Frontiers in Molecular Biosciences最新文献

Objective: To investigate the molecular interaction patterns between CD46/TREM1 and LC3B/ATG5 in the development of oral squamous cell carcinoma (OSCC), providing novel targets for elucidating the mechanism of inflammatory-to-cancer progression and for the early diagnosis and treatment of OSCC.

Methods: An oral inflammation-to-cancer progression animal model was established using 4-Nitroquinoline-N-oxide (4-NQO) drinking water and/or lipopolysaccharide (LPS). Clinical oral leukoplakia (OLK), OSCC, and adjacent non-cancerous tissues were collected. Immunohistochemistry assessed CD46, TREM1, LC3B, ATG5 protein expression and PI3K-AKT/TNF pathway alterations in animal and clinical tissues. Enzyme-Linked Immunosorbent Assay (ELISA) measured inflammatory cytokine levels in serum and saliva. High-throughput sequencing analyzed key pathways.

Results: Immunohistochemistry revealed elevated CD46/TREM1 expression and reduced LC3B/ATG5 expression in OSCC tissues (P < 0.05). Serum levels of IL-6, IL-8, and GROα/CXCL1 progressively increased with advancing inflammation-to-cancer progression in rats, whereas salivary expression peaks occurred during the inflammatory phase. In human saliva and serum, TNF-α, IL-8, and IL-6 exhibited an increasing trend among healthy individuals, oral leukoplakia patients, and OSCC patients (P < 0.05). Transcriptome analysis revealed a significant increase in differentially expressed genes during the transformation from OLK to OSCC, predominantly downregulated genes. Among these, Col4a6 and Csf2 genes participated in inflammation-to-cancer progression by regulating the PI3K-Akt and TNF pathways.

Conclusion: CD46 and TREM1 are highly expressed in OSCC and serve as key initiating factors in the progression from OLK to OSCC. Bioinformatics analysis identified critical candidate genes (Col4a6, Csf2) and pathways (PI3K-Akt, TNF) in inflammation-to-cancer conversion. Activation of the PI3K-AKT-mTOR pathway is associated with inhibited autophagy and malignant progression of OSCC. Additionally, inflammation-to-cancer transition is a core mechanism in the development of OSCC, with the tumor inflammatory microenvironment acting as a "promoter" in the progression from OLK to OSCC. This study provides novel insights into the molecular mechanisms and targeted therapies for OSCC, holding significant theoretical and clinical application value.

Background: Hypertension is a crucial risk factor for cardiovascular diseases. Previous studies have revealed the serum metabolic profiles of patients with hypertension, laying the groundwork for accurate diagnosis and potential therapeutic target identification. While hypertension has well-documented biochemical signatures, TCM classifies it into distinct syndromes based on patterns of clinical manifestations and underlying pathophysiological concepts. From the perspective of Traditional Chinese Medicine (TCM), hypertension can be classified into several distinct syndromes, including Liver Yang Rising (LYR), Internal Phlegm-Dampness Accumulation (IPDA), and Liver-Kidney Yin Deficiency (LKYD). The present study aimed to identify the metabolic biomarkers for TCM syndromes by metabolomic analysis.

Methods: Metabolomic profiling of LYR, IPDA, and LKYD was performed (10 cases per group, sampled randomly) among thirty hypertensive patients and ten healthy controls recruited from the First Hospital of Hunan University of Chinese Medicine, Changsha, China. Hypertension and TCM syndrome classification were confirmed by clinicians, and participants with severe organ dysfunction or acute illnesses were excluded. Ultra-performance liquid chromatography-tandem mass spectrometry was used to identify differentially expressed metabolites (DEMs), weighted correlation network analysis (WGCNA) was applied to construct syndrome-associated networks, and multivariate ROC-based exploratory analysis identified key biomarkers with high diagnostic performance.

Results: Thirty-seven DEMs were identified for each syndrome comparison (LYR vs. control, IPDA vs. control, and LKYD vs. control), with 26 shared DEMs enriched in multiple metabolic pathways. Pairwise comparisons among TCM syndromes revealed distinct metabolic profiles, including glycated amino acids and tryptophan derivatives. WGCNA identified hub metabolites such as p-Xylene and Octinoxate. Multivariate ROC analysis yielded ten biomarkers with high diagnostic accuracy (AUC = 0.944), offering potential for distinguishing TCM-based hypertension subtypes and guiding targeted interventions.

Conclusion: Distinct metabolic signatures of TCM-based hypertension syndromes were identified, along with serum biomarkers showing high diagnostic accuracy. These findings support more precise syndrome differentiation and offer potential targets for personalized hypertension management.

Introduction: Gastric cancer (GC) is a common malignancy of digestive system with high morbidity and mortality. Cisplatin (CDDP) is often applied in GC clinical treatment, particularly in the postoperative adjuvant chemotherapy, where it improves patient survival and reduces recurrence risk. However, the development of drug resistance following prolonged use poses an obstacle in its clinical use. This study investigated the role of tumor necrosis factor receptor-associated protein 1 (TRAP1) in modulating the sensitivity of GC cells to CDDP through oxidative stress pathway.

Methods: Bioinformatic analysis was employed to assess TRAP1 expression in GC tissues compared to adjacent normal gastric tissues, and to evaluate its association with patient prognosis. Using lentivirus transfection and RNA interference, GC cell models with TRAP1 overexpression and silencing were established, then reactive oxygen species (ROS), mitochondrial membrane potential (MMP), DNA damage and cell death were measured following treatment with CDDP alone or in combination with antioxidant N-acetyl-L-cysteine (NAC).

