The combination of multi-approach studies to explore the potential therapeutic mechanisms of imidazole derivatives as an MCF-7 inhibitor in therapeutic strategies.

Breast cancer covers a large area of research because of its prevalence and high frequency all over the world. This study is based on drug discovery against breast cancer from a series of imidazole derivatives. A 3D-QSAR and activity atlas model was developed by exploring the dataset computationally, using the machine learning process of Flare. The dataset of compounds was divided into active and inactive compounds according to their biological and structural similarity with the reference drug. The obtained PLS regression model provided an acceptable r 2 = 0.81 and q2 = 0.51. Protein-ligand interactions of active molecules were shown by molecular docking against six potential targets, namely, TTK, HER2, GR, NUDT5, MTHFS, and NQO2. Then, toxicity risk parameters were evaluated for hit compounds. Finally, after all these screening processes, compound C10 was recognized as the best-hit compound. This study identified a new inhibitor C10 against cancer and provided evidence-based knowledge to discover more analogs.

Effectiveness and Quality of Life with Montelukast in Asthma - A double-blind randomized control trial.

OBJECTIVE: To determine the role of montelukast - a leukotriene receptor antagonist (LTRA) - in improving the quality of life (QOL) and asthma control of adult patients with mild to moderate persistent asthma. METHODS: Randomized, double-blind, placebo-controlled, non-crossover trial was conducted from March 2017 till November 2018 in three hospitals of Karachi and Hyderabad. Adults of age 15 years or more with mild to moderate persistent asthma. Treatment group was administered tablet montelukast 10mg once daily; the other group was given a similar looking placebo; as an adjuvant to the current medication. QOL was assessed with Asthma Quality of Life Questionnaire - Standard (AQLQ-S) before and after the treatment. Asthma control was monitored via Asthma Control Test (ACT). RESULTS: After 4 weeks, the mean ± SD of overall QOL on AQLQ-S improved from 3.74±0.88 to 5.06±0.89 for montelukast group and from 3.58±0.92 to 4.71±0.97 for placebo group (p=0.02). The improvement in sub-domains of symptoms, activity, and emotional functions was not significant; however, the sub-domain "environmental stimuli" significantly improved with 5.06±0.89 for montelukast group and 4.71±0.97 for placebo group (p=0.02). The mean ± SD of ACT, after four weeks, for montelukast group was 18.19±2.91 and for placebo group 17.28±3.36. Only on ACT, Montelukast did not show any statistically insignificant results. CONCLUSION: The role of montelukast in improving QOL of adult patients with mild to moderate persistent asthma is quite beneficial. It improves patient quality of life. It has the ease of once daily oral administration and also eradicates side effects associated with long-term adherence to steroids.

Biological Evaluation of Endothall, a Dicarboxylic Acid Analog of Norcantharidin, and Cantharidin on Oriental Leafworm, Spodoptera litura (Lepidoptera: Noctuidae).

Cantharidin is a highly potent toxin produced by insects belonging to the order Coleoptera and family Meloidae. The insecticidal activity of cantharidin against different orders of insects has been well documented. Although it is highly effective, its extraction and synthesis is very tedious. Consequently, much work is underway to synthesize the bioactive analogs of norcantharidin and study their relative structures. In this study, we investigate the acute and chronic toxicological effects of cantharidin and endothall, an analog of norcantharidin, using an age-stage-based two-sex life table methodology. Results reveal the acute toxicity of these compounds to Spodoptera litura Fabricius (Lepidoptera: Noctuidae), with the LC50 of cantharidin being 2.10 and endothall being 3.72 ppm, after 72 h posttreatment. Although both the compounds negatively affected the intrinsic rate of population increase (r), finite rate of increase (λ), net reproduction rate (R0), mean generation time (T), doubling time (DT), relative fitness (Rf), biotic potential, and longevity, cantharidin was slightly more effective. Among the reproductive parameters, fecundity was severely affected by cantharidin, which reduced offspring to 42 compared to 528 per female in the control cohort. Both cantharidin and endothall caused similar physiological changes such as weight reduction, wing malformation, and pupal deformities. These findings demonstrate that both cantharidin and endothall are highly toxic to S. litura, particularly in their chronic effects on population parameters. This will help us to understand the biological and ecological interactions in agricultural cropping systems and how their application will modify insect herbivory.

Cantharidin Impedes Activity of Glutathione S-Transferase in the Midgut of Helicoverpa armigera Hübner.

Previous investigations have implicated glutathione S-transferases (GSTs) as one of the major reasons for insecticide resistance. Therefore, effectiveness of new candidate compounds depends on their ability to inhibit GSTs to prevent metabolic detoxification by insects. Cantharidin, a terpenoid compound of insect origin, has been developed as a bio-pesticide in China, and proves highly toxic to a wide range of insects, especially lepidopteran. In the present study, we test cantharidin as a model compound for its toxicity, effects on the mRNA transcription of a model Helicoverpa armigera glutathione S-transferase gene (HaGST) and also for its putative inhibitory effect on the catalytic activity of GSTs, both in vivo and in vitro in Helicoverpa armigera, employing molecular and biochemical methods. Bioassay results showed that cantharidin was highly toxic to H. armigera. Real-time qPCR showed down-regulation of the HaGST at the mRNA transcript ranging from 2.5 to 12.5 folds while biochemical assays showed in vivo inhibition of GSTs in midgut and in vitro inhibition of rHaGST. Binding of cantharidin to HaGST was rationalized by homology and molecular docking simulations using a model GST (1PN9) as a template structure. Molecular docking simulations also confirmed accurate docking of the cantharidin molecule to the active site of HaGST impeding its catalytic activity.