1-Methylnicotinamide (1-MNA) inhibits the activation of the NLRP3 inflammasome in human macrophages

Sidor, Karolina; Jeznach, Aldona; Hoser, Grazyna; Skirecki, Tomasz

doi:10.1016/j.intimp.2023.110445

Cited by 14 publications

(5 citation statements)

References 40 publications

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“…Recently, two publications reported that 1‐MNA exhibits inhibitory effect on IFN‐γ expression by T cells and the activation of NLRP3 inflammasome in human macrophages. [ 21 , 47 ] All these overturn the previous idea that 1‐MNA is a small inert metabolite excreted in urine. However, the underlying mechanism and intracellular target of 1‐MNA still remain elusive.…”

Section: Discussionmentioning

confidence: 72%

NNMT/1‐MNA Promote Cell‐Cycle Progression of Breast Cancer by Targeting UBC12/Cullin‐1‐Mediated Degradation of P27 Proteins

Ma,

Huang,

Wang

et al. 2023

Advanced Science

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Cell cycle dysregulation is a defining feature of breast cancer. Here, 1‐methyl‐nicotinamide (1‐MNA), metabolite of nicotinamide N‐methyltransferase(NNMT) is identified, as a novel driver of cell‐cycle progression in breast cancer. NNMT, highly expressed in breast cancer tissues, positively correlates with tumor grade, TNM stage, Ki‐67 index, and tumor size. Ablation of NNMT expression dramatically suppresses cell proliferation and causes cell‐cycle arrest in G0/G1 phase. This phenomenon predominantly stems from the targeted action of 1‐MNA, resulting in a specific down‐regulation of p27 protein expression. Mechanistically, 1‐MNA expedites the degradation of p27 proteins by enhancing cullin‐1 neddylation, crucial for the activation of Cullin‐1‐RING E3 ubiquitin ligase(CRL1)—an E3 ubiquitin ligase targeting p27 proteins. NNMT/1‐MNA specifically up‐regulates the expression of UBC12, an E2 NEDD8‐conjugating enzyme required for cullin‐1 neddylation. 1‐MNA showes high binding affinity to UBC12, extending the half‐life of UBC12 proteins via preventing their localization to lysosome for degradation. Therefore, 1‐MNA is a bioactive metabolite that promotes breast cancer progression by reinforcing neddylation pathway‐mediated p27 degradation. The study unveils the link between NNMT enzymatic activity with cell‐cycle progression, indicating that 1‐MNA may be involved in the remodeling of tumor microenvironment.

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Section: Discussionmentioning

confidence: 72%

NNMT/1‐MNA Promote Cell‐Cycle Progression of Breast Cancer by Targeting UBC12/Cullin‐1‐Mediated Degradation of P27 Proteins

Ma,

Huang,

Wang

et al. 2023

Advanced Science

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“…Several studies have indicated that oxidative stress also enhances NLRP3 inflammasome activation 49 , 50 , 51 , 52 , 53 ; thus, we investigated whether the inhibitory effects of CMPK2 knockdown on NLRP3 inflammasome activation were reliant on ROS generation. However, we found that CMPK2 knockdown did not change the level of mtROS production in primary microglial cells after LPS plus ATP stimulation ( Figures S8 A and S8B).…”

Section: Resultsmentioning

confidence: 99%

Microglial CMPK2 promotes neuroinflammation and brain injury after ischemic stroke

Guan,

Zhu,

Song

et al. 2024

Cell Reports Medicine

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“…1-MNA has been studied to decrease cellular ROS production in a dose-dependent manner [59], and abundant oxidative stress exhibited by increased ROS generation in RA patients has been demonstrated [60]. Therefore, we also studied the effect of E2 on ROS generation in RA-FLS and observed the decreased DCFDA fluorescence intensity in RA-FLS after E2 exposure (Figure 6A,B).…”

Section: Estradiol Ameliorates Ros Production In Ra-fls Regulated By ...mentioning

confidence: 88%

Unveiling the Nexus: Cellular Metabolomics Unravels the Impact of Estrogen on Nicotinamide Metabolism in Mitigating Rheumatoid Arthritis Pathogenesis

Malik,

Chakraborty,

Agnihotri

et al. 2024

Metabolites

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Rheumatoid arthritis (RA) is a metabolic joint disorder influenced by hormonal regulation, notably estrogen, which plays a cytoprotective role against inflammation. While estrogen’s impact on RA pathogenesis has been studied, the altered metabolite expression under estrogen’s influence remains unexplored. This study investigated the changes in the metabolome of synovial fibroblasts isolated from RA patients under 17β-estradiol (E2) using the liquid chromatography with tandem mass spectrometry (LC-MS/MS) approach followed by multivariate and biological pathway analysis along with in vitro validation. Results identified 3624 m/z, among which eight metabolites were significant (p < 0.05). Nicotinate and nicotinamide metabolism was found to be highly correlated with the treatment of E2, with metabolites NAD+ and 1-methynicotinamide (1-MNA) upregulated by E2 induction in RA-FLS. PharmMapper analysis identified potential gene targets of 1-MNA, which were further matched with RA gene targets, and thus, STAT1, MAPK14, MMP3, and MMP9 were concluded to be the common targets. E2 treatment affected the expression of these gene targets and ameliorated the development of oxidative stress associated with RA inflammation, which can be attributed to increased concentration of 1-MNA. Thus, an LC-MS/MS-based metabolomics study revealed the prominent role of estrogen in preventing inflammatory progression in RA by altering metabolite concentration, which can support its therapeutic capacity in remitting RA.

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1-Methylnicotinamide (1-MNA) inhibits the activation of the NLRP3 inflammasome in human macrophages

Cited by 14 publications

References 40 publications

NNMT/1‐MNA Promote Cell‐Cycle Progression of Breast Cancer by Targeting UBC12/Cullin‐1‐Mediated Degradation of P27 Proteins

NNMT/1‐MNA Promote Cell‐Cycle Progression of Breast Cancer by Targeting UBC12/Cullin‐1‐Mediated Degradation of P27 Proteins

Microglial CMPK2 promotes neuroinflammation and brain injury after ischemic stroke

Unveiling the Nexus: Cellular Metabolomics Unravels the Impact of Estrogen on Nicotinamide Metabolism in Mitigating Rheumatoid Arthritis Pathogenesis

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