Search Results (4,953)

Parkinson’s disease (PD) is pathologically characterized by the abnormal aggregation of α-synuclein and the progressive loss of dopaminergic neurons, with microglia-mediated neuroinflammation acting as a pivotal driver of pathogenesis. Ferroptosis, an iron-dependent form of regulated cell death, significantly contributes to PD progression. However, the precise mechanisms governing microglial ferroptosis under α-synuclein pathology, particularly the regulatory role of the master antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), remain elusive. Here, we employed an in vitro BV2 microglial model and an in vivo A53T transgenic mouse model to elucidate the regulatory effects and underlying mechanisms of Nrf2 on ferroptosis-associated phenotypes induced by α-synuclein pre-formed fibrils (PFFs). In vitro, PFF treatment significantly downregulated microglial Nrf2 expression, triggering ferroptosis-associated phenotypes characterized by reactive oxygen species (ROS) accumulation, ferrous iron (Fe²⁺) overload, and elevated lipid peroxidation. Genetic knockdown of Nrf2 exacerbated these ferroptosis-associated phenotypes and accelerated α-synuclein aggregation. Conversely, Nrf2 overexpression or pharmacological activation via dimethyl fumarate (DMF) profoundly suppressed α-synuclein pathology and mitigated ferroptosis-associated signatures. In vivo, microglial activation in the substantia nigra of PD mice was accompanied by marked Nrf2 downregulation. Strikingly, microglia-specific Nrf2 overexpression significantly reversed motor and non-motor deficits (including olfactory and locomotor impairments), demonstrating the sufficiency of microglial protection. Furthermore, systemic administration of the Nrf2 activator DMF not only ameliorated motor dysfunction but also concurrently rescued nigral dopaminergic neurons and reduced striatal α-synuclein aggregation. Taken together, our findings identify Nrf2 downregulation-driven microglial ferroptosis-associated phenotypes as a critical pathogenic mechanism, and demonstrate that targeting this pathway in vivo ameliorates motor and non-motor deficits while preserving dopaminergic neurons in PD mice. These findings support further research on Nrf2 activation and DMF as potential therapeutic strategies for PD. Full article

Background/Objectives: Based on the central nervous system-related activity potential of 1,3,4-thiadiazole derivatives, novel 1,3,4-thiadiazole compounds were synthesized, and their possible antidepressant-like and anxiolytic-like effects were investigated. Methods: The chemical structures of the compounds were elucidated using several spectroscopic techniques. Antidepressant-like effects of compounds were evaluated using the tail suspension and the modified forced swimming tests, while anxiolytic-like effects were assessed using the hole board, elevated plus maze, and open field tests in male Balb/c mice. Motor activities of the animals were examined using the activity-meter device. Mechanistic and computational in silico studies were also performed. Results: The results demonstrated that compounds 4e–4i exhibited antidepressant-like effects, whereas only compound 4e showed an anxiolytic-like effect. None of the compounds produced significant alterations in motor activities of animals, indicating that the observed behavioral effects were specific. The antidepressant-like effects of compounds 4e–4i were abolished by p-chlorophenylalanine methyl ester (PCPA) and α-methyl-para-tyrosine methyl ester (AMPT) pre-administration indicating that the antidepressant-like effects of these test compounds are related to both serotonergic and catecholaminergic mechanisms. Furthermore, the anxiolytic-like effect of compound 4e was reversed by flumazenil and NAN-190 pre-administrations, indicating the participation of the GABA-A benzodiazepine receptor complex and 5-HT_1A receptors in its pharmacological activity. Computational in silico studies revealed that compounds have good ADME profiles; compounds 4e–4i interact with the serotonin transporter; compound 4e shows affinity for GABA-A and 5-HT_1A receptors; and all interactions remain stable under dynamic conditions. Conclusions: These findings supported the previous papers reporting the antidepressant-like and anxiolytic-like effects of 1,3,4-thiadiazole derivatives. Full article

