Molecular medicine reports最新文献

R‑loops, three‑stranded nucleic acid structures composed of an RNA:DNA hybrid and displaced single‑stranded DNA, have emerged as important regulators of gene expression and genome maintenance. Although physiological R‑loops participate in normal cellular processes, their dysregulation can threaten genomic integrity by inducing DNA damage and replication stress. The present review explores the role of R‑loops in hepatocellular carcinoma (HCC), a malignancy characterized by marked genomic instability. In the present review, the formation mechanisms of R‑loops, their dual functions in transcriptional regulation and DNA damage, and their specific implications for HCC pathophysiology were discussed. HCC cells exhibit altered R‑loop homeostasis with aberrant accumulation linked to hepatitis B virus infection, inflammatory signaling and oncogene activation. The present review highlighted how HCC cells exploit or manage R‑loops to promote tumor progression, particularly through the epigenetic silencing of differentiation genes and modulation of replication stress responses. Furthermore, emerging therapeutic strategies targeting R‑loop biology were examined, including small molecules that induce synthetic lethality, gene‑based interventions and combination approaches that exploit R‑loop vulnerabilities. Challenges in targeting R‑loops and future directions, including multi‑omics profiling and biomarker development, were also addressed. Understanding the complex interplay between R‑loops and HCC offers promising avenues for novel diagnostic and therapeutic approaches for this malignancy.

Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, represents a substantial global health challenge with limited treatment options. The voltage‑dependent anion channel (VDAC), a critical mitochondrial outer membrane protein, has emerged as a pivotal regulator in HCC pathogenesis. Dysregulation of VDAC expression and function disrupts mitochondrial metabolism, confers resistance to apoptosis and promotes tumor proliferation. Mechanistically, VDAC facilitates HCC progression through metabolic reprogramming, evasion of programmed cell death and crosstalk with multiple oncogenic signaling pathways. Current VDAC‑targeted therapeutic approaches, including small‑molecule inhibitors and metabolic modulators, have demonstrated promising preclinical efficacy in inducing apoptosis and suppressing tumor growth. Notably, these agents may overcome therapeutic resistance and exhibit synergistic effects with conventional therapies. However, several challenges persist, particularly in elucidating isoform‑specific functions, optimizing pharmacokinetic profiles and identifying predictive biomarkers for patient stratification. The present comprehensive review critically evaluates the mechanistic involvement of VDAC in HCC progression, assesses emerging targeting strategies and proposes future research directions to establish VDAC as a viable precision medicine target for HCC management.

Liquid‑liquid phase separation (LLPS) contributes to multiple cellular bioprocesses; however, its clinicopathological relevance to oral squamous cell carcinoma (OSCC) remains largely unexplored. In the present study an integrative multi‑omics analysis investigating the prognostic value and molecular functions of LLPS‑related genes (LLPSRGs) in OSCC was conducted by leveraging transcriptomics and clinical data from 302 cases in The Cancer Genome Atlas database and LLPSRGs. A total of two prognostically distinct molecular subtypes were stratified by unsupervised clustering analysis, and a robust prognostic signature comprising seven key LLPSRGs was developed through LASSO regression and multivariate Cox analysis. Functional enrichment analysis highlighted the involvement of this signature in epithelial‑mesenchymal transition (EMT), with PHLDB2 emerging as a core regulator. Notably, the PHLDB2 protein underwent LLPS and formed droplet condensates both outside and in OSCC cells. Moreover, functional experiments revealed that PHLDB2 depletion attenuated the malignant biological behavior of OSCC cells, including cell proliferation, stemness, invasion and migration, and PHLDB2 promoted OSCC progression by regulating the PI3K‑Akt signaling pathway and PIK3CA expression. Retrospective clinical cohort and public dataset analyses validated that high expression of PHLDB2 was significantly associated with lymph node metastasis, higher pathological grade and reduced survival in patients with OSCC. Collectively, the present study established an LLPS‑based prognostic signature for OSCC, and revealed that phase separation of PHLDB2 may drive OSCC progression through regulating EMT and PIK3CA.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease whose etiology remains incompletely understood. As the proposal and progress of the 'mucosal origin hypothesis', the role of the 'gut‑joint axis' mechanism in the pathological process of RA is gradually being revealed. Changes in the intestinal microbiota, damage to the mucosal barrier, mucosal immune dysfunction and disorders of microbial‑derived metabolites all regulate the occurrence and development of RA. Natural compounds, bioactive entities isolated from natural sources, have demonstrated distinct therapeutic advantages across a broad spectrum of diseases. The intestine may be the key for these compounds to exert their therapeutic effects on diseases. The present review summarized the 'gut‑joint axis' in RA and the natural compounds that exert therapeutic effects via this pathway. It emphasized that improving intestinal microecology may be a potential treatment method for RA, and natural compounds are expected to become promising treatment strategies for RA in this way. However, there are still numerous problems that need to be urgently solved to complete the clinical transformation of these natural compounds.2.

