Search Results (7,931)

Background: Contrast media are essential tools in diagnostic and interventional imaging, but their relationship with acute kidney injury remains clinically relevant and conceptually debated. This narrative review aimed to synthesize current evidence on contrast media-associated nephrotoxicity, including terminology, epidemiology, pathophysiology, risk stratification, prevention, pharmacotherapeutic management, and clinical decision-making. Methods: A structured literature search was conducted in major biomedical databases and complemented by international guidelines and consensus statements addressing contrast-associated and contrast-induced acute kidney injury in adults exposed to intravascular contrast media. Discussion: Contemporary evidence emphasizes the distinction between contrast-associated acute kidney injury, which reflects a temporal association after exposure, and contrast-induced acute kidney injury, which implies causality. The renal risk directly attributable to modern intravenous iodinated contrast media appears to have been historically overestimated, although clinically relevant risk persists in vulnerable patients. Proposed mechanisms include renal vasoconstriction, medullary hypoxia, oxidative stress, mitochondrial dysfunction, tubular epithelial injury, endothelial dysfunction, and inflammatory or apoptotic pathways. Preventive strategies should be individualized, with isotonic saline remaining the main intervention when indicated, whereas routine pharmacologic prophylaxis is not supported by consistent clinically meaningful benefit. Conclusions: Renal safety in contrast-enhanced imaging requires a balanced approach that minimizes avoidable kidney injury in high-risk patients without unnecessarily delaying clinically indicated diagnostic or therapeutic procedures. Full article

Depression is a leading cause of disability worldwide, and currently available antidepressants are limited by delayed therapeutic onset, inadequate efficacy in some patients, and adverse effects. G protein-coupled receptors (GPCRs), the largest family of membrane receptors in the central nervous system, regulate neurotransmission, neuroplasticity, neuroinflammation, stress responses, and reward processing, and are therefore important targets for antidepressant drug development. Natural products are a rich source of structurally diverse bioactive compounds, many of which show antidepressant-like effects through the modulation of GPCR-mediated signaling pathways. In this narrative review, we summarize the roles of major GPCR families implicated in depression and provide an updated overview of natural products that modulate these receptors. We particularly emphasize receptor-specific mechanisms, downstream signaling networks, and the pharmacological actions of representative natural compounds. We also highlight emerging concepts in GPCR biology, including receptor heteromerization, signaling bias, and allosteric modulation, that may create new opportunities for antidepressant discovery. Finally, we discuss current challenges related to target validation, pharmacokinetics, and clinical translation. Collectively, these insights support further investigation of natural product-derived GPCR modulators as potential leads for next-generation antidepressant development. Full article

Gliomas, and glioblastoma in particular, remain difficult to model because molecular heterogeneity, diffuse invasion, blood–brain and blood–tumour barrier effects, immune suppression and repeated therapeutic escape converge in the same disease. Two-dimensional cultures, glioma stem cell (GSC) systems, acute tumour slices and animal models remain indispensable for mechanistic research, pharmacology and in vivo validation. Glioma organoids are complementary research platforms, not components of routine diagnostic or treatment procedures. This review links model construction, microenvironmental validation, treatment perturbation and evidence-graded interpretation. We compare patient-derived glioma organoids, GSC-derived organoids, brain organoid–glioma co-cultures, genetically engineered brain tumour organoids, and vascular-associated, immune-cell-containing and chip-based platforms. We distinguish phenotypic resemblance from physiological fidelity, tumour-intrinsic drug sensitivity from delivery competence, and proof-of-concept activity from demonstrated clinical utility. We also examine temozolomide resistance, radiotherapy, targeted and combination therapy, antiangiogenic treatment, tumour-treating fields, immune-cell therapy, oncolytic viruses, multi-omic quality control and prospective validation. Organoids should not substitute for animal models or clinical trials. Their most defensible role is to provide a patient-derived functional layer between mechanism, regimen ranking and molecular tumour-board interpretation, with claims limited by assay reproducibility, clinically achievable exposure and outcome linkage. Full article

