Search Results (827)

Background and Objectives: Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and current therapies provide only limited symptomatic relief without effectively slowing its progression. Increasing evidence suggests that aberrant activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling cascade contributes to AD-associated neuroinflammation. This study investigated the therapeutic potential and molecular mechanisms of JAK inhibitors in AD using integrated bioinformatics and network pharmacology approaches. Materials and Methods: Potential anti-AD targets of JAK inhibitors were identified using the SwissTargetPrediction and GeneCards databases. Functional enrichment, protein–protein interaction (PPI) analysis, transcriptomic validation using public datasets, regulatory network construction, molecular docking, normal mode analysis (NMA), and absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction were performed to investigate the potential mechanisms of action of these drugs in AD. Results: Our analysis identified 163 shared targets between JAK inhibitors and AD. Enrichment analysis revealed that these genes were primarily involved in protein phosphorylation and were enriched in key signaling pathways, including the neurotrophin, phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), and mitogen-activated protein kinase (MAPK) signaling pathways. PPI analysis identified AKT1, BCL2, SRC, STAT3, and TNF as five highly ranked hub targets across multiple topological algorithms. Transcriptomic validation confirmed significantly higher expression of these targets in the prefrontal cortex of individuals with AD compared with normal subjects. Molecular docking indicated that pacritinib and momelotinib showed relatively favorable predicted interactions with the hub proteins, while NMA revealed differences in the predicted flexibility of the docked complexes. Furthermore, ADMET prediction showed that pacritinib possesses favorable pharmacokinetic properties for the treatment of AD. Conclusions: Collectively, these findings provide mechanistic insights into the potential effects of JAK inhibitors in AD and identify pacritinib as a computationally prioritized candidate that warrants experimental validation in appropriate AD models. However, as this study is based solely on computational analyses without wet-lab validation, the findings should be considered hypothesis-generating in silico evidence, and the potential safety concerns of pacritinib require further investigation. Full article

C-C chemokine receptor type 5 (CCR5) is the primary co-receptor mediating the entry of R5-tropic human immunodeficiency virus type 1 (HIV-1) into CD4+ T cells and macrophages, making it one of the most promising therapeutic targets in HIV cure research. The naturally occurring CCR5Δ32 mutation which abolishes surface CCR5 expression in homozygous individuals has provided strong clinical evidence for CCR5-directed strategies after multiple cases of sustained HIV remission following allogeneic hematopoietic stem cell transplantation (HSCT) from CCR5Δ32 donors. This review summarizes the current understanding of the evolutionary origin and global distribution of the CCR5Δ32 allele, as well as the clinical evidence from landmark transplantation cases. We also discuss recent findings demonstrating that durable HIV remission may be achieved following transplantation from heterozygous CCR5 wild-type/Δ32 donors, suggesting that factors such as donor chimerism, conditioning regimens and graft-versus-reservoir effects contribute substantially to reservoir clearance alongside CCR5 disruption. In addition, we examine emerging evidence that pharmacological inhibition of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway can reversibly suppress CCR5 expression, reduce HIV replication, limit reservoir establishment, and attenuate immune activation. Collectively, these advances highlight the evolving landscape of CCR5-targeted therapies and support the development of safer and more broadly applicable approaches toward durable HIV remission and, ultimately, an HIV cure. Full article

Cells of higher organisms express numerous cell surface proteins, and their spectrum and level of expression are directly related to cells’ functions. The technology of mass cell selection based on the surface protein expression levels may be highly important both for basic research and cell therapy applications. We have previously developed a method of magnetic selection of cells differing in surface marker expression levels, which we term here MACS-MEL (Magnetic-Assisted Cell Selection by Marker Expression Levels). The method demonstrated its effectiveness in the artificial model system, namely retrovirally transduced NIH 3T3 cells. However, whether it was also applicable to complex natural cell populations remained unclear. In the current study, we validated the MACS-MEL approach by separating mouse bone marrow (BM) cells into fractions according to the expression of pan-hematopoietic marker CD45. In the basic protocol, two-stage fractionation of CD45⁺ cells from BM was performed using selection of cells consecutively with 2 μL and 8 μL of anti-CD45 magnetic beads, resulting in isolation of CD45^high and CD45^int cell populations. To explore in full the potential of the method, the extended protocol was also tested, where a third selection stage with 30 μL of anti-CD45 beads was added. The isolated cell fractions were analyzed by flow cytometry for CD45 expression, as well for CD11b, Gr-1, CD117, CD115 and CD19 markers, while their in vitro progenitor function was assessed by quantitating colony-forming units (CFUs) in methyl cellulose. The results of analysis demonstrate that the isolated cell fractions significantly differed both in their surface phenotypes and CFU potential. In particular, cell fractions with progressively reduced CD45 expression were characterized by decreasing expression of myeloid differentiation markers CD11b and Gr-1, as well as B-lymphoid marker CD19. The expression of stem/progenitor cell marker CD117, on the contrary, significantly increased. The CFU frequency also strongly correlated with decrease in CD45 expression, while the differentiation potential of CFUs differed substantially in various cell fractions. In general, our results demonstrate that less differentiated hematopoietic cells in mouse BM studied using in vitro tests are characterized by lower CD45 expression levels, in full accordance with data obtained in human system. Successful validation of the MACS-MEL in a BM system, characterized by existence of multiple cell types and high phenotypic and functional heterogeneity, demonstrated the effectiveness, simplicity and affordability of this method. The MACS-MEL approach can be applied for mass selection of cells based on differential marker expression and may yield cell subsets suitable for advanced cell therapy applications. Full article

