scholarly journals Synthesis and in silico screening of a library of β-carboline-containing compounds

2012 ◽  
Vol 8 ◽  
pp. 1048-1058 ◽  
Author(s):  
Kay M Brummond ◽  
John R Goodell ◽  
Matthew G LaPorte ◽  
Lirong Wang ◽  
Xiang-Qun Xie
Keyword(s):  
In Silico ◽  
Therapeutic Potential ◽  
Chemical Properties ◽  
Mitogen Activated Protein Kinase ◽  
In Silico Screening ◽  
Mitogen Activated Protein ◽  
Histone Deacetylase 4 ◽  
Synthetic Intermediates ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

The synthesis of a library of tetrahydro-β-carboline-containing compounds in milligram quantities is described. Among the unique heterocyclic frameworks are twelve tetrahydroindolizinoindoles, six tetrahydrocyclobutanindoloquinolizinones and three tetrahydrocyclopentenoneindolizinoindolones. These compounds were selected from a virtual combinatorial library of 11,478 compounds. Physical chemical properties were calculated and most of them are in accordance with Lipinski’s rules. Virtual docking and ligand-based target evaluations were performed for the β-carboline library compounds and selected synthetic intermediates to assess the therapeutic potential of these small organic molecules. These compounds have been deposited into the NIH Molecular Repository (MLSMR) and may target proteins such as histone deacetylase 4, endothelial nitric oxide synthase, 5-hydroxytryptamine receptor 6 and mitogen-activated protein kinase 1. These in silico screening results aim to add value to the β-carboline library of compounds for those interested in probes of these targets.

scholarly journals Overfeeding during Lactation in Rats is Associated with Cardiovascular Insulin Resistance in the Short-Term

Nutrients ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 549 ◽  
Author(s):  
Daniel González-Hedström ◽  
Lucía Guerra-Menéndez ◽  
Antonio Tejera-Muñoz ◽  
Sara Amor ◽  
María de la Fuente-Fernández ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Transporter ◽  
Mitogen Activated Protein Kinase ◽  
Lactation Period ◽  
Cardiovascular Comorbidities ◽  
Rat Pups ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Childhood obesity is associated with metabolic and cardiovascular comorbidities. The development of these alterations may have its origin in early life stages such as the lactation period through metabolic programming. Insulin resistance is a common complication in obese patients and may be responsible for the cardiovascular alterations associated with this condition. This study analyzed the development of cardiovascular insulin resistance in a rat model of childhood overweight induced by overfeeding during the lactation period. On birth day, litters were divided into twelve (L12) or three pups per mother (L3). Overfed rats showed a lower increase in myocardial contractility in response to insulin perfusion and a reduced insulin-induced vasodilation, suggesting a state of cardiovascular insulin resistance. Vascular insulin resistance was due to decreased activation of phosphoinositide 3-kinase (PI3K)/Akt pathway, whereas cardiac insulin resistance was associated with mitogen-activated protein kinase (MAPK) hyperactivity. Early overfeeding was also associated with a proinflammatory and pro-oxidant state; endothelial dysfunction; decreased release of nitrites and nitrates; and decreased gene expression of insulin receptor (IR), glucose transporter-4 (GLUT-4), and endothelial nitric oxide synthase (eNOS) in response to insulin. In conclusion, overweight induced by lactational overnutrition in rat pups is associated with cardiovascular insulin resistance that could be related to the cardiovascular alterations associated with this condition.

scholarly journals Endothelial nitric oxide synthase is regulated by ERK phosphorylation at Ser602

2014 ◽  
Vol 34 (5) ◽  
Author(s):  
John C. Salerno ◽  
Dipak K. Ghosh ◽  
Raj Razdan ◽  
Katy A. Helms ◽  
Christopher C. Brown ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Nitric Oxide Synthase ◽  
Binding Site ◽  
Endothelial Nitric Oxide Synthase ◽  
Mitogen Activated Protein Kinase ◽  
Erk Phosphorylation ◽  
Mitogen Activated Protein ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

eNOS (endothelial nitric oxide synthase) contains a MAPK (mitogen-activated protein kinase)-binding site associated with a major eNOS control element. Purified ERK (extracellular-signal-regulated kinase) phosphorylates eNOS with a stoichiometry of 2–3 phosphates per eNOS monomer. Phosphorylation decreases NO synthesis and cytochrome c reductase activity. Three sites of phosphorylation were detected by MS. All sites matched the SP and TP MAPK (mitogen-activated protein kinase) phosphorylation motif. Ser602 lies at the N-terminal edge of the 42-residue eNOS AI (autoinhibitory) element. The pentabasic MAPK-binding site lies at the opposite end of the AI, and other critical regulatory features are between them. Thr46 and Ser58 are located in a flexible region associated with the N terminus of the oxygenase domain. In contrast with PKC (protein kinase C), phosphorylation by ERK did not significantly interfere with CaM (calmodulin) binding as analysed by optical biosensing. Instead, ERK phosphorylation favours a state in which FMN and FAD are in close association and prevents conformational changes that expose reduced FMN to acceptors. The close associations between control sites in a few regions of the molecule suggest that control of signal generation is modulated by multiple inputs interacting directly on the surface of eNOS via overlapping binding domains and tightly grouped targets.

Downregulation of human endothelial nitric oxide synthase promoter activity by p38 mitogen-activated protein kinase activation

2006 ◽  
Vol 84 (5) ◽  
pp. 780-789 ◽  
Author(s):  
Feiyue Xing ◽  
Yong Jiang ◽  
Jing Liu ◽  
Kesen Zhao ◽  
Yongyan Mo ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
P38 Mapk ◽  
Endothelial Nitric Oxide Synthase ◽  
Promoter Activity ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Enos Gene ◽  
Mitogen Activated Protein ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Human endothelial nitric oxide synthase (eNOS) plays a crucial role in maintaining blood pressure homeostasis and vascular integrity. eNOS gene expression may be upregulated by a signaling pathway, including PI-3Kγ → Jak2 → MEK1 → ERK1/2 → PP2A. It remains unclear whether other mitogen-activated protein kinase (MAPK) family members, such as JNK, p38 kinase, and ERK5/BMK1, also modulate eNOS gene expression. Our purpose, therefore, is to shed light on the effect of the p38 MAPK signaling pathway on the regulation of eNOS promoter activity. The results showed that a red fluorescent protein reporter gene vector containing the full length of the human eNOS promoter was first successfully constructed, expressing efficiently in ECV304 cells with the characteristics of real time observation. The wild-types of p38α, p38β, p38γ, and p38δ signal molecules all markedly downregulated promoter activity, which could be reversed by their negative mutants, including p38α (AF), p38β (AF), p38γ (AF), and p38δ (AF). Promoter activity was also significantly downregulated by MKK6b (E), an active mutant of an upstream kinase of p38 MAPK. The reduction in promoter activity by p38 MAPK could be blocked by treatment with a p38 MAPK specific inhibitor, SB203580. Moreover, the activation of endogenous p38 MAPK induced by lipopolysaccharide resulted in a prominent reduction in promoter activity. These findings strongly suggest that the activation of the p38 MAPK signaling pathway may be implicated in the downregulation of human eNOS promoter activity.

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