Frontiers in bioscience (Landmark edition)最新文献

As an evolutionarily conserved timekeeping system, the circadian clock orchestrates physiological adaptations to diurnal environmental cues through transcriptional-translational feedback loops (TTFLs). Accumulating evidence reveals that circadian regulation governs immunological processes, with the immune system-a critical host defense mechanism-exhibiting robust circadian rhythmicity in functional organization. This review synthesizes recent advances in circadian modulation of pathogen-host interactions, immune cell trafficking, effector functions, circadian light hygiene-gut immune crosstalk, and tumor immunobiology. We examine the bidirectional crosstalk between circadian oscillators and immune pathways while addressing the clinical implications for immune-related pathologies. Significantly, we advocate chrono-immunotherapy as a transformative paradigm that leverages circadian principles to optimize therapeutic timing, enhancing efficacy while minimizing adverse effects. Future research directions aimed at elucidating mechanistic foundations and accelerating clinical translation are outlined. A comprehensive understanding of circadian-immune system dynamics not only provides fundamental insights into biological regulation but also establishes a chronobiological framework for precision medicine in immune-mediated disorders.

Background: In recent years, neuroglia has become a therapeutic target for neurodegenerative diseases. Despite the recognition of a variety of microglial morphologies associated with the neuroinflammatory process that involve diverse functionalities for this glial type, it is still unknown its beneficial or harmful role to the surrounding tissue.

Methods: The study presented here proposes a novel approach to the neurodegenerative progression based on the reliability of its results due to the use of a natural model. Morphological alterations in microglia were assessed in cerebellar samples from prion-affected individuals at different stages of the natural disease (pre-clinical, clinical and terminal).

Results: Immunohistochemical profiles confirmed that the abundance and morphology of the cells were found irrespective of the stage of the disease. Only an evident association of dystrophic pattern with advanced stages of the neurodegenerative process of scrapie was consistently demonstrated.

Conclusions: Overall, we conclude that the observations described here support a potential failure of microglial cells that could perhaps lead to their inability to perform some of their physiological functions, maybe due to a senescent state. Gaining insight into the multifaceted roles of neuroglia in central nervous system (CNS) diseases is of critical importance in knowledge and understanding of CNS disease pathogenesis, but also in generating novel therapeutic strategies.

Glutamate excitotoxicity is one of the key factors in the pathophysiology of the secondary injury cascade following traumatic brain injury (TBI) and spinal cord injury (SCI). These neurotraumatic conditions remain major causes of long-term disability and mortality worldwide, yet therapeutic options remain limited. Excessive glutamate release after neurotrauma leads to the overactivation of glutamate receptors, triggering calcium influx and the activation of destructive enzymes and signaling pathways that drive progressive neuronal death and tissue degeneration. This review examines the molecular mechanisms of glutamate-mediated excitotoxicity in neurotrauma, particularly focusing on TBI and SCI, and evaluates current and emerging therapeutic strategies aimed at modulating glutamate levels, receptor activity, and downstream signaling pathways. Particular attention is given to glutamate receptor antagonists, agents enhancing glutamate clearance, and neuroprotective compounds. A critical analysis of preclinical successes versus clinical failures reveals key translational barriers, including narrow therapeutic windows, patient heterogeneity, poor drug penetration across the blood-brain barrier, and adverse off-target effects. Delayed treatment relative to the peak of excitotoxic activity has also limited clinical efficacy. This review highlights the importance of understanding the temporal dynamics of glutamate toxicity and the necessity for precisely timed, stratified therapeutic interventions. This work contributes to the broader scientific effort to develop more effective neuroprotective therapies by identifying the mechanistic underpinnings and translational challenges of anti-excitotoxic strategies. Given the global burden of TBI and SCI, advancing targeted interventions for glutamate excitotoxicity holds significant promise for improving neurological outcomes and quality of life for affected individuals.

Background: The C-X-C motif chemokine receptor 3 (CXCR3) antagonist AMG 487 has been shown to alleviate acute lung injury (ALI) in mice. Other CXCR3 antagonists, including NBI-74330, TAK-779, and SCH 546738, exhibit anti-inflammatory effects in various diseases, including apical periodontitis, arthritis, and acute respiratory distress syndrome (ARDS). However, with the exception of AMG 487, the roles of these antagonists in ALI remain poorly understood. Macrophages can differentiate into various phenotypes and play a crucial role in the progression of inflammatory and autoimmune diseases.

