Serum N1-Methylnicotinamide is Associated With Coronary Artery Disease in Chinese Patients.

BACKGROUND: We previously reported that serum N1-methylnicotinamide (me-Nam), an indicator of nicotinamide N-methyltransferase activity, is associated with obesity and diabetes mellitus in Chinese patients. However, whether nicotinamide N-methyltransferase plays a role in human coronary artery disease (CAD) remains to be elucidated. We aim to investigate the associations of serum me-Nam with CAD in Chinese patients. METHODS AND RESULTS: Serum me-NAM was measured by liquid chromatography-mass spectrometry in patients with (n=230) or without (n=103) CAD as defined by coronary angiography. The severity of CAD was expressed by number of diseased coronary arteries. Serum me-Nam was higher (7.65 ng/mL versus 4.95 ng/mL, P<0.001) in patients with CAD than in those without. Serum me-Nam was positively correlated with high-sensitivity C-reactive protein and negatively correlated with high-density lipoprotein before and after adjustment for potential confounding variables (P≤0.002). In multivariable logistic regression analyses, compared with those in the lowest tertile of serum me-NAM levels, patients in the top tertile had the highest risks for CAD (odds ratio, 4.21; 95% CI, 1.97-8.97 [P<0.001]). After adjustment for potential confounding variables, serum me-NAM was also increased from 0- to 3-vessel disease (P for trend=0.01). CONCLUSIONS: Serum me-Nam is strongly associated with presence and severity of CAD, suggesting nicotinamide N-methyltransferase as a potential target for treating atherosclerosis in humans.

Composite three-marker assay for early detection of kidney cancer.

BACKGROUND: Early detection of renal cell carcinoma using serum/plasma biomarkers remains challenging. To validate clinical performance of potential candidate markers for kidney tumors, three-marker assay composed of nicotinamide N-methyltransferase (NNMT), L-plastin (LCP1), and nonmetastatic cells 1 protein (NM23A) was evaluated. METHODS: Patients with kidney cancer and control group were included in the clinical evaluation. Participants were divided into cohorts representing the training group of control group including healthy and benign tumors (n = 102) and patients with kidney cancer (n = 87) that were used to identify criteria for scoring. Then, we developed a three-marker assay that was validated with a cohort of test group samples (n = 100). A scoring method based on the cut-point of each of the three markers was used to evaluate the diagnostic performance of the marker combination. RESULTS: Plasma levels of NNMT, LCP1, and NM23A were highly elevated in patients with kidney cancer (P < 0.0001). In 289 blind sample tests with control subjects (n = 175) and patients with kidney cancer (n = 114), the diagnostic accuracy of NNMT alone and the three-marker assay was 0.913 and 0.932, respectively. When 90% specificity was defined, the sensitivity of NNMT and the three-marker assay was 71.9% and 95.7%, respectively. The predictive value of the three-marker assay was 87.2% (+PPV) and 97% (-PPV). CONCLUSIONS: The composite assay with NNMT, LCP1, and NM23A was a promising novel serum marker assay for the early detection of malignant kidney tumors covering subtypes of RCC with high diagnostic characteristics. IMPACT: NNMT/LCP1/NM23A triple markers could be a helpful screening assay to detect early RCC.

Assessment of gene expression profiles in peripheral occlusive arterial disease.

BACKGROUND: Molecular events responsible for the onset and progression of peripheral occlusive arterial disease (POAD) are incompletely understood. Gene expression profiling may point out relevant features of the disease. METHODS: Tissue samples were collected as operatory waste from a total of 36 patients with (n = 18) and without (n = 18) POAD. The tissues were histologically evaluated, and the patients with POAD were classified according to Leriche-Fontaine (LF) classification: 11% with stage IIB, 22% with stage III, and 67% with stage IV. Total RNA was isolated from all samples and hybridized onto Agilent 4×44K Oligo microarray slides. The bioinformatic analysis identified genes differentially expressed between control and pathologic tissues. Ten genes with a fold change ≥ 2 (1 with a fold change ≥ 1.8) were selected for quantitative polymerase chain reaction validation (GPC3, CFD, GDF10, ITLN1, TSPAN8, MMP28, NNMT, SERPINA5, LUM, and FDXR). C-reactive protein (CRP) was assessed with a specific assay, while nicotinamide N-methyltransferase (NNMT) was evaluated in the patient serum by enzyme-linked immunosorbent assay. RESULTS: A multiple regression analysis showed that the level of CRP in the serum is correlated with the POAD LF stages (r(2) = 0.22, P = 0.046) and that serum NNMT is higher in IV LF POAD patients (P = 0.005). The mRNA gene expression of LUM is correlated with the LF stage (r(2) = 0.45, P = 0.009), and the mRNA level of ITLN1 is correlated with the ankle-brachial index (r(2) = 0.42, P = 0.008). CONCLUSIONS: Our analysis shows that NNMT, ITLN1, LUM, CFD, and TSPAN8 in combination with other known markers, such as CRP, could be evaluated as a panel of biomarkers of POAD.

