Search Results (11,629)

Glioblastoma (GBM) is characterized by hypoxia-driven metabolic adaptation and profound therapeutic resistance. Ferroptosis, an iron-dependent lipid peroxidation-related cell death process, has emerged as a potential vulnerability; however, its relationship with hypoxia signaling remains incompletely defined. In this study, we performed integrative transcriptomic and single-cell RNA sequencing analyses to investigate the relationship between hypoxia signaling and ferroptosis-related gene signatures in GBM. Intersection analysis of hypoxia-associated differentially expressed genes and curated ferroptosis-related gene sets identified 29 core candidate genes. FerroScore stratification revealed that tumors with higher ferroptosis-related transcriptional signatures were significantly associated with poor overall survival. Among these genes, HILPDA emerged as a hypoxia-associated gene consistently linked to ferroptosis-related gene expression patterns and immune-related transcriptional programs. HILPDA expression showed significant correlations with iron-ROS axis components, including HMOX1, NOX4, and STEAP3, and was associated with immune microenvironment changes characterized by T cell depletion and inflammatory infiltration. Single-cell RNA-seq analysis further supported the cellular-level association between HILPDA expression and hypoxia-related transcriptional states. Structural equation modeling suggested that the relationship between HILPDA expression and ferroptosis-related gene signatures may be mediated through hypoxia-related pathways. Collectively, these findings indicate a transcriptomic association between hypoxia signaling and ferroptosis-related gene signatures in GBM and identify HILPDA as a candidate gene associated with this axis. Full article

Aneurysmal subarachnoid hemorrhage (SAH) remains a devastating cerebrovascular disorder with high morbidity and mortality, despite advances in aneurysm securing and neurocritical care. Clinical outcomes are determined by early brain injury (EBI), delayed cerebral ischemia (DCI), hydrocephalus, and long-term cognitive impairment, extending beyond the traditional focus on large-vessel vasospasm alone. Emerging evidence identifies the dysfunction of the glymphatic system and meningeal lymphatic pathway, the brain’s primary clearance pathways, as a central and unifying mechanism linking acute hemorrhagic injury to delayed and chronic neurological sequelae. Following SAH, acute intracranial pressure elevation, subarachnoid blood clot burden, loss of arterial pulsatility, venous congestion, astrocytic aquaporin-4 perivascular depolarization, and neuroinflammation converge to suppress cerebrospinal fluid–interstitial fluid exchange and outflow in glymphatic system and subsequent meningeal lymphatic drainage. Persistent clearance failure promotes the retention of blood breakdown products, inflammatory mediators, and metabolic waste, amplifying microvascular dysfunction, cortical spreading depolarizations, blood–brain barrier disruption, and secondary ischemic injury. Importantly, accumulating data highlight venous pathology and meningeal lymphatic impairment as critical, yet underappreciated, contributors to delayed injury and post-SAH hydrocephalus. In this review, we synthesize the current knowledge of the physiological organization of glymphatic and meningeal lymphatic systems, delineate the mechanistic and molecular drivers of their dysfunction after SAH, and discuss clinical implications for EBI, DCI, hydrocephalus, and long-term cognitive outcomes. We further outline future directions, including translational imaging, biomarker development, and therapeutic strategies targeting clearance pathways, to advance disease-modifying approaches in SAH. Full article

The global spread of COVID-19 led to the rapid authorization of remdesivir as the first antiviral therapy. However, accumulating clinical evidence has linked its use to cardiac adverse effects. Understanding the mechanisms underlying remdesivir-induced cardiotoxicity is critical for optimizing its clinical use and ensuring patient safety. This study investigates the electrophysiological and molecular features underlying remdesivir-induced cardiac toxicity in male and female guinea pigs, aiming to elucidate the sex-dependent differences in cardiac dysfunction and the role of mitochondria in mediating these effects. A cardiac injury model was established via intraperitoneal administration of remdesivir. In vivo telemetry and ex vivo electrocardiography were used for continuous monitoring of cardiac electrical activity, while optical mapping enabled the assessment of action potential parameters and conduction properties. The histopathological alterations and mitochondrial ultrastructure were examined by hematoxylin–eosin staining and transmission electron microscopy. ELISA and Western blot analyses were performed to explore the inflammatory signaling, apoptosis, and mitochondrial dynamics. Remdesivir induced distinct sex-specific patterns of cardiac toxicity. Compared with female guinea pigs, male guinea pigs had significantly more severe myocardial injury, which was characterized by extensive inflammatory cell infiltration, marked mitochondrial disruption, and a higher incidence of sustained ventricular tachyarrhythmia. Overall, remdesivir was associated with sex-dependent cardiac toxicity, accompanied by mitochondrial impairment and inflammatory activation. Male guinea pigs were more susceptible to electrophysiological instability and mitochondrial dysfunction. These findings highlight the importance of carefully evaluating remdesivir’s cardiac effects and support the need for individualized, sex-specific considerations in its clinical administration. Full article