Background Aflatoxin B1 (AFB1) is a potent hepatotoxic mycotoxin that induces severe oxidative liver damage. Kaempferol (Kae), a natural flavonoid with known antioxidant properties, has unclear protective effects against AFB1-induced hepatotoxicity. This study aimed to evaluate the hepatoprotective role of Kae and elucidate its underlying mechanism using integrated in vivo, in silico, and in vitro approaches. Methods: In vivo (AFB1-challenged mice) and in vitro (hepatocyte) models were employed, combined with network pharmacology, molecular docking, and molecular dynamics simulations. Liver injury indices, oxidative stress markers, antioxidant enzyme activities, and Keap1/Nrf2 pathway expression were assessed. Results: Kae co-treatment reversed AFB1-induced increases in liver index, serum ALT/AST, histological lesions, and reduced antioxidant capacity in mice. Network pharmacology revealed 59 common targets, with NFE2L2 (Nrf2) as a key node. In vitro, Kae pretreatment significantly lowered AFB1-elevated ROS, MDA, ALT, and AST, while restoring GSH and total antioxidant capacity. Kae reversed AFB1-induced Keap1 upregulation and Nrf2 downregulation, and increased mRNA levels of HO-1, NQO1, SOD, GPX1, and CAT. Molecular docking and simulation showed stable Kae–Keap1 binding (−9.6 kcal/mol) with critical hydrogen bonds (VAL-606) and van der Waals contacts. Conclusions: Kae directly binds Keap1, activates Nrf2 signaling, upregulates antioxidant gene expression, and mitigates AFB1-induced oxidative liver injury. These findings support Kae as a promising candidate for preventing AFB1 hepatotoxicity. Full article

Kaempferol is a natural flavonol compound widely present in various single-herb remedies and compound formulations used for the treatment of ocular diseases. Despite its inherent pharmaceutical limitations, accumulating evidence indicates that kaempferol exerts broad protective effects against diverse ocular disorders through multiple biological pathways, highlighting its potential as a multi-target therapeutic candidate in ophthalmology. However, current evidence regarding kaempferol-based ophthalmic applications remains fragmented across different ocular diseases and mechanistic investigations, and a comprehensive evaluation of its therapeutic potential, translational challenges, and existing limitations is still lacking. This review systematically summarizes the research progress on kaempferol in the treatment of eye diseases, encompassing its source distribution, structural characteristics, ocular delivery strategies, disease spectrum coverage, molecular mechanisms, and safety profile. By critically evaluating currently available evidence, this review further identifies unresolved issues and translational barriers that hinder the clinical application of kaempferol in ophthalmology. Regarding delivery strategies, carriers such as gelatin nanoparticles, porous bovine serum albumin membranes, platelet-derived extracellular vesicles, and polyvinylpyrrolidone-based nanocomposites have preliminarily improved ocular surface retention and corneal permeability of kaempferol in models of corneal neovascularization and alkali burns. In terms of therapeutic indications, kaempferol has demonstrated protective effects in diverse experimental models, including age-related macular degeneration (AMD), diabetic retinopathy, diabetic cataract, dry eye disease, fungal keratitis, corneal transplant rejection, acute glaucoma, and retinoblastoma. At the mechanistic level, kaempferol exerts comprehensive pharmacological actions—anti-inflammatory, antioxidant, metabolic regulation, anti-angiogenic, and immunomodulatory—by modulating multiple signaling pathways, including MAPK, NF-κB, STAT1/IRF7, Nrf2/HO-1, VEGF/PI3K/Src/Akt/ERK, aldose reductase, estrogen-related receptor alpha (ERRα), and the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome. Available safety assessments suggest that kaempferol exhibits a generally favorable safety profile across ocular, cellular, systemic, and genetic evaluations. Despite these advances, the clinical translation of kaempferol in ophthalmology remains limited by insufficient clinical and pharmacokinetic evidence, underdeveloped targeted delivery strategies, and a lack of integrated understanding of its molecular basis in ocular protection. By systematically integrating evidence from ocular disease models, molecular mechanisms, delivery strategies, and safety evaluations, this review bridges fragmented knowledge regarding kaempferol-based ophthalmic applications and provides an integrated framework for understanding its therapeutic potential and translational prospects. Overall, this review highlights kaempferol as a promising multi-target therapeutic candidate for ocular diseases and provides insights into its future translational development. Full article