Migrasomes are novel extracellular organelles that were first reported in 2015. The present review summarizes the discovery, structural characteristics, biological functions and relationships of this new cellular organelle with diseases. Migrasomes are annular organelles that extend from the trailing edge of cells during cell migration and are rich in proteins, lipids, nucleic acids and other biomolecules. They serve important roles at multiple levels, including roles in cell‑cell communication, tissue remodeling and immune regulation. The formation and function of migrasomes are associated with the regulation of various molecules and signaling pathways, including nucleation, expansion and maturation. Migrasomes also have important roles in organ morphogenesis, angiogenesis, mitochondrial quality control and immune regulation. In addition, migrasomes are closely associated with the development of various diseases, including kidney diseases, pneumonia after stroke, neurodegenerative diseases and cancer, providing new perspectives and potential targets for disease diagnosis and treatment. For example, in cancer, migrasomes can act as positioning signals, regulating the invasion of liver cancer cells. In neurodegenerative diseases, migrasomes may have a role in clearing damaged mitochondria, thereby helping to alleviate inflammatory responses and cellular dysfunction. Collectively, these findings suggest that migrasomes have notable potential for use in clinical disease diagnosis and treatment.

Hemorrhagic shock and resuscitation (HSR) induces pulmonary inflammation, leading to acute lung injury (ALI). Notably, blocking β1 receptors can lead to organ protection through anti‑inflammatory and anti‑apoptotic effects. Additionally, although the β1 receptor pathway is blocked by the β1 blocker, the β2 receptor pathway may be preserved and activate the 5' adenosine monophosphate‑activated protein kinase (AMPK) pathway. The present study aimed to examine whether administration of the β1 blocker landiolol could achieve lung protection in a model of HSR‑ALI, alongside improvements in inflammation and apoptosis. Male Sprague‑Dawley rats underwent hemorrhage keeping their mean arterial pressure at 30 mmHg for 1 h. Resuscitation by reinfusion was initiated to restore blood pressure to pre‑hemorrhage levels for >15 min, followed by a 45‑min stabilization period to create the HSR‑ALI model. Landiolol (100 mg/kg/min) or saline was continuously administered after resuscitation. The lung tissues, which were collected for assessing inflammation and apoptosis‑related damage, underwent analyses, including histological examination, neutrophil count, assessment of lung wet/dry weight ratio, detection of the mRNA levels of tumor necrosis factor‑α (TNF‑α) and inducible nitric oxide synthase (iNOS), identification of terminal deoxynucleotidyl transferase dUTP nick‑end labeling (TUNEL)‑positive cells, and evaluation of caspase‑3 expression. In addition, phosphorylated AMPKα (pAMPKα) expression was tested via western blotting. Compared with the HSR/saline group, the HSR/landiolol group demonstrated a reduction in lung tissue damage score, and significant reductions in neutrophil count, lung wet/dry weight ratio, lung TNF‑α and iNOS mRNA levels, TUNEL‑positive cells and cleaved caspase‑3 expression. Furthermore, landiolol administration following HSR treatment increased pAMPKα expression. No significant hypotension occurred between the HSR/landiolol and HSR/saline groups; and blood loss did not differ significantly between the groups. In conclusion, landiolol administration after HSR reduced lung inflammation and apoptosis, suggesting a potential improvement in tissue damage. Furthermore, pAMPKα activation in the HSR/landiolol group may be the mechanism underlying the pulmonary protective effects of landiolol.

Sepsis refers to the state of the body exhibited after an uncontrolled reaction to infection. This is marked by the impaired function of multiple organs, with the lungs often being impacted. Individuals affected by sepsis often suffer acute lung injury, which may advance to a more serious acute respiratory distress syndrome. Inflammatory responses and apoptosis are key in the onset and progression of sepsis‑induced acute lung injury (SALI). The present review examines the pathogenesis of SALI, emphasizing the synergistic roles of inflammatory responses and apoptosis as well as their effect on lung tissue. An overactivated inflammatory response can exacerbate lung tissue damage and promote the occurrence of apoptosis. Meanwhile, excessive apoptosis can further intensify the inflammatory response, therefore resulting in a vicious cycle. The present review also discusses therapeutic strategies that target the synergistic effects of inflammation and apoptosis, including NF‑κB pathway inhibitors, MAPK signaling pathway inhibitors, antioxidants, mesenchymal stem cell therapy and biologics. Despite the progress made to date in understanding the synergistic effects of inflammation and apoptosis, there are still numerous areas that require further exploration, such as the complex molecular regulatory networks connecting inflammation and apoptosis as well as the impact of clinical individual differences on this synergy, which require further investigation to ultimately translate mechanistic findings into targeted therapies, thus providing new insights and approaches for the treatment of SALI.

