Synthesis, biological evaluation and molecular dynamic simulations of novel Benzofuran-tetrazole derivatives as potential agents against Alzheimer's disease.

A series of novel Benzofuran-tetrazole derivatives were successfully synthesised by integrating multicomponent Ugi-azide reaction with the molecular hybridization approach. Interestingly, a number of synthesized derivatives (5c, 5d, 5i, 5l, 5q and 5s) exhibited significant reduction of aggregation of "human" amyloid beta peptide, expressing on transgenic Caenorhabditis elegans (C. elegans) strain CL4176. Further, in silico docking results have evidenced the exquisite interaction of active compounds with the help of TcAChE-E2020 complex. These findings underscore the potential of these hybrids as lead molecules against Alzheimers's disease.

HIV-1 Nef physically associate with CAMKIIδ - ASK-1 complex to inhibit p38MAPK signalling and apoptosis in infected cells.

Human immunodeficiency type 1 virus accessory protein Nef is a key modulator of AIDS pathogenesis. With no enzymatic activity, Nef regulated functions in host cells largely depends on its ability to form multi-protein complex with the cellular proteins. Here, we identified Calcium (Ca2+)/Calmodulin dependent protein kinase II subunit delta (CAMKIIδ) as novel Nef interacting host protein. Further, we confirmed that Nef mediated [Ca2+]I promote formation of Nef-CAMKIIδ - apoptosis signal-regulating kinase (ASK-1) heterotrimeric complex. The assembly of Nef with CAMKIIδ - ASK-1 inhibits the downstream p38MAPK phosphorylation resulting in abrogation of apoptosis. Further, using competitive peptide inhibitors against Nef binding domains to CAMKIIδ, identified in the present study and ASK-1, individually blocked physical interaction of Nef with CAMKIIδ-ASK-1 complex and restored p38MAPK phosphorylation and apoptosis. Altogether, our study indicates that HIV-Nef modulates cytosolic [Ca2+]I and blocks CAMKIIδ - ASK-1 kinase activity to inhibit apoptosis of infected cells.

Biocompatible fluorescent carbon quantum dots prepared from beetroot extract for in vivo live imaging in C. elegans and BALB/c mice.

Luminescent carbon quantum dots (CQDs) prepared from aqueous beetroot extract were developed as unique fluorescent nanomaterials for in vivo live animal imaging applications. Blue (B) and green (G) emitting environmentally benign CQDs (particle size of 5 nm and 8 nm, respectively) exhibited bright fluorescence in aqueous medium and were found to be biocompatible, photostable and non-toxic in animal models. The in vivo imaging and toxicity evaluation of both CQDs were performed for the first time in the Caenorhabditis elegans (C. elegans) model, which revealed consistent fluorescence in the gut tissues of the worms without exerting any sign of toxic effects on the nematodes. The in vivo bio-distribution of G-CQDs given by tail vein injection in live BALB/c mice showed optical signals in the lower abdominal regions, mainly in the intestine, and cleared from the body through faeces. The tremendous potential shown by these eco-friendly CQDs in the C. elegans and mice models advocates new hopes for greener CQD nanomaterials as diagnostic tools in the biomedical field.

Circular RNAs: the Emerging Class of Non-coding RNAs and Their Potential Role in Human Neurodegenerative Diseases.

The exciting world of research with RNAs has to its credit some breakthrough findings that led to newer insights on multiple problems including that of human diseases. After the advent of siRNA, microRNA, and lncRNA, exciting novel molecules called circular RNAs (circRNAs) have been recently described. circRNAs are a class of non-coding RNAs, which are produced by scrambling of exons at the time of splicing. They are primarily produced in the brain region and are naturally present inside the cell. The best known ones so far include a particular type of circRNA namely "circular RNA sponge for miR-7" (ciRS-7 and CDR1as) which is the inhibitor of miR-7 microRNA-known to regulate various diseases like, cancer, neurodegenerative diseases, diabetes, and atherosclerosis. Similarly, another circRNA molecule called circmbl modulates the ratio of linear mRNA by competing with linear muscleblind gene through which it is synthesized. Considering the complex association of these molecules with critical microRNAs and gene families, circRNAs might have important roles in the cause and progression of human diseases. In particular, the multi-factorial nature of neurodegenerative diseases does warrant studies employing novel approaches towards identifying underlying root causes of these ailments. The non-coding RNAs, like circRNAs and microRNAs, could well present a common genetic trigger to multiple factors associated with neurodegenerative diseases. A specific fingerprint of a combination of various marker circRNAs could be explored for early diagnostic purpose as well. Herein, we review the possibility of exploring the role of circRNAs in the context of the central nervous system (CNS) and age-associated neurodegenerative diseases.

A Systematic RNAi Screen of Neuroprotective Genes Identifies Novel Modulators of Alpha-Synuclein-Associated Effects in Transgenic Caenorhabditis elegans.

Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder, defined clinically by degeneration of dopaminergic neurons and the development of neuronal Lewy bodies. Current treatments of PD are inadequate due to a limited understanding of molecular events of the disease, thus calling for intense research efforts towards identification of novel therapeutic targets. We carried out the present studies towards identifying novel genetic modulators of PD-associated effects employing a transgenic Caenorhabditis elegans model expressing human alpha-synuclein. Employing a systematic RNA interference (RNAi)-based screening approach, we studied a set of neuroprotective genes of C. elegans with an aim of identifying genes that exhibit protective function under alpha-synuclein expression conditions. Our results reveal a novel set of alpha-synuclein effector genes that modulate alpha-synuclein aggregation and associated effects. The identified genes include those from various gene families including histone demethylase, lactate dehydrogenase, small ribosomal subunit SA protein, cytoskeletal protein, collapsin response mediator protein, and choline kinase. The functional characterization of these genes reveals involvement of signaling mechanisms such as Daf-16 and acetylcholine signaling. Further elucidation of mechanistic pathways associated with these genes will yield additional insights into mediators of alpha-synuclein-induced cytotoxicity and cell death, thereby helping in the identification of potential therapeutic targets for PD.