Vijaya Dubey

α-(-)-bisabolol reduces pro-inflammatory cytokine production and ameliorates skin inflammation.

α-(-)-bisabolol is a natural monocyclic sesquiterpene present in the essential oil has generated considerable interest in the chemical and pharmaceutical industries and currently in use in various formulations, mainly in cosmetics. This study was undertaken to evaluate its therapeutic profile against skin inflammation using in-vitro, in-vivo and in-silico assays. Lipopolysachharide (LPS) and 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced production of proinflammatory cytokines (TNF-α and IL-6) in macrophage cells as well as in TPA-induced skin inflammation in mice was significantly inhibited by α-(-)-bisabolol. TPA-induced ear thickness, ear weight and lipid peroxidation and histopathological damage in the ear tissue were also significantly inhibited by topical application of α-(-)-bisabolol in a dose dependent manner. In-vitro and in-vivo toxicity profiles indicate that it is safe for topical application on skin. Molecular docking study also revealed its strong binding affinity to the active site of the pro-inflammatory proteins. These findings suggested that α-(-)-bisabolol may be a useful therapeutic candidate for the treatment of skin inflammation.

Synthesis of cyclic 1,9-acetal derivatives of forskolin and their bioactivity evaluation.

A new series of 1,9-acetals of forskolin were synthesized by treating with aromatic and aliphatic aldehydes using Ceric ammonium nitrate as catalyst and evaluated for anticancer and α-glucosidase inhibition activities. Among the synthesized compounds 2a, 2b and 3a showed potential cytotoxic activity towards human cancer cell lines MCF-7 (Human Breast Adenocarcinoma), MDA-MB (Human Breast Carcinoma), HeLa (Human Cervix Adenocarcinoma), A498 (Human Kidney Carcinoma), K562 (Human Erythromyeloblastoid leukemia), SH-SY5Y (Human Neuroblastoma), Hek293 (Human Embryonic Kidney) and WRL68 (Human Hepatic) with IC50 values ranging between 0.95 and 47.96 μg/ml. Osmotic fragility test revealed compound 3a as non-toxic to human erythrocytes at the tested concentrations of 50 and 100 μg/ml. Compounds 1g (IC50 value 0.76 μg/ml) and 1p (IC50 value 0.74 μg/ml) significantly inhibited α-glucosidase in in vitro system. In silico based docking, ADME and toxicity risk assessment studies also showed discernible α-glucosidase activity for compounds 1g, 1p compared to standard acarbose.

Antiproliferative and antimicrobial efficacy of the compounds isolated from the roots of Oenothera biennis L.

Oenothera biennis L., commonly known as evening primrose, harbours the flavonoids, steroids, tannins, fatty acids and terpenoids responsible for a diverse range of biological activity, such as antitumour, anti‐arthritic and anti‐inflammatory effects. In addition to the previous reports from aerial parts of this plant, studies related to antiproliferative or antimicrobial activity from the roots are warranted.

Synthesis of 3,5-dihydroxy-7,8-dimethoxy-2-(4-methoxyphenyl)benzopyran-4-one derivatives as anticancer agents

Different alkyl amide (15a-l) and alkyl amine (16a-e) derivatives of 7,8-dimethoxy-3-hydroxy-2-(4-methoxyphenyl)benzopyran-4-one were synthesized and evaluated for their anticancer activity against five different cancer cell lines using SRB assay. Compounds 15e, 15i, 15j and 16a-e showed significant anticancer activity within the range of IC50 2.58-34.86μM. The most promising molecule, 16c, was further analyzed for its effect on cell cycle and apoptosis of estrogen receptor positive cancer cells (MCF-7 cells) which showed that 16c triggered apoptosis in MCF-7 cells and arrested cells population at sub-G0 (apoptotic) and G2M phase. In tubulin polymerization assay, 16c interfered with kinetics of tubulin polymerization.

Water Molecules Increases Binding Affinity of Natural PI3Kγ Inhibitors Against Cancer

The PI3K pathway is a signal transduction process including oncogenes and receptor tyrosine kinase regulating cellular functions i.e., survival, protein synthesis, and metabolism. In the present work, we have investigated the role of water molecules on inhibitors binding orientation in crystal structures of PI3K pathway targets using molecular docking approach. AutoDock v4.2 docking software was employed to dock PI3Kγ and its known inhibitors viz., wortmannin, quercetin, myricetin and pyridyl-triazine. Besides, serpentine was also docked on the same binding pocket, subsequently its anticancer activity was evaluated through in vitro experiment. Docking studies have been performed in the presence as well as in absence of water molecules at the binding pocket, and results were compared with crystallographic structural data. The comparison was done on the basis of binding energy, RMSD, inhibition constant (Ki), conserved and bridging water molecules, and found that, while considering water molecules during docking experiments, it increases the binding affinity of PI3K inhibitors.