Regular exercise mediates inter-tissue communication between skeletal muscle and the immune system through skeletal muscle-derived secretory factors, providing an important molecular basis for the beneficial effects of exercise on chronic inflammation, metabolic dysregulation, and impaired tissue repair. As key effector cells of the innate immune system, macrophages do not simply conform to a dichotomous classification of classically activated M1 macrophages and alternatively activated M2 macrophages; rather, their functional states constitute a dynamic spectrum shaped by exercise load, recovery time window, tissue microenvironment, and disease context. This review focuses on recent advances in exercise-induced skeletal muscle secretory factors involved in macrophage functional remodeling. Representative signals, including interleukin-6 (IL-6), irisin, meteorin-like protein (METRNL), fibroblast growth factor 21 (FGF21), oncostatin M (OSM), decorin, myostatin, chemokines, and extracellular vesicles, are systematically summarized in terms of their exercise responsiveness, evidence for skeletal muscle origin, and evidence supporting macrophage regulation. Based on these dimensions, an evidence-strength grading framework is further proposed. Moreover, this review integrates key signaling axes, including glycoprotein 130 (gp130)/Janus kinase (JAK)/signal transducer and activator of transcription (STAT), signal transducer and activator of transcription 6 (STAT6)/peroxisome proliferator-activated receptor gamma (PPARγ), AMP-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (Nrf2)/nuclear factor kappa B (NF-κB), transforming growth factor beta (TGF-β)/Smad, and chemokine receptor pathways, to explain how exercise-induced secretory networks participate in the dynamic regulation of the macrophage functional spectrum through immune cell recruitment, inflammatory clearance, immunometabolic reprogramming, matrix remodeling, and repair-niche formation. Current evidence indicates the translational potential of exercise-induced skeletal muscle secretory factors in skeletal muscle repair, metabolic inflammation, aging-related functional decline, and cancer rehabilitation. However, this field still faces several major challenges, including insufficient tracing of skeletal muscle-derived signals, limited direct causal validation, a lack of human tissue-level evidence, and unclear exercise dose–response relationships. Future studies should combine tissue-specific genetic interventions, receptor blockade, single-cell and spatial omics, metabolic flux analysis, and standardized human exercise interventions to further clarify the mechanistic basis and application boundaries of exercise-induced skeletal muscle–macrophage communication, thereby providing a theoretical foundation for precision exercise prescription and chronic inflammation intervention. Full article