Erythropoiesis-targeted doping remains a major challenge for sports medicine because pharmacological and genetic manipulation of erythropoiesis can improve oxygen transport and endurance performance while increasing the risk of serious cardiovascular complications. Erythropoiesis-targeting strategies extend beyond recombinant erythropoietin (EPO) to include hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs), modified erythropoietin receptor (EPOR) agonists, transforming growth factor beta (TGF-β) signaling inhibitors, cytoprotective EPO derivatives, and gene- or cell-based approaches, and require complementary detection strategies based on direct analytical methods and the Athlete Biological Passport (ABP). Although they may enhance oxygen delivery and endurance performance, excessive stimulation of erythropoiesis may increase blood viscosity, impair vascular function, and elevate the risk of hypertension, thromboembolic complications, and other cardiovascular (CV) events. Erythropoiesis-targeted doping has evolved beyond recombinant EPO into a diverse group of pharmacological and genetic strategies that require increasingly sophisticated detection approaches. A thorough understanding of their molecular mechanisms and cardiovascular consequences is essential for improving anti-doping surveillance and protecting athlete health. This review summarizes current erythropoiesis-targeting agents, their mechanisms of action, detection strategies, cardiovascular risks, and implications for anti-doping practice. Full article

Melanoma is a highly aggressive malignancy characterized by pronounced metastatic potential, marked heterogeneity, and complex therapeutic resistance. Although immunotherapy and targeted therapy have improved the prognosis of some patients, their long-term clinical application remains constrained by limited therapeutic responses, drug resistance, and adverse effects. In this study, widely targeted metabolomics, network pharmacology, molecular docking, and molecular dynamics simulations were integrated to systematically investigate the potential mechanisms underlying the anti-melanoma effects of Inonotus hispidus SH-18. Fruiting bodies of Sang Huang at the Juvenile, Growth, and Maturation stages were analyzed using UPLC-MS/MS, identifying 1575 metabolites across 13 chemical classes. PCA explained 67.91% of the total variance (PC1, 43.54%; PC2, 24.37%), while the OPLS-DA models yielded Q² values of 0.964, 0.966, and 0.981 for IH-G vs. IH-J, IH-M vs. IH-G, and IH-M vs. IH-J, respectively. A total of 1099 differentially accumulated metabolites were identified, including 304 (140 up-accumulated and 164 down-accumulated), 311 (195 up-accumulated and 116 down-accumulated), and 484 (278 up-accumulated and 206 down-accumulated) in the three respective comparisons. Based on the experimentally detected metabolites, network pharmacology and bioinformatics analyses suggested that the active constituents of Sang Huang may synergistically suppress melanoma cell proliferation, survival, immune evasion, angiogenesis, invasion, and metastasis by regulating multiple pathways and signaling axes, including the TP53-p21 axis. Molecular docking showed that the candidate active compounds exhibited binding potential with core targets, among which ursolic acid displayed favorable binding capacity toward all core targets. Molecular dynamics simulations further supported the stability of these interactions. Notably, ursolic acid was most abundant in samples from the Juvenile stage, suggesting that this stage may be preferred for ursolic acid enrichment and subsequent activity evaluation. These findings suggest the potential therapeutic value of Sang Huang in melanoma treatment. Full article

