Impaired Fibroblast Growth Factor 21 (FGF21) Associated with Visceral Adiposity Leads to Insulin Resistance: The Core Defect in Diabetes Mellitus.

The Central nervous system (CNS) is the prime regulator of signaling pathways whose function includes regulation of food intake (consumption), energy expenditure, and other metabolic responses like glycolysis, gluconeogenesis, fatty acid oxidation, and thermogenesis that have been implicated in chronic inflammatory disorders. Type 2 diabetes mellitus (T2DM) and obesity are two metabolic disorders that are linked together and have become an epidemic worldwide, thus raising significant public health concerns. Fibroblast growth factor 21 (FGF21) is an endocrine hormone with pleiotropic metabolic effects that increase insulin sensitivity and energy expenditure by elevating thermogenesis in brown or beige adipocytes, thus reducing body weight and sugar intake. In contrast, during starvation conditions, FGF21 induces its expression in the liver to initiate glucose homeostasis. Insulin resistance is one of the main anomalies caused by impaired FGF21 signaling, which also causes abnormal regulation of other signaling pathways. Tumor necrosis factor alpha (TNF-α), the cytokine released by adipocytes and inflammatory cells in response to chronic inflammation, is regarded major factor that reduces the expression of FGF21 and modulates underlying insulin resistance that causes imbalanced glucose homeostasis. This review aims to shed light on the mechanisms underlying the development of insulin resistance in obese individuals as well as the fundamental flaw in type 2 diabetes, which is malfunctioning obese adipose tissue.

Current Insights of Nanocarrier-Mediated Gene Therapeutics to Treat Potential Impairment of Amyloid Beta Protein and Tau Protein in Alzheimer's Disease.

Alzheimer's disease (AD), is the major type of dementia and most progressive, irreversible widespread neurodegenerative disorder affecting the elderly worldwide. The prime hallmarks of Alzheimer's disease (AD) are beta-amyloid plaques (Aß) and neurofibrillary tangles (NFT). In spite of recent advances and developments in targeting the hallmarks of AD, symptomatic medications that promise neuroprotective activity against AD are currently unable to treat degenerating brain clinically or therapeutically and show little efficacy. The extensive progress of AD therapies over time has resulted in the advent of disease-modifying medications with the potential to alleviate AD. However, due to the presence of a defensive connection between the vascular system and the neural tissues known as the blood-brain barrier (BBB), directing these medications to the site of action in the degenerating brain is the key problem. BBB acts as a highly selective semipermeable membrane that prevents any type of foreign substance from entering the microenvironment of neurons. To overcome this limitation, the revolutionary approach of nanoparticle(NP)/nanocarrier-mediated drug delivery system has marked the era with its unique property to cross, avoid, or disrupt the defensive BBB efficiently and release the modified drug at the target site of action. After comprehensive data mining, this review focuses on the detailed understanding of different types of nanoparticle(NP)/nanocarrier-mediated drug delivery system like liposomes, micelles, gold nanoparticles(NP), polymeric NPs, etc. which have promising potential in carrying the desired drug(cargo) to the location in the degenerated brain thus mitigating the Alzheimer's disease.

Dynamics of Mycobacteriophage-Mycobacterial Host Interaction.

Mycobacterium sp. is exhibiting complex evolution of antimicrobial resistance (AMR) and can therefore be considered as a serious human pathogen. Many strategies were employed earlier to evade the pathogenesis but AMR became threatened. Molecular tools employing bacteriophage can be an alternative to effective treatment against Mycobacterium. Phage treatment using phage-encoded products, such as lysins, causes lysis of cells; particularly bacteria could be used instead of direct use of these bacteriophages. Modern technologies along with bacteriophage strategies such as in silico immunoinformatics approach, machine learning, and artificial intelligence have been described thoroughly to escape the pathogenesis. Therefore, understanding the molecular mechanisms could be a possible alternative to evade the pathogenesis.

Integrating pharmacophore mapping, virtual screening, density functional theory, molecular simulation towards the discovery of novel apolipoprotein (apoE ε4) inhibitors.

AIM: An integrated protocol of virtual screening involving molecular docking, pharmacophore probing, and simulations was established to identify small novel molecules targeting crucial residues involved in the variant apoE ε4 to mimic its behavior as apoE2 thereby eliminating the amyloid plaque accumulation and facilitating its clearance. MATERIALS AND METHODS: An excellent ligand-based and structure-based approach was made to identify common pharmacophoric features involving structure-based docking with respect to apoE ε4 leading to the development of apoE ε4 inhibitors possessing new scaffolds. An effort was made to design multiple-substituted triazine derivatives series bearing a novel scaffold. A structure-based pharmacophore mapping was developed to explore the binding sites of apoE ε4 which was taken into consideration. Subsequently, virtual screening, ADMET, DFT searches were at work to narrow down the proposed hits to be forwarded as a potential drug likes candidates. Further, the binding patterns of the best-proposed hits were studied and were forwarded for molecular dynamic simulations of 10 ns for its structural optimization. RESULTS: Selectivity profile for the most promising candidates was studied, revealing significantly C13 and C15 to be the most potent compounds. The proposed hits can be forwarded for further study against apoE ε4 involved in neurological disorder Alzheimer's.