Methods and results: In this study, we demonstrate that the CXCR3 agonist C-X-C motif chemokine ligand 10 (CXCL10) enhances macrophage efferocytosis and polarizes inflammatory macrophages toward the M1 phenotype, thereby exacerbating ALI in mice. Conversely, nine CXCR3 antagonists were found to inhibit macrophage efferocytosis and promote the polarization of inflammatory macrophages toward the M2 phenotype, resulting in the alleviation of ALI in mice. Subsequently, molecular docking techniques were employed to analyze interactions between nine CXCR3 antagonists and the CXCR3 protein, with the aim of screening for superior antagonist structures and designing more effective compound configurations targeting the CXCL10-CXCR3 axis. Notably, TAK-779 exhibited the most stable binding affinity to the CXCR3 protein. Furthermore, two newly modified compounds-TAK-779 from imidazolium 1 and TAK-779, 2745583-demonstrated enhanced efficacy compared to the original TAK-779 compound.

Conclusions: All nine CXCR3 antagonists were shown to influence macrophage function to varying degrees and confer protective effects against ALI. These finding suggest that comparative evaluation of CXCR3 antagonists and the discovery of novel compounds may provide new therapeutic targets for the treatment of inflammatory diseases.

Background: Bladder outlet obstruction (BOO) frequently accompanies benign prostate hyperplasia (BPH) in aging males and often leads to bladder fibrosis, a secondary pathological change that contributes to bladder dysfunction. The role of Cathepsin S (CTSS), a cysteine protease associated with immune responses, in this process remains to be fully elucidated.

Methods: Bladder tissues from BOO model mice were analyzed using microarray profiling, followed by Gene Ontology (GO) and pathway enrichment analyses. Candidate genes, including CTSS, C-X-C Motif Chemokine Ligand 17 (CXCL17), and Angiopoietin Like 7 (ANGPTL7), were identified. CTSS was selected for further investigation based on its association with fibrotic processes. The functional role of CTSS in smooth muscle cell hypertrophy and fibrosis was verified both in vivo and in vitro. A co-culture system of smooth muscle cells and monocyte-macrophages was used to explore the underlying mechanism.

Results: Microarray and bioinformatic analysis identified CTSS as a key candidate gene associated with immune response in BOO-induced bladder fibrosis. CTSS expression was upregulated in BOO bladders and was demonstrated to promote smooth muscle cell hypertrophy and fibrotic changes. Mechanistically, CTSS mediated proteolytic cleavage of the interleukin-6 receptor (IL-6R) on immune cells, generating soluble IL-6R (sIL-6R). This process facilitated IL-6 trans-signaling, which in turn promoted smooth muscle cell hypertrophy and exacerbated bladder fibrosis.

Conclusions: These findings indicate that CTSS contributes to BOO-induced bladder dysfunction and fibrosis by activating IL-6 trans-signaling through cleavage of IL-6R. CTSS may represent a potential therapeutic target for mitigating bladder fibrosis in BPH.

Background: Research on the molecular progression of esophageal squamous dysplasia to cancer remains limited. The majority of prior studies have focused on morphological precancerous lesions sampled adjacent to tumors, and have relied primarily on the analysis of data from whole-exome sequencing.

Methods: To investigate the development of esophageal squamous cell carcinoma (ESCC), whole genome analysis was conducted on 13 precancerous tissues and 15 ESCC tissues. Field effects were avoided by using biopsies of squamous dysplasia from patients without concurrent tumor, thereby allowing study of molecular alterations associated with the true precancerous state.