Background: Former and current smokers in lung cancer screening remain at elevated risk for lung cancer despite smoking cessation. We and others have shown that curcumin (CUR) exhibits anti-inflammatory and antiproliferative effects but is limited by poor bioavailability. However, since CUR is lipophilic, co-administration with ω-3 FAs represents a mechanistically rational strategy to enhance delivery and target complementary pathways, including signal transducer and activator of transcription 3 (STAT3) and the transcription factor NF-κB (NF-κB) signaling for lung cancer chemoprevention. Methods: We conducted a randomized, single-blind, placebo-controlled Phase II pilot study evaluating CUR combined with ω-3 FAs in high-risk former and current smokers with CT-detected pulmonary nodules. Participants received intervention agents with active-dose groups (low dose = 3; high dose = 9) or a placebo (n = 7) for 6 months. Primary endpoints included radiologic changes in nodule size, number, and density. Secondary endpoints included safety, adherence to the study agent and exploratory biomarker analyses. Correlation analyses of imaging-derived metrics were performed to assess relationships among LDCT parameters. Results: Nineteen participants were enrolled (intervention, n = 12; placebo, n = 7). Eighteen (11 intervention, 7 placebo) subjects completed post-intervention imaging. One subject was unable to complete follow-up and study-related procedures. Data from the treatment arms were pooled for analysis and comparison with the placebo arm. No statistically significant between-group differences were observed in primary imaging endpoints. The intervention was well tolerated, with predominantly grade 1 adverse events. Exploratory analyses demonstrated consistent positive correlations among established imaging biomarkers, with clustering of size-based metrics (mean diameter, volume, sum of longest diameters) and density-based parameters. Multidimensional scaling supported this structure, indicating internal coherence among imaging-derived endpoints. Conclusions: Although no statistically significant treatment effect on the image biomarkers was observed, this pilot study demonstrates feasibility challenges and identifies coherent imaging biomarkers that may serve as intermediate endpoints in early-phase chemoprevention trials. These results support further investigation of strategies utilizing agent combinations with enhanced bioavailability and safety and refinement of trial design in high-risk lung cancer patient populations. Full article

Chronic respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, cystic fibrosis, and chronic bronchitis, are characterized by persistent airway inflammation and mucus hypersecretion, leading to airway remodeling and progressive pulmonary dysfunction. Although current therapies improve disease control, they often fail to adequately target the complex molecular mechanisms underlying chronic airway diseases and may cause adverse effects during long-term use. Natural products have therefore emerged as promising multitarget therapeutic agents because they simultaneously regulate oxidative stress, inflammatory signaling, epithelial dysfunction, and mucus production. Recent evidence demonstrates that marine-derived bioactive compounds and plant-derived phytochemicals modulate key signaling pathways, including nuclear factor-kappa B (NF-κB), mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), Janus kinase/signal transducer and activator of transcription (JAK/STAT), the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, and nuclear factor erythroid 2-related factor 2 (Nrf2), thereby suppressing airway inflammation, oxidative stress, goblet cell differentiation, and MUC5AC overexpression. Advances in nanoformulation, pulmonary drug delivery, multi-omics, artificial intelligence-assisted drug discovery, and network pharmacology are expected to accelerate clinical translation. Collectively, natural products represent promising candidates for the development of evidence-based functional foods, nutraceuticals, and novel therapeutic strategies for chronic respiratory diseases. Full article

Ultralight bosonic dark matter (UBDM) that couples to electromagnetism can generate an oscillating magnetic-field signal at the Earth’s surface. This is referred to as the “Earth transducer” effect, as the Earth converts UBDM into a detectable magnetic field. Similar DM-induced fields in laboratory experiments typically scale with the size L of the experiment. Because the Earth transducer signal instead scales with the large radius of the Earth, R, it is one of the most powerful direct probes of UBDM with masses $m_{\mathrm{DM}}\lesssim 1/R\sim 3\times {10}^{-14}\mathrm{eV}$. It has many other favorable properties, such as high spatial and temporal coherence and robustness to atmospheric modeling. In this review, we derive the Earth transducer effect and its properties for multiple UBDM models, and we discuss current and future prospects to detect it. Full article

Strawberry is a globally important yet stress-sensitive crop, increasingly threatened by combined abiotic and biotic stresses. Unlike single stresses, combined stresses elicit unique, non-additive responses through complex signaling and gene regulatory networks. This review synthesizes current knowledge on the molecular mechanisms underlying strawberry responses to combined stresses, focusing on signal perception and transduction as well as gene regulation. We examine how combined stresses are perceived by membrane-localized sensors and calcium channels, and how these signals are transduced through MAPK (mitogen-activated protein kinase) cascades, CDPKs (calcium-dependent protein kinases), and hormonal crosstalk involving ABA (abscisic acid), JA (jasmonic acid), and ethylene. At the gene regulation level, we discuss the roles of key transcription factors (WRKY, NAC (NAM, ATAF1, ATAF2 and CUC2), GRAS (GAI-RGA-and-SCR), DREB (Dehydration-Responsive Element-Binding protein), bZIP (basic leucine zipper transcription factor), CAMTA (calmodulin-binding transcription activator), ARF (auxin response factor), and LAV (Leafy Cotyledon2–Abscisic Acid Insensitive3–Val)), transcriptional cascades, epigenetic regulation via DNA methylation, and post-transcriptional (miRNAs such as Fan-miR73) and post-translational (ubiquitination and phosphorylation) control mechanisms. The review also evaluates emerging mitigation strategies informed by these molecular insights, including genomic selection, and explores future directions such as CRISPR (clustered regularly interspaced short palindromic repeats)-based genome editing and multi-omics integration. We conclude that understanding the integrated signaling and gene regulatory networks is essential for developing climate-resilient strawberry cultivars capable of withstanding increasingly complex stress combinations. Full article

