Design and development of Tetrahydro-Quinoline derivatives as dual mTOR-C1/C2 inhibitors for the treatment of lung cancer.

Lung cancer is one of the most prevailed cancer worldwide. Many genes get mutated in lung cancer but the involvement of EGFR, KRAS, PTEN and PIK3CA are more common. Unavailability of potent drugs and resistance to the available drugs are major concern in the treatment of lung cancer. In the present research, mTOR was selected as an important alternative target for the treatment of lung cancer which involves the PI3K/AKT/mTOR pathway. We studied binding interactions of AZD-2014 with the mTOR protein to identify important interactions required to design potent mTOR inhibitors which was supported by QSAR studies. Pharmacophore based virtual screening studies provided core scaffold, THQ. Based on molecular docking interactions, 31 THQ derivatives were synthesized and characterized. All compounds were screened for cellular mTOR enzyme assay along with antiproliferative activity against the panel of cancerous cell lines, from which 6 compounds were further screened for colony forming assay. Two most potent compounds, HB-UC-1 and HB-UC-5, were further screened for flow cytometry analysis, gene expression study and western blot analysis. Gene expression study revealed the efficiency of compound HB-UC-1 against both mTORC1 and mTORC2 by affecting downstream regulators of mTORC1 (E4BP4, eIF4EBP1) and mTORC2 (PCK1), respectively. In western blot analysis, both compounds, inhibited phosphorylation of AKT S473 which proved the efficiency these compounds against the mTORC2. These two compounds were further screened for in-vivo biological evaluation. Both compounds increased lifespan of cancer-bearing animals with improvement in mean survival time. Further, in bezopyrene induced lung cancer animal model, both compounds showed effectiveness through the biochemical parameters and histopathological evaluation of the lung tissue. In future, potent hit compound from this series could be modified to develop lead mTOR inhibitors for the treatment of lung cancer.

Ellagic acid: Insights into its neuroprotective and cognitive enhancement effects in sporadic Alzheimer's disease.

Sporadic Alzheimer's disease (SAD), an age-associated dementia, is described as neuronal loss and marked cognitive impairment. Ellagic acid (EA) is a phenolic phytoconstituent obtained from grains and fruits, having evident antioxidant effects and known to modulate several endogenous molecular signals in humans in a beneficial way. The current study evaluated the safety profile of EA in the SH-SY5Y human neuroblastoma cell line, performing anti-oxidative effect by DPPH assay, and evaluating anti-AchE (acetylcholinesterase) effect against AchE enzyme from Electrophorus electricus. The observations were further confirmed by in vivo therapeutic effects in streptozotocin (STZ)-induced SAD rats in the context of altered biochemical and behavioral features. Treatment with EA (50 mg/kg, p.o.) for 30 days revealed reduction in STZ (3 mg/kg i.c.v.) prompted SAD and associated biochemical abnormalities in experimental rats which included diminished oxidative stress profile, pro-inflammatory markers i.e. GFAP and CRP; AchE level, and amyloid-ß plaque level. Moreover, an elevated level of synaptophysin indicated improved synaptic connectivity, and intact neural architecture showed neuroprotection in the EA group. Furthermore, the behavioral investigation by maze paradigms revealed reduced locomotor behavior, irregular spontaneous alternation, declination in memory score and increased memory errors in SAD rats. EA treatment normalized these SAD-associated abnormal behavioral representations in rats. Hence our findings suggest neuroprotective effects of EA and improvement in cognitive behavior in SAD rats.

Reduction of liver tumerogenic effect of N-nitrosodiethylamine by treatment with ɣ-oryzanol in Balb/C mice.

In recent years, naturally occurring phytochemicals with antioxidant capacity have generated surmount interest in their therapeutic usage against a wide range of pathological and toxicological conditions. The present study was designed to evaluate potential of ɣ-oryzanol (OZ), a bio-active natural antioxidant against hepatocellular carcinoma effect of the carcinogen N-nitrosodiethylamine in Balb/c mice. OZ inhibited the proliferation of Hep-3B cell line in concentration dependent manner. Administration of OZ to N-nitrosodiethylamine induced Balb/c mice for 16 and 32 weeks showed reduction in levels of liver injury markers, restored the levels of liver tumor markers, suppressed the hepatic nodular incidence and multiplicity, and favorably modulated the liver antioxidant status in a time dependent manner. Histologically, no obvious signs of neoplasia in the liver tissues were observed in OZ supplemented rats with N-nitrosodiethylamine induced liver tumerogenesis. OZ was found to be effective for reduction of N-nitrosodiethylamine induced hepatocellular carcinoma.

Anti-Inflammatory and Antioxidative Stress Effects of Oryzanol in Glaucomatous Rabbits.

Purpose. γ-Oryzanol works by anti-inflammatory and radical scavenging activity as a neuroprotective, anticancer, antiulcer, and immunosuppressive agent. The present study was conducted to investigate effect of oryzanol in acute and chronic experimental glaucoma in rabbits. Methods. Effect of oryzanol was evaluated in 5% dextrose induced acute model of ocular hypertension in rabbit eye. Chronic model of glaucoma was induced with subconjunctival injection of 5% of 0.3 ml phenol. Treatment with oryzanol was given for next two weeks after induction of glaucoma. From anterior chamber of rabbit eye aqueous humor was collected to assess various oxidative stress parameters like malondialdehyde, superoxide dismutase, glutathione peroxidase, catalase, nitric oxide, and inflammatory parameters like TNF-α and IL-6. Structural damage in eye was examined by histopathological studies. Results. In acute model of ocular hypertension oryzanol did not alter raised intraocular pressure. In chronic model of glaucoma oryzanol exhibited significant reduction in oxidative stress followed by reduction in intraocular pressure. Oryzanol treatment reduced level of TNF-α and IL-6. Histopathological studies revealed decreased structural damage of trabecular meshwork, lamina cribrosa, and retina with oryzanol treatment. Conclusions. Oryzanol showed protective effect against glaucoma by its antioxidative stress and anti-inflammatory property. Treatment with oryzanol can reduce optic nerve damage.