Frontiers in bioscience (Landmark edition)最新文献

Melatonin, a highly conserved indoleamine produced by the pineal gland and also in the mitochondria of many, perhaps all, extrapineal tissues, has emerged as a powerful antioxidant molecule. This review explores its role in counteracting lipid peroxidation (LP), a process that damages cellular membranes through the oxidative degradation of lipids. LP is involved in numerous pathological conditions, including neurodegenerative diseases, cancer, cardiovascular disorders, and aging. The article discusses how melatonin prevents, mitigates, or even reverses LP-induced cellular damage by acting as both a direct free radical scavenger and as an indirect regulator of antioxidant enzymes. A key point is melatonin's amphiphilic nature, which enables it to access both lipid and aqueous cellular compartments, allowing for broad protection and supporting its diverse antioxidant, cytoprotective, and regulatory functions within the cell. Melatonin and its metabolites, such as N¹-acetyl-N²-formyl-5-methoxykynuramine and N¹-acetyl-5-methoxykynuramine, interact with reactive oxygen and nitrogen species (ROS and RNS), effectively reducing the LP chain reaction. This series of protective actions is known as the melatonin antioxidant cascade. This highlights that melatonin not only inhibits the initiation and propagation phases of LP but may also contribute to the repair of oxidized membrane components. We further summarize the experimental and clinical evidence supporting melatonin's therapeutic potential in conditions in which LP plays a central role. Its ability to cross the blood-brain barrier and its synthesis in multiple tissues, combined with its low toxicity and minimal side effects, make it a promising therapeutic candidate. Additionally, melatonin modulates mitochondrial function and membrane fluidity, offering additional protection against oxidative stress. This positions melatonin not just as a passive antioxidant, but as an active therapeutic agent against oxidative damage. We advocate for deeper exploration of melatonin-based therapies in LP-driven diseases, proposing it as a multifunctional molecule with significant clinical value.

Background: Glioma, the most common brain tumor in adults, exhibits marked hypoxia and invasiveness. Endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) have been implicated in tumor progression, while epithelial mesenchymal transition (EMT) drives invasion and metastasis.

Methods: This study explored the role of ERS, particularly the PKR-like endoplasmic reticulum kinase (PERK) pathway, in promoting EMT and malignancy in glioma. Based on publicly available bulk transcriptomic data, we analyzed PERK activity in high-grade and hypoxic gliomas. PERK activation across glioma subtypes was compared using publicly available single-cell sequencing, and its correlation with EMT upregulation was evaluated using pseudotime analysis. The effects of PERK on glioma migration and invasion in a hypoxic environment were investigated using PERK-silenced glioma cell lines. In vivo tumorigenicity was assessed in nude mice by measuring tumor size and EMT marker expression. Intercellular communication was examined using CellChat analysis. Hypoxic niche regions were identified using publicly available spatial transcriptomics with PERK-EMT co-localization.

Results: Hypoxia-induced PERK activation promoted EMT, enhancing glioma cell migration and tumor growth. High PERK signatures correlated with EMT activation in aggressive gliomas. Genetic silencing of PERK reduced the expression of EMT-related proteins, an effect partially reversed by hypoxia. Inhibition of PERK signaling decreased tumor size in mice. PERK-activated glioma subpopulations exhibited stronger cell-cell communication through secreted phosphoprotein 1 (SPP1)-CD44 interactions. Spatial transcriptomic analysis confirmed enrichment of the PERK/EMT pathway in hypoxic niches alongside SPP1-CD44 co-localization.

Conclusion: These findings reveal PERK-driven EMT as a key mechanism linking ER stress to glioma progression, with hypoxia reinforcing this axis. Targeting the PERK signaling axis or SPP1-CD44 interactions may offer novel therapeutic strategies against aggressive gliomas.