Results: Results indicated that TRAP1 was upregulated in GC tissues and elevated TRAP1 was related with poor prognosis. In GC cells exposed to CDDP, TRAP1 reduced ROS, stabilized MMP and mitigated DNA damage, leading to diminished cell death. TRAP1 overexpression potentiated the protective effects of NAC, while TRAP1 silencing counteracted the protective effects.

Discussion: These findings indicated that TRAP1 attenuated CDDP sensitivity in GC cells by reducing cell death caused by CDDP-induced oxidative stress. TRAP1 represented a potential biomarker and a therapeutic target in GC treatment. This study provided a new strategy for improving the efficacy of CDDP-based chemotherapy through individualized treatment approaches.

Biomolecular condensates are at the forefront of understanding biological concepts, representing one of the most revolutionary areas in cell biology over the last decade. Numerous proteins, peptides, and nucleic acids have been shown to form membrane-less organelles, also known as condensates, in cells, demonstrating their functional relevance. Multiple research approaches in the fields of physics, chemistry, and biophysics investigate the underlying multivalent interactions that influence the phase separation of biomolecules. As failure to regulate condensate properties, such as formation and/or dissolution has been postulated as a driver of the misfolding and aggregation of proteins in stress, aging, and neurodegeneration disorders, understanding the fundamentals of condensate assembly has been considered of utmost importance. In this review, we will focus on the key regulators and biophysical drivers of phase separation and protein aggregation, evidenced in the literature. We will elaborate on the dynamic interplay between phase separated and aggregated state, highlighting the emergent properties of condensates that can contribute to the misfolding of proteins in the context of physiology and diseases. An in-depth understanding of condensate pathology can reveal novel avenues for targeting proteinopathies linked to misfolding.

[This retracts the article DOI: 10.3389/fmolb.2021.620683.].

Ovarian cancer has the worst prognosis among major gynecological cancers. Current therapies include platinum, Taxol, angiogenesis inhibitors, and poly[ADP-ribose]polymerase (PARP) inhibitors. However, resistance develops in most ovarian cancer patients. Identification of more pro-tumor factors in ovarian cancer may provide insights into ovarian cancer biology and therapy. In this study, we find ZKSCAN3, a zinc-finger transcription factor, is overexpressed in ovarian cancer. We show that ZKSCAN3 promotes ovarian cancer cell proliferation. Through RNA-Seq and chromatin immunoprecipitation (ChIP)-seq, HSPB1 is identified as a target gene of ZKSCAN3. HSPB1 expression is significantly decreased upon suppressing ZKSCAN3 expression. Suppressing HSPB1 expression also inhibits ovarian cancer cell proliferation. In contrast, expressing exogenous HSPB1 partially rescues the cell proliferation in ZKSCAN3 knockdown cells, which supports HSPB1 as a functional target gene of ZKSCAN3. Collectively, our study uncovers a functional ZKSCAN3-HSPB1 axis that promotes ovarian cancer cell proliferation.

Background: Rosacea is a chronic inflammatory skin disease characterized by vascular and neurological dysregulation, presenting with diverse clinical subtypes whose pathological mechanisms remain incompletely elucidated. Recent studies suggest that metabolic dysregulation may play a key role in disease onset and progression; however, systematic metabolomic studies targeting different subtypes remain limited.

Objective: This study employed untargeted metabolomic analysis to systematically compare plasma metabolic characteristic differences between patients with erythematotelangiectatic rosacea (ETR), papulopustular rosacea (PPR), and healthy controls (HC), aiming to identify potential disease biomarkers and provide new insights for understanding the pathogenesis of rosacea.

Methods: Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was used to compare metabolic profiles of plasma samples from ETR, PPR, and HC groups. Key differential metabolites identified were subjected to correlation analysis with disease severity and skin physiological parameters.

Results: ETR patients primarily involved amino acid metabolism, carbon metabolism, and cholesterol metabolism pathways, with key metabolites including upregulated SSA and 2,3-DHPA, and downregulated TCDCA and Met. PPR patients primarily involved tryptophan and linoleic acid metabolism pathways, with key metabolites including upregulated 12-HSA, DGLA, and 5-ALA, and downregulated 5-HTP and 3-HPPA. Metabolic differences between different rosacea subtypes were associated with steroid hormone biosynthesis. DGLA showed positive correlation with disease severity, while 5-HTP showed negative correlation with disease severity. Met was closely related to skin barrier function. Both 12-HSA and DGLA showed positive correlation with sebum secretion.

Conclusion: These findings elucidate the metabolic characteristics of rosacea and their associations with disease severity and skin physiological parameters, providing new theoretical foundation and potential targets for subtype diagnosis and precision treatment of the disease.

Turner syndrome (TS) arises from partial or complete loss of a sex chromosome, yet the mechanistic basis for Y chromosome loss (LoY), which may contribute to a subset of TS cases, remains unclear. This article addresses the existing gap in knowledge by proposing a hypothesis linking a transient physiological window of elevated HSATII RNA levels during preimplantation embryogenesis to recent bioinformatic predictions indicating that Y-linked HSATII arrays possess uniquely high triplex-forming propensity. In this context, HSATII-derived RNAs could form RNA-DNA triplexes in early embryogenesis preferentially at Y-linked HSATII tracts. If unresolved, these structures may stall replication forks and promote Y chromosome instability which may ultimately lead to complete or partial LoY. The proposed model reframes part of the TS etiology from a stochastic segregation error toward a definable process, and motivates experimental validation of its predictions. If supported by experimental evidence, this framework could further guide the search for modifying factors - such as interindividual variation in the Y-linked HSATII sequence or triplex-resolution efficiency - and, in the longer term, enable risk stratification for Y chromosome instability in potential embryos based on parental molecular profiles. In a broader context, the hypothesis underscores pericentromeric satellite biology as a potentially underexplored contributor to genome stability in early human development.