Octamethylcyclotetrasiloxane (D4) is a highly volatile cyclic siloxane used to produce silicone polymers. D4 has been shown to attenuate the LH surge in rats, resulting in reduced litter sizes. However, it has been hypothesized that these biological effects observed only at high dose levels of D4 may be because of changes in membrane microviscosity (fluidity) leading to a non-specific mode of action. Here, we set out to determine if D4 increases membrane microviscosity and link this to membrane domain function alterations. The studies reported here support the hypothesis that D4 affects ovulation via a concentration-dependent, physical-chemical mode of action that is not specific for any particular component of the neuro-endocrine system and is, therefore, not endocrine disruption but a non-specific effect. Furthermore, D4 also increases the membrane fluidity of the hypothalamic cell membrane in vitro. It is expected that a similar response would occur in vivo. This alteration in membrane fluidity decreases the release of GnRH and kisspeptin. GnRH and kisspeptin are necessary for the pre-ovulatory LH surge from the pituitary. In the absence of a GnRH and kisspeptin release, there is no signal to the pituitary for the driver of the LH surge. D4 can change membrane fluidity in vitro and likely in vivo and associated behaviors of membrane proteins/lipoproteins of various kinds via non-specific mechanisms.

The metabolic environment provided by the culture medium plays a critical role in shaping cellular function and mitochondrial activity . In this study, we investigated the effects of metabolic priming on the metabolism and morphology of Normal Human Dermal Fibroblasts (NHDFs) by manipulating glucose availability in the culture medium. Our strategy involved transitioning NHDFs from traditional high-glucose medium (HGm) to either a medium with physiological glucose levels (LGm) or a glucose-free, galactose-containing medium (OXm). Prior to cellular characterization, we confirmed the absence of glucose in the culture media and fetal bovine serum using H nuclear magnetic resonance (NMR) spectroscopy. Given previous observations of elevated reactive species under glucose-free conditions, we explored the cellular adaptations associated with a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS). Cells cultured in OXm exhibited increased metabolic activity, elevated protein content, and substantial metabolic remodeling. Morphological analysis revealed enlargement of the cell body, cytoplasm, mitochondria, and nuclei, indicative of extensive structural adaptation. Notably, oxygen consumption rate (OCR) nearly doubled within 24 h of exposure to OXm, reflecting a rapid mitochondrial response to metabolic stress. The presence of the antioxidant N-acetyl cysteine (NAC) attenuated this increase, suggesting that redox signaling plays a key role in mitochondrial bioenergetic adaptation. These findings underscore the complex interplay between metabolic context, oxidative stress, and cellular morphology, and highlight the importance of appropriate normalization strategies in metabolic studies. See also the graphical abstract(Fig. 1).

Extracellular vesicles (EVs) and microRNAs, involved in intercellular communication, have emerged as potential biomarkers in liver diseases. This study aimed to evaluate EV characteristics and microRNA transport across the full spectrum of metabolic dysfunction-associated steatotic liver disease (MASLD). 168 patients with MASLD and 50 controls were recruited. Biochemical and clinical variables were evaluated. EVs were isolated from serum and characterized by nanoparticle tracking analysis, flow cytometry, and Western blotting. Using MiRWalk 3.0 and the TarPmiR algorithm, candidate EV-associated microRNAs related to MASLD were identified. The expression of miR-4758, miR-188, miR-1226, and miR-122, was evaluated in EVs and serum. EV size and concentration varied significantly across disease stages (p<0.001 and p<0.05, respectively), with early MASLD dominated by exosome, and later stages showing a shift toward microvesicles. In MASLD patients, interestingly, miR-122 was lower in EVs compared to serum (p<0.05). In steatosis, it was higher in serum than EVs (p<0.05), without significant differences in later stages. miR-122 in EVs increased in association with GGT and cholesterol, and decreased with elevated creatinine. Serum miR-122 was also elevated in patients with high cholesterol. In MASLD miR-4758 was higher in EVs than in serum (p<0.05), expressed in steatosis and cirrhosis (p<0.05), suggesting it is a good disease marker, and detected exclusively in serum in HCC (p<0.05). miR-4758-EVs increased with high glucose. MiR-188 and miR-1226 were exclusively expressed in serum (p<0.05), and miR-1226 was elevated in patients with high cholesterol. EV size was reduced in individuals with high triglycerides and albumin, suggesting interaction between EVs, biochemical parameters and disease stage. These findings suggest that microRNA expression and transport in EVs and serum vary across MASLD stages and associate with key biochemical parameters, supporting the clinical value of jointly assessing both compartments as potential biomarkers to distinguish early disease from advanced stages such as HCC. See also the graphical abstract(Fig. 1).

