Search Results (1,010)

Carbon dots have emerged as promising nanocarriers for drug delivery due to their unique physicochemical properties and biocompatibilities. Here, the potential of leaf-derived carbon dots (named as SBL_CD), derived from Seabuckthorn (Hippophae rhamnoides L.), was illustrated as a novel nano-formulation for bioactive compound delivery. Seabuckthorn leaves, rich in flavonoids, are the waste product during the production of Seabuckthorn fruits. The wasted leaves were utilized to synthesize carbon dots via a hydrothermal method. The resulting SBL_CD, characterized by TEM, FT-IR and Raman spectroscopy, exhibited a diameter of ~5 nm in both amorphous and quasi-crystalline forms. Applications of SBL_CD in cultures demonstrated robust properties of anti-inflammation and inducing neuronal cell differentiation. Furthermore, SBL_CD was able to encapsulate luteolin, a bioactive flavonoid. The enhanced delivery efficiency translated to superior biological activity, with SBL_CD-luteolin requiring only 1.50 μg/mL in achieving the EC₅₀ efficacy, as compared to 6.82 μg/mL for free luteolin in pNF200-Luc expression assays. This approach not only valorizes Seabuckthorn leaf by-products but also potentially improves the efficacy of encapsulated flavonoids. The development of SBL_CD as a multifunctional platform for flavonoid delivery represents a promising strategy in enhancing the efficacy of neuroactive compounds, combining anti-inflammatory effects (>70% cytokine suppression) with enhanced cellular uptake (4.5-fold increase). Full article

Autocollimators are widely used for sensor calibration. It is crucial to suppress systematic errors and enhance the measurement accuracy of autocollimators. However, the influence mechanism of systematic errors originating from the collimator objective—such as aberrations, and particularly the coupled effect of aberrations and assembly deviation—on measurement accuracy is not well understood. By switching between the perspectives of ray tracing and aberration, we analyzed the influence mechanism of aberrations. The results indicate that only coma aberrations of various orders affect the accuracy. Then we applied nodal wave aberration theory and found that the influence of assembly deviation is a factor only related to the aberration under a certain offset (composed of translational and rotational components). In this work, we defined the sensitivity of assembly deviation as the ratio of this factor and the offset. In the experimental part based on a homemade autocollimator, the maximal errors of yaw angle are decreased from 2.09 arcsecs to 1.41 arcsecs, while the one of pitch angle is decreased from 2.32 arcsecs to 1.63 arcsecs, within a measuring interval of ±500 arcsecs. The sensitivity of assembly deviation of the collimator objective used is 0.004 arcsec per micron, which agrees with the theoretical analysis. Full article

Background/Objectives. Prostate cancer (PCa) is among the leading causes of death from cancer in men. Frequent use of androgen receptor inhibitors induces PCa transdifferentiation, leading to poorly differentiated neuroendocrine PCa (NEPC). ROR2 is critical for NEPC pathogenesis by activating ASCL1, promoting lineage plasticity. Protein lysine methylation mediated by N-lysine methyltransferases SMYD2 and its downstream effector EZH2 upregulates the NEPC marker ASCL1 and enhances c-MET signaling, promoting PCa aggression. Epidemiological studies suggest a lower incidence of certain malignancies in Mediterranean populations due to their intake of an olive-phenolics-rich diet. Methods. Cell viability, gene knockdown, and immunoblotting were used for in vitro analyses. A nude mouse NEPC xenograft model evaluated the anti-tumor efficacy of purified and crude oleocanthal. Xenograft tumors were subjected to RNA-seq, qPCR, and Western blot analyses, with clinical validation performed using tissue microarrays. Results. A tissue microarray analysis showed that SMYD2 expression was significantly elevated in PCa tissues with higher IHS versus normal prostate tissue cores. The olive phenolic S-(-)-oleocanthal (OC) suppressed the de novo NEPC NCI-H660 cells proliferation. Male athymic nude mice xenografted with the NCI-H660-Luc cells were used to assess OC effects on de novo NEPC progression and recurrence. Male NSG mice transplanted with LuCaP 93 PDX tumor tissues generated a heterogeneous in vivo model used to assess OC effects against t-NEPC progression. Daily oral 10 mg/kg OC administration significantly suppressed the NCI-H660-Luc tumor progression and locoregional recurrence after primary tumor surgical excision. OC treatments effectively suppressed the progression of LuCaP 93 PDX tumors. OC-treated tumors revealed downregulation of ROR2, ASCL1, SMYD2, and EZH2, as well as activated c-MET levels versus the placebo control. RNA sequencing of the collected treated NEPC tumors showed that OC disrupted NEPC splicing, translation, growth factor signaling, and neuronal differentiation. Conclusions. This study’s findings validate OC as a novel lead entity for NEPC management by targeting the ROR2-ASCL1-SMYD2-EZH2-c-MET axis. Full article

