Nicotinamide promotes cardiomyocyte derivation and survival through kinase inhibition in human pluripotent stem cells

Nicotinamide, the amide form of Vitamin B3, is a common nutrient supplement that plays important role in human fetal development. Nicotinamide has been widely used in clinical treatments, including the treatment of diseases during pregnancy. However, its impacts during embryogenesis have not been fully understood. In this study, we show that nicotinamide plays multiplex roles in mesoderm differentiation of human embryonic stem cells (hESCs). Nicotinamide promotes cardiomyocyte fate from mesoderm progenitor cells, and suppresses the emergence of other cell types. Independent of its functions in PARP and Sirtuin pathways, nicotinamide modulates differentiation through kinase inhibition. A KINOMEscan assay identifies 14 novel nicotinamide targets among 468 kinase candidates. We demonstrate that nicotinamide promotes cardiomyocyte differentiation through p38 MAP kinase inhibition. Furthermore, we show that nicotinamide enhances cardiomyocyte survival as a Rho-associated protein kinase (ROCK) inhibitor. This study reveals nicotinamide as a pleiotropic molecule that promotes the derivation and survival of cardiomyocytes, and it could become a useful tool for cardiomyocyte production for regenerative medicine. It also provides a theoretical foundation for physicians when nicotinamide is considered for treatments for pregnant women.

Topical Delivery of Niacinamide: Influence of Binary and Ternary Solvent Systems

Niacinamide (NIA) is the amide form of vitamin B3 and has been widely used in pharmaceutical and personal care formulations. Previously, we reported a comparative study of NIA permeation from neat solvents using the Skin Parallel Artificial Membrane Permeability Assay (PAMPA) and mammalian skin. A good correlation between NIA permeation in the different models was found. In the present work, ten binary and ternary systems were evaluated for their ability to promote NIA delivery in the Skin PAMPA model, porcine skin and human epidermis. Penetration enhancement was evident for binary systems composed of propylene glycol and fatty acids in human skin studies. However, propylene glycol and oleic acid did not promote enhancement of NIA compared with other systems in the Skin PAMPA model. A good correlation was obtained for permeation data from Skin PAMPA and porcine skin. However, data from the Skin PAMPA model and from human skin could only be correlated when the PG-fatty acid systems were excluded. These findings add to our knowledge of the potential applications of Skin PAMPA for screening dermal/transdermal preparations.

The Effects of a Novel Series of KTTKS Analogues on Cytotoxicity and Proteolytic Activity

KTTKS is a matrikine that originates from the proteolytic hydrolysis of collagen. This peptide stimulates ECM production and types I and III collagen expression in vitro. A more stable form of KTTKS is pal-KTTKS, known as Matrixyl® or palmitoyl pentapeptide-3. A series of novel pentapeptides, analogues of KTTKS with the general formula X-KTTKS-OH(NH2), where X = acetyl, lipoyl, palmitoyl residues, was designed and synthesized. Their effect on amidolytic activity of urokinase, thrombin, trypsin, plasmin, t-PA, and kallikrein were tested. Cytotoxic tests on fibroblasts, as well as collagen and DNA biosynthesis tests for selected peptides, were also carried out. The test results showed that the most active plasmin inhibitors were palmitoyl peptides, whether in acid or amide form. No biological effects of lysine modification to arginine in the synthesized peptides were found. None of the synthesized peptides was not cytotoxic on fibroblasts, and three of them showed cell growth. These three compounds showed no concentration-activity relationship in the collagen and DNA biosynthesis assays.