This review analyzes case reports of adverse drug reactions (ADRs) attributed to etoricoxib, with particular emphasis on Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), fixed drug eruptions (FDE), atrial fibrillation, hypertension, thrombocytopenia (TP), immune hemolytic anemia (IHA), acute generalized exanthematous pustulosis (AGEP), maculopapular rash, pretibial erythema with edema, and reversible cerebral vasoconstriction syndrome (RCVS). Although infrequent, these severe hypersensitivity and cardiovascular events pose significant clinical risks due to their association with substantial morbidity and, in some cases, mortality. The primary aim of this review is to consolidate available clinical evidence to evaluate the causality, characteristic clinical presentations, and broader safety implications of etoricoxib in relation to these adverse outcomes. While SJS/TEN are marked by widespread epidermal necrosis and detachment, FDE typically recurs at fixed sites with residual pigmentation. Hematological complications such as drug-induced (TP) and Drug-induced IHA have also been reported, presenting as sudden platelet decline or severe hemolysis, respectively. These adverse effects often appear within hours to weeks of initiating therapy. Cutaneous manifestations, including exanthematous pustulosis and maculopapular rashes, further complicate the drug's safety profile. Etoricoxib's pro-thrombotic potential, possibly linked to COX-2 selectivity, remains a cardiovascular concern. Causality assessments via the Naranjo Scale and WHO-UMC often support a probable link. These findings underscore the necessity for careful evaluation of patient history, immediate drug discontinuation upon clinical suspicion, and strengthened pharmacovigilance systems to better capture and characterize the full range of these rare yet serious reactions. See also the graphical abstract(Fig. 1).

Sepsis remains a global health problem that causes millions of deaths each year. A rapid and accurate diagnosis is highly desired to allow a rapid use of appropriate antibiotics. A better understanding of the associated pathophysiology has been achieved these recent years. The initial appropriate immune response to infection evolves towards an overwhelmed inflammatory response involving both pro- and anti-inflammatory players that act concomitantly. It also includes cell deaths and cellular dysfunctions of leukocytes, endothelial cells and epithelial cells, associated with mitochondrial dysfunction. These dysregulations are responsible for organ impairment and alteration of immune status of circulating leukocytes. In contrast, within the tissues, an over-activation exists as illustrated by transcriptomic analyses of organs of patients deceased of sepsis, and revealed by the presence of a macrophage activation syndrome within the bone marrow. Despite progresses in understanding the mechanisms underlying sepsis and despite successful therapies in animal models, no real new therapies have emerged these recent decades. This failure may reflect the yin yang aspect of the same players of the host response such as fever, release of cytokines, or coagulation which can display both a beneficial or a detrimental role. Great hopes are now expected from precision medicine, based on patients' endotypes which should help to decipher the patient's sub-groups who could benefit from the different treatments, or to define some appropriate time windows for a given treatment. 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 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).

