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Stefan Chlopicki - One of the best experts on this subject based on the ideXlab platform.
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Functional and Biochemical Endothelial Profiling In Vivo in a Murine Model of Endothelial Dysfunction; Comparison of Effects of 1-Methylnicotinamide and Angiotensin-converting Enzyme Inhibitor.
Frontiers in pharmacology, 2017Co-Authors: Anna Bar, Ryszard T. Smolenski, Mariola Olkowicz, Urszula Tyrankiewicz, Edyta Kus, Krzysztof Jasiński, Tomasz Skórka, Stefan ChlopickiAbstract:Although it is known that 1-Methylnicotinamide (MNA) displays vasoprotective activity in mice, as yet the effect of MNA on endothelial function has not been demonstrated in vivo. Here, using magnetic resonance imaging (MRI) we profile the effects of MNA on endothelial phenotype in mice with atherosclerosis (ApoE/LDLR-/-) in vivo, in comparison to angiotensin-converting enzyme inhibitor (perindopril), with known vasoprotective activity. On a biochemical level, we analyzed whether MNA or perindopril induced improvement in endothelial function results in changes in ACE/angiotensin(Ang) II and ACE2/Ang-(1-7) balance, and L-arginine/asymmetric dimethylarginine (ADMA) ratio. Endothelial function and permeability were evaluated in the brachiocephalic artery (BCA) in 4-month-old ApoE/LDLR-/- mice that were non-treated or treated for 1 month or 2 months with either MNA (100mg/kg/day) or perindopril (10mg/kg/day). The 3D IntraGate®FLASH sequence was used for evaluation of BCA volume changes following acetylcholine (Ach) administration, and for relaxation time (T1) mapping around BCA to assess endothelial permeability using an intravascular contrast agent. Activity of ACE/Ang II and ACE2/Ang-(1-7) pathways as well as metabolites of L-arginine/ADMA pathway were measured using liquid chromatography/mass spectrometry-based methods. In non-treated 6-month-old ApoE/LDLR-/- mice, Ach induced a vasoconstriction in BCA that amounted to -7.2%. 2-month-treatment with either MNA or perindopril resulted in the reversal of impaired Ach induced response to vasodilatation (4.5% and 5.5%, respectively) and a decrease in endothelial permeability (by about 60% for MNA-, as well as perindopril-treated mice). Improvement of endothelial function by MNA and perindopril was in both cases associated with the activation of ACE2/Ang-(1-7) and the inhibition of ACE/Ang II axes as evidenced by an approximately 2-fold increase in Ang-(1-9) and Ang-(1-7) and a proportional decrease in Ang II and its active metabolites. Finally, MNA and perindopril treatment resulted in an increase in L-arginine/ADMA ratio (by 107% (MNA) and 140% (perindopril), as compared to non-treated mice. Functional and biochemical endothelial profiling in ApoE/LDLR-/- mice in vivo revealed that 2-month-treatment with MNA (100mg/kg/day) displayed a similar vasoprotective effect as 2-month-treatment with perindopril (10mg/kg/day) and afforded an improvement in endothelial function that was associated with the beneficial changes in ACE/Ang II and ACE2/Ang-(1-7) balance and in L-arginine/ADMA ratio in plasma.
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Pharmacokinetic Profile of 1-Methylnicotinamide Nitrate in Rats.