Cellular senescence is defined as a state of permanent cell cycle arrest, providing a natural barrier against cancer. However, senescent cells are very metabolically active and secrete a complex mixture of bioactive molecules collectively known as the senescence-associated secretory phenotype (SASP), which play a dual role in cancer biology. While the SASP can suppress tumors by facilitating immunosurveillance, it can also promote tumor progression by fostering a pro-inflammatory milieu, stimulating angiogenesis, enhancing invasiveness, and enabling immune evasion. In Head and Neck Cancers (HNCs), a highly heterogeneous group of malignancies, SASP has emerged as a critical player in disease progression and treatment resistance. Persistent DNA damage response (DDR) signaling drives SASP and thereby contributes to the progression of head and neck cancer by modulating the tumour microenvironment. It influences the tumor microenvironment (TME) by facilitating epithelial-to-mesenchymal transition (EMT), promoting cancer stem cell-like properties, and impairing the efficacy of radiotherapy, chemotherapy, and immune checkpoint inhibitors. These effects underscore the need for targeted interventions to regulate SASP activity. This review presents a comprehensive overview of the molecular mechanisms underlying SASP generation and its effects on HNCs. We discuss the dual roles of SASP in tumor suppression and progression, its contribution to therapy resistance, and emerging therapeutic strategies, including novel senolytic and senomorphic drugs. Finally, we highlight key challenges and future directions for translating SASP-targeted therapies into clinical practice, emphasizing the need for biomarker discovery, and a deeper understanding of SASP heterogeneity. By targeting the SASP, there is potential to enhance therapeutic outcomes and improve the management of HNCs. Full article

Background/Objectives: Postbiotics derived from lactic acid bacteria are emerging as promising antimicrobial agents due to their antibacterial, antibiofilm, and immunomodulatory properties. Among their metabolites, lactic acid (LA) is thought to play a major role in antimicrobial activity. This study investigated the proteomic response of Pseudomonas aeruginosa and Staphylococcus aureus to Lacticaseibacillus rhamnosus cell-free supernatant (CFS) and compared it with that elicited by LA alone. Methods: Overnight bacterial cultures were exposed to sub-MIC LA or CFS (1:10 for P. aeruginosa and 1:8 for S. aureus; ~12.5–15.6 mM LA) for 6 h at 37 °C. Intracellular proteins were harvested and subsequently quantified and purified to be analysed by HPLC–MS/MS, for quantitative label-free proteomics. Results: Proteomic analysis revealed clear separation of treated samples from controls, with largely overlapping responses to CFS and LA. Hallmark acid-stress adaptations were observed, including urease-mediated pH buffering, confirming that part of the response was driven by mild organic acid. In P. aeruginosa, treatments suppressed virulence pathways (phenazines, T3SS), while shifting metabolism toward lactate utilisation and reinforcing the outer membrane (lipid A, polyamine). In S. aureus, decreased abundance of the SaeRS-regulated immune-evasion factor Sbi, together with changes in envelope, ROS and translation-related proteins, suggested a bacteriostatic-like state. S. aureus differences between CFS and LA were more pronounced; CFS uniquely increased cell-wall defences, oxidative stress (SodA, SodM) and chaperone expression (GroS, GrpE), suggesting stress beyond acidification alone. Conclusions: These findings shed light on the molecular mechanisms underlying bacterial adaptation to CFS and highlight their potential as a novel antimicrobial approach. Full article

