1-Methylnicotinamide protects against liver injury induced by concanavalin A via a prostacyclin-dependent mechanism: A possible involvement of IL-4 and TNF-α

Jakubowski, Andrzej; Sternak, Magdalena; Jabłoński, Konrad; Ciszek-Lenda, Marta; Marcinkiewicz, Janusz; Chłopicki, Stefan

doi:10.1016/j.intimp.2015.11.032

Cited by 23 publications

(17 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is supported by in vitro experiments showing that direct stimulation of human skeletal muscle myoblasts with IL-6, TNFα and TGFβ all increase NNMT expression [55]. The role of NNMT and MNAM in these inflammatory states needs to be more fully elucidated but is thought to represent a protective compensatory response to injury [55,60]. …”

Section: Nnmt and Nad+ Metabolismmentioning

confidence: 99%

Nicotinamide N -Methyltransferase: More Than a Vitamin B3 Clearance Enzyme

Pissios

2017

Trends in Endocrinology & Metabolism

184

180

View full text Add to dashboard Cite

Nicotinamide N-methyltransferase (NNMT) was originally identified as the enzyme responsible for the methylation of nicotinamide (NAM), one of the forms of vitamin B3. Methylated NAM (MNAM) is eventually excreted from the body. Recent evidence has expanded the role of NNMT beyond clearance of excess vitamin B3. NNMT has been implicated in the regulation of multiple metabolic pathways in tissues such as the adipose tissue and liver, as well as cancer cells, through consumption of methyl donors and generation of active metabolites. This review examines recent findings regarding the function of NNMT in physiology and disease and highlights potential new avenues for therapeutic intervention. Finally, key gaps in our knowledge for this enzymatic system and future areas of investigation are discussed.

show abstract

Section: Nnmt and Nad+ Metabolismmentioning

confidence: 99%

Nicotinamide N -Methyltransferase: More Than a Vitamin B3 Clearance Enzyme

Pissios

2017

Trends in Endocrinology & Metabolism

184

180

View full text Add to dashboard Cite

show abstract

“…Altogether, our results suggest that MNA displayed a similar pattern of vasoprotective activity as perindopril, a representative of ACE-Is, and both compounds affected ACE/Ang II-ACE2/Ang-(1–7) balance and L -Arg/ADMA ratio that could contribute to their vasoprotective effects. Given that correction of endothelial function by ACE-Is contributes significantly to their clinical benefits and their anti-inflammatory, anti-thrombotic, anti-diabetic, and vasoprotective actions reported in numerous experimental and clinical papers (Chłopicki and Gryglewski, 2005), the findings of endothelial profile of MNA being similar to perindopril in in vivo settings bring important novel perspectives to understanding the therapeutic efficacy of MNA reported previously (Gebicki et al, 2003; Wozniacka et al, 2005; Chlopicki et al, 2007; Bartuś et al, 2008; Bryniarski et al, 2008; Brzozowski et al, 2008; Watała et al, 2009; Sternak et al, 2010; Przyborowski et al, 2015; Blazejczyk et al, 2016; Jakubowski et al, 2016; Mateuszuk et al, 2016). …”

Section: Discussionmentioning

confidence: 70%

“…Furthermore, functional improvement of endothelial function by MNA or perindopril treatment was in both cases associated with the inhibition of ACE/Ang II axis, the parallel activation of ACE2/Ang-(1–7) axis, and an increase in L -Arg/ADMA ratio in plasma. Given that improvement in endothelial function by ACE-Is contributes to their therapeutic efficacy (Chłopicki and Gryglewski, 2005), presented in the current study findings of endothelial profile of MNA being similar to ACE-I (perindopril) in in vivo settings bring important novel perspectives to understand therapeutic efficacy of MNA (Gebicki et al, 2003; Wozniacka et al, 2005; Chlopicki et al, 2007; Bartuś et al, 2008; Bryniarski et al, 2008; Brzozowski et al, 2008; Watała et al, 2009; Sternak et al, 2010; Przyborowski et al, 2015; Blazejczyk et al, 2016; Jakubowski et al, 2016; Mateuszuk et al, 2016). Moreover, our approach for the in vivo assessment of endothelial phenotype based on a retrospectively self-gated 3D gradient-echo sequence, MRI-based technique, concomitant with the biochemical assays of two important systems of endothelial regulation, ACE/Ang-II-ACE2/Ang-(1–7) and L -Arg/ADMA, proves to be a useful tool for the in vivo endothelial profiling of compounds to demonstrate convincingly their beneficial effects on endothelial function.…”

Section: Resultsmentioning

confidence: 77%

“…Furthermore, MNA can improve endurance exercise capacity in mice with diabetes, and may decrease the cardiovascular risk of exercise (Przyborowski et al, 2015). MNA was demonstrated to have hepatoprotective activity against concanavalin A-induced liver injury through the downregulation of IL-4 and TNF-α signaling (Sternak et al, 2010; Jakubowski et al, 2016), and to inhibit metastasis formation in a murine model of metastatic mammary gland cancer (4T1) in BALB/c mice (Blazejczyk et al, 2016). Interestingly, 1-MNA has also been shown to restore endothelial function in diabetic hypertriglycemic rats (Bartuś et al, 2008) analyzed ex vivo in isolated aorta, suggesting that the improvement in endothelial function may represent an important target of MNA activity and may explain therapeutic efficacy of MNA in various diseases including diabetes (Watała et al, 2009) and atherosclerosis (Mateuszuk et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2017

Self Cite

View full text Add to dashboard Cite

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 (Ang) -converting enzyme (ACE) 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/Ang II-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 (100 mg/kg/day) or perindopril (10 mg/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 twofold 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 (100 mg/kg/day) displayed a similar profile of vasoprotective effect as 2-month treatment with perindopril (10 mg/kg/day): i.e., the improvement in endothelial function that was associated with the beneficial changes in ACE/Ang II-ACE2/Ang (1–7) balance and in L-arginine/ADMA ratio in plasma.

show abstract

“…Mechanistically, increasing NNMT expression or 1-MNA levels stabilizes the sirtuin 1 protein, an effect that is required for its metabolic benefits (36). Increased NNMT expression and 1-MNA release have been reported in humans and rodent models of inflammation, including those involving Con Ainduced acute liver injury and pulmonary hypertension (37)(38)(39), indicating a protective role for NNMT in compensating for inflammation. We demonstrated that increased NNMT expression in the liver following DSS-Con A administration was abrogated by gut sterilization, suggesting potential regulation of NNMT expression in the liver by gut microbes.…”

Section: Discussionmentioning

confidence: 99%