Journal of pharmaceutical sciences, 2017Co-Authors: Małgorzata Szafarz, Kamil Kus, Maria Walczak, Agnieszka Zakrzewska, Michał Niemczak, Juliusz Pernak, Stefan ChlopickiAbstract:Abstract Treatment with 1-Methylnicotinamide (MNA), a major metabolite of nicotinamide, exerts antithrombotic, anti-inflammatory, and vasoprotective effects. Yet, pharmacokinetic (PK) profile of MNA has not been fully characterized. In the present work, we analyze the PK profile of the MNA given as a nitrate (MNANO 3 ) in comparison to nitrite (MNANO 2 ) or chloride (MNACl) in rats. The bioavailability of MNA administered as MNANO 3 equaled 22.4% as compared to MNANO 2 or MNACl (9.2% and 9.1%, respectively). Moreover, in single-pass intestinal perfusion experiments, effective permeability of MNA given as MNANO 3 was higher as compared to MNA administered as MNANO 2 or MNACl. In turn, t max was the shortest and C max the highest (0.22 h and 56.65μM) for intragastrically administered MNANO 2 comparing to MNANO 3 (1.92 h, 21.74μM) or MNACl (0.63 h, 16.13μM). Transfer constant between central and peripheral compartments (k cp ) and volume of distribution (V ss ) for MNANO 3 (0.33 h −1 and 1.96 L/kg) were higher as compared to MNANO 2 or MNACl (0.11 h −1 , 0.08 h −1 for k cp and 1.05 L/kg, 0.76 L/kg for V ss , respectively). In conclusion, we characterized PK profile of MNA and demonstrated that nitrate ion augmented bioavailability and favorably modified PK profile of MNA. Furthermore, given vasoprotective properties of MNA as well as nitrate, MNANO 3 represents a bifunctional compound.
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stress. Role of endogenous prostacyclin and sensory nerves
2016Co-Authors: Tomasz Brzozowski, Stefan Chlopicki, Peter C. Konturek, Zbigniew Sliwowski, Agata Ptak-belowska, Slawomir Kwiecien, Danuta Drozdowicz, Robert Pajdo, Stanislaw J. Konturek, Wieslaw W. PawlikAbstract:Title: Therapeutic potential of 1-Methylnicotinamide against acute gastric lesions induced b
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1-Methylnicotinamide and its structural analog 1,4-dimethylpyridine for the prevention of cancer metastasis
Journal of experimental & clinical cancer research : CR, 2016Co-Authors: Agnieszka Blazejczyk, Jerzy Gebicki, Stefan Chlopicki, Marta Switalska, Andrzej Marcinek, Marcin Nowak, Anna Nasulewicz-goldeman, Joanna WietrzykAbstract:Background 1-Methylnicotinamide (1-MNA), an endogenous metabolite of nicotinamide, has recently gained interest due to its anti-inflammatory and anti-thrombotic activities linked to the COX-2/PGI2 pathway. Given the previously reported anti-metastatic activity of prostacyclin (PGI2), we aimed to assess the effects of 1-MNA and its structurally related analog, 1,4-dimethylpyridine (1,4-DMP), in the prevention of cancer metastasis.
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1-Methylnicotinamide protects against liver injury induced by concanavalin A via a prostacyclin-dependent mechanism: A possible involvement of IL-4 and TNF-α.
International immunopharmacology, 2015Co-Authors: Andrzej Jakubowski, Magdalena Sternak, Janusz Marcinkiewicz, Konrad Jabłoński, Marta Ciszek-lenda, Stefan ChlopickiAbstract:We have recently demonstrated that concanavalin A (Con A)-induced hepatitis is associated with the release of endogenous 1-Methylnicotinamide (MNA). Here we study the mechanism by which exogenous MNA alleviates Con A-induced liver inflammation and injury in vivo. The involvement of prostacyclin (PGI2) in hepatoprotective action of MNA (30-100 mg kg(-1); i.v.) was studied by the use of IP receptor antagonist RO3244794 (10 mg kg(-1); p.o.) given prior to Con A (5-20 mg kg(-1); i.v.). Liver damage was assessed by measurements of: liver specific transaminases in plasma (alanine aminotransferase; aspartate aminotransferase); cytokines release (IL-4, IFN-γ and TNF-α); liver histopathology; and 24h survival rates. Additionally, the effect of a stable analog of prostacyclin (carbaprostacyclin) on IL-4, IFN-γ and TNF-α production by isolated spleen lymphocytes in response to Con A was analyzed. MNA diminished Con A-induced rise in liver specific transaminases, alleviated histopathological injury and improved 24h survival rates, the latter effect in a degree comparable with the pretreatment of animals with dexamethasone (0.5 mg kg(-1); i.p.). MNA inhibited also a rise in IL-4 and TNF-α concentration in plasma measured 2 h after Con A administration, while IFN-γ was less affected. The effects of MNA were reversed by pretreatment with IP antagonist RO3244794. In isolated spleen lymphocytes, carbaprostacyclin profoundly decreased production of IL-4, the effect on TNF-α was modest with no effect on IFN-γ production. In conclusion, MNA attenuated Con A-induced hepatitis by a prostacyclin-dependent mechanism involving the inhibition of lymphocytes-derived IL-4 and the inhibition of Kuppfer-cells derived TNF-α.