Background: Incomplete microwave ablation (iMWA) of lung cancer often leads to rapid recurrence and metastasis, yet the underlying mechanisms remain unclear. This study explored whether iMWA promotes tumor progression by activating the cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) signaling pathway and its downstream effector ZEB1 in tumor cells. Materials and Methods: An in vivo iMWA model was established in nude mice bearing H1650 lung tumors, and an in vitro sublethal heat treatment model was used to mimic incomplete ablation. Transcriptomic profiling, molecular assays and functional analyses assessed cellular behavior and signaling activity changes post-iMWA; genetic and pharmacologic interventions modulated STING signaling and autophagy. Results: Post-iMWA residual cells exhibited enhanced proliferation and invasion. Thermal injury induced necrosis and inhibited mitophagy, causing cytosolic mtDNA accumulation that activated the intrinsic cGAS–STING pathway. This upregulation of ZEB1 drove epithelial–mesenchymal transition and dissemination. Notably, silencing STING or ZEB1, or pharmacologically restoring autophagy, significantly suppressed tumor growth and metastasis. Conclusions: iMWA drives malignant progression of lung cancer through an mtDNA–cGAS–STING–ZEB1 signaling axis. Targeting this pathway—by inhibiting STING or enhancing autophagy—may represent a promising therapeutic strategy to mitigate recurrence and metastasis following microwave ablation. Full article

Objectives: Endothelial apoptosis is a central event in atherosclerotic vascular injury, yet the contribution of the INO80 chromatin-remodeling subunit INO80E to this process remains unclear. This study examined whether INO80E is altered during atherosclerosis (AS)-associated endothelial injury and explored its functional role in ox-LDL-triggered apoptosis. Methods: Atherosclerotic mouse models were used to examine INO80E expression in vascular tissues, and ox-LDL-treated HUVECs were applied as an in vitro model of endothelial injury. The functional role of INO80E was evaluated using lentiviral overexpression and siRNA-mediated knockdown approaches, while apoptosis was measured by flow cytometry and TUNEL staining. Mechanistic experiments included co-immunoprecipitation, immunofluorescence, YY1 acetylation analysis, and pharmacological inhibition with the pan-HDAC inhibitor trichostatin A (TSA). In addition, YY1-silencing rescue experiments were performed in INO80E-overexpressing cells to determine whether YY1 contributes to the protective effect of INO80E against ox-LDL-induced endothelial apoptosis. Results: INO80E expression was reduced in the endothelial layer of ApoE^−/− aortas and in ox-LDL-treated HUVECs. INO80E overexpression attenuated ox-LDL-induced apoptosis and increased the Bcl-2/BAX ratio, whereas INO80E knockdown produced the opposite effect. INO80E colocalized with HDAC1, increased the HDAC1-YY1 association, decreased YY1 acetylation, and prolonged YY1 protein stability. TSA treatment weakened the anti-apoptotic phenotype associated with INO80E overexpression, and rescue experiments showed that YY1 knockdown partially reversed the INO80E overexpression-associated regulation of Bcl-2 and BAX. Conclusions: These findings suggest that INO80E protects endothelial cells from ox-LDL-induced apoptosis, at least in part by promoting HDAC-associated YY1 deacetylation and stabilization. The INO80E-HDAC1-YY1 pathway may represent a candidate protective mechanism in AS that requires further validation. Full article

Acute kidney injury (AKI) is a critical clinical syndrome with limited effective therapies, in which renal tubular epithelial cell (RTEC) pyroptosis mediated by the NLRP3 inflammasome represents an important pathological contributor. Stress granules (SGs), dynamic membrane-less condensates, enable cells to adapt to various stress conditions, yet their role and regulatory mechanism in AKI remain unclear. Here, we identify SG persistence as a protective mechanism against AKI and show that poly(ADP-ribosyl)ation (PARylation)-mediated regulation of SG dynamics alleviates pyroptosis during renal injury. We found that SGs were prominently formed in RTECs from AKI patients, cisplatin-induced AKI mice, and cisplatin-stimulated HK-2 cells. Poly(ADP-ribose) glycohydrolase (PARG), the key enzyme for reversing PARylation, was significantly upregulated in injured renal tissues and cells. Genetic or pharmacological inhibition of PARG delayed SG disassembly, enhanced SG persistence, and mitigated renal injury. Mechanistically, persistent SGs regulated DDX3X availability and reduced DDX3X-NLRP3 inflammasome activation, thereby attenuating RTEC pyroptosis. These findings uncover a novel mechanism of SG-mediated renoprotection and highlight SG dynamics as a potential therapeutic target in AKI. Full article