Cardiovascular and cerebrovascular diseases are among the leading causes of death worldwide. Development of these diseases occurs following pathological structural remodeling and functional changes in the vascular wall. Emerging evidence suggests that histone acetyltransferases (HATs) play a role in the pathological processes of the arterial wall. However, there is currently a lack of comprehensive reviews examining the role of HATs in vascular diseases. The aim of this research is therefore to systematically describe the pathological effects of various risk factors on different layers of cells in the arterial vascular wall. The risk factors include abnormal activation of the renin-angiotensin system, hyperglycemia, high-sodium diets, and intermittent hypoxia. The effects regulated by HATs involve the nuclear factor kappa-B (NF-κB)-NOD-like receptor family pyrin domain containing 3 (NLRP3) and AMP-activated protein kinase (AMPK) pathways, and the mitogen-activated protein kinase (MAPK) and vascular endothelial growth factor receptor 2 (VEGFR2) signaling pathways. We also explore the dual role of HATs in vascular protection and injury. Additionally, this study focuses on the prospects of future therapeutic strategies targeting HATs, including innovative approaches such as HAT inhibitors, epigenetic degraders, non-coding RNA interventions, and epigenetic editing technologies. The aim of this review is to provide a basis for the development of selective subtype HAT inhibitors.

Background: Intracranial hemorrhage (ICH) poses a serious risk to human health. The shift between pro-inflammatory (M1) and anti-inflammatory (M2) microglial phenotypes is a complex dynamic process. Quiescin sulfhydryl oxidase 1 (QSOX-1) plays a role in protecting cells from damage caused by oxidative stress and in cellular remodeling processes. This study explored how neuron-derived QSOX-1 protein influences the shift in microglial polarization between the M1 and M2 states, and its subsequent impact on nerve function after ICH.

Methods: QSOX-1 expression in the ICH mouse model was detected. Neuroinflammation, nerve damage, microglial phenotype, nerve function changes, and related signaling pathways were observed in mouse or cell models treated with QSOX-1.

Results: After ICH, mass spectrometry analysis identified 353 differential proteins, of which the key role of QSOX-1 was verified by bioinformatics analysis. QSOX-1 in the ICH model was highly expressed in the neurons. After treatment with recombinant QSOX-1, the ICH model exhibited reduced neuroinflammation and nerve damage, improved nerve function, and a shift in microglia towards predominantly anti-inflammatory (M2) phenotypes. In vitro, QSOX-1 intervention led to reduced inflammation and neuronal cell death. When QSOX-1 expression was upregulated in microglia, the cells primarily shifted towards the M2 phenotype. This shift was accompanied by reduced levels of phosphorylated nuclear factor kappa B (NF-kB) and thioredoxin (TRX)-interacting protein (TXNIP)/NLR family pyrin domain containing 3 (NLRP3) protein, along with increased levels of phosphorylated inhibitor of NF-kB alpha (IkB-α) and TRX.

Conclusion: Neuron-derived QSOX-1 protein reduces neuroinflammation and promotes nerve function recovery after ICH by regulating microglia phenotype changes, which may be related to the IkB-α/NF-kB and TRX/TXNIP/NLRP3 axis.

Epinephrine (Epi, adrenaline) is routinely used during cardiopulmonary resuscitation (CPR) for cardiac arrest and is a first line treatment according to the international advanced life support (ALS) guidelines, which recommend 1 mg Epi be administered every 3-5 minutes during CPR. However, specific pharmacological factors that may distinguish Epi from other vasopressor agents used during CPR are unclear. This opinion article argues that one such factor, perhaps even the most important, is the activation of the β₂-adrenergic receptor (AR) subtype, which only Epi, among all vasopressor hormones, can induce. β₂AR activation equips Epi with more robust capabilities for pulse generation in the pacemaker cells (sinoatrial node) for the heart and of restoring contractile function in ischemic/hypoxic cardiomyocytes via sodium/potassium pump activation, compared to all other vasopressor hormones, including the closely related catecholamine norepinephrine (NE, noradrenaline). These additional actions of Epi via the β₂AR, which are probably not shared by NE or other vasopressor agents, may make it particularly useful in situations where simple blood pressure elevation is insufficient, such as cardiac arrest.

Background: Pancreatic neoplasms, particularly pancreatic adenocarcinoma (PAAD), are aggressive malignancies marked by extensive infiltration of cancer-associated fibroblasts (CAFs) and a highly complex tumor immune microenvironment. These pathological features are strongly associated with poor patient survival. However, the precise mechanisms underlying the role of CAFs in PAAD have not been determined.

Methods: To systematically analyze the functions of CAFs in PAAD and their associations patient outcomes, an integrative approach combining multi-omics data with experimental validation was used.