Richard B. Parsons - One of the best experts on this subject based on the ideXlab platform.
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Neuroprotective Effects of Nicotinamide N-Methyltransferase and its Metabolite 1-Methylnicotinamide
Journal of Biochemical and Molecular Toxicology, 2013Co-Authors: Zeinab H. Milani, David B. Ramsden, Richard B. ParsonsAbstract:Nicotinamide N-methyltransferase (NNMT, E.C. 2.1.1.1) catalyses the N-methylation of nicotinamide to 1-Methylnicotinamide (MeN). We have previously shown that the ectopic expression of NNMT in SH-SY5Y human neuroblastoma cells increased adenosine triphosphate synthesis and complex I activity, effects of which were replicated by the addition of MeN. In this study, we investigated whether NNMT expression in SH-SY5Y conferred protection against mitotoxicity induced by rotenone, potassium cyanide (KCN), 2,4-dinitrophenol, and 6-hydroxydopamine, and whether any effects observed were mediated via increased MeN production. NNMT expression abolished the toxic effects of KCN, 2,4-dinitrophenol, and 6-hydroxydopamine, and reduced that of rotenone. In contrast, although MeN significantly reduced the toxicity of rotenone, it had no effect upon the toxicity of KCN, 2,4-dinitrophenol, and 6-hydroxydopamine. These data show that NNMT is cytoprotective against toxins that inhibit various aspects of mitochondrial function, and that these are not mediated solely via increased MeN production, but in combination with other unidentified mechanisms. © 2013 Wiley Periodicals, Inc. J BiochemMol Toxicol 27:451-456, 2013; View this article online at wileyonlinelibrary.com. DOI 10.1002/jbt.21508
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HPLC-UV method for measuring nicotinamide N-methyltransferase activity in biological samples: evidence for substrate inhibition kinetics.
Journal of Chromatography B, 2013Co-Authors: Misha Patel, Muhammad M. Vasaya, Daniel S. Asker, Richard B. ParsonsAbstract:Abstract Nicotinamide N-methyltransferase (NNMT, E.C. 2.1.1.1) N-methylates nicotinamide to produce 1-Methylnicotinamide. Enhanced NNMT activity is a feature of many types of cancer, and has been linked to processes such as tumour metastasis, resistance to radiotherapy and tumour drug resistance. As such, inhibition of NNMT activity is a promising therapeutic target for cancer therapy. To screen for NNMT inhibitors, there is a need for a standardised, rapid and cost-effective NNMT assay. Here, we describe a cell-free assay coupled with ion-pairing reverse-phase HPLC–UV detection of 1-Methylnicotinamide which requires minimal sample manipulation, is linear over 2.5 orders of magnitude with limits of detection and quantification of 0.05 and 0.15 nmol 1-Methylnicotinamide/100 μL injection respectively. The assay was sufficiently sensitive to measure basal hepatic 1-Methylnicotinamide concentration and NNMT activity in mouse, rabbit and human liver. 1-Methylnicotinamide concentration and the NNMT kinetic parameters specific activity, Vmax and Km all demonstrated species differences. NNMT also demonstrated substrate inhibition kinetics in all three species, which again was species-specific in term of calculated Ki. This assay demonstrates improved sensitivity over other previously published methods whilst lacking many of their drawbacks such as extensive sample preparation, use of non-physiological substrates and radioisotopic labelling.