Cancer is a multifactorial disease with cellular proliferative molecular networks and immune evasion properties. The well-known cancer intra- and inter-tumoral heterogeneity presents a notable limitation of the current histological and diagnostic techniques. Thus, biasing the risk of invasiveness and restricting its broader application in oncology in prognostic, survival, and treatment response differences between patients. Monolayer cell cultures have been a consistent model in cancer research throughout time. However, this system fails to replicate the complex pathogenesis of this disease, as key mechanisms underlying initiation, metastasis, drug resistance, and recurrence remain poorly understood. 3D culture models are presented as the most suitable model to better reflect the patient's tumor development. Some methods to introduce the third dimension into cell cultures is by promoting cell-cell interactions to give 3D cell structures, using scaffolds to promote growth beyond monolayers and introducing microfluidic platforms to the system. The present review provides an overview of different techniques to develop 3D culture models in oncology, the advantages compared between monolayer cell cultures, their applications, limitations, and applicability in oncology research. 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 ( strokes per lane) and running ( 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, η = 0.513), high intensity (p < 0.001, η = 0.518) and average pace (p < 0.001, η = 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.

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).

Bilateral force control and coordination in upper and lower limbs are important functions for executing activities of daily living. Although upper and lower limbs may reveal distinct bilateral motor control patterns because of different motor networks involvements, no one has examined the possibility that upper and lower limbs reveal distinct bilateral force control and coordination patterns. This study investigated bilateral force control and coordination patterns between upper and lower limbs in healthy young adults. Thirty-two healthy young adults (mean±SD of age = 23.2±2.2 years; 16 Females) performed bilateral hand-grip and ankle-dorsiflexion force control tasks at 10 % and 40 % of maximal voluntary contraction. Bilateral force control performances were evaluated by calculating mean force, force symmetry, force accuracy, and force variability. To estimate bilateral force coordination, we used cross-correlation with time lag. Further, we examined the relationship between bilateral force control and coordination patterns of upper and lower limbs by conducting Pearson's correlation analysis. Bilateral maximal and mean forces of lower limbs were significantly less than those for upper limbs. At higher targeted force level, force accuracy and variability in lower limbs were significantly lower than those for upper limbs. More negative correlation coefficient values appeared in lower limbs as compared with upper limbs. Finally, bilateral force control performances in upper limbs were related to those in lower limbs although no significant correlation was observed for interlimb coordination patterns. These findings suggest that bilateral motor control and coordination patterns were different between upper and lower limbs although the level of bilateral upper and lower motor control capabilities was presumably influenced by shared motor control processes for each individual. 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).

This study investigated the therapeutic impact of dual immune checkpoint inhibition targeting TIGIT and VISTA in non-small cell lung cancer (NSCLC). Current monotherapies have failed to produce consistent and durable responses owing to tumor heterogeneity and immune evasion. By evaluating the biological and immunomodulatory roles of TIGIT and VISTA, this study provides a rationale for their simultaneous blockade. Preclinical models have shown that this dual strategy not only revitalizes T-cell function but also alters the suppressive tumor microenvironment, leading to improved antitumor immunity in mice. Preliminary clinical data suggest potential survival benefits; however, the long-term outcomes and resistance dynamics remain uncertain. These findings suggest a paradigm shift toward precision-designed, multi-target immunotherapies. Future studies should integrate molecular profiling, adaptive clinical trial designs, and follow-up models to optimize patient selection and sustain therapeutic benefits. See also the graphical abstract(Fig. 1).

Neuroinflammation is a key characteristic associated with neurological disorders, particularly depression and anxiety. This study aims to evaluate the neuroprotective and antidepressant-like effects of pine needle (PN) extracts in an LPS-induced neuroinflammation mouse model. Following seven days of oral administration of PN, the tail suspension test demonstrated a significant reduction in immobility time in PN-treated mice compared to LPS controls, surpassing the effect of the standard antidepressant bupropion. To elucidate the underlying mechanisms, we conducted a whole-genome microarray analysis. This analysis highlighted pathways related to neuroprotection, synaptic plasticity, and pro-inflammatory cytokine regulation, with a notable enrichment in the Apelin signaling pathway. Quantitative PCR analysis revealed that PN treatment increased the levels of Apelin and its receptor while decreasing proinflammatory cytokines and in the hippocampus. ELISA further demonstrated elevated levels of key neurotransmitters, including dopamine and noradrenaline, in the mouse hippocampus. Additionally, we performed GC/MS analysis to identify bioactive compounds in PN, revealing D-Pinitol and Shikimic acid as major constituents. Importantly, catechol exhibited significant neuroprotective effects, and similar protective effects were also noted in the mixed compositions. The MTT assay showed that PN and its compounds significantly improved cell metabolic activity against dexamethasone-induced cytotoxicity. In conclusion, our findings highlight the potential of PN as a natural therapeutic agent for depressive symptoms, promoting neuroprotection, enhancing neurotransmitter levels, and modulating inflammatory responses. See also the graphical abstract(Fig. 1).

