Search Results (1,696)

Impairment of the intestinal epithelial barrier, accompanied by local and systemic inflammation, underlies numerous human pathologies, including inflammatory bowel diseases, celiac disease, sepsis, as well as severe acute malnutrition. Bifidobacterium longum subsp. infantis and Lacticaseibacillus rhamnosus GG (LGG^®) have been shown in preclinical studies to strengthen the gut epithelial barrier and attenuate inflammation. This study aimed to compare the ability of four commercial strains of B. infantis, LGG, and their combination to mitigate inflammation-mediated epithelial damage using an in vitro immunocompetent intestinal model. A microfluidic mid-throughput platform OrganoPlate^® was used to co-culture intestinal epithelial cells (Caco-2) with peripheral blood mononuclear cells (PBMCs). Epithelial damage was induced by stimulating PBMCs with lipopolysaccharide (LPS), and probiotic-conditioned media were applied to the apical side of Caco-2 cells to assess effects on barrier integrity, cytokine secretion, and gene transcription. All tested probiotics significantly protected the epithelium by modulating tight junction protein expression and promoting transcription of homeostatic cytokines, resulting in a “leak-tight” phenotype. These findings indicate that metabolites produced by B. infantis and/or LGG can protect the intestinal epithelium in vitro, warranting further in vivo studies to evaluate the translational relevance of this effect. Full article

Background: Recent studies suggest that erythroferrone (ERFE), an iron-regulating protein whose primary role is to inhibit hepcidin synthesis, may affect glucose and lipid metabolism, and its serum concentration is reduced in obese and diabetic individuals. The aim of this study was to evaluate the association of ERFE concentration with selected cardiometabolic risk factors in apparently healthy young adults. Methods: This preliminary study consisted of 122 (63 females, 59 males) normoglycemic, non-smoking subjects aged 25–40 years. In all participants, anthropometric measurements and the following laboratory tests were performed: fasting plasma glucose, glycated hemoglobin (HbA1c) and serum iron, lipid profile, insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), C-reactive protein (CRP), ERFE and hepcidin. Results: The serum ERFE concentration was significantly lower in men compared to women (p = 0.009) and in subjects who were overweight (p < 0.001) and had abdominal obesity (p < 0.001). ERFE showed significant negative correlations with body mass index, waist–hip ratio, HbA1c, CRP, insulin, HOMA-IR and triglycerides. In the logistic regression analysis, ERFE was significantly associated with being overweight (OR = 0.051; p = 0.004), abdominal obesity (OR = 0.372; p < 0.001), HOMA-IR ≥ 2.0 (OR = 0.584; p = 0.013), CRP > 1 mg/L (OR = 0.648; p = 0.020) and triglycerides (OR = 0.521; p = 0.033). A relevant predominance in the prevalence of cardiometabolic risk factors was observed in subjects with ERFE levels in the first tertile (<1.35 ng/mL), compared to the third tertile (>2.19 ng/mL). Conclusions: Serum ERFE is inversely associated with being overweight, increased waist circumference, CRP, and markers of insulin resistance and lipid abnormalities, suggesting its potential relevance as a marker of early cardiometabolic risk in apparently healthy young adults. Full article