Corneal alkali burn induces severe inflammation and tissue damage, leading to loss of corneal transparency and vision impairment. In this study, we evaluated the therapeutic potential of rapamycin (RAPA) compared with cyclosporine A (CsA) in a mouse model of corneal alkali burn, focusing on nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)–mediated inflammatory signaling and its impact on corneal wound healing and repair. Notably, RAPA robustly suppressed NF-κB activation, reduced infiltration of F4/80 macrophages and MPO neutrophils, and downregulated pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6. RAPA also markedly inhibited corneal neovascularization, as evidenced by decreased VEGF expression, reduced CD31 vessel formation, and suppression of Ang-2. RAPA substantially inhibited pathological fibrotic remodeling by reducing TGF-β1 expression, attenuating myofibroblast activation (α-SMA), decreasing collagen III deposition, and modulating matrix remodeling through suppression of MMP-9. Crucially, RAPA preserved epithelial barrier integrity by maintaining occludin expression, supported proper epithelial differentiation through sustained expression of CK12, and enhanced mucin layer stability by increasing MUC1 expression. It also restored tear production, reduced apoptotic cell death (TUNEL), and decreased dysregulated epithelial proliferation (Ki67). In conclusion, RAPA showed superior efficacy compared with CsA, primarily by enhancing corneal wound healing and facilitating structural and functional outcomes in the burned cornea. These findings underscore RAPA as a promising therapeutic candidate for ocular surface repair and vision restoration in extensive corneal injury. Full article

Conventional hormonal and clinical models inadequately clarify the complex and diverse aspects of female infertility, resulting in poor reproductive outcomes and reduced egg viability. A growing body of research indicates that female reproductive failure is mostly due to disruptions in cellular homeostasis, especially concerning organelle quality control. Oxidative stress has emerged as a crucial mediator connecting metabolic, inflammatory, and ageing-related processes to ovarian failure, however its downstream impacts on intracellular organelle turnover remain insufficiently clarified. Our narrative review encapsulates the existing data for a unified pathogenic concept focused on the redox-regulated mitochondria–lysosome axis. We examine the interaction of oxidative stress, mitochondrial malfunction, compromised mitophagy, and lysosomal deficiency in granulosa cells and oocytes. Prolonged oxidative stress may disrupt this equilibrium, leading to defective mitochondria accumulation and impaired mitophagy. This self-perpetuating cycle may ultimately jeopardises reproductive viability and oocyte integrity. The integrated axis offers a shared molecular foundation for various infertility-related diseases, such as inadequate ovarian response, obesity-associated infertility, polycystic ovary syndrome, and ovarian ageing. Ultimately, we analyse new findings suggesting that specific antioxidant chemicals modify mitophagy and lysosomal function while also neutralising reactive oxygen species, highlighting their potential use in precision fertility treatments. Our research redefines female infertility as a condition of redox-dependent organelle quality control, thereby introducing novel avenues for identifying biomarkers, categorising patients, and targeting treatments in assisted reproduction. Full article

Gabapentin is widely used for epilepsy and neuropathic pain. Beyond neurological indications, preclinical evidence suggests that gabapentin may exert anti-inflammatory effects that have not been systematically reviewed. A systematic review (2015–2025) was performed, resulting in thirteen in vitro and in vivo studies evaluating gabapentin’s impact on inflammatory signaling pathways, cytokine production, immune cell activity, and tissue inflammation. Outcomes included molecular pathways, inflammatory mediators, histopathological changes, and functional inflammatory measures. Risk of bias and study quality were assessed using the SYRCLE RoB tool for in vivo studies and the SciRAP approach for in vitro studies. Gabapentin demonstrated potential modulation of inflammatory responses in neuropathic pain, neuroinflammation, uveitis, and sepsis models through inhibition of MAPK and NF-κB signaling, reduction in pro-inflammatory cytokines, modulation of PPAR signaling pathways, and activation of Nrf2/HO-1 pathway. Gabapentin’s pharmacological actions extend beyond neuronal excitability to include modulation of inflammatory pathways, supporting a broader biological role for gabapentin. Although preclinical data support gabapentin’s potential anti-inflammatory properties, further targeted experimental and clinical studies are warranted to confirm these findings. Full article