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The expression of nicotinamide N-methyltransferas increases ATP synthesis and protects SH-SY5Y neuroblastoma cells against the toxicity of complex I inhibitors
Biochemical Journal, 2011Co-Authors: Richard B. Parsons, Shylesh Aravindan, Anusha Kadampeswaran, Emily A. Evans, Kanwaljeet K. Sandhu, Elizabeth Levy, Martin G Thomas, Brian M Austen, David B. RamsdenAbstract:Nicotinamide N-methyltransferase (NNMT, E.C. 2.1.1.1) catalyses the N-methylation of nicotinamide to 1-Methylnicotinamide. NNMT expression is significantly elevated in a number of cancers, and we have previously demonstrated that NNMT expression is significantly increased in the brains of patients who have died of Parkinson's disease. To investigate the cellular effects of NNMT overexpression, we overexpressed NNMT in the SH-SY5Y cell-line, a tumour-derived human dopaminergic neuroblastoma cell-line with no endogenous expression of NNMT. NNMT expression significantly decreased SH-SY5Y cell death, which correlated with increased intracellular ATP content, ATP:ADP ratio, Complex I activity and a reduction in the degradation of the NDUFS3 subunit of Complex I. These effects were replicated by incubation of SH-SY5Y cells with 1-Methylnicotinamide, suggesting that 1-Methylnicotinamide mediates the cellular effects of NNMT. Both NNMT expression and 1-Methylnicotinamide protected SH-SY5Y cells from the toxicity of the Complex I inhibitors MPP+ and rotenone by reversing their effects upon ATP synthesis, ATP:ADP ratio, Complex I activity and the NDUFS3 subunit. These results raise the possibility that the increase in NNMT expression that we observed in vivo may be a stress response of the cell to the underlying pathogenic process. Furthermore, these results also raise the possibility of using inhibitors of NNMT for the treatment of cancer.
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The expression of nicotinamide N-methyltransferase increases ATP synthesis and protects SH-SY5Y neuroblastoma cells against the toxicity of Complex I inhibitors.
The Biochemical journal, 2011Co-Authors: Richard B. Parsons, Shylesh Aravindan, Anusha Kadampeswaran, Emily A. Evans, Kanwaljeet K. Sandhu, Brian M Austen, Elizabeth R. Levy, Martin Thomas, David B. RamsdenAbstract:NNMT (nicotinamide N -methyltransferase, E.C. 2.1.1.1) catalyses the N-methylation of nicotinamide to 1-Methylnicotinamide. NNMT expression is significantly elevated in a number of cancers, and we have previously demonstrated that NNMT expression is significantly increased in the brains of patients who have died of Parkinson9s disease. To investigate the cellular effects of NNMT overexpression, we overexpressed NNMT in the SH-SY5Y cell line, a tumour-derived human dopaminergic neuroblastoma cell line with no endogenous expression of NNMT. NNMT expression significantly decreased SH-SY5Y cell death, which correlated with increased intracellular ATP content, ATP/ADP ratio and Complex I activity, and a reduction in the degradation of the NDUFS3 [NADH dehydrogenase (ubiquinone) iron–sulfur protein 3] subunit of Complex I. These effects were replicated by incubation of SH-SY5Y cells with 1-Methylnicotinamide, suggesting that 1-Methylnicotinamide mediates the cellular effects of NNMT. Both NNMT expression and 1-Methylnicotinamide protected SH-SY5Y cells from the toxicity of the Complex I inhibitors MPP+ (1-methyl-4-phenylpyridinium ion) and rotenone by reversing their effects upon ATP synthesis, the ATP/ADP ratio, Complex I activity and the NDUFS3 subunit. The results of the present study raise the possibility that the increase in NNMT expression that we observed in vivo may be a stress response of the cell to the underlying pathogenic process. Furthermore, the results of the present study also raise the possibility of using inhibitors of NNMT for the treatment of cancer.
David B. Ramsden - One of the best experts on this subject based on the ideXlab platform.