This work reports the design and validation of a reusable platinum (Pt) electrode platform (ST-E) for green electrochemical analysis. The device integrates Pt working and counter electrodes with an external Ag/AgCl reference and is engineered for repeated regeneration and refunctionalization. Surface renewal by alumina polishing followed by electrochemical activation in 0.5 M H₂SO₄ restores a clean, reproducible Pt surface, as confirmed by diffusion-controlled, reversible ferricyanide voltammetry over 5–150 mV s⁻¹ with near-Nernstian peak separation and i_pa/ipc ≈ 1. Platform versatility is demonstrated in two applications. First, ST-E is functionalized with PFOA-selective molecularly imprinted nanoparticles on an APTES layer, enabling trace determination of perfluorooctanoic acid (1–5 pg mL⁻¹), with a detection limit of 0.50 pg mL⁻¹ and sensitivity of 3.16 μA (pg mL⁻¹)⁻¹. Responses correlate with an equivalently modified commercial screen-printed electrode (r = 0.990, p < 0.005), with Bland–Altman analysis confirming concordance. Second, after regeneration, electropolymerization of o-phenylenediamine yields an insulating poly(o-phenylenediamine) film that attenuates redox currents and increases ΔE_p, illustrating compatibility with diverse surface chemistries. Green metrics (AGREE, AGREEprep ≈ 0.80; BAGI = 75.0) highlight reduced waste and solvent use versus single-use transducers and compatibility with portable potentiostats, supporting circular electrochemical sensing. Full article

Myocardial and aortic stiffness are increasingly recognized as clinically relevant biomarkers for cardiovascular disease, yet their noninvasive quantification remains challenging. Magnetic resonance elastography (MRE) has emerged as a promising technique for the spatial mapping of tissue biomechanics by visualizing and analyzing propagating shear waves. This narrative review summarizes the current state of cardiovascular MRE, spanning technical developments in wave generation (acoustic, electromagnetic, gravitational, and transducer-free approaches), pulse sequence design (echo-planar imaging, gradient-recalled echo, spiral, and free-breathing three-dimensional acquisitions), and inversion algorithms (local frequency estimation, direct inversion, finite element methods, and multifrequency elastography). We present evidence from phantom validation, animal models (myocardial infarction, hypertension, right ventricular hypertrophy), and human studies encompassing cardiac amyloidosis, hypertrophic cardiomyopathy, diastolic dysfunction, and abdominal aortic aneurysm. Additionally, we discuss current challenges, including waveguide effects, standardization needs, and clinical translation barriers, and highlight emerging solutions through artificial intelligence, multifrequency methods, and transducer-free cardiac MRE. Full article

Emerging evidence links gut microbiota (GM) dysbiosis to hyperuricemia (HUA). The GM plays a critical role in regulating host health and homeostasis by producing a diverse array of metabolites, including short-chain fatty acids, bile acids and uremic toxins. Dysregulation of the microbial metabolite profile has been implicated in the pathogenesis of HUA. Given the urgent need for green and safe urate-lowering therapies for HUA, recent years have seen an increasing focus on interpreting the ability of natural products to modulate these microbial metabolites. Such interventions enhance beneficial metabolites and suppress uremic toxins, thereby alleviating HUA through coordinated regulation of urate transporters, restoration of intestinal barrier integrity, reprogramming of systemic metabolic disturbances, and inhibition of inflammation via Toll-like receptor 4 (TLR4)/ nuclear factor kappa B (NF-κB), Janus kinase (JAK)/ signal transducer and activator of transcription (STAT), and Phosphatidylinositol-3-kinase (PI3K)/ protein kinase B (AKT) pathways. Furthermore, a comprehensive translational roadmap has been proposed, grounded in a critical appraisal of current trial limitations. Overall, this review consolidates evidence for the protective effects of natural products against HUA and related comorbidities, with an emphasis on GM-derived metabolites, aiming to expand clinical applications and provide insights for future studies. Full article