One-pot Synthesis of Pyrazolone Sulfones by Iodine-catalyzed Sulfenylation of Pyrazolones with Aryl Sulfonyl Hydrazides Followed by Oxidation in Water

Aim and Objective: Pyrazolone sulfones have been reported to exhibit herbicidal and antibacterial activities. In spite of their good bioactivities, only a few methods have been developed to prepare pyrazolone sulfones. However, the substrate scope of these methods is limited. Moreover, the direct sulfonylation of pyrazolone by aryl sulfonyl chloride failed to give pyrazolone sulfones. Thus, developing a more efficient method to synthesize pyrazolone sulfones is very important. Materials and Method: Pyrazolone, aryl sulphonyl hydrazide, iodine, p-toluenesulphonic acid and water were mixed in a sealed tube, which was heated to 100°C for 12 hours. The mixture was cooled to 0°C and m-CPBA was added in batches. The mixture was allowed to stir for 30 min at room temperature. The crude product was purified by silica gel column chromatography to afford sulfuryl pyrazolone. Results: In all cases, the sulfenylation products were formed smoothly under the optimized reaction conditions, and were then oxidized to the corresponding sulfones in good yields by 3-chloroperoxybenzoic acid (m-CPBA) in water. Single crystal X-ray analysis of pyrazolone sulfone 4aa showed that the major tautomer of pyrazolone sulfones was the amide form instead of the enol form observed for pyrazolone thioethers. Moreover, the C=N double bond isomerized to form an α,β-unsaturated C=C double bond. Conclusion: An efficient method to synthesize pyrazolone thioethers by iodine-catalyzed sulfenylation of pyrazolones with aryl sulfonyl hydrazides in water was developed. Moreover, this method was employed to synthesize pyrazolone sulfones in one-pot by subsequent sulfenylation and oxidation reactions.

Studying the Specific Activity of the Amide Form of HLDF-6 Peptide using the Transgenic Model of Alzheimer’s Disease

The neuroprotective and nootropic activities of the amide form (AF) of the HLDF-6 peptide (TGENHR-NH2 ) were studied in transgenic mice of the B6C3-Tg(APPswe,PSEN1de9)85Dbo (Tg+) line (the animal model of familial Alzheimers disease (AD)). The study was performed in 4 mouse groups: group 1 (study group): Tg+ mice intranasally injected with the peptide at a dose of 250 g/kg; group 2 (active control): Tg+ mice intranasally injected with normal saline; group 3 (control 1): Tg- mice; and group 4 (control 2): C57Bl/6 mice. The cognitive functions were evaluated using three tests: the novel object recognition test, the conditioned passive avoidance task, and the Morris water maze. The results testify to the fact that the pharmaceutical substance (PhS) based on the AF of HLDF-6 peptide at a dose of 250 g/kg administered intranasally efficiently restores the disturbed cognitive functions in transgenic mice. These results are fully consistent with the data obtained in animal models of Alzheimers disease induced by the injection of the beta-amyloid (A) fragment 25-35 into the giant-cell nucleus basalis of Meynert or by co-injection of the A fragment 25-35 and ibotenic acid into the hippocampus, and the model of ischemia stroke (chronic bilateral occlusion of carotids, 2VO). According to the overall results, PhS based on AF HLDF-6 was chosen as an object for further investigation; the dose of 250 g/kg was used as an effective therapeutic dose. Intranasal administration was the route for delivery.

A Model Study on the Possible Effects of an External Electrical Field on Enzymes Having Dinuclear Iron Cluster [2Fe-2S]

Hydrogenases which catalyze the H2↔ 2H++ 2e−reaction are metalloenzymes that can be divided into two classes, the NiFe and Fe enzymes, on the basis of their metal content. Iron-sulfur clusters [2Fe-2S] and [4Fe-4S] are common in ironhydrogenases. In the present model study, [2Fe-2S] cluster has been considered to visualize the effect of external electric field on various quantum chemical properties of it. In the model, all the cysteinyl residues are in the amide form. The PM3 type semiempirical calculations have been performed for the geometry optimization of the model structure in the absence and presence of the external field. Then, single point DFT calculations (B3LYP/6-31+G(d)) have been carried out. Depending on the direction of the field, the chemical reactivity of the model enzyme varies which suggests that an external electric field could, under proper conditions, improve the enzymatic hydrogen production.