Results: Integrated weighted gene co-expression network and protein-protein interaction network analyses revealed CAF-related genes with functional significance. Experimental verification was performed to examine the influence of candidate CAF-related genes identified using multi-database analyses on tumor cell behavior. COL28A1, TGFB2, TGFBI, PLOD2, and COL22A1 were core genes closely associated with CAFs. Patients in the high-risk group demonstrated a higher immune escape ability and lower predictive response rate to immunotherapy than those in the low-risk group. Several potential targeted therapeutic compounds were identified, including dihydrorotenone and sorafenib. Single-cell RNA sequencing and expression analyses confirmed elevated expression of TGFBI and PLOD2 in CAFs. Functional experiments demonstrated that PLOD2 promotes tumor progression by regulating extracellular matrix remodeling.

Conclusions: This study provides insights into the molecular mechanisms underlying PAAD and establishes a theoretical foundation for the development of CAF-targeting therapeutic strategies.

Background: Vascular dementia (VaD) is a prevalent cognitive disorder associated with cerebrovascular pathologies, in which hippocampal dysfunction plays a critical role. Impaired zinc homeostasis, mediated by the zinc transporters 3 (ZnT3) and transmembrane protein 163 (TMEM163), has been implicated in neuronal damage. However, the underlying mechanisms remain unclear. The purpose of this study is to elucidate the molecular mechanisms by which these zinc transporters may contribute to VaD pathogenesis, and to determine whether these mechanisms are involved in the development of VaD.

Methods: Rat primary hippocampal neurons were subjected to oxygen-glucose deprivation (OGD) to simulate ischemic conditions. To investigate the roles of ZnT3 and TMEM163, we employed siRNA-mediated silencing and plasmid-based overexpression. Neuronal viability was assessed using the methyl thiazolyl tetrazolium (MTT) assay, while apoptosis was quantified via TdT-mediated dUTP nick-end labeling (TUNEL) staining. Intracellular and extracellular zinc levels were measured using FluoZin-3 fluorescence and ELISA, respectively. Protein and mRNA expression levels were analyzed by western blot and real-time quantitative polymerase chain reaction (RT-qPCR). Protein-protein interactions were examined through co-immunoprecipitation, and subcellular localization was determined via cell surface biotinylation.

Results: OGD induced significant extracellular zinc overload, neuronal apoptosis, and reduced cell viability, concomitant with upregulated expression of ZnT3 and TMEM163 (all p < 0.001). Overexpression of these transporters exacerbated zinc efflux and neuronal damage under OGD, whereas their silencing attenuated zinc overload and neuronal degeneration (p < 0.001). Co-immunoprecipitation confirmed a physical interaction between ZnT3 and TMEM163. Furthermore, OGD triggered the translocation of both proteins from the cell membrane to the cytoplasm (p < 0.001), suggesting ischemia-induced dysregulation of zinc transport dynamics. These findings demonstrate that ZnT3 and TMEM163 cooperatively modulate zinc homeostasis and that their dysregulation during OGD contributes to neuronal injury.

Conclusion: ZnT3 and TMEM163 are critical regulators of zinc homeostasis in hippocampal neurons. Their dysregulation under ischemic conditions promotes extracellular zinc overload and exacerbates neuronal damage, highlighting their potential therapeutic relevance in VaD.

Background: Ischemic stroke leads to significant neuronal damage, and impaired angiogenesis remains a critical factor limiting post-stroke recovery. Ginkgolide B (GB), a key component of Ginkgo biloba extract, has shown potential neuroprotective effects, but its pro-angiogenic mechanisms remain unclear.

Methods: To investigate the effects of GB, we established an oxygen-glucose deprivation/reperfusion (OGD/R) model using bEnd.3 cells. Potential molecular targets of GB were explored through a combination of network pharmacology analysis, protein-protein interaction (PPI) network construction, pathway enrichment, and molecular dynamics simulations. Based on these predictions, a series of in vitro assays-including Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) incorporation, wound-healing, Transwell migration, and Matrigel tube formation tests-were performed to evaluate cell viability, proliferation, migration, and angiogenic activity. Western blotting was conducted to detect AKT serine/threonine kinase 1 (AKT1), vascular endothelial growth factor (VEGF), and Angiogenin (Ang) expression and clarify the role of the AKT1/VEGF/Ang pathway.

