Abstract: Introduction: Alzheimer’s Disease (AD) is a complex neurodegenerative condition characterized by limited treatment effectiveness, attributed to inadequate Blood-Brain Barrier (BBB) permeability and low medication absorption. Curcumin and ibuprofen possess anti-inflammatory and neuroprotective properties but are limited by pharmacokinetic constraints. This study aimed to synthesize a curcumin–ibuprofen mutual prodrug (CIP), formulate it into chitosan-based microspheres (CIPM), and evaluate its neuroprotective potential for brain-targeted delivery in AD. Methods: CIP was synthesized via ethylenediamine carbodiimide (EDCI) mediated esterification and confirmed through IR, NMR, LC-MS, and DSC. CIPM microspheres were prepared using emulsion crosslinking, characterized by scanning electron microscopy, drug entrapment efficiency (85.5%), zeta potential, particle size analysis, and DSC. In silico tools (SwissADME, ProTox-II) and molecular docking were used to assess ADMET profiles and target binding (AChE, BACE1, β-secretase). Network pharmacology identified overlapping targets between curcumin and AD. In vivo evaluation was conducted in a TMT (Trimethyltin)- induced neurodegeneration rat model through behavioral Morris Water Maze (MWM), Novel Object Recognition (NOR), Social Recognition Test (SRT), and biochemical and histological assessments. Results: CIP demonstrated strong binding affinity with AD-related targets (−10.0 to −8.5 kcal/mol) and favorable ADMET properties. Network analysis identified 226 overlapping targets and key hub genes. CIPM significantly improved cognitive performance, antioxidant enzyme levels, and neuronal integrity compared to individual drugs and showed comparable efficacy to donepezil. Discussion: The present study demonstrates that the curcumin–ibuprofen conjugate, when delivered through chitosan-based microspheres, effectively enhances brain targeting and overcomes pharmacokinetic barriers. The formulation not only improved drug bioavailability but also showed superior neuroprotective and cognitive benefits compared to individual drugs. Molecular docking and network pharmacology further confirmed its multi-target potential, suggesting a synergistic mechanism in modulating key AD pathways. These outcomes highlight CIPM as a promising candidate that warrants further pharmacokinetic and clinical validations for Alzheimer’s therapy. Conclusion: The curcumin–ibuprofen prodrug-loaded microspheres present a promising brain-targeted treatment approach for Alzheimer's disease by improving bioavailability, engaging multiple targets, and providing neuroprotection.
Abstract: Background: Pulmonary fibrosis (PF) is a progressive and fatal interstitial lung disease characterized by the depletion of alveolar epithelial cells (AECs) and the pathological accumulation of extracellular matrix (ECM). Despite its high mortality rate, the molecular drivers of PF progression remain partially understood. Recent evidence suggests that pyroptosis, a pro-inflammatory programmed cell death, plays a pivotal role in orchestrating the inflammatory cascade and fibrotic remodeling in the lung. Methods: This study employed bibliometric and visual analysis via CiteSpace 6.2.4 to systematically map the research landscape of pyroptosis in PF using the Web of Science Core Collection (2010-2025). Based on the identified hotspots, a comprehensive review of the molecular activation pathways and cell-specific mechanisms was conducted. Results: Bibliometric analysis (Modularity Q=0.5381, Silhouette S=0.8236) revealed a significant shift in research focus from basic pathological descriptions (2010-2015) to detailed pyroptotic mechanisms (2015- 2020), with immune checkpoint inhibitors emerging as the latest frontier since 2020. Mechanistically, we propose an "Initiation-Amplification-Persistence" model: AEC pyroptosis initiates epithelial barrier disruption; macrophage pyroptosis amplifies the inflammatory storm and polarizes the immune microenvironment; and fibroblast activation sustains ECM deposition. Furthermore, we summarized potential therapeutic interventions, including small molecule synthetic compounds (Nintedanib, Pirfenidone, MCC950, VX-765, etc.), natural products (Lycorine, Tanshinone IIA, etc.) and biologically active substances (Canakinumab, Anakinra) that exhibit multi-pathway synergistic effects. Conclusion: Targeting the pyroptosis signaling axis offers a promising strategy for reversing PF progression. Future research should prioritize the identification of pyroptosis- related biomarkers and the development of lung-targeted delivery systems to facilitate clinical translation and precision intervention.