Gammaherpesviruses are oncogenic viruses that reprogram host cell metabolism to support viral production. Among these, murine herpesvirus 68 (MHV-68) serves as a model system for studying lytic gammaherpesvirus infection and associated host cell changes. To characterize host transcriptional alterations induced throughout lytic gammaherpesvirus infection and identify novel host pathways that may be therapeutically targeted, we performed temporal bulk RNA-sequencing of mock- and MHV-68-infected NIH 3T3 cells at various timepoints throughout the lytic cycle. Our analysis revealed widespread and progressive host gene expression changes, including robust innate immune pathways and extensive remodeling of metabolic gene expression. We further identified a strong activation of the pentose phosphate pathway (PPP) genes, accompanied by increased abundance in PPP metabolic intermediates. Pharmacological inhibition of the PPP with 6-aminonicotinamide (6-AN) reduced infectious virus production. Moreover, at the intersection of metabolic and transcriptional reprogramming, we identified infection-associated gene expression changes in chromatin-modulating enzymes, including Tet2, and their metabolite co-factors, such as α-KG. Pharmacological inhibition of Ten-Eleven Translocation (TET) enzymatic activity led to a marked decrease in infectious MHV-68 production. Collectively, these findings define a novel metabolic–epigenetic crosstalk that supports productive gammaherpesvirus replication and identifies host pathways that can be targeted to treat lytic gammaherpesvirus infections. Full article

Background and Objectives: SGLT2 inhibitors increase hemoglobin and hematocrit in multiple clinical settings, an effect increasingly attributed to stimulation of erythropoiesis rather than hemoconcentration. However, most mechanistic evidence derives from diabetic populations, leaving uncertainty as to whether this response depends on diabetes-related metabolic changes. To evaluate whether dapagliflozin stimulates erythropoiesis in non-diabetic patients with heart failure and to determine whether hematologic changes correlate with renal, cardiac, inflammatory, hepatic, or iron-related parameters. Materials and Methods: In this retrospective observational study, each of 68 non-diabetic heart failure patients served as their own control. Hematologic, renal, cardiac, inflammatory, hepatic, and iron parameters were assessed at three time points: one year prior to dapagliflozin initiation, at baseline, and one year after initiation of therapy. Changes were analyzed using paired tests and correlation analyses. Results: Hemoglobin, hematocrit, and red blood cell count were significantly lower at the baseline compared with values recorded one year before dapagliflozin initiation and increased significantly during the year following treatment (all p < 0.001), while mean corpuscular indices remained stable. Serum iron decreased before treatment and increased significantly after dapagliflozin initiation (p < 0.05 vs. baseline); however, changes in serum iron did not correlate significantly with changes in hemoglobin after treatment. Inflammatory markers showed a modest reduction in C-reactive protein after treatment, while composite inflammatory indices remained largely stable. Liver enzymes showed no significant longitudinal changes. Correlation analyses demonstrated no association between changes in hemoglobin and changes in eGFR (ρ = 0.202, p = 0.098) or NT-proBNP (ρ = −0.003, p = 0.981) after treatment. Hematologic variables remained strongly intercorrelated, whereas cross-system correlations were minimal, indicating that erythropoietic stimulation occurred largely independently of renal or cardiac functional trajectories. Conclusions: Dapagliflozin robustly stimulates erythropoiesis in non-diabetic patients with heart failure, independent of improvements in kidney or cardiac function. Although serum iron levels improved after treatment, the absence of a direct correlation with hemoglobin suggests that iron mobilization may act as a permissive rather than a primary driver of erythropoietic response. These findings support the concept that erythropoiesis represents a diabetes-independent pharmacologic action of SGLT2 inhibitors and may involve renal, hepatic, inflammatory, and iron-regulatory pathways beyond those described in diabetic physiology. Dedicated mechanistic studies in non-diabetic populations are warranted. Full article

