Insight Into Nicotinamide Adenine Dinucleotide Homeostasis as a Targetable Metabolic Pathway in Colorectal Cancer

Colombo, Giorgia; Gelardi, Edoardo Luigi Maria; Balestrero, Federica Carolina; Moro, Marianna; Travelli, Cristina; Genazzani, Armando A.

doi:10.3389/fphar.2021.758320

Cited by 5 publications

(2 citation statements)

References 177 publications

(204 reference statements)

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“…Downregulation of Nmrk1 and Nmrk2 observed in the Winnie mouse colon may contribute to inflammation-associated ENS damage reported in a previous study ( 38 ), as in homeostatic conditions, Nmrk allosterically upregulates to safeguard neurons against axonopathy if NAD + is depleted or under attack by NAD-consuming enzymes ( 102 ). Reduced expression of Naprt observed in our study can inhibit the production of NAD + and prevent the protection of colon tissues from oxidative stress ( 103 ). The colitis in Winnie mice exhibits manifestations closely resembling IBD, such as tight junction damage, early intestinal cell death, and cellular stress responses ( 37 , 39 , 41 , 104 – 109 ), which may be linked to glutamine deficiency.…”

Section: Discussionmentioning

confidence: 71%

Alterations in tryptophan metabolism and de novo NAD+ biosynthesis within the microbiota-gut-brain axis in chronic intestinal inflammation

Devereaux,

Robinson,

Stavely

et al. 2024

Front. Med.

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BackgroundInflammatory bowel disease is an incurable and idiopathic disease characterized by recurrent gastrointestinal tract inflammation. Tryptophan metabolism in mammalian cells and some gut microbes comprise intricate chemical networks facilitated by catalytic enzymes that affect the downstream metabolic pathways of de novo nicotinamide adenine dinucleotide (NAD+) synthesis. It is hypothesized that a correlation exists between tryptophan de novo NAD+ synthesis and chronic intestinal inflammation.MethodsTranscriptome analysis was performed using high-throughput sequencing of mRNA extracted from the distal colon and brain tissue of Winnie mice with spontaneous chronic colitis and C57BL/6 littermates. Metabolites were assessed using ultra-fast liquid chromatography to determine differences in concentrations of tryptophan metabolites. To evaluate the relative abundance of gut microbial genera involved in tryptophan and nicotinamide metabolism, we performed 16S rRNA gene amplicon sequencing of fecal samples from C57BL/6 and Winnie mice.ResultsTryptophan and nicotinamide metabolism-associated gene expression was altered in distal colons and brains of Winnie mice with chronic intestinal inflammation. Changes in these metabolic pathways were reflected by increases in colon tryptophan metabolites and decreases in brain tryptophan metabolites in Winnie mice. Furthermore, dysbiosis of gut microbiota involved in tryptophan and nicotinamide metabolism was evident in fecal samples from Winnie mice. Our findings shed light on the physiological alterations in tryptophan metabolism, specifically, its diversion from the serotonergic pathway toward the kynurenine pathway and consequential effects on de novo NAD+ synthesis in chronic intestinal inflammation.ConclusionThe results of this study reveal differential expression of tryptophan and nicotinamide metabolism-associated genes in the distal colon and brain in Winnie mice with chronic intestinal inflammation. These data provide evidence supporting the role of tryptophan metabolism and de novo NAD+ synthesis in IBD pathophysiology.

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Section: Discussionmentioning

confidence: 71%

Alterations in tryptophan metabolism and de novo NAD+ biosynthesis within the microbiota-gut-brain axis in chronic intestinal inflammation

Devereaux,

Robinson,

Stavely

et al. 2024

Front. Med.

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“…A unique feature of glioma cells is the high demand for energetic molecules namely adenosine triphosphate (ATP), to sustain their rapid growth rate and the biosynthesis of DNA and proteins ( 18 , 19 ). Products of NAD+ degradation, NAD+ pathway metabolites and many molecules converted from NAD+ were closely associated with the development and progression of gliomas ( 12 , 14 , 20 – 22 ). Nevertheless, there were no systematic researches about NAD+ metabolism related genes to predict the survival of patients with glioma.…”

Section: Discussionmentioning

confidence: 99%

Development of prognostic indicator based on NAD+ metabolism related genes in glioma

Chen

Wang

et al. 2023

Front. Surg.