In recent years, lactate has transitioned from being considered a mere metabolic end-product to being regarded as a critical signaling molecule that links cellular metabolism with gene regulation. Protein lactylation, a post-translational modification (PTM) mediated by lactate, is central to this functional transformation. In vascular diseases, the lactate–lactylation process demonstrates a marked double-edged sword characteristic, with its regulatory effects highly dependent on cell type, disease stage, and the pathological microenvironment. On one hand, lactylation can exert protective roles by promoting reparative gene expression, driving anti-inflammatory cell polarization, and maintaining myocardial structural integrity; on the other hand, aberrant lactylation can exacerbate inflammatory responses, promote fibrosis, and induce cell death and vascular calcification, thereby driving the development and progression of atherosclerosis, heart failure, and stroke. This review systematically delineates the paradoxical yet unified dual roles of lactylation across various vascular diseases and explores the molecular bases that underlie these functional differences. We propose that deciphering and precisely modulating the ‘double-edged sword’ of lactylation—selectively enhancing its protective functions while suppressing its pathological actions—represents a central challenge and a critical opportunity for translating basic research into clinical applications. Such advances could provide a novel theoretical framework for the development of diagnostic biomarkers and cell-specific precision therapeutic strategies. Full article

The substantial interest in plant-based drugs or plant-derived phytocompounds drives researchers to conduct comprehensive investigations on their therapeutic properties. Mollugin, one of the major active constituents of Rubia cardifolia, has been well-studied for its pharmacological properties, demonstrating potent anti-inflammatory properties by suppressing the TAK-1-mediated activation of NF-κB/MAPK and enhancing the Nrf2/HO-1-mediated antioxidant response. It exhibits strong anticancer effects through ferroptosis via IGF2BP3/GPX4 pathways, induces mitochondrial apoptosis, and targets NF-κB, ERK, and PI3K/Akt/mTOR to suppress tumor progression. Mollugin also inhibits JAK2/STAT and PARP1 pathways, suppressing IL-1β expression via the modulation of ZFP91. Moreover, it regulates the MAPK/p38 pathway, promotes neuroprotection, and improves cognitive performance through GLP-1 receptor activation. Mollugin promotes osteogenesis by activating the BMP-2/Smad1/5/8 signaling pathway and downregulates MAPK, Akt, and GSK3β expression, leading to the inhibition of osteoclastogenesis. It overcomes multidrug resistance by downregulating MDR1/P-gp, CREB, NF-κB, and COX-2 through AMPK activation. Its antibacterial effect is mediated by strong binding to FUR, UDP, and IpxB proteins in Enterobacter xiangfangensis. Mollugin mitigates Klebsiella pneumoniae infection, suppresses adipogenesis without causing cytotoxicity, and protects endothelial cells via the BDNF/TrkB-Akt signaling pathway. Synthetic derivatives of mollugin, such as oxomollugin and azamollugin, have shown enhanced anticancer and anti-inflammatory effects by regulating EGFR, PKM2, TLR4/MyD88/IRAK/TRAF6, and NF-κB/IRF3 pathways with improved solubility and stability. Collectively, these findings emphasize the broad-spectrum activity of mollugin. This review provides a critical interpretation of the mechanistic pathways regulated by mollugin and its derivatives, emphasizing their pharmacological significance and exploring their potential for future translation as multitarget drug candidates. Full article