Role of Nicotinamide in DNA Damage, Mutagenesis, and DNA Repair

Nicotinamide is a water-soluble amide form of niacin (nicotinic acid or vitamin B3). Both niacin and nicotinamide are widely available in plant and animal foods, and niacin can also be endogenously synthesized in the liver from dietary tryptophan. Nicotinamide is also commercially available in vitamin supplements and in a range of cosmetic, hair, and skin preparations. Nicotinamide is the primary precursor of nicotinamide adenine dinucleotide (NAD+), an essential coenzyme in ATP production and the sole substrate of the nuclear enzyme poly-ADP-ribose polymerase-1 (PARP-1). Numerousin vitroandin vivostudies have clearly shown that PARP-1 and NAD+status influence cellular responses to genotoxicity which can lead to mutagenesis and cancer formation. This paper will examine the role of nicotinamide in the protection from carcinogenesis, DNA repair, and maintenance of genomic stability.

Preparation, Investigation and Theoretical Study of α-chloroacetamide-N-(p-substituted) phenyl

Six new compounds of α-chloroacetamide-N-(p-substituted) phenyl of general formula ClCH2CONHPhX; where X = H, Me, OMe, Br, Cl and NO2 have been prepared and investigated spectroscopically and theoretically. AM1 and PM3 semi empirical methods were confirmed that compounds existed as amide form. Keywords: IR; 13CNMR; α-chloroacetamide-(N-P-X) phenyl; Correlation analysis; AM1 semi-empirical calculation.© 2009 JSR Publications. ISSN: 2070-0237 (Print); 2070-0245 (Online). All rights reserved. DOI: 10.3329/jsr.v1i3.2301 J. Sci. Res. 1 (3), 576-582 (2009)

N-(Benzothiazol-2-yl)-3-chlorobenzamide

The title molecule, C14H9ClN2OS, exists in the solid state in its amide form with a typical C=O bond length, as well as shortened C—N bonds. The plane containing the HNCO atoms subtends dihedral angles of 12.3 (4) and 8.1 (3)° with the planes of the phenyl ring and benzothiazole group, respectively, whereas the dihedral angle between the planes of the phenyl ring and the benzothiazole group is 5.96 (6)°. In the crystal, molecules form intermolecular N—H...N hydrogen bonds, generating independent scissor-likeR22(8) dimers.

Molecular and Crystal Structure of Benzohydroxamic Acid and Its Ring-Substituted Derivatives

Crystal structure of benzohydroxamic acid and its ring-substituted derivatives RC6H4C(O)NHOH (R = 4-Me, 4-NO2, 4-Cl, 3-Cl and 2-Cl) was determined by single-crystal X-ray diffraction. In all the compounds, the hydroxamic group is in the planar amide form and the structures differ mainly in the tilt of the aromatic and hydroxamic acid planes. For the 2-chloro derivative, the dihedral angle of the two planes is 46.1° which corresponds to the intramolecular van der Waals contact of the ortho-substituents. In other compounds, the tilt originates from intermolecular hydrogen bonding and varies between 3.5 and 22.0°; four crystallographically independent molecules present in the structure of benzohydroxamic acid also differ significantly in this tilt, as well as three independent molecules of the 4-nitro derivative do. Although there are only two types of hydrogen bonding in all the compounds, a short one between OH and O-N and a second longer between NH and O=C, bonded network in the crystal is of three different types. In unsubstituted acid, its 4-Me, 4-Cl and 3-Cl derivative, the molecules are assembled into hydrogen-bonded layers stacked loosely along the largest cell parameter. As a result of the large tilt of the molecular planes in the 2-Cl compound, its molecules are linked into chains with unusual, strongly bent orientation of the aromatic groups. The self-assembly of the remaining 4-nitro compound is quite unique, consisting of pseudohexagonal, partly interpenetrating stacks. In several cases, the hydrogen bonding is supported by π-interaction of the aromatic rings.