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BackgroundStudies have shown that Nicotinamide adenine dinucleotide (NAD+) metabolism can promote the occurrence and development of glioma. However, the specific effects and mechanisms of NAD+ metabolism in glioma are unclear and there were no systematic researches about NAD+ metabolism related genes to predict the survival of patients with glioma.MethodsThe research was performed based on expression data of glioma cases in the Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. Firstly, TCGA-glioma cases were classified into different subtypes based on 49 NAD+ metabolism-related genes (NMRGs) by consensus clustering. NAD+ metabolism-related differentially expressed genes (NMR-DEGs) were gotten by intersecting the 49 NMRGs and differentially expressed genes (DEGs) between normal and glioma samples. Then a risk model was built by Cox analysis and the least shrinkage and selection operator (LASSO) regression analysis. The validity of the model was verified by survival curves and receiver operating characteristic (ROC) curves. In addition, independent prognostic analysis of the risk model was performed by Cox analysis. Then, we also identified different immune cells, HLA family genes and immune checkpoints between high and low risk groups. Finally, the functions of model genes at single-cell level were also explored.ResultsConsensus clustering classified glioma patients into two subtypes, and the overall survival (OS) of the two subtypes differed. A total of 11 NAD+ metabolism-related differentially expressed genes (NMR-DEGs) were screened by overlapping 5,995 differentially expressed genes (DEGs) and 49 NAD+ metabolism-related genes (NMRGs). Next, four model genes, PARP9, BST1, NMNAT2, and CD38, were obtained by Cox regression and least absolute shrinkage and selection operator (Lasso) regression analyses and to construct a risk model. The OS of high-risk group was lower. And the area under curves (AUCs) of Receiver operating characteristic (ROC) curves were >0.7 at 1, 3, and 5 years. Cox analysis showed that age, grade G3, grade G4, IDH status, ATRX status, BCR status, and risk Scores were reliable independent prognostic factors. In addition, three different immune cells, Mast cells activated, NK cells activated and B cells naive, 24 different HLA family genes, such as HLA-DPA1 and HLA-H, and 8 different immune checkpoints, such as ICOS, LAG3, and CD274, were found between the high and low risk groups. The model genes were significantly relevant with proliferation, cell differentiation, and apoptosis.ConclusionThe four genes, PARP9, BST1, NMNAT2, and CD38, might be important molecular biomarkers and therapeutic targets for glioma patients.

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Stepwise Stiffening/Softening of and Cell Recovery from Reversibly Formulated Hydrogel Interpenetrating Networks

Kopyeva,

Goldner,

Hoye

et al. 2024

Advanced Materials

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Biomechanical contributions of the extracellular matrix underpin cell growth and proliferation, differentiation, signal transduction, and other fate decisions. As such, biomaterials whose mechanics can be spatiotemporally altered‐ particularly in a reversible manner‐ are extremely valuable for studying these mechanobiological phenomena. Herein, a poly(ethylene glycol) (PEG)‐based hydrogel model consisting of two interpenetrating step‐growth networks is introduced that are independently formed via largely orthogonal bioorthogonal chemistries and sequentially degraded with distinct recombinant sortases, affording reversibly tunable stiffness ranges that span healthy and diseased soft tissues (e.g., 500 Pa–6 kPa) alongside terminal cell recovery for pooled and/or single‐cell analysis in a near “biologically invisible” manner. Spatiotemporal control of gelation within the primary supporting network is achieved via mask‐based and two‐photon lithography; these stiffened patterned regions can be subsequently returned to the original soft state following sortase‐based secondary network degradation. Using this approach, the effects of 4D‐triggered network mechanical changes on human mesenchymal stem cell morphology and Hippo signaling, as well as Caco‐2 colorectal cancer cell mechanomemory using transcriptomics and metabolic assays are investigated. This platform is expected to be of broad utility for studying and directing mechanobiological phenomena, patterned cell fate, and disease resolution in softer matrices.

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Insight Into Nicotinamide Adenine Dinucleotide Homeostasis as a Targetable Metabolic Pathway in Colorectal Cancer

Cited by 5 publications

References 177 publications

Alterations in tryptophan metabolism and de novo NAD+ biosynthesis within the microbiota-gut-brain axis in chronic intestinal inflammation

Alterations in tryptophan metabolism and de novo NAD+ biosynthesis within the microbiota-gut-brain axis in chronic intestinal inflammation

Development of prognostic indicator based on NAD+ metabolism related genes in glioma

Stepwise Stiffening/Softening of and Cell Recovery from Reversibly Formulated Hydrogel Interpenetrating Networks

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