EXCLI Journal最新文献

Head and neck squamous cell carcinoma (HNSCC) encompasses a diverse group of tumors with varying etiology, biology, and response to therapy. Among its subtypes, human papillomavirus positive HNSCC is associated with better prognosis and enhanced sensitivity to radiotherapy, chemotherapy, and immunotherapy. However, resistance still occurs and is often driven by complex molecular mechanisms that remain incompletely understood. Recent evidence highlights the pivotal role of RNA modifications-particularly N6-methyladenosine (m⁶A)-in regulating key processes such as gene expression, immune response, and treatment resistance. Dysregulation of m⁶A machinery, including methyltransferases (METTL3, METTL14), demethylases (FTO, ALKBH5), and m⁶A readers (YTHDFs, IGF2BPs), has been implicated in oncogenesis, immune evasion, and therapy failure in multiple cancers, including HNSCC. These epitranscriptomic changes intersect with hypoxia-driven signaling pathways, which reshape the tumor microenvironment, promote immunosuppression, and impair DNA repair, further contributing to resistance to conventional and targeted therapies. Moreover, in HPV-related HNSCC, viral oncoproteins modulate both RNA methylation and host immune dynamics, creating a unique biological context where m⁶A modifications may serve as mediators of HPV-specific oncogenic programs and therapeutic vulnerabilities. This review integrates current knowledge on the interplay between hypoxia, m⁶A RNA methylation, and HPV infection in HNSCC, emphasizing their combined role in shaping tumor progression and resistance. A deeper understanding of these pathways may offer new opportunities for biomarker discovery and the development of rational combination therapies. See also the graphical abstract(Fig. 1).

This study investigates the effect of pasteurized Bacteroides thetaiotaomicron (PB.t) and its extracellular vesicles (B.t-EVs) on metabolic parameters, diabetes- and inflammation-related gene expression, and microbiota composition in type 2 diabetes mellitus (T2DM). A total of forty-eight male Wistar rats were randomly divided into normal controls (NC, n=24) and T2DM-induced rats (n=24), and each group was further subdivided to receive phosphate-buffered saline (PBS), PB.t, or B.t-EVs by gavage daily for five consecutive weeks. The effects on obesity indices, glycemic markers, lipid profile, expression of diabetes- and inflammation-related genes in the liver and colon, and targeted changes in gut microbiota were assessed. Treatment with B.t-EVs and PB.t was associated with reductions in obesity indices (body weight, body mass index, and Lee index) and fasting blood glucose compared to the T2DM-PBS group; however, this reduction was significant only in T2DM-B.t-EVs rats (P≤0.0142). Both interventions yielded significant improvements in metabolic parameters, as demonstrated by decreased serum insulin, triglyceride, and total cholesterol levels, reduced homeostatic model assessment for insulin resistance (HOMA-IR), and improved glucose tolerance (all P≤0.0382). Both treatments reduced with downregulation of endocannabinoid system receptor 1 (CB1) expression and increased CB2 and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) gene expression in the liver (all P≤0.0018). In the colon, PB.t and B.t-EVs significantly downregulated interleukin (IL)-1β, IL-6, and CB1 genes. They also upregulated IL-4, IL-10, and CB2 genes (all P≤0.0004). Targeted microbiota analysis showed increased abundances of Bacteroidetes, Faecalibacterium prausnitzii, and B.t, accompanied by a reduced level of Firmicutes, Actinobacteria and Firmicutes/Bacteroidetes (F/B) ratio (P≤0.0492). Additionally, treatment with B.t-EVs increased the abundance of Clostridium cluster IV (P=0.0085). Histological findings indicated reduced pancreatic damage in the treated groups. Altogether, these results suggest that PB.t and B.t-EVs, as paraprobiotic and postbiotic candidates, may improve metabolic health, reduce inflammation, and modulate gut microbiota composition in T2DM. See also the graphical abstract(Fig. 1).

