International Journal of Molecular Sciences最新文献

The characterization of tumors as either "hot" or "cold" is determined by intrinsic properties of the cancer cells, the characteristics of the tumor immune landscape, the composition of the tumor microenvironment (TME), and underlying signaling mechanisms. These biological factors are critical in defining the clinical outcomes and therapeutic responses observed in cancer patients. The TME of glioblastoma exemplifies a case of "cold" TME, which significantly hinders antitumor immunity. This constitutes the predominant rationale underlying the ineffectiveness of immunotherapy. This review provides a thorough analysis of contemporary immunotherapeutic strategies that have been developed for the purpose of altering the immunological characteristics of tumors, with a view to achieving their effective elimination. The core mechanisms of action and future clinical applications of immune checkpoint inhibitors, adoptive cellular therapy, and oncolytic viruses (OV) are delineated. A combination of preclinical and clinical evidence suggests that OV-based combinations could be an effective treatment strategy for "cold" tumors.

Hepatic encephalopathy is a severe complication of liver failure, traditionally investigated through brain-liver interactions; however, the involvement of extrahepatic organs remains poorly understood. This study examined splenic histopathological changes in a mouse model of acute hepatic encephalopathy induced by ammonium acetate administration, focusing on iron metabolism and macrophage activation. Although conventional hematoxylin and eosin staining revealed no overt structural abnormalities, unstained spleen sections demonstrated abundant black deposits, predominantly in the red pulp. Prussian blue staining confirmed a significant increase in hemosiderin-positive cells; however, a subset of black deposits was iron-negative. Immunohistochemical analyses revealed that these iron-negative pigments were localized within F4/80-positive macrophages and colocalized with heme oxygenase-1 (HO-1), suggesting enhanced heme degradation. Ultrastructural observations further identified electron-dense granules consistent with hematin accumulation in splenic macrophages. Hematological analyses revealed significant reductions in red blood cell count and hemoglobin levels, indicating accelerated erythrocyte destruction. Collectively, these findings demonstrate that acute hepatic encephalopathy induces splenic macrophage activation, accompanied by disordered iron metabolism and hematin accumulation. This study highlights the spleen as a previously underappreciated extrahepatic organ involved in the pathophysiology of hepatic encephalopathy and suggests that splenic heme-iron handling may represent a novel therapeutic target.

Penile squamous cell carcinoma (PSCC) is rare, but a biologically aggressive malignancy. Recent comprehensive genomic profiling (CPG) efforts revealed the underlying genomic landscape of PSCC, identifying TP53, TERT, CDKN2A, PIK3CA, NOTCH1, and FAT1 as frequently altered genes with potential roles in penile oncogenesis. In addition, recurrent mutations encoded in the GPS1 gene have been observed in 7.4% of cases in a particular PSCC cohort. Functional studies demonstrated loss of function due to GPS1 Exon 9 missense mutations, proposing a possible role for these alterations as oncogenic driver events in PSCC. However, no other study confirmed the occurrence of GPS1 gene mutations in PSCC. To elucidate the biological function of GPS1 exon 9 mutations in PSCC pathogenesis, we utilized a comprehensive in-house cohort of 106 PSCC cases to explore their frequency and occurrence. Albeit, the previously reported GPS1 mutations p.D382H and p.M384I were not observed in this large cohort of PSCC cases; this analysis, however, revealed two novel GPS1 alterations in exon 9 in two (1.9%) of the analyzed cases: p.S372F (c.1115C>T) and p.A375D (c.1124C>A). This observation suggests that GPS1 exon 9 sequence is a target of genetic alteration during PSCC pathogenesis. However, the non-recurrent nature of these alterations indicates that they are unlikely to represent oncogenic drivers in this disease.

Adult neurogenesis is a regulated form of brain plasticity shaped by interactions between hormonal systems and environmental context. Social experience has been identified as an important modulator of neuronal proliferation, differentiation, and survival across the lifespan, although effects vary across species, developmental stages, and experimental paradigms. This review synthesizes evidence indicating that diverse social behaviors-including isolation, social hierarchy, parenting, sexual interaction, social buffering, and social learning-engage neuroendocrine, neurochemical, and stress-related pathways that are associated with modulation of hippocampal and olfactory neurogenesis. Affiliative and reproductive contexts have been linked in multiple models to enhanced neurogenic indices via gonadal hormones, oxytocinergic and vasopressinergic signaling, and neurotrophic mechanisms, whereas chronic isolation or social defeat has frequently been associated with reduced neurogenic markers, particularly within stress-sensitive regions of the ventral dentate gyrus. Sex differences further shape these patterns, reflecting both biological regulation and uneven sampling across paradigms. Comparative findings in prairie voles, eusocial mole-rats, nonhuman primates, songbirds, and teleost fish indicate that social organization can be accompanied by either increased or constrained neurogenic activity, depending on ecological pressures and life-history strategies. Collectively, the available evidence suggests that adult neurogenesis represents a context-dependent plastic process embedded within vertebrate social systems, while underscoring the need for integrative and evidence-graded interpretations.