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Neuroprotective Effects of Nicotinamide N-Methyltransferase and its Metabolite 1-Methylnicotinamide
Journal of Biochemical and Molecular Toxicology, 2013Co-Authors: Zeinab H. Milani, David B. Ramsden, Richard B. ParsonsAbstract:Nicotinamide N-methyltransferase (NNMT, E.C. 2.1.1.1) catalyses the N-methylation of nicotinamide to 1-Methylnicotinamide (MeN). We have previously shown that the ectopic expression of NNMT in SH-SY5Y human neuroblastoma cells increased adenosine triphosphate synthesis and complex I activity, effects of which were replicated by the addition of MeN. In this study, we investigated whether NNMT expression in SH-SY5Y conferred protection against mitotoxicity induced by rotenone, potassium cyanide (KCN), 2,4-dinitrophenol, and 6-hydroxydopamine, and whether any effects observed were mediated via increased MeN production. NNMT expression abolished the toxic effects of KCN, 2,4-dinitrophenol, and 6-hydroxydopamine, and reduced that of rotenone. In contrast, although MeN significantly reduced the toxicity of rotenone, it had no effect upon the toxicity of KCN, 2,4-dinitrophenol, and 6-hydroxydopamine. These data show that NNMT is cytoprotective against toxins that inhibit various aspects of mitochondrial function, and that these are not mediated solely via increased MeN production, but in combination with other unidentified mechanisms. © 2013 Wiley Periodicals, Inc. J BiochemMol Toxicol 27:451-456, 2013; View this article online at wileyonlinelibrary.com. DOI 10.1002/jbt.21508
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The expression of nicotinamide N-methyltransferas increases ATP synthesis and protects SH-SY5Y neuroblastoma cells against the toxicity of complex I inhibitors
Biochemical Journal, 2011Co-Authors: Richard B. Parsons, Shylesh Aravindan, Anusha Kadampeswaran, Emily A. Evans, Kanwaljeet K. Sandhu, Elizabeth Levy, Martin G Thomas, Brian M Austen, David B. RamsdenAbstract:Nicotinamide N-methyltransferase (NNMT, E.C. 2.1.1.1) catalyses the N-methylation of nicotinamide to 1-Methylnicotinamide. NNMT expression is significantly elevated in a number of cancers, and we have previously demonstrated that NNMT expression is significantly increased in the brains of patients who have died of Parkinson's disease. To investigate the cellular effects of NNMT overexpression, we overexpressed NNMT in the SH-SY5Y cell-line, a tumour-derived human dopaminergic neuroblastoma cell-line with no endogenous expression of NNMT. NNMT expression significantly decreased SH-SY5Y cell death, which correlated with increased intracellular ATP content, ATP:ADP ratio, Complex I activity and a reduction in the degradation of the NDUFS3 subunit of Complex I. These effects were replicated by incubation of SH-SY5Y cells with 1-Methylnicotinamide, suggesting that 1-Methylnicotinamide mediates the cellular effects of NNMT. Both NNMT expression and 1-Methylnicotinamide protected SH-SY5Y cells from the toxicity of the Complex I inhibitors MPP+ and rotenone by reversing their effects upon ATP synthesis, ATP:ADP ratio, Complex I activity and the NDUFS3 subunit. These results raise the possibility that the increase in NNMT expression that we observed in vivo may be a stress response of the cell to the underlying pathogenic process. Furthermore, these results also raise the possibility of using inhibitors of NNMT for the treatment of cancer.
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The expression of nicotinamide N-methyltransferase increases ATP synthesis and protects SH-SY5Y neuroblastoma cells against the toxicity of Complex I inhibitors.
