Inhibition of Aβ(1-42)Oligomerization, Fibrillization and Acetylcholinesterase Activity by Some Anti-Inflammatory Drugs: An in vitro Study.

BACKGROUND: Number of contradictory reports are available on the effects of antiinflammatory drugs on Alzheimer's disease (AD) including beneficial, adverse and stage dependent effects. We provide insights of the effects exerted by some anti-inflammatory drugs on the chemistry of AD. METHODS: Three different doses of dexamethasone (0.015, 0.030, 0.060 µM), piroxicam (5, 7.5, 10 µM), indomethacin (1, 1.25, 1.50 µM), diclofenac (0.6, 0.8, 1.0 µM), aspirin (90, 120, 150 µM) and celecoxib (30, 45, 60 µM) were used. Rivastigmine, methylene blue and butylated hydroxyanisole were used as standard drug, oligomerization inhibitor and antioxidant, respectively. Oligomerization and fibrillization reactions were performed using Aß1-42 peptides. Results-Indomethacin and aspirin mainly inhibited oligomerization, while rivastigmine and piroxicam inhibited fibrillization. Diclofenac and celecoxib inhibited both oligomerization and fibrillization almost equally. Dexamethasone showed poor efficiency on both the processes, but exert comparably more inhibition of oligomerization than fibrillization. Inhibition of acetylcholinesterase activity was also potent and was in the following order: celecoxib> piroxicam> diclofenac> aspirin> indomethacin> dexamethasone. Strong radical scavenging (More than 50%) activity was showed by indomethacin and aspirin for NO radicals. CONCLUSION: Present study consistently revealed that anti-inflammatory drugs have potential to Modulate chemistry of AD progression. Inclusion of anti-inflammatory drugs in low doses along with routine therapies may provide therapeutically and economically more efficient therapies for AD. However, further studies are warranted, because the overall therapeutic effect seems to be the function of stage of disease, dose of drug, main underlying mechanism of action(s).

Bioconversion of 16-dehydropregnenolone Acetate to Exclusively 4-androstene-3,17-dione by Delftia acidovorans MTCC 3363.

Delftia acidovorans MTCC 3363 was found to convert 16-dehydropregnenolone acetate (16-DPA) exclusively to 4-androstene-3, 17-dione (AD). Addition of 9α-hydroxylase inhibitors was not required for preventing the accumulation of byproducts. The effect of pH, temperature, substrate concentration, surfactants and carrier solvents on this bioconversion has been studied. 16-DPA was maximally converted in buffered medium at pH 7.0, at temperature 30°C and 0.5 mg ml-1 substrate concentration. Detergent addition and temperature above 35°C had deleterious effect on bioconversion. Dioxan was found to be the best carrier solvent for biotransformation of 16-DPA to AD.

Virtual Screening Approaches in Identification of Bioactive Compounds Akin to Delphinidin as Potential HER2 Inhibitors for the Treatment of Breast Cancer.

Small molecule tyrosine kinase inhibitors targeting HER 2 receptors have emerged as an important therapeutic approach in inhibition of downstream proliferation and survival signals for the treatment of breast cancers. Recent drug discovery efforts have demonstrated that naturally occurring polyphenolic compounds like delphinidin have potential to inhibit proliferation and promote apoptosis of breast cancer cells by targeting HER2 receptors. While delphinidin may thus reduce tumour size, it is associated with serious side effects like dysphonia. Owing to the narrow therapeutic window of delphinidin, the present study aimed to identify high affinity compounds targeting HER2 with safer pharmacological profiles than delphinidin through virtual screening approaches. Delphinidin served as the query parent for identification of structurally similar compounds by Tanimoto-based similarity searching with a threshold of 95% against the PubChem database. The compounds retrieved were further subjected to Lipinski and Verber's filters to obtain drug like agents, then further filtered by diversity based screens with a cut off of 0.6. The compound with Pubchem ID: 91596862 was identified to have higher affinity than its parent. In addition it also proved to be non-toxic with a better ADMET profile and higher kinase activity. The compound identified in the study can be put to further in vitro drug testing to complement the present study.

Structural basis for the in vitro known acyl-depsipeptide 2 (ADEP2) inhibition to Clp 2 protease from Mycobacterium tuberculosis.