Coronary artery disease presents heterogeneous clinical manifestations ranging from stable coronary syndrome (SCS) to acute coronary syndrome (ACS). Epigenetic mechanisms, particularly DNA methylation, may contribute to both chronic disease progression and acute plaque destabilization. However, genome-wide methylation differences between ACS, SCS, and healthy individuals remain incompletely characterized. Genome-wide DNA methylation analysis was performed in patients with ACS, patients with SCS, and healthy controls using pairwise comparisons (ACS vs. control, SCS vs. control, and ACS vs. SCS). Differentially methylated regions were identified using logistic regression implemented in the methylKit package in R. Regions with a false discovery rate-adjusted q-value < 0.05 and an absolute methylation difference (|Δβ|) > 20% were considered significant. Unsupervised hierarchical clustering revealed clear separation between ACS, SCS, and control samples, indicating distinct epigenetic profiles. ACS showed the most pronounced methylation alterations compared to controls, whereas SCS exhibited more moderate changes consistent with chronic epigenetic remodeling. Direct comparison between ACS and SCS identified dynamic, state-dependent methylation differences. Pathway analysis demonstrated enrichment of stress response, apoptotic signaling, and cell adhesion pathways in ACS, while SCS was primarily associated with pathways related to intercellular communication and vascular signaling. Our findings demonstrate that acute and stable coronary syndromes are characterized by distinct DNA methylation landscapes and pathway signatures. Epigenetic regulation of stress, adhesion, and signaling pathways may contribute to disease acuity and progression, highlighting DNA methylation as a potential molecular marker in coronary artery disease.

Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options. Emerging evidence shows that mechanotransduction, driven by matrix stiffness and mechanical signaling, promotes TNBC invasion and metastasis. As breast cancer progresses, expansion of fibroblasts and tumor-reactive stroma increases extracellular matrix deposition, generating matrix tension and enhancing mechanotransduction, which promotes cell proliferation, invasion, and metastatic potential through altered gene expression patterns. To investigate the molecular mechanisms underlying these changes, human TNBC cells were subjected to constant or oscillatory strain, followed by comprehensive transcriptomic analysis. Results revealed pronounced differential expression of genes involved in cell migration, adhesion, and transforming growth factor-β (TGFβ) signaling, with RT-PCR validation confirming SKI Like Proto Oncogene (SKIL) as the most strongly upregulated gene. Analysis of The Cancer Genome Atlas (TCGA) datasets indicated that SKIL is highly expressed in multiple breast cancer subtypes. Cross-sectional comparison of oscillatory strain-induced genes with TCGA data revealed coordinated upregulation of TGFβ, SKIL, and other genes associated with invasive phenotypes, immune suppression, and drug resistance, highlighting the vital role of TGFβ signaling. Transcription factor enrichment analysis further identified regulators linked to oncogenic pathways, including TGFβ effectors and Hippo signaling, supporting a mechanotransduction-driven transcriptional program in breast cancer.

The field of extracellular vesicle (EV) research offers a compelling example of a biological concept refined through continuous methodological innovation. This review traces the historical trajectory of the discipline chronologically, beginning with early observations in haemostasis, from Malpighi's descriptions of blood clots and Chargaff and West's identification of a procoagulant sedimentable plasma fraction, to Wolf's "platelet dust," Crawford's microparticles characterised by electron microscopy, and the seminal work by Stahl and Johnstone demonstrating regulated vesicle biogenesis during reticulocyte maturation via multivesicular bodies. We highlight a pivotal conceptual shift, from viewing EVs as cellular debris to recognising them as regulated "communicasomes," catalysed by Raposo's discovery of antigen-presenting exosomes and subsequent evidence for EV-mediated transfer of functional receptors and nucleic acids, including the influential and sometimes debated model proposed by Ratajczak. By integrating findings from matrix vesicles, plant-derived vesicles, and diverse tissue contexts, we frame EV release as an evolutionarily conserved process with profound implications for immunity, regeneration, oncology, and cardiovascular pathology. A second central aim of this review is practical and methodological. We map how the expansion of biological claims has driven urgent standardisation efforts, notably through the establishment of the International Society for Extracellular Vesicles (ISEV) and the successive MISEV guidelines (2014, 2018, 2023). These are complemented by community resources such as EV-TRACK, MIFlowCyt-EV, and the databases ExoCarta and Vesiclepedia. We summarise core experimental choices across isolation and characterisation techniques, including ultracentrifugation, size exclusion chromatography, density gradients, flow cytometry, nanoparticle tracking analysis, and electron microscopy, while outlining persistent bottlenecks in purity, standardised nomenclature, and experimental reproducibility. Finally, we provide concise biographical sketches of key contributors and an overview of major EV-focused journals and ISEV meetings that anchor consensus-building and the translation of fundamental knowledge into clinical and industrial applications.