Chronic obstructive pulmonary disease (COPD), which includes chronic bronchitis and emphysema, is highly prevalent worldwide and is the third leading cause of death. While some aspects of the disease were known since the Enlightenment, Laennec’s work in the 19th century began the process of our current understanding of this disease. In this narrative review, 13 clinicians and scientists with over three centuries of cumulative experience treating and studying COPD give their perspectives on the science underpinning our modern concept of this disease and its management. These include (1) the challenges of coming up with a name for what is a complex syndrome; (2) the evolution of our thinking on the natural history of the disease; (3) the importance of particulate matter inhalation in its pathogenesis; (4) the often-overlooked but important—and often treatable—systemic effects of the disease that contribute to its morbidity and mortality; (5) the changes in our perspective of not just addressing pathologic or physiologic abnormalities but also measuring outcomes, such as breathlessness or health-related quality of life, that are of considerable importance to the patient; (6) the role of pharmacologic therapy in not only providing symptomatic relief by increasing airway caliber but also in disease modification, especially by reducing exacerbation frequency; (7) lung hyperinflation as an essential feature of COPD pathophysiology, driving symptom burden, exercise limitation, and mortality risk; (8) long-term oxygen therapy, despite being demonstrated to prolong survival in a defined set of hypoxemic patients with COPD, still having unanswered questions regarding its application and delivery; and (9) pulmonary rehabilitation, a major component of the non-pharmacologic treatment of COPD patients and prominently situated in clinical guidelines for this disease. While this, by necessity, must be a brief review of a very complex disease, the perspectives of these esteemed clinicians and scientists should be of use to other clinicians in understanding and managing this disease. Full article

Icariin (ICA), a prenylated flavonoid glycoside from Epimedium (Yin Yang Huo), exhibits multi-organ pharmacological effects and has emerged as a promising candidate for osteoporosis therapy and bone tissue regeneration because of its capacity to modulate diverse osteogenic, anti-inflammatory, and angiogenic signaling pathways. Preclinical studies in osteoporotic models suggest that ICA improves trabecular microarchitecture and increases bone mineral density. Mechanistically, ICA modulates bone remodeling bidirectionally: it promotes osteoblast differentiation and extracellular matrix mineralization via activation of pro-osteogenic pathways, including Wnt/β-catenin and PI3K/Akt signaling, while simultaneously inhibiting osteoclastogenesis and bone resorption by suppressing RANKL-mediated NF-κB activation, thus reestablishing remodeling equilibrium. Despite these benefits, clinical advancement is hindered by the suboptimal oral bioavailability of ICA, stemming from poor intestinal absorption and extensive first-pass metabolism. To address this, innovative delivery systems have been engineered to enhance localized bioavailability and sustain therapeutic efficacy, such as hydrogel depots, nanoparticle formulations, and 3D-printed scaffolds enabling precise, controlled release. In bone tissue engineering applications, ICA-incorporated biomaterials—either standalone or in combination with osteogenic factors or exosomes—foster a regenerative niche by mitigating inflammation and oxidative stress, while synergistically promoting osteogenesis and angiogenesis, thereby expediting bone defect healing and osseointegration. Overall, these mechanistic elucidations and delivery advancements underscore ICA’s potential as a translational candidate for osteoporosis treatment and bone regenerative therapies. This review aims to critically and systematically synthesize current evidence on ICA-mediated bone repair and regeneration, with a particular emphasis on the molecular regulation of osteogenic signaling, the restoration of bone-remodeling homeostasis, and delivery-system-enabled strategies that may facilitate translational application. Full article

Tauopathies, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal lobar degeneration with tau pathology, are unified by pathogenic tau misfolding, post-translational modification, aggregation, and network-level spread. Yet decades of drug development that predominantly pursued single nodes (e.g., one kinase, one aggregation inhibitor, one monoclonal antibody epitope) have repeatedly delivered late-stage disappointments, underscoring a central lesson: tauopathy behaves less like a linear pathway and more like a coupled system of proteostasis failure, neuroinflammation, synaptic-mitochondrial stress, and metabolic dysregulation. This review examines rhizomes (notably Zingiberaceae genera such as Curcuma, Zingiber, Alpinia, Kaempferia, and Boesenbergia) as chemically diverse “multi-target platforms” whose bioactives can engage several tau-relevant nodes simultaneously. We synthesise evidence across tau phosphorylation (GSK-3β/CDK5 and upstream stress signalling), tau aggregation and seeding, autophagy-lysosome and proteasome pathways, redox-mitochondrial resilience, neuroinflammatory circuits (NF-κB/NLRP3), and neuro-metabolic signalling (insulin-PI3K-AKT, AMPK-mTOR). A translational lens is applied throughout, focusing on drug-likeness and CNS multiparameter optimisation; BBB permeability and efflux; metabolism and bioavailability constraints; and formulation strategies (nanoparticles, phytosomes, engineered exosomes) that may render rhizome-derived scaffolds more clinically plausible. We conclude that rhizomes offer credible mechanistic hypotheses for tau modulation, but progress depends on rigorous standardisation, realistic exposure matching, biomarker-driven study design, and a shift from “single-compound optimism” to network pharmacology with translational discipline. Full article