The Biochemical journal, 2011Co-Authors: Richard B. Parsons, Shylesh Aravindan, Anusha Kadampeswaran, Emily A. Evans, Kanwaljeet K. Sandhu, Brian M Austen, Elizabeth R. Levy, Martin Thomas, David B. RamsdenAbstract:NNMT (nicotinamide N -methyltransferase, E.C. 2.1.1.1) catalyses the N-methylation of nicotinamide to 1-Methylnicotinamide. NNMT expression is significantly elevated in a number of cancers, and we have previously demonstrated that NNMT expression is significantly increased in the brains of patients who have died of Parkinson9s disease. To investigate the cellular effects of NNMT overexpression, we overexpressed NNMT in the SH-SY5Y cell line, a tumour-derived human dopaminergic neuroblastoma cell line with no endogenous expression of NNMT. NNMT expression significantly decreased SH-SY5Y cell death, which correlated with increased intracellular ATP content, ATP/ADP ratio and Complex I activity, and a reduction in the degradation of the NDUFS3 [NADH dehydrogenase (ubiquinone) iron–sulfur protein 3] subunit of Complex I. These effects were replicated by incubation of SH-SY5Y cells with 1-Methylnicotinamide, suggesting that 1-Methylnicotinamide mediates the cellular effects of NNMT. Both NNMT expression and 1-Methylnicotinamide protected SH-SY5Y cells from the toxicity of the Complex I inhibitors MPP+ (1-methyl-4-phenylpyridinium ion) and rotenone by reversing their effects upon ATP synthesis, the ATP/ADP ratio, Complex I activity and the NDUFS3 subunit. The results of the present study raise the possibility that the increase in NNMT expression that we observed in vivo may be a stress response of the cell to the underlying pathogenic process. Furthermore, the results of the present study also raise the possibility of using inhibitors of NNMT for the treatment of cancer.
Andrew Seal - One of the best experts on this subject based on the ideXlab platform.
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Quantitation of the niacin metabolites 1-Methylnicotinamide and l-methyl-2-pyridone-5-carboxamide in random spot urine samples, by ion-pairing reverse-phase HPLC with UV detection, and the implications for the use of spot urine samples in the assessm
Journal of chromatography. B Analytical technologies in the biomedical and life sciences, 2005Co-Authors: Paul I. Creeke, Andrew SealAbstract:A simple ion-pairing reverse-phase HPLC method, with UV diode array detection, was developed and validated for quantitation of the urinary niacin metabolites 1-Methylnicotinamide and l-methyl-2-pyridone-5-carboxamide in a single run. Urine samples were purified using a polymer-based mixed mode anion exchange reverse-phase cartridge. Analysis was performed on a reverse-phase C18 column, using a methanol gradient elution system, containing phosphate buffer pH 7.0, 1-heptanesulphonic acid as the ion-pairing agent and trimethylamine as a modifier. The assay was applied to the measurement of the niacin status of two subjects using spot urine samples. The samples were collected over 4 consecutive days and at four time points during 1 day. Status, expressed as the concentration ratios (2-PYR or 1-MN)/creatinine and 2-PYR/l-MN, varied within and between days and was least for fasting samples. This work illustrates the potential of spot urine sampling for niacin status assessment, but highlights the need for further validation prior to its use in field nutritional surveys.
Cezary Watala - One of the best experts on this subject based on the ideXlab platform.
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N-Methyl-2-pyridone-5-carboxamide is 1-Methylnicotinamide metabolite of low cyclooxygenase-dependent vasodilating activity
Journal of Physiology and Biochemistry, 2012Co-Authors: Tomasz Przygodzki, Bartlomiej Grobelski, Piotr Kazmierczak, Cezary WatalaAbstract:1-Methylnicotinamide (MNA) is a primary metabolite of nicotinamide recently proven to cause systemic increase in PGI_2 plasma levels in an unknown mechanism. Our present study was aimed at verifying whether the increased production of PGI_2, a vasodilating prostanoid, in response to MNA, its metabolite N -methyl-2-pyridone-5-carboxamide (Met2PY), and nicotinamide may be reproduced under in vitro conditions. Since prostacyclin is a vasodilating prostanoid, we also performed the functional tests in the ex vivo model of coronary vascular bed perfusion to evaluate the vasoactive properties of those compounds. We did not observe any significant effect of the tested drugs on either PGI_2 or PGE_2 secretion in our in vitro model. Nicotinamide at the concentrations of 10 and 100 μmol/l and 100 μmol/l Met2PY slightly but significantly increased coronary flow in rat heart. These increases, however, remained very low when compared to that induced by the reference compound, bradykinin (100 nmol/l). Perfusion of rat hearts with Met2PY in the presence of 50 μmol/l indomethacin resulted in decreased coronary flow, which proves that the effect is cyclooxygenase dependent. We conclude that MNA metabolites should be more carefully addressed in reference to pro-prostacyclin activity and that systemic mechanism of MNA-induced PGI_2 production needs further clarification.
