Background: Leishmaniasis is caused by a protozoan parasite, Leishmania. It is common in more than 98 countries throughout the world. Due to insufficient availability of antileishmanial chemotherapeutics, it is an urgent need to search for new molecules which have better efficacy, low toxicity and are available at low cost. Objectives: There is a high rate of diabetic cases throughout the world that is why we planned to test the antileishmanial activity of glyburide, an effective sugar lowering drug used for the treatment of diabetes. In this study, glyburide showed a significant decrease in the parasite growth and survival in vitro in a dose-dependent manner. Methods: Anti-leishmanial activity of glyburide was checked by culturing Leishmania donovani promastigotes in the presence of glyburide in a dose and time dependent manner. Docking study against Leishmania donovani-Trypanothione synthetase (LdTrySyn) protein was performed using Autodock Vina tool. Results: Growth reversibility assay shows that growth of treated parasite was not reversed when transferred to fresh culture media after 7 days. Moreover, docking studies show efficient interactions of glyburide with key residues in the catalytic site of Leishmania donovani- Trypanothione synthetase (LdTrySyn), a very important leishmanial enzyme involved in parasite’s survival by detoxification of Nitric Oxide (NO) species, generated by the mammalian host as a defense molecule. Thus this study proves that the drug-repurposing is a beneficial strategy for identification of new and potent antileishmanial molecules. Conclusion: The results suggest that glyburide binds to LdTrySyn and inhibits its activity which further leads to the altered parasite morphology and inhibition of parasite growth. Glyburide may also be used in combination with other anti-leishmanial drugs to potentiate the response of the chemotherapy. Overall this study provides information about combination therapy as well as a single drug treatment for the infected patients suffering from diabetes. This study also provides raw information for further in vivo disease model studies to confirm the hypothesis.
A statistical multi-step self-consistent (SMSSC) micromechanical model for predicting elastic and plastic properties of a three-dimensional Representative Volume Element (RVE) is proposed in this research. A body with randomly distributed rough penny-shaped microcracks is considered for the first time in which the distribution of cracks is included through different well-known statistical distributions. Initially, the solution for a rough cohesive penny-shaped crack is developed, and the relationship between crack nominal length and roughness is derived. Consequently, Crack Opening Displacement (COD) and the corresponding volume crack opening are calculated as a function of surface roughness. Next, the SMSSC is used to study the effects of nominal crack length distribution on a fractured medium's mechanical properties with a known statistical distribution of crack sizes. This is done by determining the energy release and evaluating its share in material degradation (elastic, plastic). The elastic properties calculated using SMSSC indicated that the fractality of crack trajectories leads to lower values of volume crack opening and, consequently, resulted in a lower level of stiffness degradation compared with previous smooth crack approximations. It is also reached that the statistical distribution of rough cracks influences the mechanical properties due to the interrelation between length and roughness. Regarding the plastic behavior, the proposed micromechanical methodology is implemented to construct a capped pressure-sensitive yielding potential function that explicitly highlights the influence of crack size statistical distribution on the yielding of cracked solids. It is evident that the statistical distribution of crack sizes which are interrelated with crack roughness, can significantly alter the corresponding yield surface of fractured media.
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