Structural dynamics and anti-biofilm screening of novel imidazole derivative to explore their anti-biofilm inhibition mechanism against Pseudomonas Aeruginosa.

The biofilm formation is still prevalent mechanism of developing the drug resistance in the Pseudomonas aeruginosa, gram-negative bacteria, known for its major role in nosocomial, ventilator-associated pneumonia (VAP), lung infections and catheter-associated urinary tract infections. As best of our knowledge, current study first time reports the most potent inhibitors of LasR, a transcriptional activator of biofilm and virulence regulating genes in, Pseudomonas aeruginosa LasR, utilizing newly functionalized imidazoles (5a-d), synthesized via 1,3-dipolar cycloaddition using click approach. The synthesized ligands were characterized through Mass Spectrometry and 1H NMR. The binding potency and mode of biding of ligands. Quantum Mechanical(QM) methods were utilized to investigate the electronic basis, HOMO/LUMO and dipole moment of the geometry of the ligands for their binding potency. Dynamics cross correlation matrix (DCCMs) and protein surface analysis were further utilized to explore the structural dynamics of the protein. Free energy of binding of ligands and protein were further estimated using Molecular Mechanical Energies with the Poisson-Boltzmann surface area (MMPBSA) method. Molecular Docking studies revealed significant negative binding energies (5a - 10.33, 5b -10.09, 5c - 10.11, and 5d -8.33 KJ/mol). HOMO/LUMO and potential energy surface map estimation showed the ligands(5a) with lower energy gaps and larger dipole moments had relatively larger binding potency. The significant change in the structural dynamics of LasR protein due to complex formation with newlyfunctionalized imidazoles ligands. Hydrogen bond surface analysis followed by MMPBSA calculations of free energy of binding further complemented the Molecular docking revelations showing the specifically ligand (5a) having the relatively higher energy of binding(-65.22kj/mol).Communicated by Ramaswamy H. Sarma.

Molecular marker identification, antioxidant, antinociceptive, and anti-inflammatory responsiveness of malonic acid capped silver nanoparticle.

Nano-sized silver has drawn a great deal of attention in the field of health sciences owing to its remarkable therapeutic applications. Interestingly, the method applied to synthesize nanoparticles and the choice of reagents considerably influence their therapeutic potential and toxicities. Current research has explored the toxicity, anti-inflammatory, antinociceptive, and antioxidant responses of the malonic acid-capped silver nanoparticles (MA-AgNPs (C) by using sodium borohydride as a reducing agent at low temperatures by employing both in vitro and in vivo approaches. Furthermore, it has highlighted the synergistic effect of these novel compounds with conventional anti-inflammatory therapeutic agents. Acute and sub-acute toxicity analysis performed following OECD guidelines showed that the studied MA-AgNPs (C) are safer, and prominent toxic signs have not been detected at the highest studied dose of 2,000 mg/kg. Cytotoxicity evaluation through brine shrimp lethality revealed 20% lethality at the highest concentration of 169.8 µg/mL. Significantly, positive anti-inflammatory and analgesic responses alone as well as synergism with the standard were identified through in vitro as well as in vivo methods which were more potent at a lower dose (200 mg/kg). Notably synergistic outcomes were more pronounced than individual ones, indicating their prominent effect as a feasible drug delivery system. IL-6 and TNF-α assessment in excised paw tissue through RTPCR technique further supported their anti-inflammatory potential. DPPH assay revealed eminent in vitro antioxidant activity which was further corroborated by in vivo antioxidant assessment through evaluation of SOD in excised paw tissue.

Antibacterial, antifungal and enzymatic activities of azithromycin-heavy metal complexes: Newly synthesized and characterized.