Inhibition of Mycobacterium tuberculosis Clp 2 protease has emerged as an attractive therapeutic option for treatment. Acyldepsipeptides (ADEPs) is known as an inhibitor for Clp 2 protease. Therefore, it is of interest to document its affinity, enzyme activity and ADME profiles. We report the predicted binding affinity of all known Clp 2 inhibitors like IDR-10001 and IDR-10011 against Clp2 protease using MolDock algorithm aided molecular docking. The predicted activity (using Molinspiration server) and ADMET properties (AdmetSAR server) were estimated for these compounds. This data suggest ADEP2 having improved binding features with Mtb Clp 2 having acceptable ADMET properties. This is in agreement with known in vitro data for ADEP2 inhibition with Mtb Clp 2 protease.

Anti-Inflammatory Role of Thyroid Hormones on Rat Air Pouch Model of Inflammation.

BACKGROUND: Many studies showed anti-inflammatory potential of thyroid hormones, but no direct report available showing influence of thyroid hormones on inflammation state. Therefore, in present study anti-inflammatory and antioxidative role of thyroid hormones being evaluated on rat air pouch model of inflammation. METHODS: Reference doses of both the thyroid hormones triiodothyronine (T3) and thyroxine (T4) were administered to rat airpouches. Air pouch model was developed by injecting air into intra-scapular region of animals, followed by carrageenan administration (AP+C). Control animals injected only with air (AP). RESULTS: In AP+C, group an increase was observed in exudate levels of TNF-α, total leukocytes, polymophonuclear cells and mononuclear cells. An increase was also observed in exudates and tissue lipid peroxidation, nitrite and reduced glutathione. These changes were reverted back by the administration of indomethacin (I) or T3or T4. However, effect was more pronounced in case of T3, as compared to other groups on most of the studied parameters. Histopathological changes were also observed in AP+C group, as compared to AP alone and these alterations were also normalized by the administration of I or T3 or T4. In silico interaction of both the thyroid hormones with cyclooxygenase (COX-2) was studied and compared with standard drugs indomethacin and celecoxib. CONCLUSION: We conclude thyroid hormones have anti-inflammatory potential i.e. mainly mediated through their structural similarity with anti-inflammatory drugs.

Molecular docking approaches in identification of High affinity inhibitors of Human SMO receptor.

Inappropriate activation of the Hh signaling pathway has been implicated in the development of several types of cancers including prostate, lung, pancreas, breast, brain and skin. Present study identified the binding affinities of eight established inhibitors viz., Cyclopamine, Saridegib, Itraconazole, LDE-225, TAK-441, BMS-833923 (XL139), PF-04449913 and Vismodegib targeting SMO receptor - a candidate protein involved in hedgehog pathway and sought to identify the best amongst the established inhibitors through by molecular docking. Exelxis® BMS 833923 (XL 139) demonstrated superior binding affinity aided by MolDock scoring docking algorithm. Further BMS 833923 (XL 139) was evaluated for pharmacophoric features which revealed appreciable ligand receptor interactions.

Combined effects of quercetin and atenolol in reducing isoproterenol-induced cardiotoxicity in rats: possible mediation through scavenging free radicals.

In this investigation, combined effects of quercetin and atenolol in the regulation of isoproterenol (ISO)-induced cardiotoxicity have been evaluated in rats. While ISO administration increased the levels of serum creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH) and glutamate pyruvate transaminase (SGPT) as well as cardiac malondialdehyde (MDA); it reduced the activities of superoxide dismutase, catalase, glutathione peroxidase and the level of reduced glutathione. ISO-induced rats also exhibited ST-segment elevation and tachycardia. Oral administration of atenolol (6 mg/kg) and quercetin (5 mg/kg), along with ISO (5 mg/kg, subcutaneously) every day for 10 days markedly reduced the serum CK-MB, LDH and SGPT levels. Concomitantly the test drugs improved the status of antioxidative enzymes, decreased the cardiac MDA and nearly normalized the electrocardiogram. Electron paramagnetic resonance study also revealed a decrease in 5,5'-dimethyl-1-pyroline-N-oxide-hydroxyl radicals signal intensity when atenolol and quercetin were administered together to ISO-treated rats. In conclusion, the combined treatment of atenolol and quercetin appears to produce a better cardioprotective effect in ISO-induced animals as compared to their individual treatments, and possibly the beneficial actions are associated with the free radical scavenging action of quercetin.