Neurological disorders and cardiovascular disease (CVD) remain leading causes of global morbidity and mortality and often coexist, in part through shared mechanisms of chronic inflammation and oxidative stress. Neuroinflammatory signaling, including microglial activation, cytokine release, and impaired autonomic regulation, contributes to endothelial dysfunction, atherosclerosis, hypertension, and stroke, while cardiac and metabolic disturbances can reciprocally exacerbate brain pathology. Increasing evidence shows that several antidiabetic agents exert pleiotropic anti-inflammatory and antioxidant effects that extend beyond glycemic control. Metformin, SGLT2 inhibitors, DPP-4 inhibitors, and GLP-1 receptor agonists modulate key pathways such as AMPK, NF-κB, Nrf2 activation, and NLRP3 inflammasome suppression, with demonstrated vascular and neuroprotective actions in preclinical models. Clinically, GLP-1 receptor agonists and SGLT2 inhibitors reduce major cardiovascular events, improve systemic inflammatory markers, and show emerging signals for cognitive benefit, while metformin and DPP-4 inhibitors exhibit supportive but less robust evidence. This review synthesizes molecular, preclinical, and clinical data across drug classes, with particular emphasis on GLP-1 receptor agonists, and highlights outstanding translational questions including blood–brain barrier penetration, biomarker development, optimal patient selection, and timing of intervention. We propose a unified framework to guide future trials aimed at leveraging antidiabetic therapies such as DDP-4 anti-inflammatory and antioxidant interventions for neurological and cardiovascular diseases. Full article

This work investigates how the vehicle-to-tube suspension gap governs compressible flow physics and operating margins in Hyperloop-class transport at 10 kPa. To our knowledge, this is the first study to apply adjoint aerodynamic optimization to mitigate gap-induced choking and shock formation in a full pod–tube configuration. Using a steady, pressure-based Reynolds-averaged Navier-Stokes (RANS) framework with the GEnerlaized K-Omega (GEKO) turbulence model, a simulation for the cruise conditions was performed at M = 0.5–0.7 with a mesh-verified analysis (medium grid within 0.59% of fine) to quantify gap effects on forces and wave propagation. For small gaps, the baseline pod triggers oblique shocks and a near-Kantrowitz condition with elevated drag and lift. An adjoint shape update—primarily refining the aft geometry under a thrust-equilibrium constraint—achieves 27.5% drag reduction, delays the onset of choking by ~70%, and reduces the critical gap from d/D ≈ 0.025 to ≈0.008 at M = 0.7. The optimized configuration restores a largely subcritical passage, suppressing normal-shock formation and improving gap tolerance. Because propulsive power at fixed cruise scales with drag, these aerodynamic gains directly translate into operating-power reductions while enabling smaller gaps that can relax tube-diameter and suspension mass requirements. The results provide a gap-aware optimization pathway for Hyperloop pods and a compact design rule-of-thumb to avoid choking while minimizing power. Full article

Acute injuries to the central nervous system (CNS) share a rapid disruption of arousal, autonomic stability, and neuroimmune balance. Among the neuromodulatory systems affected, the orexin (hypocretin) network is uniquely positioned at the intersection of wakefulness, autonomic control, and motivated behavior. Experimental evidence across ischemic, hemorrhagic, traumatic, and systemic models shows that orexin signaling is sharply suppressed during the early post-injury collapse and gradually recovers as arousal circuits and homeostatic functions stabilize. Controlled enhancement of orexinergic tone has been found to improve arousal state, modulate inflammatory responses, and support behavioral engagement, although these effects are highly dependent on timing, receptor subtype, and physiological context. This review synthesizes evidence from ischemia, hemorrhagic stroke, traumatic brain and spinal cord injury, and systemic inflammatory states, and examines the conceptual and translational rationale for targeting orexin pathways. We summarize available pharmacological, peptide-based, neuromodulatory, and physiological strategies to boost orexinergic tone, highlighting the growing development of selective OX₂ agonists and experimental approaches to enhance endogenous orexin activity. By integrating findings across etiologies within a timing-aware framework, this review addresses a gap in the current literature, which has largely treated these injuries in isolation. While clinical testing in acute CNS injury has not yet been performed, the mechanistic convergence across etiologies suggests that orexinergic modulation may offer a phase-sensitive means to stabilize arousal and support recovery. Taken together, orexin emerges as a state-dependent integrator whose modulation could complement existing therapies by linking early arousal stabilization with longer-term motivational and functional recovery. Full article