HerCanPred, a machine-learning-based pathogenicity classifier specifically optimized for 63 cancer-predisposition genes, was developed to improve the interpretation of missense variants in hereditary cancer syndromes. This model integrates sequence conservation with structural features derived from AlphaFold2 (AF2) structures. HerCanPred achieved a strong performance, outperforming 23 established predictors. SHAP analysis identified AF2-derived structural features, specifically local pLDDT confidence scores and relative solvent accessible area, as the strongest predictors of variant impact. Benchmarking the strengths and limitations of HerCanPred against existing methods showed that misclassification of pathogenic variants was concentrated in disordered and surface-exposed regions, whereas benign failures were more broadly distributed. HerCanPred and three established predictors were also applied to over 57,000 variants of uncertain significance (VUS) from the same gene set. Notably, 166 VUS were reassigned as pathogenic and 75 as benign, with an enrichment of the NF1, FH, and MLH1 genes. By combining gene-specific training with 3D structural information, HerCanPred provides a robust framework for reducing diagnostic uncertainty. Our findings demonstrate that targeted, structure-aware tools can contribute to resolving VUS, providing a rational basis for systematic variant reinterpretation and more informed medical management in hereditary cancer care.

Bacterial poly(A) polymerases (PAPs) play an important role in RNA metabolism but remain poorly characterized outside Gammaproteobacteria. Here, we cloned and biochemically characterized the first PAP from Alphaproteobacteria, specifically from Marinobacter lipolyticus (Mli PAP). Using homology-based screening against E. coli PAP-1, we identified Mli PAP, sharing 54.8% sequence identity with its E. coli counterpart. The enzyme was expressed in E. coli but formed insoluble inclusion bodies; the active enzyme was purified as a fusion protein with the DsbA protein and used for functional assays. Mli PAP exhibited optimal activity at 30 °C and similar thermostability to E. coli PAP-1. ATP was the preferred substrate, with K_m comparable to E. coli PAP-1 (1.61 mM and 1.70 mM, respectively), and Mg²⁺ (10 mM) was identified as the optimal cofactor. Mli PAP displayed salt-dependent activity, with the most effective polyadenylation in KCl and inhibition by NaCl and ammonium salts, contrasting with the halophilic nature of its host. This study provides the first functional insights into PAPs from Alphaproteobacteria, broadening the understanding of PAP diversity and biochemical properties, as well as the potential applications of PAPs in biotechnology.

Systemic lupus erythematosus (SLE) is characterized by chronic immune activation, enhanced type I interferon signaling, and epigenetic dysregulation, conditions that may promote the reactivation of human endogenous retroviruses (HERVs). Whether HERV activation in SLE is global or selective, however, remains unclear. We analyzed the expression of HERV-H, HERV-K, and HERV-W, along with the HERV-derived envelope genes Syncytin-1 and Syncytin-2, in samples from lupus patients and healthy controls. In parallel, we assessed the expression of the epigenetic repressors TRIM28 and SETDB1. HERV-H expression was comparable between groups, whereas HERV-K and HERV-W were significantly overexpressed in lupus patients. Syncytin-1 and HERV-W env transcripts were markedly increased in SLE, while Syncytin-2 expression was unchanged. Lupus patients showed reduced TRIM28 and increased SETDB1 expression, consistent with altered regulation of HERV repression pathways. Notably, HERV-H and HERV-W pol expression correlated with the type I interferon score, suggesting an association between interferon signaling and selective HERV activation. These findings indicate that SLE is associated with the selective activation of immunostimulatory HERV families, particularly HERV-W. The observed associations with interferon signaling suggest that HERV-W-related transcripts may represent disease-associated molecular signatures, warranting further mechanistic investigation.