Results: Our results revealed frequent copy number alterations (CNAs) and structural variants (SVs) in esophageal squamous dysplasia. These changes were also detected in ESCC, indicating that genomic instability markers such as CNAs and SVs occur at an early stage and persist throughout ESCC evolution. The detection of TP53 mutations and CASP8 deletions in both premalignant lesions and ESCC suggests they may be early driving events during esophageal carcinogenesis. Mutations in MUC5B were observed in 7.7% of precancerous lesions and 6.7% of ESCC. Moreover, these mutations were associated with a higher tumor mutational burden (TMB) and an immune "hot" tumor microenvironment. Apolipoprotein B mRNA-editing catalytic polypeptide-like (APOBEC) enzyme-associated mutational signatures were exclusively identified in ESCC and may further exacerbate genomic instability in the more advanced stages of tumorigenesis. Significantly higher ploidy alterations levels were detected in ESCC compared to squamous dysplasia. Moreover, the cohort that underwent local recurrence of dysplasia within two years had significantly elevated ploidy alterations levels compared to those with no long-term recurrence. These results indicate that elevated levels of aneuploidy and genomic instability were associated with tumor progression and local recurrence of dysplasia.

Conclusions: Mutations in TP53 and MUC5B, as well as deletion of CASP8, may be early driver events in carcinogenesis and could precede the emergence of the APOBEC mutation signature. Moreover, ploidy alterations confer a selective advantage to genomically unstable cells, thereby promoting their progression toward malignant transformation. Collectively, our results demonstrate that genomic instability is prevalent in precancerous lesions and intensifies during the late stages of tumor progression. Cells with a certain level of genomic instability appear to possess a competitive advantage for malignant transformation.

Background: Since its introduction in 2008, sorafenib has remained the standard first-line systemic treatment for advanced hepatocellular carcinoma (HCC). Nevertheless, its clinical benefits are often compromised by the rapid emergence of drug resistance. This study explores the molecular mechanisms underlying sorafenib resistance, with particular emphasis on the involvement of connective tissue growth factor (CCN2/CTGF) in the regulation of c-Met signaling pathways.

Methods: We began by evaluating CCN2 expression levels in HCC tissue samples via immunohistochemistry and analyzing their correlation with clinicopathological characteristics. To functionally characterize CCN2, we established stable HCC cell lines with either knockdown or overexpression of the gene using lentiviral transduction. The effects of CCN2 on cellular proliferation and drug resistance were evaluated using cell counting kit-8 (CCK-8) and colony formation assays. To elucidate the downstream signaling mechanisms, a tyrosine kinase PCR array was employed to identify expression changes within the tyrosine kinase superfamily after CCN2 knockdown. Further investigation into the molecular mechanism by which CCN2 promotes sorafenib resistance was conducted using real-time quantitative PCR (RT-qPCR), western blotting, and immunofluorescence. Finally, the therapeutic potential of co-targeting CCN2 and sorafenib was validated in a nude mouse xenograft tumor model.

Results: Our results establish that CCN2 overexpression significantly enhances HCC proliferation, while also inducing resistance to sorafenib. Mechanistically, we identified that CCN2 binds to integrin αV, triggering focal adhesion kinase (FAK) phosphorylation, which in turn promotes yes-associated protein (YAP) nuclear translocation and leads to the transcriptional upregulation of c-Met. This proposed signaling axis was consistently supported by tyrosine kinase PCR array, co-immunoprecipitation, and western blot analyses. Ultimately, in vivo experiments confirmed that simultaneously targeting CCN2 and administering sorafenib produces a synergistic effect, markedly inhibiting tumor growth and restoring therapeutic sensitivity.

Conclusion: These results not only elucidate a novel CCN2/FAK/YAP/c-Met axis in sorafenib resistance but also provide a mechanistic rationale for dual-targeting strategies to improve outcomes in advanced HCC.

Ionizing radiations (IRs), commonly used in both diagnostic imaging and cancer therapy, generate reactive oxygen species (ROS) and free radicals, causing significant DNA damage that can lead to genetic mutations, cell death, and tissue injury in both normal and tumor tissues. In response to the oxidative stress, the nuclear factor erythroid 2-related factor 2 (NRF2) is activated to induce target genes involved in antioxidant and detoxifying pathways, thereby playing a pivotal role in protecting cells from IR-induced oxidative damage. In clinical diagnostics, IR exposure from imaging techniques can result in DNA damage, inflammation, and increased risk of IR-induced pathologies, including cancer. NRF2 activation in response to these diagnostic exposures can help to protect normal tissues from damage by boosting antioxidant defenses. In radiotherapy, IR induces DNA damage to kill malignant cells, although it may also harm surrounding healthy tissue. Cancer cells exploit NRF2 activation to resist IR-induced cell damage, thereby maintaining redox balance and protecting themselves from oxidative stress. In that case, NRF2 inhibition could sensitize cancer cells to IR effects by disrupting their antioxidant defense, leading to increased ROS accumulation, enhanced DNA damage, and greater cell death. This review will summarize the role of NRF2 in mediating the response to IR in both healthy and cancerous cells, with a focus on its effects in clinical diagnostic and radiotherapy.

