Protein Tyrosine Phosphatase 1B (PTP1B): A Comprehensive Review of Its Role in Pathogenesis of Human Diseases.

Overexpression of protein tyrosine phosphatase 1B (PTP1B) disrupts signaling pathways and results in numerous human diseases. In particular, its involvement has been well documented in the pathogenesis of metabolic disorders (diabetes mellitus type I and type II, fatty liver disease, and obesity); neurodegenerative diseases (Alzheimer's disease, Parkinson's disease); major depressive disorder; calcific aortic valve disease; as well as several cancer types. Given this multitude of therapeutic applications, shortly after identification of PTP1B and its role, the pursuit to introduce safe and selective enzyme inhibitors began. Regrettably, efforts undertaken so far have proved unsuccessful, since all proposed PTP1B inhibitors failed, or are yet to complete, clinical trials. Intending to aid introduction of the new generation of PTP1B inhibitors, this work collects and organizes the current state of the art. In particular, this review intends to elucidate intricate relations between numerous diseases associated with the overexpression of PTP1B, as we believe that it is of the utmost significance to establish and follow a brand-new holistic approach in the treatment of interconnected conditions. With this in mind, this comprehensive review aims to validate the PTP1B enzyme as a promising molecular target, and to reinforce future research in this direction.

Design and discovery of anthranilamide derivatives as a potential treatment for neurodegenerative disorders via targeting cholinesterases and monoamine oxidases.

Neurodegenerative diseases with progressive cellular loss of the central nervous system and elusive disease etiology provide a continuous impetus to explore drug discovery programmes aiming at identifying robust and effective inhibitors of cholinesterase and monoamine oxidase enzymes. We herein present a concise library of anthranilamide derivatives involving a palladium-catalyzed Suzuki-Miyaura cross-coupling reaction to install the diverse structural diversity required for the desired biological action. Using Ellman's method, cholinesterase inhibitory activity was performed against AChE and BuChE enzymes. In vitro assay results demonstrated that anthranilamides are potent inhibitors with remarkable potency. Compound 6k emerged as the lead candidate and dual inhibitor of both enzymes with IC50 values of 0.12 ± 0.01 and 0.49 ± 0.02 µM against AChE and BuChE, respectively. Several other compounds were found as highly potent and selective inhibitors. Anthranilamide derivatives were also tested against monoamine oxidase (A and B) enzymes using fluorometric method. In vitro data revealed compound 6h as the most potent inhibitor against MAO-A, showing an IC50 value of 0.44 ± 0.02 µM, whereas, compound 6k emerged as the top inhibitor of MAO-B with an IC50 value of 0.06 ± 0.01 µM. All the lead inhibitors were analyzed for the identification of their mechanism of action using Michaelis-Menten kinetics experiments. Compound 6k and 6h depicted a competitive mode of action against AChE and MAO-A, whereas, a non-competitive and mixed-type of inhibition was observed against BuChE and MAO-B by compounds 6k. Molecular docking analysis revealed remarkable binding affinities of the potent inhibitors with specific residues inside the active site of receptors. Furthermore, molecular dynamics simulations were performed to explore the ability of potent compounds to form energetically stable complexes with the target protein. Finally, in silico ADME calculations also demonstrated that the potent compounds exhibit promising pharmacokinetic profile, satisfying the essential criteria for drug-likeness. Altogether, the findings reported in the current work clearly suggest that the identified anthranilamide derivatives have the potential to serve as effective drug candidates for future investigations.

E3 ligases and DUBs target ferroptosis: A potential therapeutic strategy for neurodegenerative diseases.

Ferroptosis is a form of cell death mediated by iron and lipid peroxidation (LPO). Recent studies have provided compelling evidence to support the involvement of ferroptosis in the pathogenesis of various neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD). Therefore, understanding the mechanisms that regulate ferroptosis in NDDs may improve disease management. Ferroptosis is regulated by multiple mechanisms, and different degradation pathways, including autophagy and the ubiquitinproteasome system (UPS), orchestrate the complex ferroptosis response by directly or indirectly regulating iron accumulation or lipid peroxidation. Ubiquitination plays a crucial role as a protein posttranslational modification in driving ferroptosis. Notably, E3 ubiquitin ligases (E3s) and deubiquitinating enzymes (DUBs) are key enzymes in the ubiquitin system, and their dysregulation is closely linked to the progression of NDDs. A growing body of evidence highlights the role of ubiquitin system enzymes in regulating ferroptosis sensitivity. However, reports on the interaction between ferroptosis and ubiquitin signaling in NDDs are scarce. In this review, we first provide a brief overview of the biological processes and roles of the UPS, summarize the core molecular mechanisms and potential biological functions of ferroptosis, and explore the pathophysiological relevance and therapeutic implications of ferroptosis in NDDs. In addition, reviewing the roles of E3s and DUBs in regulating ferroptosis in NDDs aims to provide new insights and strategies for the treatment of NDDs. These include E3- and DUB-targeted drugs and ferroptosis inhibitors, which can be used to prevent and ameliorate the progression of NDDs.

Influencia de mecanismos colinergicos nos processos neurodegenerativos relacionados a formacao de amiloide e a fosforilacao da proteina TAU / Cholinergic mechanisms influence in neurodegenerative process related to amyloid formation and phosphorylation of TAU protein

Na doenca de Alzheimer (DA), os principais eventos associados a neurodegeneracao sao a formacao de placas senis e de emaranhados neurofibrilares. Estes fenomenos relacionam-se respectivamente a deposicao de beta-amiloide (Ab) e a alteracoes do estado de fosforilacao da proteina Tau. Esta e componente essencial dos microtubulos, onde se encontra em estado polimerizado. A estabilidade do polimero depende do grau de fosforilacao da Tau, tornando-se mais instavel quanto mais fosforilada a proteina. Consequentemente, a hiperfosforilacao da Tau relaciona-se com menor estabilidade do citoesqueleto, favorecendo a morte neuronal. O Ab e produzido pela clivagem da proteina precursora do amiloide (APP) por acao da enzima beta-secretase, em detrimento da acao mais fisiologica da alfa-secretase, que da origem ao fragmento APPs. As fibras de Ab tem diversos efeitos neurotoxicos, alem de ocorrerem associadamente a uma presumivel perda funcional do metabolito secretado APPs...