Metabolic syndrome (MetS), is a non-communicable disorder caused by impaired management and storage of energy, primarily associated with unhealthy diets, sedentary lifestyles and stress. It is diagnosed when any three of the following conditions are observed, obesity (primary factor), hyperglycemia, low HDL, hypertriglyceridemia, and hypertension (ATP III guidelines). MetS affects approximately 14-34 % of the global population, highlighting significant public health concern. If left untreated, it leads to the development of other serious metabolic diseases like atherosclerosis, diabetes, PCOS, NAFLD, NASH, thyroid, cancer, sleep disturbance, osteoarthritis, anxiety, and depression. Despite ongoing research, no first-line drug currently exists for the comprehensive management of MetS. Its multifactorial nature often requires lifelong polytherapy with lifestyle intervention, raising concern over chronic drug use, drug-drug interactions, increasing morbidity and mortality. Therefore, there is a need highlighting the requirement of a single and targeted pharmacotherapy which offers a safer and more specific therapeutic approach. This review aims to identify and analyse ten key molecular targets in managing the pathogenesis of Metabolic Syndrome (MetS). These targets can further pave the way for a targeted and safer approach in the treatment of MetS. See also the graphical abstract(Fig. 1).

Interferon-gamma (IFN-γ), as a pleiotropic cytokine, plays a pivotal role in antitumor immunity. Its remarkable immunostimulatory, antiproliferative, and pro-apoptotic effects make it a promising candidate for tumor immunotherapy. Here, we highlight the dual role of IFN-γ in the tumor microenvironment during tumor development and treatment. IFN-γ can enhance antigen presentation, boost cytotoxic T cell and natural killer cell activity, and inhibit angiogenesis, promoting tumor regression and correlating with favorable therapeutic outcomes. However, prolonged exposure may induce the upregulation of immune checkpoint molecules such as programmed death-ligand 1, trigger T cell exhaustion, and recruit regulatory T cells, phenomena associated with the development of treatment resistance in cancer therapy. This dual nature poses significant challenges for harnessing IFN-γ in tumor treatment, necessitating an in-depth understanding of its mechanisms within specific microenvironments. Although numerous studies have explored IFN-γ-based tumor therapies, their outcomes have been inconsistent. Thus, although IFN-γ-based therapeutic strategies hold considerable promise, their clinical translation requires precise modulation to fully exploit its antitumor effects while mitigating potential protumor risks. See also the graphical abstract(Fig. 1).

Berberine (BBR) is a plant-derived alkaloid that has been traditionally used in Chinese medicine to treat diarrhea. In recent years, accumulating evidence has highlighted its broad therapeutic potential across multiple organ systems. This review systematically examines the pharmacological mechanisms and therapeutic applications of BBR in cancer, as well as in digestive, metabolic, cardiovascular, and neurological diseases. The effects of BBR on endogenous factors-such as energy metabolism, immune responses, cellular homeostasis, and gene expression-are discussed, along with its regulation of cellular functions and inflammatory responses. In addition, we explore BBR's actions on exogenous factors, particularly the gut microbiota. The review also summarizes emerging molecular targets of BBR and addresses current clinical applications, as well as novel strategies to improve its low oral bioavailability. By integrating findings from basic, translational, and clinical research, this review provides a comprehensive overview of BBR's therapeutic potential and supports its integration into modern medical practice. See also the graphical abstract(Fig. 1).