Background: Sepsis is a life-threatening condition characterized by a dysregulated host response to infection, often leading to multiorgan dysfunction. Despite their clinical importance, early diagnostic biomarkers that reflect organ-specific damage remain inadequately characterized.

Methods: Targeted metabolomic profiling of amino acids, organic acids, fatty acids, nucleosides, and kynurenine pathway metabolites was performed on lung, kidney, spleen, and liver tissues obtained from a lipopolysaccharide-induced mouse model of sepsis, using liquid chromatography-tandem mass spectrometry and gas chromatography-tandem mass spectrometry. Univariate and multivariate statistical analyses (principal component analysis and partial least squares discriminant analysis) were performed to identify potential biomarkers, followed by pathway analysis to elucidate their biological relevance.

Results: Twenty-nine metabolites were significantly altered across the four tissues, exhibiting organ-specific metabolic signatures. Tyrosine, epinephrine, 5-hydroxytryptophan, and kynurenic acid in the kidney; serine, 4-hydroxyproline, normetanephrine, xanthosine, uridine, adenosine, succinic acid, cis-aconitic acid, linoleic acid, and eicosadienoic acid in the spleen; alanine, α-aminobutyric acid, ornithine, uridine, adenosine, 5'-deoxy-5'-methylthioadenosine, succinic acid, and cis-aconitic acid in the lung; and α-aminobutyric acid, pipecolic acid, uridine, inosine, adenosine, glycolic acid, and oxaloacetic acid in the liver were identified as potential biomarkers reflecting organ-specific dysfunction in sepsis.

Conclusions: This study highlights the distinct organ-specific metabolic alterations in sepsis and identifies candidate biomarkers that may reflect early organ dysfunction. These findings provide a foundation for the development of precise diagnostic and medical strategies for sepsis.

Background: Macrophage infiltration is prevalent in lung cancer tissues, significantly influencing disease progression and clinical outcomes. Lung squamous cell carcinoma (LUSC) is often diagnosed at advanced stages, resulting in poor prognosis. Identifying effective diagnostic biomarkers, particularly those associated with macrophage infiltration, is crucial for early detection and improved treatment outcomes. This study aims to identify diagnostic markers specifically linked to M1 macrophages in LUSC.

Methods: Differential gene expression analysis and immune cell infiltration assessment were conducted using the limma and CIBERSORT packages. The WGCNA algorithm was then applied to identify genes in modules related to M1 macrophages. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to investigate the biological functions of M1 macrophage-related differentially expressed genes (DEGs). To identify M1 macrophage-associated biomarkers in LUSC, a diagnostic model was developed using four machine learning algorithms, with validation through nomogram visualization, calibration curves, and external datasets. Finally, immunohistochemical staining was performed to further confirm the expression of hub genes and the predictive accuracy of M1 macrophage-related biomarkers in LUSC.

Results: A total of 143 M1 macrophage-related DEGs were identified, which were involved in regulating immune response pathways. The support vector machine (SVM) model based on these genes demonstrated exceptional performance, with area under the curve (AUC) values of 0.995 in the training cohort and 1.000 in three external validation datasets. Immunohistochemical analysis further confirmed the diagnostic accuracy of Matrix metalloproteinase-7 (MMP7), Reticulon-1 (RTN1), Zinc finger protein ZIC 2 (ZIC2), Killer cell lectin-like receptor subfamily B member 1 (KLRB1), and C-X-C motif chemokine 13 (CXCL13), yielding an AUC of 0.992. These results highlight the strong diagnostic capability of the 5 hub genes in LUSC.

Conclusion: The study highlights the pivotal role of M1 macrophage-related DEGs in LUSC tumorigenesis. The newly identified 5 hub genes provide a highly accurate diagnostic tool for LUSC, offering potential improvements for both diagnostic and therapeutic strategies.