Transportation noise from road, rail, and aircraft traffic is now recognized as a major cardiovascular risk factor. In Europe, more than 113 million people are chronically exposed to levels above 55 dB(A), resulting in an estimated 1.3 million healthy life-years lost annually from traffic-related noise. Large epidemiological studies consistently demonstrate associations with ischemic heart disease, heart failure, stroke, and type 2 diabetes, with additional links to hypertension, atrial fibrillation, and obesity. Translational and experimental research has clarified the biological plausibility of these findings. The central "noise reaction model" involves activation of the sympathetic nervous system and hypothalamic-pituitary-adrenal axis, with subsequent release of catecholamines and cortisol. These stress responses provoke endothelial dysfunction, vascular inflammation, and oxidative stress, largely through NADPH oxidase 2 activation and nitric oxide synthase uncoupling. At the molecular level, noise alters gene expression networks, disrupts circadian clock regulation, downregulates FOXO3, and induces pro-inflammatory epigenetic modifications. Neuroimaging studies reveal chronic noise activates the amygdala, linking stress perception to vascular inflammation and major adverse cardiovascular events. Adverse effects are most pronounced at night, when noise fragments restorative sleep and amplifies neurohormonal imbalance. Importantly, these pathways overlap with mechanisms of traditional cardiovascular risk factors - diabetes, hypertension, smoking, and hyperlipidemia - suggesting that noise accelerates vascular aging through convergent mechanisms. Combined exposure to noise and air pollution further exerts additive or synergistic effects, underscoring the value of the exposome concept in identifying vulnerable populations. Transportation noise should therefore be considered an established cardiovascular risk factor, requiring equal priority in prevention guidelines and public health policy. See also the graphical abstract(Fig. 1).

Chronic wounds are characterized by prolonged healing durations and disrupted progression through the normal phases of wound healing, hemostasis, inflammation, proliferation, re-epithelialization and remodeling. These wounds are often complicated by persistent infections and underlying conditions like diabetic mellitus, which hinders effective tissue regeneration. Traditional dressings provide limited therapeutic benefits; therefore, recent advancements in wound care have introduced peptide-based therapies that have gained considerable attention for their multifunctional roles in modulating wound repair. Peptides possess intrinsic antimicrobial, anti-inflammatory, angiogenic, and pro-regenerative properties, enabling them to regulate diverse cellular and molecular events across all stages of healing. This review highlights the mechanistic roles of therapeutic peptides in regulating and orchestrating wound healing applications. We further classify bioactive peptides derived from microbial, animal, and plant sources with documented roles in wound healing, and also address synthetic peptides engineered for wound healing. We discussed the peptide-based hydrogels, recent advancements in peptide-based hydrogels in wound healing, and also those hydrogels that are currently under investigation in clinical trials. The primary objective of this review is to provide the readers a detailed overview of the advancements in wound healing studies especially peptide incorporated hydrogels. See also the graphical abstract(Fig. 1).

Tumor Necrosis Factor Receptor 1 (TNFR1) plays a crucial role in determining whether a breast cancer cell will survive, undergo natural cell death, or die through necroptosis. It influences these outcomes via pathways such as NF-kB, caspase-8, and the RIPK1-RIPK3-MLKL axis. TNFR1 activation causes epigenetic changes in DNA methylation, histone modification, and chromatin remodeling, which reprogram cellular responses to death signals. The direct and indirect epigenetic events leading to TNFR1-mediated cell death include DNMT enrolment, H3K4me3/H3K27ac changes, and microRNA-mediated controls. TNFR1 signaling regulates DNA methyltransferase activity and histone acetyltransferases while controlling epigenesis through metabolic reprogramming and non-coding RNA networks. The necroptotic execution pathway, triggered by pro-survival complex degradation and caspase-8 inhibition, forms the RIPK1-RIPK3 necrosome, phosphorylates MLKL, and releases damage-associated molecular patterns. TNF dual role of TNF signaling in tumor growth, necroptosis, and inflammatory remodeling presents therapeutic challenges. Biomarkers include TNFR1 expression, RIPK1/RIPK3 phosphorylation, MLKL localization, and epigenetic markers. Therapeutic combinations of epigenetic modulators, SMAC mimetics, RIPK1, and immune checkpoint inhibitors show promise in overcoming treatment resistance. Challenges in patient stratification, drug sequencing, and management of inflammatory toxicity require urgent solutions. This review provides a basis for clinical trials targeting the TNFR1-necroptosis pathway with biomarker-guided therapies and epigenetic strategies for breast cancer therapy. See also the graphical abstract(Fig. 1).

Prostaglandin E₂ (PGE₂), which is traditionally recognized as a pro-inflammatory mediator target, is now recognized for its role in tissue regeneration. PGE₂ drives stem cell proliferation, M2 macrophage polarization, angiogenesis, and extracellular matrix (ECM) remodeling via E-type prostanoid (EP) receptor signaling, promoting repair in the skin, muscle, bone, heart, liver, kidney, and intestine. Despite these promising effects, the clinical translation of PGE₂ has been hindered by challenges such as a short half-life due to rapid degradation by 15-hydroxyprostaglandin dehydrogenase (15-PGDH), limited EP receptor subtype specificity, or oncogenic risks in certain contexts. This review explores the regenerative mechanisms of PGE₂, its tissue-specific roles, and innovative strategies to optimize therapeutic efficacy while minimizing adverse effects in regenerative medicine. See also the graphical abstract(Fig. 1).