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research article effects of n 1 Methylnicotinamide on oxidative and glycooxidative stress markers in rats with streptozotocin induced diabetes mellitus
2012Co-Authors: Zuzana Orszaghova, A Liptakova, Jana Muchova, Cezary WatalaAbstract:Objectives: This study was focused on the monitoring how the anti-inflammatory substance, N 1 Methylnicotinamide (MNA), could influence oxidation and glycooxidation stress markers in rats under conditions of streptozotocin (STZ)-induced diabetes mellitus. Methods: Diabetes mellitus was induced in 60 male Wistar rats by intraperitoneal injection of STZ and after 7 days diabetic animals were allocated to five groups according to the dose of MNA administered for 7 weeks. The degree of DNA damage in lymphocytes, as well as advanced glycation endproducts (AGEs), protein carbonyls, lipid peroxides, and total antioxidant capacity (TEAC) in plasma were measured. Results: Glycation damage to proteins (represented by AGEs level) was significantly increased in all diabetic groups compared to untreated non-diabetic animals. MNA did not affect TEAC of plasma in any group of diabetic rats. Supplementation of diabetic rats with MNA at the dose of 200 mg/kg resulted in decreased protein carbonyls (from 0.0818± 0.0091 to 0.0558 ± 0.0044 nmol/mg proteins; P < 0.05, n = 15) and DNA oxidation, reflected by the levels of 8-oxoG (0.6302± 0.085 vs. 0.9213± 0.108 8-oxoG/10 6 G; P < 0.05, n = 15), compared to untreated diabetic animals. Discussion: Our results demonstrated that MNA at suitable concentrations could influence oxidative modifications of proteins and DNA.
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effects of 1 Methylnicotinamide and its metabolite n methyl 2 pyridone 5 carboxamide on streptozotocin induced toxicity in murine insulinoma min6 cell line
Acta Biochimica Polonica, 2011Co-Authors: Tomasz Przygodzki, Ewa M Slominska, Ewa Polakowska, Wojciech Mlynarski, Cezary WatalaAbstract:: 1-Methylnicotinamide (MNA) is a primary metabolite of nicotinamide. In recent years several activities of MNA have been described, such as anti-inflammatory activity in skin diseases, induction of prostacyclin synthesis via COX-2, aortal endothelium protection in diabetes and hypertriglyceridaemia and increased survival rate of diabetic rats. 1-Methylnicotinamide was also suggested to protect pancreatic cells from streptozotocin in vivo. Streptozotocin toxicity is known to be mediated by poly-ADP-ribose polymerase. Nicotinamide and its derivatives have been shown to ameliorate poly-ADP-ribose polymerase-dependent nucleotide pool reduction. We aimed to verify if 1-Methylnicotinamide and its metabolite, N-methyl-2-pyridone-5-carboxamide, can protect insulinoma cells from streptozotocin-induced toxicity. We found that N-methyl-2-pyridone-5-carboxamide, but not 1-Methylnicotinamide, restores the pool of ATP and NAD+ in streptozotocin-treated cells, but neither compound improved the cell viability. We conclude that inhibition of poly-ADP-ribose polymerase-dependent nucleotide pool reduction may not be sufficient to protect cells from streptozotocin toxicity.
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1-Methylnicotinamide effects on the selected markers of endothelial function, inflammation and haemostasis in diabetic rats.
