EXCLI Journal最新文献

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).

Malignant disorders continue to represent one of the major burdens of disease globally, especially in the context of premature deaths. Targeted anticancer treatments, including kinase inhibitors (KIs), have become crucial tools to disrupt the specific signaling pathways that are responsible for cancer growth following malignant transformation. Evidence demonstrates that KIs have substantially advanced precision oncology across multiple malignancies, with clinical success most notable in hematologic cancers and specific solid tumors, such as non-small cell lung cancer. Nonetheless, their long-term efficacy is often constrained by the emergence of acquired resistance, intratumoral heterogeneity, and off-target toxicities, underscoring the need for adaptive therapeutic strategies and combination regimens. While next-generation KIs and ongoing trials of KIs have the promise to expand the therapeutic landscape, the uneven distribution of clinical benefits across different cancer types reveals a considerable gap between molecular advances and real-world outcomes, leading to unequitable improvements in survival and quality of life for patients. Research also indicates disparities in access and affordability, raising concerns about their integration into routine care in low- and middle-income countries. The present review paper aims to provide a summary and a critical synthesis of the development, therapeutic potential, and clinical performance of novel of kinase inhibitors in oncology (i.e. zongeritinib, sunvozertinib, vimseltinib, mirdametinib, avutometinib and defactinib), authorized by the US Food and Drug Administration (FDA) in 2025, aiming to highlight both their transformative role and their inherent limitations. Taken together, KIs represent both a milestone and a challenge in oncology: they highlight the success of rational drug design and targeted therapy, yet show the need for continual innovation, improved global accessibility, and integration into multimodal strategies and standards of care to achieve durable survival benefits. See also the graphical abstract(Fig. 1).

Gout, a prevalent form of inflammatory arthritis, arises from the deposition of monosodium urate crystals in joints due to chronic hyperuricemia. Current pharmacologic monotherapies such as xanthine oxidase inhibitors, uricosurics, NSAIDs, corticosteroids, and colchicine are often limited by inadequate dual-action efficacy, suboptimal bioavailability, and systemic side effects. Emerging nanocarrier-based drug delivery systems offer a promising alternative by improving pharmacokinetics and enhancing targeted delivery to inflamed tissues. While co-encapsulation of multiple therapeutics remains underexplored in gout, advances in related inflammatory diseases support its future application. This review explores the limitations of conventional gout therapies and highlights recent advancements in nanocarrier technologies, including liposomes, niosomes, and ethosomes, for delivering both anti-inflammatory and urate-lowering agents. Special attention is given to functionalization strategies that allow for site-specific delivery and sequential drug release, particularly in the acidic and oxidative microenvironments characteristic of acute gout flares. Co-delivery of agents such as allopurinol or febuxostat with NSAIDs or corticosteroids may reduce pill burden, improve therapeutic synergy, and enhance patient adherence. While clinical translation remains in early stages, the mechanistic rationale and encouraging preclinical outcomes of responsive, functionalized nanocarriers underscore their potential to advance precision medicine in gout management. See also the graphical abstract(Fig. 1).

This article updates the "virtuous circle" model, which links physical exercise with cognition. This model, which originally focused on connectivity between the salience network (SN) and central executive network (CEN), now also incorporates the default mode network (DMN). It describes a bidirectional dynamic: exercise enhances executive functions (i.e., inhibition, flexibility, updating, planning, and problem-solving), which in turn strengthen long-term exercise adherence. This virtuous circle leads to cognitive, physiological, and motivational benefits through synergistic mechanisms induced by exercise such as the effort hypothesis (effort as an investment), the neurotrophic hypothesis, the cardiovascular hypothesis, the inflammatory hypothesis and the glucocorticoid hypothesis. These mechanisms improve connectivity within large-scale neuronal networks, thereby consolidating behavioral regulation. Compared with other behavior change models (e.g., regulation, dual-process, stage-based, and integrative models), the virtuous circle model is notable in light of its circular nature and emphasis on sustainability. In this theoretical framework, adherence to exercise is defined as an evolving strength of the attitude-behavior link, which is shaped by three interconnected processes: immediate motivation (pleasure, mood improvement, social interaction, and rewards), which initiates engagement; sustained effort, which enhances executive control, reduces perceived costs, and fosters habit formation; and behavior-driven attitude change, through cognitive dissonance and effort justification, which aligns beliefs with actions. Recent longitudinal studies have supported the reciprocal associations among exercise, cognition, and brain health, although further trials are needed. This model highlights the fact that early adoption of the virtuous circle promotes the development of health-protective habits, thereby slowing both physical and cognitive aging. In contrast, sedentary lifestyles foster a vicious circle that accelerates decline. See also the graphical abstract(Fig. 1).

In this study, we examined the potential of Bruton tyrosine kinase (BTK) inhibitor ibrutinib to mitigate neuroinflammation in C8-B4 microglial cells activated by the bacterial endotoxin lipopolysaccharide (LPS). Our objective was to enhance understanding of its mechanism of action, particularly in relation to its anti-inflammatory, and antioxidant potential of ibrutinib. Here, mouse microglial C8-B4 cells were treated with ibrutinib (1 and 10 μM) or vehicle (1 % DMSO) for 1 h, followed by lipopolysaccharide (LPS 1 μg/mL) for 23 h. We observed that ibrutinib significantly decreased LPS-induced nitric oxide levels and nitric oxide synthase 3 (NOS3) expression. In parallel, ibrutinib decreased cell senescence induced by LPS in microglia. Ibrutinib notably diminished the elevation of tumor necrosis factor-α (TNF-α), triggered by LPS in C8-B4 microglia. It also modulated Toll-like receptor 4 (TLR4) expression induced by LPS. Moreover, ibrutinib markedly lowered the augmented levels of nuclear factor kappa beta (NF-κβ) and phosphorylated NF-kβ (pNF-κβ) induced by LPS, indicating its capacity to mitigate LPS-induced neuroinflammatory reactions by hindering TLR4/NF-κβ pathway. Additionally, these beneficial effects are associated with regulation of the Nrf2/HO-1 pathway. The present results suggest that treatment with ibrutinib may contribute to the preservation of mitochondrial function, as evidenced by its ability to reduce reactive oxygen species (ROS) production. While these findings provide important insights into the potential neuroprotective mechanisms of ibrutinib, the precise molecular pathways involved in mitochondrial preservation require further investigation. Collectively, these data support the therapeutic potential of ibrutinib in mitigating neuroinflammation-related mitochondrial dysfunction and highlight its promise as a candidate for treating neurodegenerative disorders characterized by oxidative stress and impaired mitochondrial integrity. See also the graphical abstract(Fig. 1).