Background: Peripheral neuropathy is a common and clinically heterogeneous neurological condition caused by metabolic, inflammatory, toxic, or traumatic factors and is associated with sensory deficits, neuropathic pain, motor impairment, and reduced functional capacity. Management remains challenging and often requires multimodal therapeutic approaches, as pharmacological monotherapy frequently provides incomplete symptom control. Objective: This narrative review explores the conceptual rationale for combining galantamine with iontophoresis and Black Sea brine-based therapy as a potential multimodal strategy for peripheral neuropathy management. Main Findings: Galantamine, a reversible acetylcholinesterase inhibitor and positive allosteric modulator of nicotinic acetylcholine receptors, has demonstrated neuroprotective, neuromodulatory, and anti-inflammatory properties in experimental settings. Iontophoresis may provide a non-invasive method for targeted local drug delivery while reducing systemic exposure. Black Sea brine, widely used in Bulgarian balneological and rehabilitation practice, has been associated with improved circulation, pain reduction, and neuromuscular support. The reviewed evidence suggests biologically plausible complementary mechanisms; however, no direct clinical studies evaluating the combined intervention were identified. Limitations: Current evidence is indirect and derived from separate investigations of galantamine, iontophoresis, and brine-based therapy, as well as heterogeneous historical and regional sources. Therefore, the proposed combination should be considered hypothesis-generating rather than evidence-established. Conclusions: The combination of galantamine, iontophoresis, and Black Sea brine represents a potentially interesting multimodal concept for peripheral neuropathy rehabilitation. Well-designed preclinical and clinical studies are required to determine safety, feasibility, optimal treatment parameters, and therapeutic efficacy. Full article

Conventional tumor therapies and traditional nanocarrier delivery systems both suffer from multiple limitations. Traditional Chinese medicine polysaccharides (TCMPs), which possess excellent biocompatibility, low toxicity, structurally modifiable characteristics and inherent pharmacological activities, have emerged as promising functional materials for constructing antitumor drug delivery systems and are being gradually applied in tumor combination therapy. This review systematically summarizes the common structural characteristics, biological functions, and structure–activity relationships of representative TCMPs. It further discusses the principal modification strategies used to construct TCMPs-based drug delivery systems and highlights recent progress in their applications in immunotherapy-centered combination therapy. In addition, it outlines their mechanistic basis and therapeutic potential for improving drug delivery efficiency and antitumor efficacy. This review provides theoretical references for the optimal design of such novel systems and guidance for their applications in precision treatment of tumors, while also pointing out some challenges in the translational research of such systems. Full article