Rutin restricts hydrogen peroxide-induced alterations by up-regulating the redox-system: An in vitro, in vivo and in silico study

&NA; Rutin, a polyphenolic plant flavonoid, is found in citrus fruits, mulberry, cranberries and buckwheat with reported anti‐diabetic, anti‐fungal, anti‐inflammatory and anti‐bacterial activity. We appraise the effect of rutin on hydrogen peroxide (H2O2) mediated deregulation of antioxidant enzyme activity, non‐enzymatic biomarkers, reactive oxygen species production (in vitro and in vivo) and on echinocyte formation (ex‐vivo). In addition to it the interaction studies (in silico) against targeted enzymes and membrane proteins were also performed. A pre‐treatment with rutin (16.3 &mgr;M) significantly attenuate the altered level of glutathione, sulfhydryl, malondialdehyde and carbonyl content. The activity and expression of catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase and glutathione‐S‐transferase were also decreased significantly (p < 0.01) in presence of H2O2, while pre‐treatment of rutin ameliorates the effect of H2O2. Furthermore, rutin at higher tested concentration protects the morphology of erythrocytes by decreasing the reactive oxygen species level (p < 0.01) as compared to H2O2 treatment. In silico analysis with selected membrane proteins and enzymes revealed that the rutin did not modulate the structure and function of the preferred proteins. In addition, rutin down regulates the inducible nitric oxide synthase expression and up‐regulate the nuclear factor (erythroid‐related factor 2) expression. Moreover, the lower mean erythrocyte fragility values of rutin (0.53 ± 0.024–0.61 ± 0.014) alone or with H2O2 (0.65 ± 0.021) indicate the protection and non‐toxic behaviour. These finding suggests that rutin; a nutritional compound can reduce oxidative stress induced by H2O2 by increasing the expression of Nrf2 and endogenous antioxidant enzymes. Graphical abstract Figure. No Caption available. HighlightsRutin maintains oxidative stress markers and deregulate the expression of iNOS.Rutin exerts its effect by inducing antioxidants levels as well as their mRNA expression.Rutin sustains the fragility of erythrocytes during stress condition.Rutin regulates the ROS level via increasing the expression of Nrf2.

In-silico & In-vitro Identification of Structure-Activity Relationship Pattern of Serpentine & Gallic Acid Targeting PI3Kγ as Potential Anticancer Target

BACKGROUND Natural products showed anticancer activity and often induce apoptosis or autophagy in cancer cells through the PI3K/Akt/mTOR signaling pathways. The potential of natural products as PI3Ks inhibitors has been reported, which suggest PI3Ks a promising anticancer target. Phosphoinositide 3-kinase is a family of related intracellular signal transducer enzymes or lipid kinases that regulate different cellular processes involved in cancer. OBJECTIVE To identify the molecular reason behind the similar target based activity of selected shikimate pathway metabolites on PI3Kγ, a detail structure-activity relationship study was performed. METHOD In the studied work, anticancer potential of plant molecules gallic acid and serpentine was evaluated against PI3Kγ isoform and compared with wortmannin, a steroid metabolite of the fungi and a non-specific covalent known inhibitor of PI3Ks by using in-silico QSAR, docking, ADMET, chemical isolation from plant, NMR and in-vitro activity. RESULTS A predictive QSAR model was developed by applying multiple linear regression which revealed identification of key structural properties regulating the inhibitory activity of serpentine and gallic acid on PI3Kγ. The model exhibited acceptable statistical parameters such as r2 0.76, r2CV 0.72, and q2 0.55. Structural elucidation was done through NMR studies. Predicted activities were further evaluated through in-vitro testing of gallic acid and serpentine targeting PI3Kγ. CONCLUSION The identified chemical features modulating the activity were amide, amine, and secondary amine groups counts, highest occupied molecule orbital (HOMO) energy and valence connectivity index (order 2). In-silico ADME and toxicity risk assessment was done for pharmacokinetic and bioavailability compliance evaluation.