Introduction: Acute liver failure (ALF) is a life-threatening condition associated with hepatic encephalopathy (HE), characterised by neurological impairments, hyperammonemia, oxidative stress, and inflammation. Diindolylmethane (DIM), a bioactive compound derived from cruciferous vegetables, has shown potential hepatoprotective and neuroprotective effects via its antioxidant and anti-inflammatory properties. Despite beneficial effects, its protective effects have not been investigated against HE. The present study evaluated the hepatoprotective and neuroprotective effects of DIM in a rat model of thioacetamide (TAA)- induced ALF and HE. Methods: ALF was induced using thioacetamide (TAA; 300 mg/kg, i.p.). DIM at doses of 12.5, 25, and 50 mg/kg, p.o., was administered for 7 days prior to TAA injection. Behavioral assessments, including the open field test and Y-maze, were performed to evaluate motor and cognitive functions. Biochemical parameters (AST, ALT, ALP, and LDH), ammonia levels, oxidative stress markers (MDA, NRF2, SOD, GSH, and catalase), inflammatory cytokines (IL-6, TNF-α, and IL-10), and apoptotic markers (cytochrome c, caspase 9, and caspase 3) were analysed. Histopathological examinations of the liver, cortex, and hippocampus were conducted using hematoxylin and eosin staining. Results: DIM pretreatment significantly reduced liver enzyme levels (AST, ALT, ALP, and LDH), normalised organ weight ratios, and decreased ammonia levels in blood, liver, and brain. DIM attenuated oxidative stress by reducing MDA levels and enhancing NRF2, SOD, GSH, and catalase activity, suggesting its antioxidant potential. Further, DIM reduced IL-6 and TNF-α levels and increased IL-10 levels, indicating its antiinflammatory effects. Furthermore, DIM reduced the apoptotic markers, including cytochrome c, caspase 9, and caspase 3, suggesting attenuation of apoptosis. Additionally, DIM improved motor activity and spatial memory and exhibited an anxiolytic effect. DIM mitigated the TAA-induced liver, hippocampal, and cortical tissue abnormalities. Discussion: The findings suggest that DIM exerts protective effects against ALF-induced HE by modulating key pathological mechanisms, including oxidative stress, neuroinflammation, and apoptosis. The reduction in hyperammonemia and restoration of biochemical and behavioral parameters indicate its potential role in preserving liver and brain function. Conclusion: DIM demonstrates significant hepatoprotective and neuroprotective effects in TAA-induced ALF and HE. These effects are mediated through multiple mechanisms, suggesting DIM as a potential therapeutic candidate for managing ALF-associated neurological complications. Future studies require investigating the in-depth mechanism of DIM against HE.
Abstract: Hyperlipidaemia is a major modifiable risk factor for cardiovascular disease and remains a global health concern. Although conventional lipid-lowering drugs are effective, their long-term use is often associated with adverse effects, prompting interest in safer dietary alternatives. Flavonoids, such as quercetin, naringenin, and catechins, have gained attention for their hypolipidemic and cardioprotective properties. This narrative review summarizes the current evidence on the therapeutic potential of quercetin, catechins, naringenin, and their bioactive metabolites in the management of hyperlipidaemia. The literature was identified through comprehensive searches of PubMed, Scopus, Web of Science, and Google Scholar for studies published between 2015 and March 2026 using combinations of the keywords flavonoids, quercetin, catechins, naringenin, metabolites, hyperlipidaemia, dyslipidaemia, lipid metabolism, cardiovascular disease, and gut microbiota. Original research articles, clinical studies, experimental investigations, and high-quality review articles published in English were considered, while duplicate, non-English, and unrelated reports were excluded from the study. Evidence indicates that flavonoids and their metabolites modulate multiple pathways involved in lipid homeostasis, including the inhibition of HMG-CoA reductase, activation of AMPK and PPARα, suppression of SREBP-1c, enhancement of LDL receptor expression, regulation of gut microbiota, and attenuation of oxidative stress and inflammation. Despite encouraging preclinical and clinical findings, limited bioavailability, extensive metabolism, inter-individual variability, and insufficient long-term clinical evidence remain important challenges. Overall, flavonoids and their metabolites represent promising adjunctive dietary strategies for improving lipid metabolism and reducing cardiovascular risk. However, welldesigned randomized clinical trials and advanced delivery systems are needed to establish their therapeutic efficacy and clinical applicability.
Abstract: Graves’ Disease (GD) is the leading cause of autoimmune hyperthyroidism and is still considered a challenging clinical condition. Antithyroid drugs, radioactive iodine, and thyroidectomy have long been used as main treatments. These approaches are generally effective in restoring euthyroidism and controlling thyroid function, even if they cannot target the underlying autoimmune mechanisms implicated in the disease. As a result, relapses after medical therapy remain frequent, whereas definitive treatments often lead to permanent hypothyroidism and the need for a lifelong thyroid hormone replacement. New results in the study of immunological mechanisms underlying GD have led to the development of targeted therapies. Targeted strategies are based on key components of disease pathogenesis, such as the thyrotropin receptor, B lymphocytes, co-stimulatory immune pathways, the insulin-like growth factor-1 receptor, and neonatal Fc receptors. A pivotal step in the development of targeted mechanism-based therapies for GD has been reached with the approval of teprotumumab. Several targeted therapies have been evaluated, such as K1-70, iscalimab, rituximab, tocilizumab, batoclimab, and the antigen-specific immunotherapy ATX-GD-59. This review highlights the limitations of currently available treatment options by examining the most promising emerging therapies and the future horizons for precision medicine in GD. Advances in the therapeutic landscape offer disease-modifying strategies that could complement and potentially replace current treatment strategies.