Background/Objectives: The blood–brain barrier (BBB) presents a major challenge for delivering therapeutics to the central nervous system (CNS) due to its highly selective permeability. Human brain microvascular endothelial cells (hBMECs), the principal cellular component of the BBB, tightly regulate molecular transport and restrict the entry of many CNS-targeted therapies. Lipid-based nanoparticles have emerged as promising carriers for BBB transport because of their biocompatibility, tunable surface properties, and cargo encapsulation capabilities. One strategy to enhance nanoparticle transport involves surface functionalization with ligands that exploit endogenous transcytosis pathways. Mannose-6-phosphate (M6P), a glycan implicated in the brain entry of certain proteins and viruses, represents a potential targeting ligand for this purpose. Methods: In this study, we established a physiologically relevant in vitro BBB model using human-induced pluripotent stem cell-derived brain microvascular endothelial cells (hiPSC-BMECs) to evaluate M6P-functionalized liposomes for BBB transport. Fluorophore-labeled liposomes were used to monitor nanoparticle uptake and transcytosis. Results: M6P-functionalized liposomes exhibited significantly enhanced uptake in hiPSC-BMECs compared with non-functionalized control liposomes. Pharmacological inhibition studies supported the involvement of a clathrin-sensitive endocytic pathway. Transcytosis assays demonstrated enhanced BBB crossing of M6P-functionalized liposomes, with transport increasing according to ligand density and reaching approximately 55% of the transport observed for transferrin under the same experimental conditions. Following transcytosis, intact M6P-functionalized liposomes showed significantly higher uptake by downstream hiPSC-derived neurons and astrocytoma cells compared with control formulations. Conclusions: Together, these findings support M6P-functionalization as a promising strategy to enhance liposome uptake and transcytosis across a human-relevant in vitro BBB model. This work provides a proof-of-concept framework for the development and optimization of glycan-functionalized nanocarriers for CNS-directed delivery. Full article

Osteoporosis is a systemic skeletal disorder characterized by low bone mass, microarchitectural deterioration, and an increased risk of fracture. Its pathogenesis is closely associated with disturbances in energy metabolism, particularly glucose metabolic reprogramming in bone cells. Under osteoporotic conditions, the balance between osteoblasts and osteoclasts is disrupted, accompanied by impaired oxidative phosphorylation, dysregulated glycolysis, and reduced tricarboxylic acid cycle efficiency, ultimately leading to mitochondrial dysfunction. These metabolic alterations result in an insufficient energy supply and accelerate bone loss. Accordingly, the modulation of key enzymes involved in glucose metabolism has emerged as a promising therapeutic strategy. Strategies include the use of natural compounds, traditional Chinese medicine formulas, and specific inhibitors to modulate glucose metabolism processes and related pathways, thereby restoring cellular energy homeostasis and bone remodeling balance. This review summarizes pharmacological agents regulating glucose metabolism and proposes a hierarchical framework for therapeutic prioritization: first, inhibiting pathological glycolysis in osteoclasts (particularly via LDHA and PKM2). Second, restoring oxidative phosphorylation in osteoblasts (e.g., via COX I–V or ATP synthase). And third, employing multi-target traditional Chinese medicine formulas as complementary strategies. By establishing this cell-type-specific and pathway-specific hierarchy, the review aims to provide a theoretical basis for future research on metabolic interventions in bone diseases. Full article

Endometriosis (EMT) is characterized by a chronic inflammatory disorder in the female reproductive system, posing significant challenges to global women’s health. Necrosis by Sodium Overload (NESCO) is a novel immunogenic programmed cell death (PCD) pattern that may potentially inhibit natural killer (NK) cell activation by increasing cytotoxicity and the inflammatory response in the EMT microenvironment. By integrating three bulk datasets to compare endometrium tissues between endometriosis patients and normal controls and the NESCO gene list from a public database, we identified NK- and NESCO (NN)-associated hub genes via integrative bioinformatic analyses utilizing Limma, WGCNA, CIBERSORT and machine learning frameworks. The diagnostic performance of NN-associated hub genes was evaluated across the three aforementioned datasets and two independent validation sets. Furthermore, their molecular and immune features were estimated at the bulk and single-cell transcriptomic levels. In addition, endometriosis patients were classified into two novel molecular subgroups based on consensus clustering of NN. Finally, the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and molecular docking were used to identify compounds in Chinese traditional medicine (CTM) that can target NN-associated hub genes for endometriosis treatment. FABP4 and SLC2A1 can be considered NN-associated hub genes that are involved in EMT pathogenesis, and natural compounds including the CTM GuiZhiFuLingWan (GZFLW) can be considered therapeutic agents for EMT treatment as they target FABP4 and SLC2A1. Our study is the first to reveal the diagnostic and druggable roles of NESCO and NK cells, the corresponding molecular and immune features of NN-associated hub genes, and the therapeutic potential of GZFLW. Full article

Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS; Lou Gehrig’s disease), represent a growing global health burden characterized by progressive neuronal loss and functional decline. Despite decades of intensive research, effective disease-modifying therapies remain limited, underscoring the urgent need for innovative therapeutic strategies. This review highlights recent advances in the understanding of disease etiology and emerging treatment approaches, with a particular focus on modalities with translational potential. We discussed novel disease-modifying interventions, including gene and cell therapies, RNA-targeting strategies, and immunotherapies aimed at clearing misfolded proteins such as amyloid-β, tau, and α-synuclein. In parallel, we examined the evolving recognition of neuroinflammation and mitochondrial dysfunction as actionable therapeutic targets, alongside progress in precision medicine and biomarker-guided approaches that enable early diagnosis and individualized treatment. Additionally, we summarized developments in repurposed pharmacological agents, neuroprotective compounds, and lifestyle interventions, emphasizing the importance of integrative, multimodal strategies. Across AD, PD, and ALS, convergent molecular mechanisms, including protein misfolding, oxidative stress, and disrupted proteostasis, present opportunities for cross-disease therapeutic targeting. Finally, we addressed key challenges and future directions, including translating preclinical efficacy into clinical success, optimizing CNS-targeted delivery systems, and navigating ethical considerations surrounding gene editing and stem cell therapies. Full article

Asthma represents a chronic inflammatory condition of the respiratory tract, where long-term bronchial inflammation serves as a primary driver of progressive airway remodeling. This complex pathology emerges from the intricate synergy between host genetic susceptibility and diverse environmental triggers, ultimately impairing pulmonary function. At the cellular level, asthmatic responses are orchestrated by a dynamic crosstalk among various immune and structural populations, including airway epithelial cells, T-lymphocytes, eosinophils, and mast cells, which collectively perpetuate the inflammatory milieu. Although inhaled corticosteroids are the conventional cornerstone of therapy, their clinical application is frequently hindered by potential systemic toxicity and the emergence of steroid-resistant phenotypes. Consequently, botanical extracts derived from both aerial and underground plant organs have gained attention as versatile multi-target candidates capable of modulating the multifaceted pathophysiological networks of asthma. This scoping review critically synthesizes the pharmacological efficacy of these plant-based interventions in regulating pivotal signaling cascades, such as MAPK, NF-κB, STAT3/6, and GATA3. Based on a systematic literature search covering the period from 2005 to 2025, this study provides a focused quantitative analysis of preclinical literature from the last decade (2016–2025) to evaluate the in vitro and in vivo models employed to validate these therapeutic effects. The assessment reveals that the vast majority of current research continues to rely on crude botanical preparations, with only a limited subset of studies utilizing enriched fractions or fully characterized isolated compounds. This predominance of unrefined extracts underscores a significant gap in chemical standardization and highlights the necessity for more rigorous mechanistic validation. Ultimately, this paper outlines strategic pathways for translating preclinical findings into clinical practice, offering a robust framework for the development of standardized plant-derived interventions in asthma management. Full article

Cataract remains the preeminent cause of reversible blindness globally, with cataract extraction and intraocular lens (IOL) implantation serving as the definitive surgical intervention. Nevertheless, its long-term efficacy is undermined by formidable postoperative complications, specifically posterior capsule opacification (PCO) and endophthalmitis, which necessitate effective prophylactic strategies. IOL modification has emerged as a pivotal paradigm to effectively mitigate these complications. Current approaches encompass surface modification, drug delivery IOLs, and photo-responsive IOLs. Driven by the rapid interdisciplinary convergence of materials science, ophthalmology and pharmacology, the field has also evolved to have combined modification strategies and multifunctional systems. This review provides a comprehensive overview of the recent progress in IOL modification for postoperative complication prophylaxis. By categorizing recent advancements into three major types—surface modification, drug delivery systems, and photo-responsive IOLs—we critically evaluate their mechanisms, advantages, and limitations. Furthermore, we offer strategic insights to accelerate the development of IOL modification and bridge the gap between innovation and clinical translation. Full article