Bone remodeling imbalance represents the fundamental pathological basis of osteoporosis. Exercise is broadly regarded as a valuable non-pharmacological strategy for preventing and managing osteoporosis; however, the precise molecular mechanisms through which exercise modulates bone metabolism remain incompletely understood. Mitophagy has recently been recognized as an important mediator linking exercise to the regulation of bone remodeling. This review centers on the “exercise–mitophagy–bone remodeling” axis, systematically outlining the biological processes and regulatory determinants of mitophagy within the bone microenvironment. Evidence suggests that mitophagy facilitates bone formation by preserving mitochondrial quality, attenuating oxidative stress, and optimizing cellular energy metabolism. Moreover, it exerts stage-specific inhibitory effects on bone resorption during osteoclast differentiation. Particular emphasis is placed on the mechanisms by which exercise activates mitophagy-related signaling pathways via metabolic, mechanical, and hypoxic stimuli. In addition, exercise may enhance the efficiency of this regulatory axis by maintaining vitamin D and calcium homeostasis and modulating estrogen signaling pathways. The differential effects of exercise modalities and durations on these processes are also critically evaluated. Finally, this review addresses current limitations in existing research and highlights future directions, including the optimization of exercise interventions targeting mitophagy and the integration of multi-omics approaches. These findings offer a theoretical basis for designing precise exercise regimens and combined therapeutic approaches in the management of osteoporosis. Full article

Background/Objectives: Neuroinflammation is increasingly recognized as a key mechanism linking infectious diseases with psychiatric disorders through interactions between peripheral immune activation, metabolic pathways, and brain network alterations. This review aimed to synthesize current evidence on the neuroimmune mechanisms and biomarkers underlying infection-associated psychiatric disorders. Methods: A narrative literature review structured according to the SANRA (Scale for the Assessment of Narrative Review Articles) criteria was conducted using the Web of Science Core Collection, PubMed/MEDLINE, Scopus and PsycINFO databases. Boolean search strategies identified studies investigating neuroinflammatory biomarkers, neuroimmune mechanisms, and psychiatric outcomes associated with infectious diseases. The search (January 2022–30 June 2026) included 76 studies in the final qualitative analyses. Results: The reviewed evidence consistently identified inflammatory cytokines and chemokines, complement proteins, blood–brain barrier markers, glial activation biomarkers, neuroaxonal injury markers, kynurenine pathway metabolites, neurotrophic factors, and neuroimaging markers as complementary indicators of infection-induced neuroimmune dysfunction. Across diverse bacterial, viral, parasitic, and systemic infections, these mechanisms converged on peripheral immune activation, blood–brain barrier disruption, microglial activation, kynurenine pathway dysregulation, impaired neurotrophic signaling, synaptic dysfunction, and altered brain network connectivity, contributing to depression, anxiety, psychosis, cognitive impairment, and fatigue. Based on these findings, a unified neuroimmune model integrating peripheral and central mechanisms is proposed. Conclusions: Neuroinflammation emerges as a shared biological pathway linking infections with transdiagnostic psychiatric phenotypes. Although no single biomarker currently demonstrates sufficient diagnostic specificity, integrated multimodal biomarker panels may improve biological stratification, facilitate earlier identification of high-risk patients, and support the development of mechanism-based precision approaches—including candidate anti-inflammatory pharmacological strategies currently under clinical investigation—for infection-associated psychiatric disorders. Full article

