels are elevated. Thejah1-1 mutant should thus be important in future studies toward understanding the mechanisms underlying the complexity of JA-mediated differential responses, which are important for plants to adapt their growth to the ever-changing environments.
文摘Indoleamine 2, 3-dioxygenase (IDO) is a rate-limiting enzyme for the tryptophan catabolism. In human and murine cells, IDO inhibits antigen-specific T cell proliferation in vitro and suppresses T cell responses to fetal alloantigens during murine pregnancy. In mice, IDO expression is an inducible feature of specific subsets of dendritic cells (DCs), and is important for T cell regulatory properties. However, the effect of IDO and tryptophan deprivation on DC func- tions remains unknown. We report here that when tryptophan utilization was prevented by a pharmacological inhibitor of IDO, 1-methyl tryptophan (1MT), DC activation induced by pathogenic stimulus lipopolysaccharide (LPS) or inflam- matory cytokine TNF-α was inhibited both phenotypically and functionally. Such an effect was less remarkable when DC was stimulated by a physiological stimulus, CD40 ligand. Tryptophan deprivation during DC activation also regu- lated the expression of CCR5 and CXCR4, as well as DC responsiveness to chemokines. These results suggest that tryptophan usage in the microenvironment is essential for DC maturation, and may also play a role in the regulation of DC migratory behaviors.