The interaction between microorganisms in the dental microfilm (plaque) at the gingival margin, the immune system, and the brain is vital for gingival health. The brain constantly receives information regarding microbial composition and inflammation status through afferent nerves and the bloodstream. It modulates immune responses via efferent nerves and hormonal systems to maintain homeostasis. This relationship determines whether the gingiva remains healthy or develops into gingivitis (non-destructive inflammation) or periodontitis (a destructive condition), collectively referred to as periodontal disease. Factors associated with severe periodontitis heighten the responsiveness of this homeostatic system, diminishing the adaptive immune system’s defence against symbiotic microorganisms with pathogenic properties, known as pathobionts. This leads to excessive innate immune system activation, effectively preventing infection but damaging the periodontium. Consequently, investigating the microbiota–brain axis is vital for understanding its impact on periodontal health and disease. Herein, we examine recent advancements in how the defence against pathobionts is organised within the brain, and how it regulates and adapts the pro-inflammatory and anti-inflammatory immune balance, controlling microbiota composition. It also discussed how pathobionts and emotional stress can trigger neurodegenerative diseases, and how inadequate coping strategies for managing daily stress and shift work can disrupt brain circuits linked to immune regulation, weakening the adaptive immune response against pathobionts. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is prevalent in adolescents with obesity and is linked to insulin resistance and cardiovascular disease (CVD). Pancreas steatosis might be associated with MASLD and early CVD. Imaging-based analyses of these associations have not been studied extensively in children. Objectives: To assess the reproducibility of liver and pancreatic steatosis and volume measurement on MRI in adolescents with obesity and MASLD and their association with homeostatic model assessment of insulin resistance (HOMA-IR) and subclinical vascular changes on ultrasound. Methods: This is an observational study on adolescents with MASLD and obesity. Hepatic and pancreatic steatosis, volume, and abdominal fat were assessed using magnetic resonance spectroscopy and proton density fat fraction. Reproducibility of these measurements was performed. Vascular markers included non-invasive vascular elastography (NIVE), carotid artery intima-media thickness (IMT), and pericardial fat thickness. Fasting blood tests measured the HOMA-IR. Bivariate correlation and simple linear regression were performed using SPSS. Results: We obtained 23 participants aged 12 to 17 years (78.3% male). Measurements were reproducible [ICC 0.807–0.998]. Liver steatosis was positively correlated with HOMA-IR (p = 0.015). Pancreas steatosis was positively correlated with HOMA-IR (p = 0.02), IMT/diameter (p = 0.002), and pericardial fat (p = 0.03). Liver steatosis was not significantly correlated with pancreas steatosis nor vascular markers. There were negative associations between NIVE metrics and visceral abdominal fat (p = 0.009) and intraperitoneal fat (p = 0.047). Conclusions: Liver and pancreas steatosis measurements on MRI are reproducible. In this exploratory study, adolescents with obesity and MASLD, pancreas steatosis, and pancreas volume show association with subclinical CVD markers. Visceral and intraperitoneal abdominal fat show association with increased vascular stiffness, suggesting a potential role of imaging-based cardiovascular risk assessment in this population if validated. These preliminary findings require validation in larger, diverse prospective cohorts. Full article

Background: Antibody-drug conjugates (ADCs) have ushered in a new era of precision oncology by combining the targeting specificity of monoclonal antibodies with the potent cytotoxicity of chemotherapeutic drugs. However, the cellular and molecular mechanisms underlying their dose-limiting ocular toxicity remain unclear. Elahere™, the first FDA-approved ADC targeting folate receptor α (FRα), demonstrates remarkable efficacy in platinum-resistant ovarian cancer but causes keratitis and other ocular toxicities in some patients. Notably, FRα is not expressed in the corneal epithelium—the primary site of damage—highlighting the urgent need to elucidate its underlying mechanisms. The aim of this study was to identify the cell-type-specific molecular mechanisms underlying Elahere-induced ocular toxicity. Methods: Sprague-Dawley rats were treated with intravenous Elahere (20 mg/kg) or vehicle weekly for five weeks. Ocular toxicity was determined by clinical examination and histopathology. Corneal single-cell suspensions were analyzed using the BD Rhapsody single-cell RNA sequencing (scRNA-seq) platform. Bioinformatic analyses to characterize changes in corneal cell populations, gene expression, and signaling pathways included cell clustering, differential gene expression, pseudotime trajectory inference, and cell-cell interaction modeling. Results: scRNA-seq profiling of 47,606 corneal cells revealed significant damage to the ocular surface and corneal epithelia in the Elahere group. Twenty distinct cell types were identified. Elahere depleted myeloid immune cells; in particular, homeostatic gene expression was suppressed in phagocytic macrophages. Progenitor populations (limbal stem cells and basal cells) accumulated (e.g., a ~2.6-fold expansion of limbal stem cells), while terminally differentiated cells decreased in corneal epithelium, indicating differentiation blockade. Endothelial cells exhibited signs of injury and inflammation, including reduced angiogenic subtypes and heightened stress responses. Folate receptor alpha, the target of Elahere, was expressed in endothelial and stromal cells, potentially driving stromal cells toward a pro-fibrotic phenotype. Fc receptor genes were predominantly expressed in myeloid cells, suggesting a potential mechanism underlying their depletion. Conclusions: Elahere induces complex, multi-compartmental ocular toxicity characterized by initial perturbations in vascular endothelial and immune cell populations followed by the arrest of epithelial differentiation and stromal remodeling. These findings reveal a cascade of cellular disruptions and provide mechanistic insights into mitigating Elahere-associated ocular side effects. Full article

