Novel alkyl-substituted 4-methoxy benzaldehyde thiosemicarbazones: Multi-target directed ligands for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder affecting mental ability and interrupts neurocognitive functions. Treating multifactorial conditions of AD with a single-target-directed drug is highly difficult. Thus, a multi-target-directed ligand (MTDL) development strategy has been developed as a promising approach for the treatment of AD. Herein, we have synthesized two novel thiosemicarbazones as MTDLs and reported their bioactivities against diverse neuropathological events involved in AD. In vitro studies revealed that both compounds exhibited promising anticholinesterase activity (AChE, IC50 = 15.98 µM, MZET and IC50 = 30.23 µM, MZMT), well supported by a detailed computational study. Both analogs have shown good thermodynamic behaviour and stability through interactions with characteristic amino acid residues throughout simulation of 100 ns against acetylcholinesterase enzyme. In an electrophysiology assay, these analogs have shown a characteristic inhibitory response against the GluN1-1a + GluN2B subunit of N-methyl-D-aspartate receptors. Pre-treatment of BV-2 microglial cells with MZET effectively decreased nitrite production compared to nitrite produced by lipopolysaccharide-treated cells alone. Further, the effect of MZMT and MZET on autophagy regulation was determined using stably transfected SH-SY5Y neuroblastoma cells. MZET significantly enhanced the autophagy flux in neuroblastoma cells. A significant decrease in copper-catalysed oxidation of amyloid-ß in presence of synthesized thiosemicarbazones was also observed. Collectively, our findings indicated that these analogs have potential as effective anti-AD candidates and can be used as a prototype to develop more safer multi-targeted anti-AD drugs.

Genome wide study of cysteine rich receptor like proteins in Gossypium sp.

Cysteine-rich receptor-like-kinases (CRKs), a transmembrane subfamily of receptor-like kinase, play crucial roles in plant adaptation. As such cotton is the major source of fiber for the textile industry, but environmental stresses are limiting its growth and production. Here, we have performed a deep computational analysis of CRKs in five Gossypium species, including G. arboreum (60 genes), G. raimondii (74 genes), G. herbaceum (65 genes), G. hirsutum (118 genes), and G. barbadense (120 genes). All identified CRKs were classified into 11 major classes and 43 subclasses with the finding of several novel CRK-associated domains including ALMT, FUSC_2, Cript, FYVE, and Pkinase. Of these, DUF26_DUF26_Pkinase_Tyr was common and had elevated expression under different biotic and abiotic stresses. Moreover, the 35 land plants comparison identified several new CRKs domain-architectures. Likewise, several SNPs and InDels were observed in CLCuD resistant G. hirsutum. The miRNA target side prediction and their expression profiling in different tissues predicted miR172 as a major CRK regulating miR. The expression profiling of CRKs identified multiple clusters with co-expression under certain stress conditions. The expression analysis under CLCuD highlighted the role of GhCRK057, GhCRK059, GhCRK058, and GhCRK081 in resistant accession. Overall, these results provided primary data for future potential functional analysis as well as a reference study for other agronomically important crops.

Tetraspanins as Potential Modulators of Glutamatergic Synaptic Function.

Tetraspanins (Tspans) comprise a membrane protein family structurally defined by four transmembrane domains and intracellular N and C termini that is found in almost all cell types and tissues of eukaryotes. Moreover, they are involved in a bewildering multitude of diverse biological processes such as cell adhesion, motility, protein trafficking, signaling, proliferation, and regulation of the immune system. Beside their physiological roles, they are linked to many pathophysiological phenomena, including tumor progression regulation, HIV-1 replication, diabetes, and hepatitis. Tetraspanins are involved in the formation of extensive protein networks, through interactions not only with themselves but also with numerous other specific proteins, including regulatory proteins in the central nervous system (CNS). Interestingly, recent studies showed that Tspan7 impacts dendritic spine formation, glutamatergic synaptic transmission and plasticity, and that Tspan6 is correlated with epilepsy and intellectual disability (formerly known as mental retardation), highlighting the importance of particular tetraspanins and their involvement in critical processes in the CNS. In this review, we summarize the current knowledge of tetraspanin functions in the brain, with a particular focus on their impact on glutamatergic neurotransmission. In addition, we compare available resolved structures of tetraspanin family members to those of auxiliary proteins of glutamate receptors that are known for their modulatory effects.