Dezhou donkey is a premium indigenous Chinese livestock breed with high economic value for meat, hide and medicinal uses, and growth rate is a core trait determining farming profitability. However, the molecular and metabolic mechanisms underlying divergent growth rates in this breed have not been fully characterized, with no integrated transcriptomic and metabolomic studies reported. Here, 12 age-matched healthy male Dezhou donkeys were assigned to faster-growing (n = 6) and slower-growing (n = 6) groups by average daily gain, followed by plasma transcriptome sequencing and untargeted LC-MS/MS metabolomics. We identified 480 differentially expressed genes, with the slower-growing group enriching in immune/inflammatory/apoptotic pathways, and the faster-growing group in energy metabolism and transmembrane transport. Lipids and lipid-like molecules represented the largest proportion (44.9%) of the differential metabolites; the slower-growing group was enriched in lipid peroxidation and pro-inflammatory mediators, while the faster-growing group was enriched in unsaturated fatty acids and antioxidants. Integrated analysis revealed core pathways (cAMP signaling, arachidonic acid/unsaturated fatty acid biosynthesis) and key candidate genes/metabolites. Our findings clarify that excessive lipid peroxidation and inflammatory imbalance restrict growth, while efficient energy metabolism promotes faster growth, providing theoretical support for genetic improvement and precision nutrition of Dezhou donkeys. Full article

Punica granatum L. is a nutritionally relevant fruit with a complex phytochemical profile that varies across its anatomical fractions, including peel, arils, juice, seeds, and seed oil. Although pomegranate is widely recognized for its health-promoting potential, the nutritional significance of its matrix-dependent composition, bioavailability, and gut microbiota-mediated metabolism remains insufficiently integrated. This review aimed to critically evaluate the phytochemical diversity of pomegranate and its nutrition-related multi-target biological functions, with particular emphasis on food matrices, bioaccessibility, and translational relevance. A structured review of peer-reviewed studies indexed in major scientific databases from 2000 to January 2026 was conducted. Eligible reports included analytical, preclinical, and clinical studies addressing the composition of pomegranate-derived materials and their biological effects, with attention to extraction matrix, processing, bioavailability, microbial biotransformation, and mechanisms of action. Pomegranate exhibits marked matrix-specific phytochemical diversity. Peel is particularly rich in ellagitannins, especially punicalagin and punicalin; arils and juices are enriched in anthocyanins and flavonols; and seed oil contains high levels of punicic acid. Reported biological activities include antioxidant, anti-inflammatory, antimicrobial, metabolic, anti-aging, and anticancer effects. These actions appear to result from synergistic interactions among multiple bioactive compounds rather than from a single dominant constituent. Importantly, gut microbiota-driven conversion of ellagitannins and ellagic acid into urolithins is a major determinant of systemic bioactivity and may contribute to interindividual variability in response. The health effects of pomegranate should be interpreted within a nutrition-focused, matrix-dependent framework integrating composition, processing, bioavailability, and microbiota-derived metabolism. Full article

Antibiotic-associated diarrhea (AAD) is primarily driven by disruption of the gut microbiota accompanied by intestinal mucosal injury. Although multiherb formulations are widely used in East Asian medicine, their collective ecological effects and integrated microbiome–host mechanisms have not been systematically synthesized. This systematic review included 17 preclinical studies that investigated multiherbal formulations in AAD models. Given the substantial heterogeneity in the formulation composition, experimental design, and analytical platforms, a descriptive synthesis was performed. The included formulations were categorized into four clusters based on their shared herbal composition: Qiwei Baizhu San (QWBZP), Lizhong Tang (LZT), Gegen Qinlian Tang (GQT), and other supportive multiherbal formulations. The cluster-based synthesis revealed distinct convergent therapeutic strategies. The QWBZP and LZT clusters primarily supported the restoration of host metabolic and digestive functions, whereas the GQT cluster exhibited potent pathogen control effects with the suppression of opportunistic taxa. Across all clusters, a convergent microbiome–host response emerged, characterized by enrichment of commensal bacteria (e.g., Lactobacillus), upregulation of tight junction proteins (e.g., ZO-1, occludin), and attenuation of pro-inflammatory mediators (e.g., TNF-α, myeloperoxidase). Multiherb formulations in AAD models not only act as microbial modulators but also function as host-directed modulators that stabilize the intestinal homeostatic niche. Botanical interventions may facilitate endogenous microbiome recovery by reinforcing mucosal integrity and reducing environmental resistance. This ecological framework provides a rationale for future translational studies evaluating integrated herbal–probiotic strategies and precise microbiome management for patients with AAD, while further clinical validation is warranted. Full article