As part of our continuous research to understand the interaction mechanism of drug and metallo-elements, heavy metal complexes of azithromycin (AZI) were synthesized with arsenic oxide, lead carbonate and silver chloride salts in molar ratio of 2: 1 (L: M). Synthesized heavy metal complexes have shown good percent yield and characterized through spectroscopic parameters including UV-Visible, TLC, FT-IR, NMR and elemental analysis (CHN). Spectroscopic characterization reveals the binding of ligand AZI with heavy metals in bi-dentate manner involving the hydroxide and 9a-NCH3 group of the aglycone ring of AZI. These newly synthesized heavy metal complexes were evaluated for their antimicrobial response against selected gram positive and gram negative organisms and antifungal species. It was noted that all newly synthesized complexes exhibits increased activity against B.subtilus whereas, AZI itself didn't show any activity, while synthesized complexes have low to moderate response against all the studied organisms. Complex A-M12 possess greater enzymatic response against both urease and alpha chymotrypsin among all the studied complexes. Results obtained were then statistically analyzed through one way ANOVA and Dunnett's test by using SPSS version 20.0 suggesting the significant response of complexes against selected organisms.

Effect of iron overload on renal functions and oxidative stress in beta thalassemia patients.

OBJECTIVES: To check the amount of cellular damage caused by serial transfusions of blood in thalassemia patients.  Methods: A cross-sectional study was conducted in the University of Lahore, Lahore, Pakistan between August 2012 and December 2012. A total of 43 thalassemia patients underwent at least 10 blood transfusions. Comprehensive biochemical analysis of blood was performed to record the levels of creatinine, urea, uric acid, albumin, liver function tests, malondialdehyde (MDA), and ferritin.  Results: Serum creatinine (0.732±0.23mg/dl) and uric acid (6.7±0.94mg/dl, p less than 0.05) were significantly higher in patient groups as compared with the control. Ferritin levels were significantly higher in patients as compared with the control (3103.9±1747.4, p less than 0.05). Hemoglobin levels were observed in controls 14±1.3g/dl and in patients 7.1±1.03g/dl. No clear relationship exists between age and hematological parameters of thalassemic patients. Serum ferritin level is positively related with serum alanine transaminase, aspartate aminotransferase, and alkaline phosphatase and MDA (p less than 0.05).  Conclusion: Serum MDA and serum ferritin of patients (r=0.593, p less than 0.05) reflects that both are crucial parameters estimating the cellular damage in patients suffering from thalassemia.

The role of epigenetics in personalized medicine: challenges and opportunities.

Epigenetic alterations are considered to be very influential in both the normal and disease states of an organism. These alterations include methylation, acetylation, phosphorylation, and ubiquitylation of DNA and histone proteins (nucleosomes) as well as chromatin remodeling. Many diseases, such as cancers and neurodegenerative disorders, are often associated with epigenetic alterations. DNA methylation is one important modification that leads to disease. Standard therapies are given to patients; however, few patients respond to these drugs, because of various molecular alterations in their cells, which may be partially due to genetic heterogeneity and epigenetic alterations. To realize the promise of personalized medicine, both genetic and epigenetic diagnostic testing will be required. This review will discuss the advances that have been made as well as the challenges for the future.

Resistance to foliage feeding aphid in wheat.

Experimental trials were conducted at Integrated Pest Management Programme, National Agriculture Research Centre Islamabad, to evaluate the resistance of host plants (cereals) against Rhopalosiphum padi (L.). For evaluation of susceptibility, twenty varieties/-advanced lines of National Uniform Wheat Yield Trails (NUWYT) Normal (N) of year 2004-2005 were used. In seedling bulk tests varieties/advanced lines were grouped into three categories resistant, moderately resistant and susceptible. Data from seedling bulk tests showed that DN-47 and PR 87 lines of wheat were resistant to aphid as compared to the other varieties/-advanced lines. In antixenosis tests varieties/-advanced lines were grouped into three categories, least preferred, moderately preferred, highly preferred. Lines V-01180, DN-47 and PR-84 were least preferred, sixteen varieties/-advanced lines were moderately preferred and only one variety V-9021 was found to be highly preferred.