Pharmacological intervention in oxidative stress as a therapeutic target in neurological disorders.

OBJECTIVES: Oxidative stress is a major cellular burden that triggers reactive oxygen species (ROS) and antioxidants that modulate signalling mechanisms. Byproducts generated from this process govern the brain pathology and functions in various neurological diseases. As oxidative stress remains the key therapeutic target in neurological disease, it is necessary to explore the multiple routes that can significantly repair the damage caused due to ROS and consequently, neurodegenerative disorders (NDDs). Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is the critical player of oxidative stress that can also be used as a therapeutic target to combat NDDs. KEY FINDINGS: Several antioxidants signalling pathways are found to be associated with oxidative stress and show a protective effect against stressors by increasing the release of various cytoprotective enzymes and also exert anti-inflammatory response against this oxidative damage. These pathways along with antioxidants and reactive species can be the defined targets to eliminate or reduce the harmful effects of neurological diseases. SUMMARY: Herein, we discussed the underlying mechanism and crucial role of antioxidants in therapeutics together with natural compounds as a pharmacological tool to combat the cellular deformities cascades caused due to oxidative stress.

Meta-analysis of HNF1A-MODY3 variants among human population.

Background: Previously, numerous case-control studies have highlighted variants responsible for Maturity onset diabetes of young (MODY). However, these studies have been conducted among diverse populations and hence yielded contradictory results. We, therefore, performed a meta-analysis to precisely find the association of SNPs with the disease for the HNF1A gene. Objective: Meta-analysis of clinically defined studies deciphering mutations in the HNF1A gene responsible for the development of MODY3 was conducted among various populations to determine associations using statistical approaches. Methods: The curation of 505 research articles published between the years 2000-2021 was carried out. Visualization of data-related protocols and statistical-analysis were conducted, which led to the identification of highly prevalent mutations among different populations (majorly Europe). Further comparison between the frequencies of the control (healthy population) and test (diseased population) dataset generated through curation was performed. Results: We identified nine MODY3 mutations (rs587776825, rs1169288, rs1800574, rs2464196, rs137853244, rs137853238, rs587780357, rs137853240 and rs137853243) at the genome-wide significance level ( p < 5.0 × 10-8). The present study confirmed that the data does not follow a normal distribution. Further, the data was confirmed to be a more homogenous type with frequencies having a significant association with the disease. Conclusion: This meta-analysis found significant associations of mutations in HNF1A with MODY3, consistent with previous studies. Our findings should help elucidate the mutations in a compiled form responsible for causing MODY3. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-022-00975-8.

Pharmacological relevance of CDK inhibitors in Alzheimer's disease.

Evidence suggests that cell cycle activation plays a role in the pathophysiology of neurodegenerative diseases. Alzheimer's disease is a progressive, terminal neurodegenerative disease that affects memory and other important mental functions. Intracellular deposition of Tau protein, a hyperphosphorylated form of a microtubule-associated protein, and extracellular aggregation of Amyloid ß protein, which manifests as neurofibrillary tangles (NFT) and senile plaques, respectively, characterize this condition. In recent years, however, several studies have concluded that cell cycle re-entry is one of the key causes of neuronal death in the pathogenesis of Alzheimer's disease. The eukaryotic cell cycle is well-coordinated machinery that performs critical functions in cell replenishment, such as DNA replication, cell creation, repair, and the birth of new daughter cells from the mother cell. The complex interplay between the levels of various cyclins and cyclin-dependent kinases (CDKs) at different checkpoints is needed for cell cycle synchronization. CDKIs (cyclin-dependent kinase inhibitors) prevent cyclin degradation and CDK inactivation. Different external and internal factors regulate them differently, and they have different tissue expression and developmental functions. The checkpoints ensure that the previous step is completed correctly before starting the new cell cycle phase, and they protect against the transfer of defects to the daughter cells. Due to the development of more selective and potent ATP-competitive CDK inhibitors, CDK inhibitors appear to be on the verge of having a clinical impact. This avenue is likely to yield new and effective medicines for the treatment of cancer and other neurodegenerative diseases. These new methods for recognizing CDK inhibitors may be used to create non-ATP-competitive agents that target CDK4, CDK5, and other CDKs that have been recognized as important therapeutic targets in Alzheimer's disease treatment.

GRSDB: a database of quadruplex forming G-rich sequences in alternatively processed mammalian pre-mRNA sequences.

Guanine-rich nucleic acids are known to form highly stable G-quadruplex structures, also known as G-quartets. Recently, there has been a tremendous amount of interest in studying G-quadruplexes owing to the realization of their biological importance. G-rich sequences (GRSs) capable of forming G-quadruplexes are found in the vicinity of polyadenylation regions and are involved in regulating 3' end processing of mammalian pre-mRNAs. G-rich motifs are also known to play an important role in alternative, tissue-specific splicing by interacting with hnRNP H protein subfamily. Whether quadruplex structure directly plays a role in regulating RNA processing events requires further investigation. To date there has not been a comprehensive effort to study G-quadruplexes near RNA processing sites. We have applied a computational approach to map putative Quadruplex forming GRSs within the transcribed regions of a large number of alternatively processed human and mouse gene sequences that were obtained as fully annotated entries from GenBank and RefSeq. We have used the computed data to build the GRSDB database that provides a unique avenue for studying G-quadruplexes in the context of RNA processing sites. GRSDB website offers visual comparison of G-quadruplex distribution patterns among all the alternative RNA products of a gene with the help of dynamic graphics. At present, GRSDB contains data from 1310 human and mouse genes, of which 1188 are alternatively processed. It has a total of 379,223 predicted G-quadruplexes, of which 54,252 are near RNA processing sites. GRSDB is a good resource for researchers interested in investigating the functional relevance of G-quadruplexes, especially in the context of alternative RNA processing. It can be accessed at http://bioinformatics.ramapo.edu/grsdb/.