Background: Insulin resistance (IR) is common in overweight or obese individuals. Dysregulation of trace elements such as cobalt (Co) and manganese (Mn) has been associated with obesity and IR markers in individuals with diabetes. However, their role in non-diabetic states is less understood. Objective: This study aimed to analyze the association between serum Co and Mn levels and IR in overweight and obese women without diabetes. Methods: A total of 112 overweight or obese women were evaluated for their anthropometric, metabolic, and biochemical characteristics. To estimate IR, the homeostatic model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), triglyceride–glucose index (TyG), and triglyceride–glucose–body mass index (TyG-BMI) were calculated. Serum Co and Mn concentrations were quantified by inductively coupled plasma mass spectrometry (ICP-MS). Results: Our results show that 77% of participants exhibited central fat accumulation and a high prevalence of IR. Fasting insulin (FINS), HOMA-IR, and TyG-BMI were significantly higher in obese women, while adiponectin (Adpn) was lower. Moreover, Co was inversely associated with FINS (p = 0.003) and HOMA-IR (p = 0.011), and positively associated with QUICKI (p = 0.011) in obese women. In contrast, serum Mn levels showed negative correlations with fasting glucose (FG) (p = 0.021) and the TyG index (p = 0.048) in overweight women. Conclusions: Co serum levels were positively associated with FG and QUICKI and negatively associated with FINS and HOMA-IR in the obese group. Mn showed negative associations with FG and the TyG index, suggesting that these trace elements may play a role in the IR in people with obesity. Full article

Background: Urinary continence relies on a complex interplay between urine storage and voiding involving both spinal reflex circuits and supraspinal brain areas to coordinate volun-tary control over emptying. Despite a vast number of studies on the pathophysiology of neurogenic bladder and urge incontinence, less is known about the central correlates of bladder filling. Methods: An ALE (activation likelihood estimation) meta-analysis including a total count of 14 studies investigating 243 participants under different conditions of bladder filling during functional neuroimaging was performed to demonstrate the neuroanatomical correlates of bladder filling. The literature search and reporting were conducted according to the PRISMA-P 2020 guideline. Data analysis was performed using the GingerAle software version 3.0.2 and was displayed with the Mango software 4.1 on an anatomical MNI template. Results: Synthesizing studies on the functional neuroanatomy of urine storage, bihemispheric clusters of activation in the thalamus, the insula and the cingulate were observed. Conclusion: The present ALE meta-analysis indicates that the supraspinal representation of urine storage involves areas of autonomous–homeostatic processing which allow for the perception of the usually unconscious inner state of bladder filling and enable postponing and voluntary voiding. Full article

