Introduction:The α-amylase enzyme plays a critical role in the digestion of complex carbohydrates. Inhibiting this enzyme offers a promising strategy for improving glucose regulation in diabetic patients. Methods:In this study, a comprehensive computational approach, combining 3D-QSAR modeling, ADMET profiling, molecular docking, molecular dynamics, ligand transport analysis, and retrosynthesis, was used to identify novel ligands with potent inhibitory activity against various indenoquinoxaline-phenylacrylohydrazide hybrids. Results:The optimal 3D-QSAR model, developed using partial least squares (PLS) and Comparative Molecular Similarity Indices Analysis (CoMSIA), demonstrated strong correlation and predictive power (Q2=0.541, R2=0.973, SEE=0.076). ADMET analysis showed that the designed ligands possess acceptable pharmacokinetic and toxicological profiles, supporting their potential for further drug development. Molecular docking revealed that the designed ligands effectively interacted with the active site of α-amylase (PDB ID: 7TAA). Furthermore, molecular dynamics simulations (100 ns) and MM-PBSA free energy calculations confirmed the stability of ligand-enzyme complexes. Ligand transport was further examined using the CaverDock program, tracking the movement of molecules from the enzyme's active site to its surface. Finally, retrosynthetic analysis was performed to propose feasible synthesis routes for the most active compound. Conclusion:Overall, the findings highlight a promising lead compound for further in vitro and in vivo investigations targeting α-amylase inhibition.
Introduction:Lactylation, an emerging post-translational modification, modulates tumor metabolism and gene expression, thereby influencing the initiation and progression of cervical squamous cell carcinoma (CESC). This study aims to identify lactylation-associated prognostic features in CESC through the integration of transcriptomic data and single-cell RNA sequencing (scRNA-seq). Methods:Publicly available datasets were utilized for this study. Lactylation-related genes (LRGs) linked to CESC prognosis were found through analysis. Key prognostic genes include PGK1, PFKP, DDX39A, RFC4, WAS, and PFKM, with PFKP identified as a risk factor. Results:The risk model demonstrated strong predictive performance, and immune infiltration analysis revealed elevated levels of immune cells, with CD8+ T cells negatively correlating with risk. ScRNA-seq analysis identified three distinct cell types, with CD8+ T cells showing a distinct developmental trajectory, marked by a reduction in early-stage cells and an accumulation of late-stage cells within the CESC microenvironment. Moreover, the expression of prognostic genes was elevated during the later stages of CD8+ T cell differentiation. Conclusion:LRGs demonstrated significant prognostic value in CESC and accurately predicted patient outcomes. Furthermore, the study underscored the pivotal role of CD8+ T cells in the progression of CESC.
Glomerulonephritis (GN) is a heterogeneous group of kidney diseases characterized by inflammation and damage to the glomeruli. Current treatments for GN remain suboptimal, creating a pressing need for innovative therapeutic strategies. Short interfering RNAs (siRNAs) represent a promising advance in the therapeutic landscape for GN, offering targeted gene silencing that could fundamentally transform the management of this significant cause of kidney disease. siRNA therapies work by selectively silencing specific genes involved in the pathogenesis of GNs, including interferon pathways, B cell activation, TGF-β, MAPK1, HMGB1, BLYSS, and SIRT1. Preclinical evidence demonstrates improved kidney function and reduced glomerular damage in experimental models. While challenges remain in translating these findings to clinical applications, ongoing research suggests that siRNA-based therapies have the potential to transform the treatment of GN, offering new hope for patients with this challenging kidney disease. This review highlights the impact of siRNA-based therapies in GN, exploring their mechanisms, delivery systems, challenges, and preclinical and clinical evidence.
Introduction:Articular cartilage has a limited intrinsic capacity for regeneration following injury, particularly in cases of severe defects. Exosome-based therapy has emerged as a promising cell-free regenerative strategy, with increasing preclinical evidence supporting its therapeutic potential in cartilage repair. As previous studies have indicated that human adipose-derived mesenchymal stem cells (hADSCs) secrete regenerative factors, whereas human umbilical cord-derived mesenchymal stem cells (hUCMSCs) exert immunomodulatory effects, the combined use of exosomes from these two sources may have complementary therapeutic benefits. Methods:In this study, exosome-enriched extracellular vesicles (EVs) isolated from hADSCs and hUCMSCs were combined, characterized, and evaluated in a cartilage defect model. The isolated EVs displayed a characteristic cup-shaped morphology under transmission electron microscopy, a size distribution ranging from 30 to 200 nm, and high expression levels of the exosomal markers CD9, CD63, and CD81. Results:Treatment with the combined EVs formulation promoted the regeneration of medial femoral condyle defects at 12 weeks post-injury compared to untreated controls, as demonstrated by an improved macroscopic appearance and scoring, radiographic evaluation, and increased deposition of total collagen, glycosaminoglycans, and aggrecan. Conclusion:The findings provide proof-of-concept evidence that a combined hADSC- and hUCMSC-derived EVs formulation represents a feasible cell-free approach to cartilage repair.
