Introduction Coronary artery disease (CAD) may progress to ischemic cardiomyopathy (ICM) and heart failure through maladaptive cardiomyocyte remodeling and myocardial fibrosis. This study aimed to identify key molecular mediators linking inflammatory and fibrotic signaling during this pathological transition.Methods Single-cell RNA sequencing data from human ventricular tissues, including 2 CAD, 3 ICM, and 3 healthy samples (12,818 cells; 7 cell clusters), were integrated for analysis. Cell-cell communication and pseudotime trajectory analyses were performed. Findings were further validated using a bulk transcriptomic dataset (GSE57338), a left anterior descending artery ligation mouse model, and in vitroexperiments in AC16 cardiomyocytes.Results Cardiomyocyte trajectory analysis revealed a progressive upregulation of SERPINE1 from CAD to ICM, accompanied by an expansion of SERPINE1 + cardiomyocytes enriched in inflammation-related pathways. Bulk transcriptomic data and in vivo experiments confirmed increased SERPINE1 expression in diseased myocardium. In vitro , IL-1 beta stimulation increased SERPINE1 expression and secretion while reducing p-SMAD2 levels. Isoproterenol (ISO) stimulation concurrently did not significantly alter SERPINE1 and SMAD2/p-SMAD2. Cardiomyocyte-specific SERPINE1 knockdown in mice partially reversed ISO-induced upregulation of fibrotic/ECM genes (Postn, Col1a1, Col3a1, Acta2), confirming its functional role in vivo.Discussion These findings indicate that SERPINE1 is associated with inflammatory signaling during disease progression and may be regulated through mechanisms that are not fully aligned with canonical TGF-beta signaling.Conclusion SERPINE1 is dynamically regulated during CAD-to-ICM progression and may serve as a marker of disease progression. Its dissociation from canonical TGF-beta signaling suggests a potential role for inflammation-related mechanisms in its regulation and in fibrotic remodeling.
Background: Psoriasis is a chronic immune-mediated inflammatory skin disorder characterized by excessive keratinocyte proliferation and persistent cutaneous inflammation. Although berberine chloride has well-documented anti-inflammatory, anti-proliferative, and immunomodulatory properties, its topical therapeutic efficacy is limited by poor retention in deeper skin layers. This study aimed to develop and optimize berberine chloride-loaded invasomes and to formulate an invasomal gel for enhanced transdermal delivery. Methods: To create a stable vesicular formulation, berberine chloride invasomes were made using a mechanical dispersion process in which all ingredients were uniformly combined and distributed while being mechanically stirred. Using a Taguchi orthogonal array design, numerical variables were set at three levels. Independent variables were egg lecithin % (X1), terpenes % (X2), ethanol % (X3), and Sonication time (min), and the dependent variables were drug entrapment efficiency and in vitro drug release. A total of nine formulations were made. The optimized formulation was evaluated based on vesicle size, polydispersity index, and surface charge. Morphological characteristics were evaluated using scanning electron microscopy. The optimized invasome was incorporated into a carbopol-based gel and evaluated for physicochemical properties, rheological behavior, ex vivo skin permeation, in vivo histology, and tissue-based pathology studies. results: Results: Optimized invasomes exhibited 324.7 nm vesicle size, uniform size distribution, spherical morphology and a moderate negative (-17.18 mV) zeta potential, indicating good colloidal stability and deformability. The invasomal gel exhibited a sustained pattern of drug release, along with significantly improved ex vivo skin permeation and greater drug retention in the skin layers compared to the conventional berberine chloride gel (p < 0.05). Ex vivo study confirmed that the gel permeation across the rat abdominal skin was 3-fold times greater with a flux of ~11.2 µg/cm²/h. Histopathological evaluation of IMQ-induced psoriatic mouse skin revealed marked restoration of normal epidermal architecture which was found from tnf-alpha, CRP and IL-6. Significant reduction in inflammatory infiltration following treatment with the gel was obtained. Results: Optimized invasomes exhibited a vesicle size of 324.7 nm, a uniform size distribution, spherical morphology, and a moderate negative (-17.18 mV) zeta potential, indicating good colloidal stability and deformability. The invasomal gel showed sustained drug release, along with significantly improved ex vivo skin permeation and greater drug retention in the skin layers than the conventional berberine chloride gel (p < 0.05). The ex vivo study confirmed that gel permeation across the rat abdominal skin was 3-fold greater, with a flux of ~11.2 μg/cm²/h. Histopathological evaluation of IMQ-induced psoriatic male Swiss albino mouse skin revealed marked restoration of normal epidermal architecture, along with significant reduction in inflammatory biomarkers indicated by TNF-α, CRP, and IL-6. Discussion: The optimized berberine chloride invasomal gel produced uniform spherical vesicles with an average size of 324.7 nm and a zeta potential of −17.18 mV, indicating acceptable colloidal stability and a deformable nature. The invasomal formulation showed a longer release profile than the conventional gel, reducing the initial burst and maintaining therapeutic drug concentrations in the skin. The spherical shape and uniform nanosize, which encourage close interaction with the stratum corneum and improve follicular and intercellular penetration, are probably responsible for the ex vivo increase in skin penetration. The action of ethanol and terpenes on the lipid barrier, which facilitated drug transport across rat abdominal skin, was probably responsible for the improved penetration into the skin. In the IMQ-induced psoriatic model, the invasomal gel showed impressive therapeutic efficiency by reducing inflammatory cell infiltration and enhancing epidermal structure. Psoriatic inflammation was successfully suppressed, as evidenced by decreased levels of inflammatory markers such as CRP, TNF-alpha, and IL-6. Improved epidermal penetration, enhanced local drug accumulation, and prolonged drug retention enabled by the invasomal delivery method may explain these positive outcomes. Conclusion: Berberine chloride-loaded invasomal gel represents a promising transdermal drug delivery system for psoriasis therapy, offering enhanced skin penetration and localized therapeutic action with reduced potential for systemic side effects.