Nicotinamide N-methyltransferase (NNMT) and 1-methylnicotinamide (MNA) in experimental hepatitis induced by concanavalin A in the mouse.

Nicotinamide N-methyltransferase (NNMT), which converts nicotinamide (NA) to 1-methylnicotinamide (MNA), is up-regulated in the cirrhotic liver. Because MNA displays PGI(2)-dependent anti-inflammatory effects, the up-regulation of NNMT may play a regulatory role in liver inflammation. In the present work, we analyzed changes in NNMT activity in the liver and concomitant changes in the concentration of endogenous MNA in plasma in T-cell dependent hepatitis induced by concanavalin A (ConA) in BALB/c mice. Furthermore, we tested whether exogenous MNA possessed a protective effect against ConA-induced hepatitis. Development of liver injury induced by ConA (10 mg/kg, iv) was characterized by measurements of plasma concentration of alanine aminotransaminase (ALT), inflammatory cytokines (INF gamma and TNFalpha) and by histopathological examination. ConA-induced hepatitis was characterized by an early activation of inflammatory cytokines (IFN gamma; from below 0.05 ng/ml to 23.72 +/- 8.80 ng/ml; TNFalpha;from 0.07 +/- 0.01 ng/ml to 0.71 +/- 0.12 ng/ml, 2 h after ConA), an elevation of ALT (from 40.65 +/- 3.2 U/l to 5,092.20 +/- 1,129.05 U/l, 8 h after ConA) and by morphological signs of severe liver inflammation and injury (24 h after ConA). In mice injected with ConA, NNMT activity in the liver was up-regulated approximately 2-fold to 3-fold, 8-24 h after ConA injection. The concentration of MNA and its metabolites (Met-2PY and Met-4PY) in plasma were elevated approximately 2-fold 8 h after ConA injection. Exogenous MNA (100 mg/kg, iv) diminished ConA-induced liver injury, and this effect was reversed by an antagonist of the prostacyclin receptor, RO 3244794 (10 mg/kg, po). In conclusion, the present study demonstrated that hepatic NNMT activity and MNA concentration in plasma significantly increased during the progression of ConA-induced hepatitis in mice. This response may play a hepatoprotective role compatible with the PGI(2)-releasing properties of MNA.

Serum levels of nicotinamide N-methyltransferase in patients with lung cancer.

PURPOSE: The aim of this study was to determine if nicotinamide N-methyltransferase (NNMT) is useful as a biomarker of lung cancer (stages I-III). METHODS: We established an ELISA system for NNMT. We determined the levels of NNMT and carcinoembryonic antigen (CEA) in sera of 113 non-small cell lung cancer (NSCLC) patients undergoing surgery and sera of 50 non-neoplastic lung disease patients with chronic obstructive pulmonary disease (COPD) and of 24 healthy donors. RESULTS: The serum levels of NNMT were significantly higher in lung cancer patients than in COPD patients and healthy donors. The relationship between the specificity and sensitivity of NNMT and CEA measurements for the detection of lung cancer was analyzed by means of receiver-operating characteristic curves. The corresponding areas under the curves were 0.703 for NNMT and 0.621 for CEA, indicating slightly better sensitivity of NNMT. With 90% specificity, the sensitivities of NNMT and CEA as lung cancer markers were 25 and 24%, respectively. There was no significant correlation between NNMT and CEA. Therefore, the sensitivity of NSCLC detection at 90% specificity increased from 25 to 32% when NNMT was used in combination with CEA. CONCLUSION: The NNMT serum level may have significance in the early detection of NSCLC patients.