Medical ultrasound imaging relies heavily on ultrasound transducers, whose properties directly determine transducer performance. Alternating current poling (ACP) serves as a domain engineering platform to enhance the dielectric and piezoelectric properties of ferroelectric single crystals, ceramics, and piezocomposites compared to conventional direct current poling (DCP). Although several reviews cover the microscopic mechanisms of ACP, researchers have not yet systematically analyzed these materials from the perspective of device applications. This mini-review focuses on the impact of ACP on transducer performance, analyzing the relationship between material properties and device performance in ultrasound imaging transducers. We systematically evaluate the optimization efficacy of ACP across different piezoelectric material forms and bridge the gaps between material parameters and device metrics such as bandwidth and sensitivity. Finally, this review discusses the engineering challenges, structural design synergies, and future trends of ACP-based transducers. Full article

With the continuous advancement of ocean exploration and development, energy supply for underwater electronic equipment has become a key bottleneck restricting long-term operation. Traditional wired power supply and battery-powered operation suffer from corrosion, high maintenance costs, limited endurance, and replacement difficulties. Underwater ultrasonic wireless power transfer (UUWPT) achieves contactless electric–acoustic–electric conversion via piezoelectric transducers. It offers unique advantages, including insensitivity to electromagnetic interference, metal-penetration capability, excellent directivity, and medium-to-long-distance transmission. This paper systematically reviews the technical principles and development history of UUWPT. We trace its evolution from early feasibility verification, through theoretical improvements, to current system engineering and industrialization. Key frontier research directions are highlighted, such as MIMO/MISO arrays, simultaneous wireless power and data transfer (SWPDT), adaptive tuning, and novel transducer structures. Application prospects in marine monitoring, AUV endurance replenishment, marine energy development, and the Internet of Underwater Things are also analyzed. Finally, we discuss remaining challenges, including the trade-off between transmission efficiency and distance, insufficient adaptability to complex marine environments, and the lack of standardized system frameworks. Future research should prioritize high-efficiency long-distance power transfer, system reliability, and engineering applications. Full article

Ovarian cancer (OVC) is a leading cause of gynecological cancer mortality due to late-stage diagnosis and chemoresistance. Among the multiple molecular mediators, oncogenic epidermal growth factor receptor (EGFR) signaling has emerged as a key regulator of tumor progression and drug resistance, ultimately governing cancer survival. Therefore, this review focused on the molecular mechanisms of aberrant EGFR signaling to promote chemoresistance in ovarian cancer through multiple interlinking pathways, including the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of the rapamycin (mTOR), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling cascades. These pathways act in concert to confer resistance, including proliferation, antiapoptotic effects, cancer stem cell maintenance, and facilitating epithelial-mesenchymal transition (EMT), which function together to decrease sensitivity towards platinum-based and taxane chemotherapies. Furthermore, we incorporate novel evidence regarding EGFR cross-talk with extracellular matrix (ECM) and metabolic reprogramming, especially their relevance to immune evasion mechanisms, hypoxia, and extracellular vesicles (EVs)-mediated signaling. In addition, we elaborated on the limitation of the current EGFR targeting therapy, which will be beneficial for further designing new combinatorial treatment approaches by using EGFR inhibitors with immunotherapy, nanocarriers, and microbiota modulators. Overall, this review highlights the updated role of EGFR signaling as a key regulator of chemoresistance in ovarian cancer, providing insights for developing targeted therapies to overcome drug resistance and improve patient survival. Full article

Background/Objectives: Essential Oils (EO), complex mixtures of organic compounds, exhibit a wide range of properties useful in the pharmaceutical, cosmetic, perfumery and agri-food fields. In particular, well-recognized EO anti-inflammatory properties push towards the investigation of the mechanisms underlying them. One of the signaling pathways targeted by EOs is the Janus Kinase Signal of Transducer and Activator of Transcription (JAK/STAT), whose hyperactivation is associated with inflammation, immune diseases and tumor progression. Methods: A comprehensive search on the major bibliographic databases was conducted; current findings and recent insights about the role of EOs in modulating the JAK/STAT Signaling Pathway were collected. Results: EOs derived from different plant species showed efficacy in attenuating the release of pro-inflammatory cytokines and mediators and in inhibiting phosphorylation of both JAK and STAT proteins. These results could be due to the EO’s multi-component nature and to the synergistic interaction occurring within these complex mixtures, both reflecting multi-target effects and modulations. Limitations concerning formulations, lack of standardization, efficacy and safety profiles, sustainable and eco-friendly approaches, and the gap between the literature and translation to the clinic were addressed. Conclusions: EOs represent emergent, promising and high-value candidates able to modulate the JAK/STAT Signaling Pathway. Full article