Introduction: Neurological problems are among the world's most significant health issues. Many conditions are considered incurable because current treatments cannot effectively cross the Blood-Brain Barrier (BBB) to exert pharmacological effects. Nanomedicine utilizing various nanoparticles offers a distinct therapeutic approach to bypass the BBB and address the complex nature of these illnesses. Methods: This review explores different nanocarrier systems—including lipid-based, polymeric, inorganic, and biological systems—that act as molecular vehicles that transport medications across the BBB by either disrupting the barrier or facilitating transcytosis. Results: The study highlights the clinical relevance of nanomedicine for treating neurological disorders, focusing on specific BBB penetration mechanisms, including receptor-mediated transcytosis, peptide-based strategies, and stimuli-responsive systems. Furthermore, it examines the application of nanoparticles as theranostics and in developing precision medicine. Discussion: Nanocarrier systems have shown immense effectiveness in Central Nervous System (CNS) applications. However, despite the promising effectiveness of nanomedicine in treating neurological disorders, further study remains crucial to thoroughly evaluate the long-term toxicity and complications associated with their clinical use. Conclusion: Nanoparticles represent a highly effective strategy for overcoming BBB limitations and improving medication delivery. While they hold great potential for precision medicine and targeted neurological therapies, addressing long-term safety and toxicity is a mandatory requirement before widespread clinical implementation.
Introduction/Objective: Prospective protein function prediction requires evaluation designs that control for temporal leakage and sequence homology while accounting for the strong imbalance of Gene Ontology (GO) labels. We developed ProteinExt3 to integrate complementary sequence- derived evidence for GO-based protein function prediction under a temporally separated and homology-controlled evaluation protocol. Methods: ProteinExt3 is a late-fusion framework that combines representations extracted from ESM- 2 layers 20 and 33, ProtT5 representations, 63 sequence-derived physicochemical features, and BLASTp homology transfer. Fusion weights were learned from out-of-fold (OOF) predictions, and final scores were propagated through the GO directed acyclic graph. The benchmark used experimentally supported GO annotations, a temporal split based on the earliest experimental annotation date, and MMseqs2 filtering between training and prospective test proteins. Results: ProteinExt3 reached Fmax values of 0.226 for Biological Process (BP), 0.547 for Cellular Component (CC), and 0.669 for Molecular Function (MF). Among the evaluated learning-based methods, ProteinExt3 achieved the highest Fmax in all three namespaces. For CC, the frequencybased Naive baseline retained the highest Fmax (0.569), whereas ProteinExt3 achieved higher AUPR and lower Smin. Ablation results showed that the effects of homology transfer, handcrafted features, and pooling differed across namespaces and metrics. Discussion: Most of the OOF gain came from combining prediction branches; optimizing their weights provided a smaller improvement. Component effects varied across GO namespaces and evaluation metrics. Conclusion: ProteinExt3 combines complementary sequence-derived evidence to support protein function annotation and downstream target prioritization.
Introduction: Prostate Cancer (PC) and Benign Prostatic Hyperplasia (BPH) are common urological diseases that may share pathological mechanisms. This study investigated the in vitro antiproliferative activity of water extracts of processed Rheum palmatum (RP) in DU-145 cells and explored the potential relevance of RP-W-associated compounds to PC- and BPH-associated molecular targets through network pharmacology and molecular docking. Methods: RP-W samples were tested against DU-145 cells. Based on previous HPLC profiling, rhein, emodin, and aloe-emodin were selected as representative RP-W-associated compounds for in silico analysis. SwissTargetPrediction identified compound-related targets, which were compared with PC and BPH-related genes. PPI networks were built with STRING and Cytoscape. GO and KEGG were used for enrichment analysis. Molecular docking was performed using Discovery Studio. Results: RP-W-3 had the lowest estimated IC50 against DU-145 cells (4.48 mg/mL). Network pharmacology identified overlapping targets between RP-W-associated compounds and PC- or BPHassociated proteins. Discussion: The predicted targets were associated with inflammatory regulation, hormone-related signaling, apoptosis regulation, DNA repair, miRNA regulation, stress response, xenobiotic response, and extracellular microenvironment-related mechanisms. Docking suggested target-specific interactions, with rhein showing higher scores for ESR1, SHBG, and CASP3 and aloe-emodin for PTGS2, ESR2, AR, and BCL2; AR relevance was restricted to the BPH context. Conclusion: RP-W-3 had the lowest estimated IC50, and based on previous HPLC profiling, rhein was the only anthraquinone marker detected in RP-W-3. These findings provide preliminary in vitro evidence of the inhibitory activity of RP-W-3 against DU-145 cells and computational evidence for the potential relevance of RP-W-associated compounds to PC- and BPH-related molecular targets.
