EXCLI Journal最新文献

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).

The most prevalent form of polyautoimmunity is autoimmune thyroid diseases (AITD), which frequently coexist with other autoimmune disorders and often act as a central conductor in the symphony of autoimmunity. Due to overlapping clinical manifestations, diagnosing polyautoimmunity presents significant clinical challenges. Patients with AITD exhibit increased susceptibility to additional autoimmune disorders, in which the exact etiology and underlying mechanisms of these associations remain incompletely understood. In this review, we aim to discuss how mechanistic insights contribute to our understanding of the associations between endocrine autoimmune diseases to recognize shared immunological, genetical, and pathological patterns for these diseases. Recent findings, including epitope spreading, cytokine imbalance, shared thyroidal and non-thyroidal autoantibodies, and common genetic susceptibilities, are highlighted. Additionally, the integration of artificial intelligence (AI) into autoimmune diagnostics is addressed, underscoring AI's potential to enhance early detection, improve diagnostic accuracy, and support personalized treatment approaches. By recognizing distinct immunological, genetical and pathological patterns within polyautoimmunity, clinicians and researchers can more effectively target the root causes of immune dysregulation, enabling improved management through personalized strategies and advanced AI-driven tools. See also the graphical abstract(Fig. 1).

Pacing in multi-day long-distance triathlons has been investigated mainly in male athletes. We analyze physiological aspects such as energy expenditure and heart rate changes as well as biomechanical aspects in swimming (e.g. strokes per lane) and running (e.g. stride frequency, stride length, vertical ratio, vertical movement, ground contact time) in the first and only female triathlete to finish 30 IRONMAN^®-distance triathlons in 30 days. The split times, lap times for swimming, cycling and running and variables were recorded with Fenix 7 Sapphire Solar with Normalized Power^® (NP^®), Intensity Factor^® (IF^®) and Training Stress Score^® (TSS^®), and were analyzed. The models' estimations for pacing were assessed with R2. Variance (ANOVA) and associative (Pearson and Spearmen) analysis were conducted at a level of significance of 5 %. Swimming pace remained stable throughout the race (linear p = 0.473), cycling pace demonstrated a significant slowdown (third-order polynomial p < 0.001), and running pace significantly improved (third-order polynomial p < 0.001). Energy expenditure slightly decreased in swimming (p = 0.099) and progressively increased for both cycling (p = 0.034) and running (p = 0.044). Moderate-intensity swimming time initially increased and later decreased, with an opposite trend for high-intensity swimming time. Cycling times at both moderate and high intensities slightly decreased. Running showed decreasing moderate-intensity time and increasing high-intensity time, consistent with improved pace. Transition times increased over the race period, with T1 increasing more prominently. Biomechanical parameters in swimming, including total stroke count and SWOLF index, showed increasing trends. Overall, significant differences were observed in running time at moderate intensity (p < 0.001, η² = 0.513), high intensity (p < 0.001, η² = 0.518) and average pace (p < 0.001, η² = 0.603). The athlete spent significantly more time at moderate intensity (p = 0.019 and p = 0.002) and significantly less time at high intensity (p = 0.011 and p = 0.005) running in the initial phase, compared to the middle and final stages of the race. All biomechanical variables decreased slightly in the opening phase of the race but then increased in the middle and final stages of the race. Overall, the results highlight that running was the discipline most affected by physiological and pacing adaptations throughout the race; while cycling and swimming parameters demonstrated weaker or no consistent associations.