Design and synthesis of novel series of 5-HT6 receptor ligands having indole, a central aromatic core and 1-amino-4 methyl piperazine as a positive ionizable group.

The exclusive distribution of 5-HT6 receptor in the brain regions and high affinity for antipsychotic and antidepressant drugs makes 5-HT6 receptor a promising target in treatment of CNS diseases. Based on a pharmacophore model reported in the literature, we designed and synthesized a novel series of 5-HT6 receptor ligands having indole as a central aromatic core and 1-amino-4-methyl piperazine as positive ionizable group. Out of 32 compounds we have successfully identified 10 new compounds as 5-HT6 receptor antagonists. The structure-activity relationship (SAR) studies have been carried out by mapping the compounds with the 3D QSAR model.

Nrf2 activator via interference of Nrf2-Keap1 interaction has antioxidant and anti-inflammatory properties in Parkinson's disease animal model.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by abnormal movement, including slowed movements, shuffling gait, lack of balance, and tremor. Oxidative stress has been shown to play a decisive role in dopaminergic neuronal cell death in PD. The nuclear factor E2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) signaling pathway provides the main defense system against oxidative stress by inducing the expression of antioxidant enzyme genes. Direct interference in the Keap1-Nrf2 protein-protein interaction (PPI) has emerged as an effective strategy for Nrf2 activation. Therefore, we searched for novel Nrf2 activators that can disrupt Nrf2-Keap1 interaction by using a virtual screening approach and identified a potent Nrf2 activator, KKPA4026. KKPA4026 was confirmed to induce the expression of the Nrf2-dependent antioxidant enzymes heme oxygenase-1, glutamate-cysteine ligase catalytic subunit, glutamate-cysteine ligase regulatory subunit, and NAD(P)H:quinone oxidoreductase 1 in BV-2 cells. Furthermore, KKPA4026 showed anti-inflammatory effects in an Nrf2-dependent manner. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD, KKPA4026 effectively attenuated PD-associated behavioral deficits and protected dopaminergic neurons. In summary, we identified KKPA4026 as a novel Nrf2 activator and suggested that Nrf2 activation through interference with the Nrf2-Keap1 interaction may be effective for PD treatment.

Upregulated bovine tuberculosis microRNAs Trigger oncogenic pathways: An In silico perception.

BACKGROUND/OBJECTIVE: Although microRNA (miRNA)-directed regulation of bovine tuberculosis (bTB) has already been reported, very little is known about the incited pathways and genes. We profiled bTB-upregulated miRNAs through an in silico methodology. METHODS: The data of upregulated miRNAs in bTB versus healthy controls were collected and clustered into three groups by their tissue specificity as follows: G1 (mammary gland-specific): bta-miR-146a; G2 (peripheral blood mononuclear cell-specific): bta-miR-155; and G3 (alveolar macrophage-specific): bta-miR-146a, bta-miR-155, bta-miR-142-5p, bta-miR-423-3p, bta-miR-21-5p, bta-miR-27a-3p, bta-miR-99b, bta-miR-147, bta-miR-223, and bta-let-7i. The miRNA-mRNA interaction network was defined by TargetScan. The gene ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways of these transcripts were examined. RESULTS: The results illustrate the induction of pathways in cancer, highly enriched, and unanimous to all three gene sets (G1, G2, and G3). Mitogen-activated protein kinase and PI3K-Akt signaling were specific to G2 and G3 with fibroblast growth factors formed the key factors. CONCLUSION: The inferred cancer cascades denote a probable modulation of innate immune response in an infectious state. These baseline pictures could lay the ground for further substantive studies.