Osteocytes, once viewed mainly as passive bone-embedded cells, are now recognized as active regulators of the metastatic bone niche. Emerging evidence indicates that these cells integrate mechanical, inflammatory, and tumor-derived cues to influence metastatic seeding, dormancy, reactivation, and lesion progression in bone. This review synthesizes current understanding of osteocyte contributions to skeletal metastasis. We discuss core signaling axes, including osteocyte-derived RANKL/OPG balance, Wnt antagonists (sclerostin/DKK1), mechanotransduction pathways (Piezo1 signaling and connexin-43 hemichannels), and osteocyte paracrine mediators (extracellular vesicles and senescence-associated factors), and examine how each axis modulates tumor cell dormancy, osteolysis, or osteoblastic progression. We then review translational strategies targeting osteocytes, recent preclinical and clinical insights. Emerging biomarkers (e.g., serum sclerostin, DKK1, bone turnover markers) and immune–skeletal imaging approaches are also considered. Controversies, including the paradoxical effects of sclerostin blockade and the identity of in vivo RANKL sources, are discussed. Finally, we outline key knowledge gaps and propose endpoints for future trials. In summary, an osteocyte-centric perspective reveals novel targets and strategies for managing bone metastases, guiding future translational research. Full article

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy worldwide, with molecular heterogeneity complicating early detection and treatment stratification. The insulin-like growth factor (IGF) axis interacts bidirectionally with immune regulatory mechanisms in ways that shape tumor phenotype and therapeutic vulnerability. This review synthesizes evidence on how IGF signaling orchestrates immunosuppression through effects on tumor-associated macrophages, regulatory T cells, and myeloid-derived suppressor cells, while inflammatory cytokines reciprocally modulate IGF bioavailability. Three mechanistic principles emerge: IGF binding protein 2 (IGFBP-2) functions as a central coordinator linking growth factor signaling to immune evasion through STAT3-dependent pathways driving M2 macrophage polarization and regulatory T cell differentiation; IGF–immune crosstalk varies considerably across molecular subtypes, with microsatellite-stable tumors exhibiting high reliance on IGF-I receptor-mediated immune silencing; and local paracrine IGF production increasingly dominates over systemic regulation as disease progresses. These bidirectional connections establish self-reinforcing circuits that determine whether tumors remain immunologically responsive or develop immune exclusion. Multi-marker panels incorporating IGFBP-2 alongside complementary biomarkers have shown improved diagnostic performances for early CRC detection, underscoring the need for the large-scale prospective clinical evaluation of IGF network components as biomarkers for CRC in diverse populations. The convergence of IGF signaling with checkpoint regulation suggests that combined targeting warrants investigation for resistance in tumors lacking effective immunotherapy options. Full article

The gut microbiota plays a central role in digestion, metabolism, immune regulation, and inflammatory processes, and is highly responsive to dietary factors, including food additives. With the increasing consumption of ultra-processed foods, growing attention has been directed toward the long-term effects of commonly used additives on gut health. This review examines the interactions between food additives and the gut microbiota, with a specific focus on the emulsifiers carboxymethyl cellulose (CMC) and carrageenan (CGN), which are widely used in processed foods. Evidence from in vitro, animal, and limited human studies indicates that both CMC and CGN can alter gut microbiota composition, disrupt intestinal barrier integrity, and promote pro-inflammatory responses, although their mechanisms of action differ. CGN has been more consistently associated with direct activation of inflammatory signalling pathways and epithelial stress, whereas CMC primarily induces microbiota-mediated effects, including altered microbial spatial organisation and mucus barrier disruption, leading to low-grade inflammation. The magnitude of these effects appears to depend on dosage, duration of exposure, and the experimental model employed. Overall, the findings summarised in this review suggest that chronic exposure to CMC and CGN may contribute to gut dysbiosis and increased inflammatory susceptibility, particularly within dietary patterns rich in ultra-processed foods. These observations highlight the need for harmonised research methodologies, more human-relevant long-term studies, and reconsideration of current food safety assessment frameworks to better account for microbiota-related outcomes. Full article

