An analysis of the interactions between folic acid and aromatic guest molecules

The formation of complexes between folate and therapeutic drug molecules is well known. In this work, we attempted to elucidate the role of the aromatic rings of folate and drug molecules in interactions between both of these molecules. A detailed molecular simulation study was carried out to explore the associative behavior of folic acid with phenylalanine and tyrosine, which show fluorescence emission following the excitation of these molecules at 257 nm and 274 nm, respectively. Therefore, studies of fluorescence emission from phenylalanine and tyrosine were performed in this work. The results of these studies indicated that folic acid associates with phenylalanine and tyrosine with binding constants ranging from 1.46 × 10⁴ to 2.66 × 10⁴ M^?1. X-ray diffraction studies suggested that folic acid self-assembly is maintained in the presence of associative interactions of the folic acid with guest molecules. These results demonstrate that the aromatic rings in the structures of the folic acid and the therapeutic drug play an important role in the encapsulation of guest molecules through folate self-assembly.     

Interaction of hematopoietic progenitor kinase 1 and c-Abl tyrosine kinase in response to genotoxic stress

The c-Abl protein tyrosine kinase is activated by certain DNA-damaging agents and regulates induction of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK). The hematopoietic progenitor kinase 1 (HPK1) has also been shown to act upstream to the SAPK/JNK signaling pathway. We report here that exposure of hematopoietic Jurkat T cells to genotoxic agents is associated with activation of HPK1. The results demonstrate that exposure of Jurkat cells to DNA-damaging agents is associated with translocation of active c-Abl from nuclei to cytoplasm and binding of c-Abl to HPK1. Our findings also demonstrate that c-Abl phosphorylates HPK1 in cytoplasm and stimulates HPK1 activity. The functional significance of the c-Abl-HPK1 interaction is supported by the demonstration that this complex regulates SAPK/JNK activation. Overexpression of c-Abl(K-R) inhibits HPK1-induced activation of SAPK/JNK. Conversely, the dominant negative mutant of HPK1 blocks c-Abl-mediated induction of SAPK/JNK. These findings indicate that activation of HPK1 and formation of HPK1/c-Abl complexes are functionally important in the stress response of hematopoietic cells to genotoxic agents.     

Biological and computational studies provide insights into Caesalphinia digyna Rottler stems

Caesalpinia digyna (Rottl.) (Family: Fabaceae) is an essential medicinal plant for it's conventional uses against a kind of human disorders. This research aims to investigate the antidiarrheal, antibacterial and antifungal properties of the methanol extract of the stems extracts of the C. digyna (MECD). The in vivo antidiarrheal activity of the stem extracts were evaluated by using castor oil-induced diarrhea, castor oil-induced enteropooling and charcoal induced intestinal transit in mice model. Besides, in vitro antimicrobial potentiality of MECD was investigated by the disc diffusion method. In silico activity of the isolated compounds were performed by Schrödinger-Maestro (Version 11.1) software. In addition, The ADME/T analysis and PASS prediction were implemented by using pass online tools. In the antidiarrheal investigation, the MECD exhibited a notable inhibition rate in all test approaches which were statistically significant (p < 0.05, p < 0.1, p < 0.01). MECD 400 mg/kg showed the maximum antidiarrheal potency in all the test methods. In vitro antimicrobial analysis unveiled that, MECD revealed higher potentiality against almost all pathogens and indicates dose-dependent activity against almost all the bacteria and fungi. In the case of in silico evaluation of anti-diarrheal, anti-bacterial and anti-fungal activity, all three isolated compounds met the pre-conditions of Lipinski's five rules for drug discovery. Pass predicted study also employed for all compounds. However, The chemical constituents of the C. digyna can be a potent source of anti-diarrheal, anti-bacterial and anti-fungal medicine and further modification and simulation studies are required to establish the effectiveness of bioactive compounds.     

Metabolic modeling of Rosmarinic acid biosynthetic pathway

Rosmarinic acid (RA) is an ester of caffeic acid and 3, 4-dihydroxyphenyllacticacid. It is commonly found in Coleus blumei, Salvia officinalis, Melissa officinalis and Rosmarinus officinalis. The biosynthesis of RA starts with precursor molecules L-phenylalanine and L-tyrosine. Simulation of RA biosynthetic pathway was done using Gepasi Software, includes the reaction kinetics of each step of the pathway and different integration methods such as Euler's method. Optimization of the significant parameters responsible for RA biosynthesis was carried out. As the goal of the work was to increase the productivity of i.e. to maximize the concentration of the RA, the final concentration of RA ([RA]t) was selected as an objective function and selected initial concentration of the Caffeoyl-3'-4'hydroxyphenyllactic acid (3'C4HPLA) as parameter constraint and varied its initial concentration as: 0≤ [3'C4HPLA]i ≤ 0.025. Several optimization methods such as Simulated annealing, Evolutionary algorithms and Genetic algorithms were used to optimize the objective function. After optimization the final concentration of RA was slightly higher (4.566132e-002 mM) than before optimization (4.047119e- 002 mM). On the basis of results obtained, it is clear that 4-hydroxyphenyllactic acid and 3'C4HPLA play major role in the high productivity of the RA.