Fritillaria pallidiflora Schrenk ex Fisch. & C.A.Mey. (Yi Beimu) is a culturally significant Beimu drug in Northwest China, officially listed in the Chinese Pharmacopoeia and traditionally used to clear heat, moisten the lung, resolve phlegm, and relieve cough and wheeze. This narrative, critical review synthesizes current evidence on ethnopharmacology, phytochemistry, pharmacology, pharmacokinetics/toxicology, and conservation of F. pallidiflora to support sustainable, evidence-based development. Literature was retrieved from major English and Chinese databases and screened for studies that unambiguously involved Yi Beimu or its key constituents. Ethnomedicinal records consistently support antitussive, expectorant, and anti-asthmatic use in Xinjiang and the Ili River Valley. Chemically, F. pallidiflora is rich in cevanine-type steroidal alkaloids (e.g., imperialine, peimine, yibeinones), steroidal saponins (pallidiflosides), polysaccharides, and minor phenolics. Preclinical data show that alkaloids relax airway smooth muscle, suppress inflammatory mediators, and contribute to antitussive and anti-asthmatic effects, while polysaccharides and total alkaloid extracts exhibit antioxidant and cytoprotective activity in cell and animal models of airway injury. Additional studies report cytotoxic saponins and seed-derived antimicrobial peptides. Pharmacokinetic work highlights low to moderate and variable oral bioavailability, shaped by P-glycoprotein efflux and CYP-mediated metabolism, and reveals potential hERG channel inhibition for peimine as a cardiac safety concern. Overharvesting and habitat loss have reduced wild resources, underscoring the need for conservation, cultivation, and marker-guided quality control. Overall, Yi Beimu shows credible ethnopharmacological rationale and promising multi-target pharmacology for respiratory disorders, but translation will require bioactivity-guided isolation coupled with PK–PD-guided in vivo studies, rigorous safety evaluation, and conservation-aware cultivation to move from traditional remedy toward validated therapeutic resource. Full article

Cell therapies hold great promise for advancing wound healing; however, translating this promise into consistent clinical benefit has proven elusive. Numerous trials have failed to reproduce the robust outcomes suggested by preclinical studies, reflecting a landscape marked by hidden traps. These include the hostile wound microenvironment, the cytotoxicity of antimicrobial dressings, poor retention and engraftment, immune clearance, and the paradoxical risk of fibrosis and scarring. Across these challenges emerge paradoxes that redefine how traps are understood. The Scarring Paradox reveals that MSCs and EVs may either suppress or reinforce fibrosis, depending on the niche context. The Immune Double-Edged Sword captures the duality of clearance and regenerative modulation. These paradoxes illustrate that traps are not static obstacles but dynamic inflection points. Recognition of these paradoxes has inspired tricks: protective biomaterial carriers, preconditioning strategies, engineered exosomes, and combinatorial therapies with anti-fibrotic, neuromodulatory, or microbiome-targeted adjuncts. Case studies illustrate how classical traps manifest in clinical practice and how paradoxes guide innovation. Emerging adjuncts, ranging from herbal bioactives and bioelectric modulation to circadian synchronization and digital twins, point toward more unconventional but increasingly plausible frameworks for niche control. This perspective review demonstrates that the future of regenerative wound therapy depends not on avoiding traps but on reframing them through paradoxes and converting them into tricks. Stem cell and exosome therapy is thus moving beyond a linear “promise versus failure” narrative toward a systemic, context-aware, programmable approach in which paradoxes drive conceptual renewal and transformative paradigms in wound care. Full article