Background: Hepatocellular carcinoma (HCC) remains a major clinical challenge due to its pronounced molecular heterogeneity and frequent resistance to conventional therapies. A key driver of therapeutic failure is the overexpression of the anti-apoptotic proteins myeloid cell leukemia-1 (Mcl-1) and B-cell lymphoma-extra large (Bcl-XL), which collectively maintain mitochondrial integrity and promote tumor cell survival. Methods: In this study, we evaluated a rational combination strategy targeting these complementary survival pathways using the histone deacetylase inhibitor panobinostat and the DNA-damaging agent bleomycin in HepG2 cells, a p53-functional HCC cell model. Results: In HepG2 cells, each agent alone produced only limited cytotoxicity, whereas their combination resulted in a marked and synergistic induction of apoptosis. This was shown by increased Annexin V positivity, mitochondrial outer membrane permeabilization (MOMP), and activation of caspases-8, -9, and -3 as well as cleavage of poly(ADP-ribose) polymerase (PARP). Mechanistically, panobinostat reduced Bcl-XL expression and primed mitochondria for apoptosis but simultaneously triggered compensatory upregulation of Mcl-1, representing an adaptive resistance response within this experimental system. Bleomycin effectively counteracted this escape mechanism by suppressing Mcl-1 induction, thereby lowering the apoptotic threshold and enabling mitochondrial permeabilization. In parallel, combined treatment potentiated caspase-8 cleavage, suggesting an additional caspase-8-associated apoptotic signal that amplified caspase-3/PARP execution. Pharmacological inhibition with zVAD-FMK confirmed that the observed cell death was predominantly caspase-dependent, supporting a coordinated engagement of both intrinsic and extrinsic apoptotic pathways. In summary, the combination of panobinostat and bleomycin overcomes anti-apoptotic defenses in HepG2 cells through synergistic and coordinated disruption of mitochondrial survival checkpoints and dual apoptosis pathway activation. Conclusions: By blocking a compensatory Mcl-1 escape response while simultaneously engaging extrinsic apoptosis signaling, this strategy produces potent synergistic cell death in this defined p53-functional HCC model and represents a promising mechanistic proof of concept that warrants further validation in additional molecularly diverse HCC models before broader translational conclusions can be drawn. Full article

Insomnia is a common sleep disorder that significantly impairs quality of life and increases the risk of various chronic diseases. Although conventional sedative–hypnotic agents are effective, their clinical use is limited by tolerance, dependence, and residual next-day effects. The orexin system plays a critical role in sleep–wake regulation through orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R), with OX2R serving as the primary mediator of wakefulness. Based on this mechanism, orexin receptor antagonists (ORAs) have been developed to promote sleep by suppressing wake-promoting signaling pathways. This review systematically summarizes the structural and functional characteristics of the orexin system, with particular emphasis on the functional divergence of OX1R and OX2R and their therapeutic relevance. Recent advances in dual orexin receptor antagonists (DORAs) and selective orexin receptor antagonists are discussed, and the pharmacological properties and clinical performance of approved and investigational agents are compared. In addition, the safety profiles, adverse effects, and clinical limitations of ORAs are reviewed. Future perspectives are highlighted, including receptor selectivity, pharmacokinetic optimization, and personalized treatment strategies. Collectively, ORAs offer a mechanism-based therapeutic approach that may improve both the efficacy and safety of insomnia treatment. Full article

Astrocytes, once regarded primarily as structural and metabolic support cells, are now increasingly recognized as active participants in neural information processing. Within respiratory control networks, astrocytes are widely distributed throughout the brainstem and spinal cord, where they engage in bidirectional communication with neurons to regulate breathing. This review summarizes current knowledge regarding the roles of astrocytes in respiratory rhythm and pattern generation, central respiratory chemoreception, hypoxic ventilatory responses, respiratory plasticity, and respiratory pathophysiology. Recent advancements in calcium imaging, optogenetics, and pharmacology have revealed that astrocytes modulate respiratory network activity through intracellular Ca²⁺ signaling and the release of gliotransmitters, particularly ATP. In the ventrolateral medulla and the parafacial respiratory group/retrotrapezoid nucleus, astrocytes contribute to central CO₂/H⁺ chemoreception through mechanisms involving connexin hemichannels, potassium channels, and purinergic signaling. Emerging evidence further suggests that astrocytes participate in central hypoxic responses and adaptive respiratory plasticity. In addition, astrocytic dysfunction has been implicated in several disorders affecting respiratory control, including brainstem astrocytoma, Rett syndrome, sudden infant death syndrome, and sudden unexpected death in epilepsy. Collectively, accumulating evidence identifies astrocytes as integral components of respiratory control networks that contribute to both the maintenance of respiratory homeostasis and the pathogenesis of respiratory dysfunction. A deeper understanding of astrocyte–neuron interactions may provide novel therapeutic opportunities for the treatment of respiratory disorders. Full article