Results: Bioinformatics analysis identified 19 potential targets, among which AKT1, Matrix Metalloproteinase 9 (MMP9), and Prostaglandin-Endoperoxide Synthase 2 (PTGS2) exhibited the highest relevance. GB showed no evident cytotoxicity at concentrations up to 40 μM and mitigated the OGD/R-induced reduction in cell viability. At this concentration range, GB also enhanced endothelial proliferation, migration, and tube formation in bEnd.3 cells. Mechanistic studies revealed that MK2206 inhibition of AKT1 markedly suppressed AKT1 expression (p < 0.01), impaired angiogenic capacity, and aggravated ischemic-hypoxic injury, whereas GB treatment significantly increased VEGF and Ang expression (p < 0.01), likely via AKT1 upregulation (p < 0.01).

Conclusion: GB promotes angiogenesis and exerts neuroprotective effects by activating the AKT1/VEGF/Ang signaling pathway, suggesting its potential therapeutic value for ischemic stroke-related injuries.

Lung cancer remains the leading cause of cancer-related mortality worldwide, with five-year survival rates below 20%, underscoring the importance of understanding key biological processes like autophagy in this disease. Autophagy, a lysosome-mediated degradation and recycling pathway, exerts context-dependent effects in lung cancer, functioning as both a tumor suppressor and a facilitator of tumor progression. On one hand, basal autophagy maintains cellular homeostasis and genomic integrity, thereby curbing malignant transformation. On the other hand, established lung cancer cells exploit autophagy to survive under metabolic stress, hypoxia, and therapeutic pressure (for example, during chemotherapy or targeted therapy), facilitating tumor growth, metastasis, and therapy resistance. This review synthesizes current insights into the molecular mechanisms of autophagy in lung cancer, detailing how core regulatory pathways-including the phosphoinositide 3 kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling axis, the liver kinase B1-AMP-activated protein kinase (LKB1-AMPK) energy-sensing pathway, and key autophagy-related genes such as Beclin 1 and autophagy related gene (ATG) proteins-intertwine with oncogenic signaling networks and cell death regulators (e.g., p53, Bcl-2). It also highlights the metabolic dimension of autophagy, illustrating how nutrient recycling and maintenance of mitochondrial function via autophagy enhance the metabolic plasticity and survival of lung tumors under stress. In addition, we critically appraise clinical attempts to modulate autophagy (e.g., with chloroquine/hydroxychloroquine (CQ/HCQ) or mTOR inhibitors), outlining reasons for mixed outcomes and proposing practical solutions for future trials. Finally, potential targeted therapeutic strategies are discussed, including approaches to inhibit cytoprotective autophagy and strategies to induce autophagy-dependent cell death using novel small-molecule activators. Collectively, the evidence supports a model in which precise, context-aware modulation of autophagy-guided by pharmacodynamic (PD) biomarkers and molecular stratification-will be key to improving outcomes in lung cancer.

Sepsis-induced acute lung injury (ALI) represents a complex and life-threatening condition with limited therapeutic options. Recent research has unveiled the role of methyltransferase-like 3 (METTL3)-mediated N6-methyladenosine (m6A) modifications in exacerbating ferroptosis via m6A-insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2)-dependent mitochondrial metabolic reprogramming, shedding light on potential therapeutic targets. This study delves into the implications, challenges, and prospects of this intricate molecular pathway in sepsis-associated ALI. METTL3-mediated M6A modifications assume a pivotal role in the pathogenesis of sepsis-induced ALI. These modifications exacerbate ferroptosis, a regulated cell death process characterized by iron-dependent oxidative damage to lipids. The involvement of m6A-IGF2BP2-dependent mitochondrial metabolic reprogramming adds another layer of complexity to this mechanism, offering potential therapeutic avenues. Understanding the intricate network of METTL3-mediated m6A modifications, IGF2BP2, and mitochondrial metabolic reprogramming poses a formidable challenge. Developing interventions that modulate this pathway while minimizing off-target effects remains a significant hurdle. Patient-specific responses and identifying reliable biomarkers further complicate the clinical translation of these findings. The unraveling of this molecular pathway holds promise for personalized medicine approaches in ALI management. Early diagnosis and tailored interventions based on individual patient profiles may significantly enhance clinical outcomes. Collaboration among multidisciplinary teams, including researchers, clinicians, and drug developers, is essential to bridge the gap between laboratory discoveries and clinical applications.