Light is the paramount environmental signal for the entrainment of endogenous circadian rhythms. Its non‑visual effects, mediated by the retina, exert a profound control over human sleep, mood and systemic physiological homeostasis. Beyond its canonical function in image formation, the retina operates as a primary irradiance detector through a specialized class of neurons, the intrinsically photosensitive retinal ganglion cells (ipRGCs), which utilize the photopigment melanopsin. These cells convey environmental light information directly to the suprachiasmatic nucleus (SCN), the brain's master circadian pacemaker, thereby synchronizing the body's internal timekeeping with the external solar cycle. Compelling evidence demonstrates that the spectral quality of light, particularly within the short‑wavelength blue range, potently modulates neuroendocrine and neural systems via the ipRGC pathway, governing melatonin synthesis, the architecture of the sleep‑wake cycle and affective regulation. The modern light environment, characterized by ubiquitous artificial light at night and pathological states of light perception resulting from ophthalmic diseases such as glaucoma and retinal degenerations, can severely disrupt this synchronization. The consequent circadian misalignment is a significant etiological factor in sleep disorders, depressive symptoms and other systemic morbidities. The retina's integral position within the light‑rhythm‑behavior axis is thus a critical nexus between the visual system and systemic physiology. In addition, the present study outlined the nitric oxide‑cyclic GMP signaling axis in SCN as a critical mediator of photic entrainment. This review provided an in‑depth analysis from an ophthalmic perspective, synthesizing evidence from animal models and human studies to dissect the complex molecular, cellular and network‑level mechanisms of retinal circadian regulation, explore how aberrant photic signaling impacts sleep and mood and critically evaluate the potential of targeted interventions such as light therapy and spectral management in the context of rhythm‑related disorders.

Diabetic keratopathy (DK) is an ocular complication of diabetes mellitus (DM). Driven by DM‑induced chronic hyperglycemia and its associated metabolic changes, DK is characterized by progressive damage to the corneal epithelium, nerves, stroma and endothelium, manifesting as corneal epitheliopathy, neuropathy, stromal lesions and endotheliopathy. Nuclear proteins (NPs) play essential roles in the regulation of gene expression and physiological activities in the nucleus, and have been implicated in the occurrence and development DM and its complications. The present review provides an overview of DK and highlights the role of core NPs in its pathogenesis, including peroxisome proliferator‑activated receptors, high‑mobility group box 1, enhancer of zeste homolog, phosphatase and tensin homolog and sirtuins. The review underscores that the roles of these NPs in DK remain incompletely understood and highlights the need for further mechanistic studies and clinical trials to advance DK management. Therefore, it is suggested that future research should focus on elucidating the molecular mechanisms of NPs in DK, and developing novel detection techniques and treatment strategies to provide more effective outcomes for patients with DK.

Psoriasis is a systemic immune‑mediated skin disease, typically considered to be incurable. Identification of meaningful biomarkers has been a notable challenge in psoriasis prevention and management. The present study aimed to determine the signature genes driving psoriasis and their underlying mechanism. Microarray datasets of psoriasis were obtained from the Gene Expression Omnibus database, and the differentially expressed genes (DEGs) were identified using the 'limma' R package. Gene Set Enrichment Analysis (GSEA) was performed using the 'clusterProfiler' R tool. Functional and pathway enrichment of DEGs were analyzed using a bioinformatics website (Wei Sheng Xin). Furthermore, the present study applied least absolute shrinkage and selection operator regression, random forest and support vector machine‑recursive feature elimination techniques to pinpoint signature genes driving psoriasis. Subsequently, CIBERSORT was used to determine whether psoriasis‑infiltrating immune cells had a strong connection with signature genes. Immunohistochemistry (IHC) was used to demonstrate the expression of TGM1 in human psoriasis samples. Cell transfection was employed to verify the function of TGM1. The top 163 significant DEGs were identified from the GSE30999 dataset, and Kyoto Encyclopedia of Genes and Genomes analysis illustrated that these genes were mostly involved in 'viral protein interaction with cytokine and cytokine receptor', as well as the 'IL‑17 signaling pathway'. The present study screened transglutaminase 1 (TGM1) as a signature gene by combining three machine learning algorithms. Through single‑gene GSEA, the present study further revealed that TGM1 was associated with 'GF‑RTK‑PI3K signaling pathway' and 'cytokine‑JAK‑STAT signaling pathway', providing valuable insights into the underlying mechanism of psoriasis. Additionally, the present study validated TGM1 expression in the GSE53552 and GSE13355 datasets, and demonstrated its elevated expression in lesional psoriatic skin using IHC. Finally, TGM1 overexpression was demonstrated to increase the expression levels of inflammatory factors and keratinocyte differentiation markers, whereas knockdown decreased their expression, especially IL‑1β, S100A8, S100A9 and K1. Together, these findings suggest that TGM1 could be a promising therapeutic target for psoriasis, highlighting its potential application in psoriasis therapy.