Head and neck squamous cell carcinoma (HNSCC) is the most common and aggressive histologic subtype of head and neck cancer (HNC), difficult to treat effectively. Here, we discuss several studies on human and mouse HNSCC cell lines arising from the mucosal epithelium of various anatomical sites, as well as recent studies using murine models, focused on targeting key checkpoints in the glutamine (Gln) metabolism pathway, either alone or in synergy with other signaling pathways, as a potential therapeutic strategy for HNSCC. Emerging evidence demonstrates a complex interplay between Gln metabolism and pathways mediating altered cellular mechanisms, including ferroptosis, immune system evasion, mitochondrial energy production, and oncogenic transcriptional control. This review examines currently available gene expression databases and protein expression analyses of Gln metabolism-related components in tissue samples from HNSCC patients. From a translational perspective, the co-administration of pharmaceutical agents and biologic products targeting distinct molecular pathways, integrated with radiotherapy (RT) or chemotherapy (CT), may produce superior anti-HNSCC efficacy, thereby improving clinical outcomes and extending patient survival. Multimodal strategies represent a key direction in precision oncology, enabling personalized therapeutic interventions to suppress metastatic dissemination and disease progression more effectively. Therefore, an integrated therapeutic approach represents a promising path to defeat HNSCC. Full article

Gut microbiota, through both its species composition and its metabolites, impacts expression and activity of intestinal drug transporters. This phenomenon directly affects absorption process of orally administered drugs and contributes to the observed inter-individual variability in pharmacotherapeutic responses. This review summarizes mechanistic evidence from in vitro and animal studies and integrates clinical observations in which alterations in gut microbiota are associated with changes in oral drug exposure, consistent with potential regulation of key intestinal drug transporters—such as P-glycoprotein (P-gp, ABCB1), Breast Cancer Resistance Protein (BCRP, ABCG2), MRP2/3 proteins (ABCC2/3), and selected Organic Anion-Transporting Polypeptides (OATPs, e.g., SLCO1A2, SLCO2B1)—by major bacterial metabolites including short-chain fatty acids (SCFAs), secondary bile acids, and tryptophan-derived indoles. The molecular mechanisms involved include activation of nuclear and membrane receptors (PXR, FXR, AhR, TGR5), modulation of transcriptional and stress-response pathways (Nrf2, AP-1) with simultaneous suppression of pro-inflammatory pathways (NF-κB), and post-translational modifications (e.g., direct inhibition of P-gp ATPase activity by Eggerthella lenta metabolites). The review also highlights the pharmacokinetic implications of, e.g., tacrolimus, digoxin, and metformin. In conclusion, the significance of “drug–transporter–microbiome” interactions for personalized medicine is discussed. Potential therapeutic interventions are also covered (diet, pre-/probiotics, fecal microbiota transplantation, modulation of PXR/FXR/AhR pathways). Considering the microbiota as a “second genome” enables more accurate prediction of drug exposure, reduction in toxicity, and optimization of dosing for orally administered preparations. Full article

Antimicrobial resistance (AMR) remains a critical global challenge, requiring novel complementary strategies beyond antibiotic development. Probiotic-fermented foods (PFFs) offer an emerging, low-cost approach to mitigate AMR risk through ecological, molecular, and immunological mechanisms. This review integrates mechanistic insights, clinical evidence, and translational frameworks linking PFFs to antimicrobial stewardship. Key mechanisms include colonization resistance, nutrient and adhesion-site competition, production of antimicrobial metabolites, such as bacteriocins, hydrogen peroxide, and organic acids and Quorum-quenching-sensing activities that suppress pathogen virulence. Randomized clinical trials indicate that fermented diets and probiotic supplementation can improve microbiome diversity, reduce inflammatory cytokines, and decrease antibiotic-associated diarrhea, though direct AMR outcomes remain underexplored. Evidence from kefir, kombucha, and other microbial consortia suggests potential for in vivo pathogen suppression and reduced infection duration. However, safe translation requires standardized starter-culture genomics, resistome monitoring, and regulatory oversight under QPS/GRAS frameworks. Integrating PFF research with One Health surveillance systems, such as the WHO GLASS platform, will enable tracking of antimicrobial consumption and resistance outcomes. Collectively, these findings position PFFs as promising adjuncts for AMR mitigation, linking sustainable food biotechnology with microbiome-based health and global stewardship policies. Full article