Aging is the result of the accumulation of a great variety of molecular and cellular damage over time. During aging, the brain undergoes changes and diseases such as depression, dementia, anxiety, Alzheimer’s, delirium, behavioral disorders and aggression, and prolonged mourning, among others, appear. The gut–brain axis suggests that the gut and the brain have a bidirectional communication, so it is important to maintain proper intestinal health to strengthen the neurological changes of this age group. The intestinal microbiota is a dynamic and highly complex ecosystem of microorganisms residing in the gastrointestinal tract. The bidirectional and dynamic communication between the homeostatic systems, such as the endocrine and immune systems, as well as the nervous system, allow us to face problems associated with several diseases. Probiotics are defined as non-pathogenic live microorganisms that provide beneficial effects to the organism and participate in the prevention and treatment of diseases, which is the reason why it is important to promote interventions that keep intestinal microbiota in eubiosis (microbiota balance). The concentration and balance of the intestinal microbiota depend on several conditions, such as diet, antibiotic consumption, and lifestyle, to mentioned a few. However, interventions with probiotics have shown improvements in both cognitive function and processes that promote neurodegeneration. It is such that the research has been directed on designing strategies that improve not only oral bioavailability but also intestinal adhesion and retention, to clarify the frequency and dosage that should be consumed. Full article

Fatty acid-binding proteins (FABPs) represent a superfamily of intracellular lipid chaperones essential for the transport of lipids and homeostatic lipid metabolism. Although well-known for their role in systemic metabolic diseases, emerging evidence has identified brain-expressed FABPs as core players in neurodegeneration. This review focuses on brain-expressed FABPs, synthesizing recent advancements that link their role in metabolic dysregulation to neurotoxicity. We present a system that integrates these proteins within a multi-tiered complex pathobiological system that involves: an advanced glial “meta-inflammation” paradigm; a novel view on proteotoxicity via liquid–liquid phase separation (LLPS); changes in the gut–brain axis; and an involvement in the regulation of ferroptosis. Additionally, we also discuss the emerging pharmacological pipeline, highlighting notable preclinical ligands and drawing important lessons from systemic disease first-in-class-targeted FABPs. These first-in-class therapies have successfully validated this target family in systemic diseases. Finally, we explore future therapeutic strategies, where we emphasize the challenges and the precision cell-type-specific delivery approaches to harness the full therapeutic potential of these pivotal proteins. Full article

The use of the HOMA (Homeostatic Model Assessment) index in veterinary medicine is emerging as a promising and valuable method for evaluating insulin resistance and beta-cell function in companion animals, particularly in dogs and cats. Originally developed for use in human medicine, HOMA enables a minimally invasive assessment of glucose and insulin homeostasis, offering clinicians a practical tool for diagnosing and monitoring diabetes mellitus in animals. Its application in veterinary practice brings several advantages, including cost-effectiveness, ease of use, and the potential for early detection of metabolic disturbances before clinical symptoms appear. Nonetheless, important limitations persist, such as inter-individual variability, the effects of stress and comorbidities on glucose and insulin values, and the absence of standardized, species-specific reference ranges. These factors highlight the need for methodological refinement and the establishment of validated protocols tailored to the unique physiological characteristics of dogs and cats. Despite these challenges, HOMA represents a promising avenue for advancing the understanding of diabetes pathophysiology in veterinary patients. Future longitudinal studies and controlled trials are essential to confirm its reliability and enhance its clinical relevance. With further development, the HOMA index could become an essential tool in improving diagnostic accuracy and optimizing the management of diabetes in companion animal practice. Full article

