Frontiers in Molecular Biosciences最新文献

Neisseria gonorrhoeae is the causative agent of the sexually transmitted disease gonorrhea. The increasing prevalence of this disease worldwide, the rise of antibiotic-resistant strains, and the difficulties in treatment necessitate the development of a vaccine, highlighting the significance of preventative measures to control and eradicate the infection. Currently, there is no widely available vaccine, partly due to the bacterium's ability to evade natural immunity and the limited research investment in gonorrhea compared to other diseases. To identify distinct vaccine candidates, we chose to focus on the uncharacterized, hypothetical proteins (HPs) as our initial approach. Using the in silico method, we first carried out a comprehensive assessment of hypothetical proteins of Neisseria gonorrhoeae, encompassing assessments of physicochemical properties, cellular localization, secretary pathways, transmembrane regions, antigenicity, toxicity, and prediction of B-cell and T-cell epitopes, among other analyses. Detailed analysis of all HPs resulted in the functional annotation of twenty proteins with a great degree of confidence. Further, using the immuno-informatics approach, the prediction pipeline identified one CD8⁺ restricted T-cell epitope, seven linear B-cell epitopes, and seven conformational B-cell epitopes as putative epitope-based peptide vaccine candidates which certainly require further validation in laboratory settings. The study accentuates the promise of functional annotation and immuno-informatics in the systematic design of epitope-based peptide vaccines targeting Neisseria gonorrhoeae.

Cardiovascular diseases are a major global health concern, responsible for a significant number of deaths each year, often linked to cardiac arrhythmias resulting from dysfunction in ion channels. Hereditary Long QT Syndrome (LQTS) is a condition characterized by a prolonged QT interval on ECG, increasing the risk of sudden cardiac death. The most common type of LQTS, LQT2, is caused by mutations in the hERG gene, affecting a potassium ion channel. The majority of these mutations disrupt the channel's trafficking to the cell membrane, leading to intracellular retention. Specific high-affinity hERG blockers (e.g., E-4031) can rescue this mutant phenotype, but the exact mechanism is unknown. This study used accelerated molecular dynamics simulations to investigate how these mutations affect the hERG channel's structure, folding, endoplasmic reticulum (ER) retention, and trafficking. We reveal that these mutations induce structural changes in the channel, narrowing its central pore and altering the conformation of the intracellular domains. These changes expose internalization signals that contribute to ER retention and degradation of the mutant hERG channels. Moreover, the study found that the trafficking rescue drug E-4031 can inhibit these structural changes, potentially rescuing the mutant channels. This research offers valuable insights into the structural issues responsible for the degradation of rescuable transmembrane trafficking mutants. Understanding the defective trafficking structure of the hERG channel could help identify binding sites for small molecules capable of restoring proper folding and facilitating channel trafficking. This knowledge has the potential to lead to mechanism-based therapies that address the condition at the cellular level, which may prove more effective than treating clinical symptoms, ultimately offering hope for individuals with hereditary Long QT Syndrome.

Introduction: Multifactorial Eye disorders are a significant public health concern and have a huge impact on quality of life. The pathophysiological mechanisms underlying these eye disorders were not completely understood since functional and low-throughput biological tests were used. By identifying biomarkers linked to eye disorders, metabolomics enables early identification, tracking of the course of the disease, and personalized treatment.

Methods: The electronic databases of PubMed, Scopus, PsycINFO, and Web of Science were searched for research related to Age-Related macular degeneration (AMD), glaucoma, myopia, and diabetic retinopathy (DR). The search was conducted in August 2023. The number of cases and controls, the study's design, the analytical methods used, and the results of the metabolomics analysis were all extracted. Using the QUADOMICS tool, the quality of the studies included was evaluated, and metabolic pathways were examined for distinct metabolic profiles. We used MetaboAnalyst 5.0 to undertake pathway analysis of differential metabolites.

Results: Metabolomics studies included in this review consisted of 36 human studies (5 Age-related macular degeneration, 10 Glaucoma, 13 Diabetic retinopathy, and 8 Myopia). The most networked metabolites in AMD include glycine and adenosine monophosphate, while methionine, lysine, alanine, glyoxylic acid, and cysteine were identified in glaucoma. Furthermore, in myopia, glycerol, glutamic acid, pyruvic acid, glycine, cysteine, and oxoglutaric acid constituted significant metabolites, while glycerol, glutamic acid, lysine, citric acid, alanine, and serotonin are highly networked metabolites in cases of diabetic retinopathy. The common top metabolic pathways significantly enriched and associated with AMD, glaucoma, DR, and myopia were arginine and proline metabolism, methionine metabolism, glycine and serine metabolism, urea cycle metabolism, and purine metabolism.

Conclusion: This review recapitulates potential metabolic biomarkers, networks and pathways in AMD, glaucoma, DR, and myopia, providing new clues to elucidate disease mechanisms and therapeutic targets. The emergence of advanced metabolomics techniques has significantly enhanced the capability of metabolic profiling and provides novel perspectives on the metabolism and underlying pathogenesis of these multifactorial eye conditions. The advancement of metabolomics is anticipated to foster a deeper comprehension of disease etiology, facilitate the identification of novel therapeutic targets, and usher in an era of personalized medicine in eye research.