Update of extracellular matrix, its receptors, and cell adhesion molecules in mammalian nephrogenesis.

One of the hallmarks of mammalian nephrogenesis includes a mesenchymal-epithelial transition that is accomplished by intercalation of the ureteric bud, an epithelium-lined tubelike structure, into an undifferentiated mesenchyme, and the latter then undergoes an inductive transformation and differentiates into an epithelial phenotype. At the same time, the differentiating mesenchyme reciprocates by inducing branching morphogenesis of the ureteric bud, which forms a treelike structure with dichotomous iterations. These reciprocal inductive interactions lead to the development of a functioning nephron unit made up of a glomerulus and proximal and distal tubules. The inductive interactions and differentiation events are modulated by a number of transcription factors, protooncogenes, and growth factors and their receptors, which regulate the expression of target morphogenetic modulators including the ECM, integrin receptors, and cell adhesion molecules. These target macromolecules exhibit spatiotemporal and stage-specific developmental regulation in the metanephros. The ECM molecules expressed at the epithelial-mesenchymal interface are perhaps the most relevant and conducive to the paracrine-juxtacrine interactions in a scenario where the ligand is expressed in the mesenchyme while the receptor is located in the ureteric bud epithelium or vice versa. In addition, expression of the target ECM macromolecules is regulated by matrix metalloproteinases and their inhibitors to generate a concentration gradient at the interface to further propel epithelial-mesenchymal interactions so that nephrogenesis can proceed seamlessly. In this review, we discuss and update our current understanding of the role of the ECM and related macromolecules with respect to metanephric development.

Sirenomelia.

Sirenomelia is a rare congenital anomaly with incidence of 1.5-4.2 per 100,000 births. Vascular steal phenomenon, posterior axial mesodermal defect or teratogenic defects have been implied in its pathogenesis. The authors present two cases with associated upper limb involvement and vertebral defects and complete absence of one lower limb bones in one case. Autopsy revealed abnormalities in internal organs. Both cases were associated with single umbilical artery and severe oligohyramnios. Sirenomelia should be suspected in antenatal period in cases presenting with severe oligohydramnios and intrauterine growth retardation for a early diagnosis and appropriate management of pregnancy.

Mixed culture bioconversion of 16-dehydropregnenolone acetate to androsta-1,4-diene-3,17-dione: optimization of parameters.

Bioconversion of 16-dehydropregnenolone acetate (16-DPA) to androsta-1,4-diene-3,17-dione (ADD), an intermediate for the production of female sex hormones, by mixed culture of Pseudomonas diminuta MTCC 3361 and Comamonas acidovorans MTCC 3362 is reported. Various physicochemical parameters for the bioconversion of 16-DPA to ADD have been optimized in shake flask cultures. Nutrient broth inoculated with actively growing co-culture proved ideal for bacterial growth and bioconversion. A temperature range of 35-40 degrees C was most suitable; higher or lower temperatures adversely affected the bioconversion. Dimethylformamide below 2% concentration was the most suitable carrier solvent. Maximum conversion was recorded at 0.5 mg mL(-1) 16-DPA. A pH of 5.0 yielded a peak conversion of 62 mol % in 120 h incubation period. Addition of 9alpha-hydroxylase inhibitors failed to prevent further breakdown of ADD to nonsteroidal products. 16-DPA conversion in a 5 L fermenter followed a similar trend.

Cladosporium bantianum meningitis in a neonate.

Cladosporium bantianum meningitis has been reported mostly in adult farmers between 20 and 30 years of age. We report a 6-day-old male neonate who was admitted with fever, focal seizures and not accepting feeds. Initial investigations suggested a diagnosis of pyogenic meningitis but antibiotic therapy for 14 days did not result in any significant clinical improvement. Repeat CSF examination after 14 days suggested a diagnosis of C. bantianum meningitis which was supported by presence of multiple abscesses in the cerebral cortex on CT scan of the head and confirmed by CSF culture. Clinical response to antifungal therapy remained unsatisfactory.