European journal of pharmacology, 2010Co-Authors: Tomasz Przygodzki, Piotr Kazmierczak, Joanna Sikora, Cezary WatalaAbstract:1-Methylnicotinamide (MNA) is a primary metabolite of nicotinamide. In recent years several activities of MNA have been described, such as anti-inflammatory activity in skin diseases, induction of prostacyclin synthesis via COX-2, aortal endothelium protection in diabetes and hypertriglyceridaemia and increasing survival rate of diabetic rats. The aim of the present study was to verify whether the increased survival rate of diabetic animals could be explained by anti-hyperglycaemic activity of MNA and/or by its protective effects on vascular endothelium. We used Sprague-Dawley male rats with an experimental streptozotocin diabetes. The animals received either MNA or pure drinking water. At the particular time intervals groups of rats were sacrificed and the blood was collected. We have shown that MNA increases levels of PGI2 in diabetic rats, but the effect is limited only to the early stage of diabetes. We were unable to prove anti-inflammatory effects of MNA, as it did not affect increased TNF-alpha in diabetic animals. We have confirmed our previous observations that MNA improved survival of diabetic animals, but contrary to our previous study, this effect was not accompanied by improvement in the parameters of long-term glycaemic control. Overall, we conclude that anti-diabetic activity of MNA manifested in the improved lifespan of diabetic animals is rather due to MNA pro-prostacyclin activity, and it may not be substantially related to glycaemic control in diabetes. Still other potential mechanism(s) await further elucidation.
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1-Methylnicotinamide (MNA) prevents endothelial dysfunction in hypertriglyceridemic and diabetic rats.
Pharmacological reports : PR, 2008Co-Authors: Magdalena Bartuś, Jan Adamus, Ewa M Slominska, Cezary Watala, Ryszard T. Smolenski, Magdalena Łomnicka, Renata B. Kostogrys, P. Kaźmierczak, Paweł M. Pisulewski, Jerzy GebickiAbstract:For many years, 1-Methylnicotinamide (MNA), a primary metabolite of nicotinamide, has been considered inactive. Recently however, it has been discovered that MNA possesses anti-thrombotic and anti-inflammatory activity. In the present study we investigated whether chronic administration of MNA to hypertriglyceridemic or diabetic rats would reverse endothelial dysfunction characterized by the impairment of nitric oxide (NO)-dependent vasodilatation. Hypertriglyceridemia in rats was induced by fructose-rich (60%) diet, while diabetes was induced by streptozotocin injection (70 mg/kg). After eight weeks, in hypertriglyceridemic or diabetic rats treated or non-treated with MNA(100 mg/kg), we analyzed the magnitude of endothelium-dependent or endothelium-independent vasodilatation in aorta induced by acetylcholine or S-nitroso-N-acetyl-penicillamine (SNAP), respectively, as well as plasma concentration of: cholesterol, triglycerides, glucose, HbA(1c), fructosamine, peptide C, endogenous MNA and its metabolites (M2PY, M4PY). In diabetic rats plasma concentration of glucose, HbA(1c) and fructosamine was elevated (402.08 +/- 19.01 vs. 82.06 +/- 5.41 mg/dl, p < 0.001; 9.55 +/- 0.56 vs. 4.93 +/- 0.24%, p = 0.052 and 2.53 +/- 0.10 vs. 1.14 +/- 0.06 mmol DTF/mg protein, p < 0.001 in diabetic and control rats, respectively). In hypertriglyceridemic rats plasma concentration of triglycerides was elevated (4.25 +/- 0.27 vs. 1.55 +/- 0.12 mmol/l, p < 0.001 in hypertriglyceridemic and control rats, respectively). In both models the NO-dependent vasodilatation in aorta induced by acetylcholine was significantly impaired as compared to control rats, while the response to SNAP was largely preserved. In hypertriglyceridemic rats, 4 weeks of treatment with MNA(100 mg/kg, po) resulted in a three to six-fold increase in endogenous levels of MNA and its metabolites (M2PY and M4PY), the fall in triglycerides concentration in plasma (from 4.25 +/- 0.27 to 2.22 +/- 0.14 mmol/l, p < 0.001), and the preservation of the NO-dependent vasodilatation. In diabetic rats chronic treatment with MNA also prevented the impairment of NO-dependent vasodilatation, while it displayed only a mild effect on hyperglycemia and did not lower triglycerides concentration. In summary, MNA treatment decreased plasma triglycerides concentration in hypertriglyceridemic, but not in diabetic rats, while it prevented the development of endothelial dysfunction in aorta in both of these models. Accordingly, the ability of MNA to reverse endothelial dysfunction seems to be independent of its hypolipemic activity.
