European Journal of Pharmaceutical Sciences最新文献

MicroRNAs (miRNAs) are small regulatory molecules that control protein synthesis, presenting promising opportunities for novel, mechanism-based therapies. Their roles are essential in the biological processes underlying thrombosis, including vascular function, coagulation, and platelet activity. Specific miRNAs, such as miR-126 and miR-223, that influence platelet activation and adhesion are particularly relevant to thrombotic disorders, including deep vein thrombosis (DVT) and pulmonary embolism (PE). This positions them as intriguing targets for new therapeutic strategies. miRNA-based treatments, using synthetic mimics or inhibitors (antagomirs), offer a potential avenue for precisely modulated anticoagulant therapy. However, these approaches remain in early-stage development. Significant challenges must be overcome before miRNA therapies can achieve widespread clinical adoption. Further research is essential to elucidate miRNA function in venous thromboembolism (VTE) fully and to translate these insights into safe and effective treatments. This review summarizes current knowledge of the role of miRNAs in VTE, underscores their substantial therapeutic potential, and addresses the critical obstacles and practical limitations that must be resolved to realize their full promise in treating thrombotic diseases.

Cystic fibrosis (CF) is an inherited condition characterised by thick mucus accumulation in the lungs, leading to recurrent pulmonary infections, inflammation and lung damage. Dornase alfa (Pulmozyme®), or recombinant human deoxyribonuclease I (rhDNase), is a mucolytic agent commonly used to decrease mucus viscosity and improve the lung function of CF patients. However, its delivery via nebulisation presents notable limitations: the process is time-intensive, requires refrigeration, and must be performed in a stationary setting-factors that collectively contribute to a high treatment burden and often reduced patient adherence. Inhalable dry powder formulations offer a promising alternative, combining portability, improved stability, and ease of use. This study explores the feasibility of converting commercially available rhDNase for nebulization into a dry powder formulation, using bovine DNase I as a model system. Co-spray drying of bovine DNase I with sodium chloride and calcium chloride dihydrate was performed at a mass ratio of 1:8.77:0.15. A quality-by-design approach, utilizing a 2³ full-factorial design of experiments, was employed to assess the effects of critical process parameters - solution flow rate, atomising air flow rate, and outlet temperature - on quality attributes, including particle size distribution, yield, and protein recovery. The resulting spray-dried powders demonstrated suitable in vitro aerosolisation characteristics suitable for pulmonary delivery, with enzymatic activity retention of up to 94%. In vitro tests on the most promising formulation showed no cell toxicity, supporting its potential for pulmonary delivery, as a patient-friendly alternative for CF therapy.

Cell-free therapies derived from the mesenchymal stromal cell (MSC) secretome and its extracellular vesicles (EVs) are emerging as a new class of biologics for inflammatory bowel disease (IBD). These acellular formulations capture the immunomodulatory and regenerative effects of MSCs while avoiding the safety, scalability, and regulatory limitations associated with live-cell products. In preclinical models of ulcerative colitis (UC), both whole secretome preparations and isolated EVs have shown consistent therapeutic effects in preclinical models, suggesting reduced inflammation and enhanced mucosal healing through intravenous, intraperitoneal, intracolonic, or intragastric delivery routes. Local administration, particularly intracolonic and intragastric, has yielded the most pronounced outcomes by targeting the affected intestinal tissue directly. Despite these promising preclinical findings, clinical translation remains limited, with only five trials initiated to date. Major challenges include product standardization, potency assessment, and large-scale manufacturing. This review highlights recent advances and persisting bottlenecks in MSC-derived cell-free approaches for IBD, outlining the technological and regulatory milestones required to achieve their clinical implementation.

Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by persistent synovial inflammation, pathological angiogenesis, and progressive joint destruction. Emerging evidence implicates the renin-angiotensin system (RAS) and neuropilin-1 (NRP-1) as key modulators of RA pathogenesis through regulation of inflammatory signaling, vascular remodeling, and osteoclastogenesis. This study explored the mechanistic interplay between RAS and NRP-1 signaling in a rat model of RA induced by complete Freund's adjuvant. Experimental groups received valsartan (VAL), an angiotensin II type-1 receptor (AT-1R) antagonist; ramipril (RAM), an ACE inhibitor or methotrexate (MTX), the standard anti-rheumatic agent. NRP-1 ligand-binding (VEGF-165/Sema3A) and dimerization-associated domain expression were evaluated via immunohistochemistry and western blot. Transcriptional expression of VEGF-165, Sema3A was quantified using qRT-PCR, while RhoA, p-ERK protein levels were assessed by ELISA. Systemic inflammatory mediators (anti-CCP, TNF-α, IL-1β) and the bone resorption marker RANKL were also determined. Histopathological and scanning electron microscopy (SEM) analyses with morphometric evaluation assessed joint integrity. Both VAL and RAM significantly modulated NRP-1 signaling, influencing ligand-receptor interactions, dimerization, and downstream mediators (RhoA, p-ERK). These effects were accompanied by reduced inflammatory activity and preservation of bone and cartilage structure, suggesting that RAS blockade may confer chondroprotective and anti-inflammatory benefits via modulation of the NRP-1 axis. Collectively, the findings highlight a potential mechanistic cross-talk between RAS and NRP-1 pathways, offering a promising direction for future studies aimed at developing novel adjunctive strategies for RA management.