Influence of Tau on Neurotoxicity and Cerebral Vasculature Impairment Associated with Alzheimer's Disease.

Alzheimer's disease is a fatal chronic neurodegenerative condition marked by a gradual decline in cognitive abilities and impaired vascular function within the central nervous system. This affliction initiates its insidious progression with the accumulation of two aberrant protein entities including Aß plaques and neurofibrillary tangles. These chronic elements target distinct brain regions, steadily erasing the functionality of the hippocampus and triggering the erosion of memory and neuronal integrity. Several assumptions are anticipated for AD as genetic alterations, the occurrence of Aß plaques, altered processing of amyloid precursor protein, mitochondrial damage, and discrepancy of neurotropic factors. In addition to Aß oligomers, the deposition of tau hyper-phosphorylates also plays an indispensable part in AD etiology. The brain comprises a complex network of capillaries that is crucial for maintaining proper function. Tau is expressed in cerebral blood vessels, where it helps to regulate blood flow and sustain the blood-brain barrier's integrity. In AD, tau pathology can disrupt cerebral blood supply and deteriorate the BBB, leading to neuronal neurodegeneration. Neuroinflammation, deficits in the microvasculature and endothelial functions, and Aß deposition are characteristically detected in the initial phases of AD. These variations trigger neuronal malfunction and cognitive impairment. Intracellular tau accumulation in microglia and astrocytes triggers deleterious effects on the integrity of endothelium and cerebral blood supply resulting in further advancement of the ailment and cerebral instability. In this review, we will discuss the impact of tau on neurovascular impairment, mitochondrial dysfunction, oxidative stress, and the role of hyperphosphorylated tau in neuron excitotoxicity and inflammation.

Identification of TBK1 inhibitors against breast cancer using a computational approach supported by machine learning.

Introduction: The cytosolic Ser/Thr kinase TBK1 is of utmost importance in facilitating signals that facilitate tumor migration and growth. TBK1-related signaling plays important role in tumor progression, and there is need to work on new methods and workflows to identify new molecules for potential treatments for TBK1-affecting oncologies such as breast cancer. Methods: Here, we propose the machine learning assisted computational drug discovery approach to identify TBK1 inhibitors. Through our computational ML-integrated approach, we identified four novel inhibitors that could be used as new hit molecules for TBK1 inhibition. Results and Discussion: All these four molecules displayed solvent based free energy values of -48.78, -47.56, -46.78 and -45.47 Kcal/mol and glide docking score of -10.4, -9.84, -10.03, -10.06 Kcal/mol respectively. The molecules displayed highly stable RMSD plots, hydrogen bond patterns and MMPBSA score close to or higher than BX795 molecule. In future, all these compounds can be further refined or validated by in vitro as well as in vivo activity. Also, we have found two novel groups that have the potential to be utilized in a fragment-based design strategy for the discovery and development of novel inhibitors targeting TBK1. Our method for identifying small molecule inhibitors can be used to make fundamental advances in drug design methods for the TBK1 protein which will further help to reduce breast cancer incidence.

A protein-miRNA biomic analysis approach to explore neuroprotective potential of nobiletin in human neural progenitor cells (hNPCs).

Chemical-induced neurotoxicity is increasingly recognized to accelerate the development of neurodegenerative disorders (NDs), which pose an increasing health burden to society. Attempts are being made to develop drugs that can cross the blood-brain barrier and have minimal or no side effects. Nobiletin (NOB), a polymethoxylated flavonoid with anti-oxidative and anti-inflammatory effects, has been demonstrated to be a promising compound to treat a variety of NDs. Here, we investigated the potential role of NOB in sodium arsenate (NA)-induced deregulated miRNAs and target proteins in human neural progenitor cells (hNPCs). The proteomics and microRNA (miRNA) profiling was done for different groups, namely, unexposed control, NA-exposed, NA + NOB, and NOB groups. Following the correlation analysis between deregulated miRNAs and target proteins, RT-PCR analysis was used to validate the selected genes. The proteomic analysis showed that significantly deregulated proteins were associated with neurodegeneration pathways, response to oxidative stress, RNA processing, DNA repair, and apoptotic process following exposure to NA. The OpenArray analysis confirmed that NA exposure significantly altered miRNAs that regulate P53 signaling, Wnt signaling, cell death, and cell cycle pathways. The RT-PCR validation studies concur with proteomic data as marker genes associated with autophagy and apoptosis (HO-1, SQSTM1, LC-3, Cas3, Apaf1, HSP70, and SNCA1) were altered following NA exposure. It was observed that the treatment of NOB significantly restored the deregulated miRNAs and proteins to their basal levels. Hence, it may be considered one of its neuroprotective mechanisms. Together, the findings are promising to demonstrate the potential applicability of NOB as a neuroprotectant against chemical-induced neurotoxicity.