Pasteurella multocida (P. multocida) is a significant pathogenic bacterium that causes serious disease and death in the yaks of the Tibetan Plateau, and the existing inactivated vaccines are limited by low protection and reactogenicity. Outer membrane vesicles (OMVs) derived from a yak-origin serogroup B P. multocida isolate were evaluated as a potential vaccine candidate in the present study. The purified OMVs were characterized by transmission electron microscopy and nanoparticle tracking analysis, which demonstrated the presence of typical bilayer vesicles ranging from 20 to 300 nm in diameter. Proteomic profiling revealed 1213 proteins, with many of them being immunologically relevant outer membrane-associated proteins like OmpA, OmpH, Omp16, OmpW, TbpA and PlpP. The functional enrichment analysis showed that these proteins were linked to translation, membrane structure, transport, metabolism, and pathways of adaptation of bacteria. In vitro OMVs were effectively taken up by RAW264.7 macrophages and stimulated robust expression of inflammatory mediators, such as TNF-α, IL-1β, IL-6, iNOS and IL-10, which is indicative of strong innate immunostimulatory capacity. OMV immunization induced significant antigen specific humoral responses in mice and yaks in vivo. In mice, intramuscular immunization was effective in giving full protection against P. multocida challenge but not intranasal immunization. Histopathology also indicated less tissue damage in vaccinated animals, especially in the lung and liver. These findings, taken together, prove that yak-derived P. multocida OMVs have high immunogenicity and protection capabilities, which show their potential as a next-generation vaccine platform to tackle P. multocida infection. Full article

Macrophage-mediated inflammation is a key driver of sepsis-induced acute lung injury (ALI). M1 macrophage polarization relies on metabolic reprogramming, yet the upstream regulatory factors remain unclear. Lysine acetyltransferase 6A (KAT6A), a MYST-family acetyltransferase, regulates transcriptional programs in immune cells, but its role in macrophage function and ALI progression remains unknown. Public single-cell and bulk transcriptomic datasets were used to assess KAT6A expression changes and its association with inflammatory and metabolic pathways in macrophages. KAT6A inhibition with WM1119 was used to evaluate effects on M1 polarization, cytokine production, metabolic reprogramming, and PI3K-AKT-mTOR signaling. The therapeutic potential of KAT6A inhibition was validated in a cecal ligation and puncture (CLP)-induced sepsis model by assessing lung injury, bacterial clearance, and survival. KAT6A expression was upregulated in sepsis and particularly enriched in M1 macrophages. Inhibition of KAT6A reduced inflammatory and glycolytic transcriptional programs, suppressed glycolysis and enhanced oxidative phosphorylation, leading to decreased cytokine production and limited M1 polarization accompanied by suppression of PI3K-AKT-mTOR pathway. In CLP-induced septic mice, treatment with the KAT6A inhibitor WM1119 alleviated lung injury, improved bacterial clearance, and prolonged survival. KAT6A expression is associated with macrophage glucose metabolism, pro-inflammatory responses, and M1 macrophage polarization in sepsis-induced acute lung injury. Pharmacologic inhibition of KAT6A may provide a promising therapeutic strategy for reducing macrophage-driven lung injury. Full article

Acute myeloid leukemia (AML) remains a highly morbid malignancy in which outcomes are constrained not only by disease refractoriness and relapse, but also by therapy-related toxicity—particularly infections, mucosal injury, and delayed hematopoietic reconstitution. The gut microbiota has emerged as a potentially modifiable layer of host vulnerability and resilience during AML treatment. Microbiome disruption is detectable already at diagnosis, even in antibiotic-naïve patients, and is often characterized by reduced community diversity, depletion of anaerobic taxa linked to short-chain fatty acids (SCFAs) production, and enrichment of pathobiont-associated profiles. During induction, cytotoxic therapy and antimicrobials precipitates diversity loss, domination events, and persistent shifts beyond discharge. Clinically, the most consistent translational signal is the association between baseline or early-treatment microbiome features and infectious outcomes, while emerging data suggest that diagnosis-time microbiome structure may also relate to hematologic recovery kinetics. Mechanistic models converge on pathways linking barrier integrity, microbial metabolites (notably butyrate and other SCFAs), immune calibration, and inflammatory translocation of microbial products. These insights support hypotheses: antimicrobial stewardship may preserve microbiome function; ecosystem repair strategies such as autologous fecal microbiota transfer (A-FMT) are feasible and can restore community structure; and metabolite or nutritional interventions merit evaluation in immunocompromised hosts. Regimen-specific microbiome effects and microbiome–drug interactions suggest that treatment choice could have downstream microbiome-mediated consequences. We synthesize evidence, outline interventional concepts, and define methodological priorities for next-generation trials assessing causality and clinical benefit. Progress will require longitudinal sampling, multi-omic integration (metabolomics, resistomics, and barrier/inflammatory biomarkers), and interventional designs linking microbiome dynamics to clinically meaningful outcomes. Full article