Cathepsin D as a Promising Target for the Discovery of Novel Anticancer Agents

BACKGROUND Cathepsin D (CATD), one of the aspartyl endoproteinase involved in different physiological processes and signaling pathways, is accountable for metabolic breakdown of intracellular proteins, the activation of growth factors, hormones, and precursors of enzyme, the processing of antigens, enzyme inhibitors and activators and the regulation of apoptosis. Implication as a Target: Studies have confirmed the role and significance of CATD in an assortment of pathological conditions like Atherosclerosis, Alzheimer, Cancer, Cardiovascular, Huntington and Parkinson diseases. Amalgamated and veiled as inactive proCATD, it undergoes diverse cleavages to attain a desired conformation in an acidic milieu to act as a functionally active protein. In search of new candidate target (s) for cancer, CATD has attracted a wide group of investigators across the globe and is being recognized as a well-defined marker in cancer especially for breast and hormone-dependent cancer. METHODS In this review, PubMed, Sci-finder and other search engines were used to gather information on Cathepsin D. The necessary and relevant information was thoroughly studied to make the article appropriate to highlight all the aspects related to Cathepsin D and its role in cancer. Findings & Conclusion: The present review illustrates structural, functional and regulatory aspects of CATD in cancer, its significant role in angiogenesis, metastasis, invasion, apoptosis, cell proliferation, and therapeutic potential besides the benefits of targeting CATD by the natural products in cancer chemoprevention.

Rutin protects t-butyl hydroperoxide-induced oxidative impairment via modulating the Nrf-2 and iNOS activity

BACKGROUND Rutin (quercetin-3-O-rutinoside), a flavonoid, is predominantly found in the buckwheat, cranberries, mulberry and citrus fruits. It is used as a restorative in the preparation of herbal medicine, multivitamin and known to reduce the fate of heart attack. HYPOTHESIS We aimed to elucidate whether rutin attenuates oxidative stress and its possible mechanism of action in ameliorating the deleterious effect of t-BHP. We also provide evidence that rutin protects the antioxidant status of erythrocytes and liver via Nrf2 and iNOS pathway from oxidative stress. STUDY DESIGN/METHOD Human erythrocytes and mice liver were used for the evaluation of rutins effect against t-BHP induced oxidative stress. The non-enzymatic (GSH, MDA, -CO, -SH) and enzymatic stress markers (SOD, CAT, GPx, GR and GST) were estimated by the colorimetric method. The level of Nrf2, iNOS, liver marker enzymes, triglycerides, cholesterol, HDL-cholesterol, albumin, BUN was measured using ELISA kits. Reactive oxygen species (ROS) was quantified using flow cytometry and fluorometry. RT-PCR was used for the quantification of Nrf2 and iNOS expression levels in the liver tissue of mice. In silico studies were done through receptor-ligand binding interaction. RESULTS Pre-treatment with the rutin ameliorated the toxic effect of t-BHP by modulating the basal level of GSH, -SH, MDA and -CO significantly (p < 0.01) with respect to untreated control. Rutin also protected the erythrocytes against the t-BHP-induced oxidative stress as evidenced by augmented activity of antioxidant enzymes (CAT, SOD, GPX, GR and GST). Furthermore, at the highest tested concentration (16.3 µM), it protected the morphology of the erythrocytes by decreasing the ROS level (p < 0.01). In addition, the lower MEF values of rutin (0.520 ± 0.005) alone or along with t-BHP (0.630 ± 0.021) indicated its non-toxic and protective behavior. The qPCR analyses revealed that t-BHP potently up-regulates the iNOS and down regulate the Nrf2 expression which was ameliorated with rutin treatment in a dose-dependent manner like silymarin. CONCLUSION Our findings demonstrate that rutin potentiates its beneficial aspect by displaying a profound role in iNOS-Nrf2 signaling pathway. Accordingly, it may be concluded that the dietary factors wherein rutin is an ingredient could be helpful in the maintenance of the intracellular redox-homeostasis and thus may be effective against oxidative stress related secondary complications.

Synthesis of 4-phenyl-5,6-dihydrobenzo[h]quinazolines and their evaluation as growth inhibitors of carcinoma cells

The synthesis of various benzo[h]quinazoline analogs (4a–f, 6a–d, 8a and 8b) was accomplished through the reaction of chalcone with guanidine. The synthesized compounds (4a–f, 6a–d, 8a and 8b) were screened for their anticancer potential against different cancer cells viz MCF-7, DLD1, A549, DU145 & FaDu cell lines. Compounds 4a, 6a–d & 8b showed significant anticancer activity in these cancer cell lines with a range of IC50 values of 1.5–12.99 μM. A functional study of promising molecule 6d at 7 μM (at the IC50 value) over 24 and 48 h showed that it possesses anticancer activity through triggering apoptosis. In a tubulin polymerization assay, 6d effectively inhibited tubulin polymerization with an IC50 of 2.27 μM. In silico docking studies of 6d revealed that 6d has good affinity with an estrogen receptor as well as a tubulin protein on its β-sheet of the colchicines binding site.