The ultrastructural organization of different cell types involved in homeostatic growth in the cerebellum of juvenile chum salmon (Oncorhynchus keta) was investigated using transmission and scanning electron microscopy. The organization of astrocytes, oligodendrocytes, dark cells, adult-type glial and non-glial progenitors, stellate neurons, and eurydendroid cells (EDCs) in the molecular and granular layers and granular eminences was characterized. The organization of dendritic bouquets of Purkinje cells and climbing fibers was studied for the first time at the ultrastructural level, and the ultrastructural features of mossy fibers and the rosettes they form were characterized. Scanning electron microscopy (SEM) revealed the presence of single and paired adult-type neural stem/progenitor cells (aNSPCs) on the cerebellar surface and stromal clusters of aNSPCs outside the dorsal matrix zone (DMZ). Immunohistochemical (IHC) verification of proliferating cell nuclear antigen (PCNA) revealed five types of proliferating cells in the cerebellum of juvenile chum salmon: neuroepithelial cells (NECs), glial aNSPCs, and non-glial aNSPCs. A glial fibrillary acidic protein-positive (GFAP) complex consisting of radial glial fibers and aNSPCs was detected in the DMZ. At the same time, a complex of GFAP+ cerebellar afferents, consisting of differentiating mossy and climbing fibers, was found to develop in the cerebellum of juvenile chum salmon. Nestin+ non-glial aNSPCs and small nestin+ resident cells were detected in the dorsal, lateral, and basal areas, as well as in the granular layer (GrL) and granular eminences (GrEm). These cell types may contribute to the homeostatic growth of the cerebellum by acting as both active participants (PCNA+) and resident (silent) aNSPCs. Studying vimentin-positive systems in the cerebellum revealed a widespread presence of proliferating glial aNSPCs that actively contribute to homeostatic growth, as well as small resident immunopositive cells throughout the cerebellum of juvenile chum salmon. Immunolocalization of the neuronal RNA-binding protein marker (HuCD) was detected in numerous molecular layer (ML) cells at the early stages of neuronal differentiation in the dorsal and lateral regions of the cerebellum of juvenile chum salmon. HuCD + EDCs were detected for the first time in the dorsal (DZ) and basal (BZ) zones, forming broad axonal arborization. Immunolabeling of HuCD in combination with transmission electron microscopy (TEM) allowed EDCs to be characterized in the cerebellum of juvenile chum salmon for the first time. Full article

MicroRNAs (miRNAs) have emerged as important biomarkers for complex neurological conditions. Modifications in synaptic morphology characterize several of these disease states, indicating a possible role of miRNA in modulating synaptic formation and plasticity. Within the third-instar larvae of Drosophila melanogaster, we uncovered a functional role for highly human-conserved miR-92 in synaptogenesis of the glutamatergic peripheral nervous system. Loss of miR-92 results in underdeveloped synaptic architecture, coinciding with significantly reduced physiological activity. We demonstrate a novel role for miR-92 glial-specific expression to support synaptic growth function and plasticity. Modifications of miR-92 within glial tissue result in aberrant glial barrier properties, including an increased uptake of external dyes. Within the glia, miR-92 regulates a V-ATPase subunit (Vha55), impairing the glial cells from forming appropriate insulating layers around the nervous system. These modifications may impact how the nervous system adapts to its environment, increasing immature ‘ghost bouton’ budding and impairing responses to changes in environmental conditions. Our work highlights the importance of glial-specific miR-92 on synaptic development, affecting glial health and function through its downstream target Vha55, and demonstrates a novel mechanism for glia in synaptogenesis and homeostatic plasticity. Full article

Despite its foundational role in the social sciences, “culture” remains a persistently ambiguous concept. This is a perennial obstacle to communicating the broader value of our work to the public and policy-makers, and particularly in clarifying its relevance to contemporary challenges. Building on our previous work, we propose a new framework defining culture as a system of adaptive information-processing. We re-frame culture not as a collection of beliefs or behaviors but as the structured organization of social information. We argue that culture consists of dynamic structural moments—norms as social information, normativity as allostatic convergence, and institutions as stabilizing homeostatic infrastructures. Integrating insights from statistical mechanics, information theory, and cultural evolution, we define culture as the unique configuration of moments across a population’s information landscape. This allows for both social change and cultural continuity by treating culture as a collective adaptation for the homeostatic convergence of lower-order allostatic information. Our model addresses the conceptual vagueness that has hindered empirical and theoretical progress across social sciences and heritage practice. In doing so, we offer a rigorous, scalable definition of culture as a multilevel, emergent, and adaptive system that can inform both sustainable policies and comparative research. Full article

Orexin is a neuropeptide produced in the hypothalamus that plays a key role in regulating slee—wake cycles, energy metabolism, feeding behavior, and physical activity. It exists in two forms, orexin-A and orexin-B, which bind to G protein-coupled receptors OX₁R and OX₂R with differing affinities. Orexin signaling is widespread in the brain and extends to peripheral tissues, including adipose tissue. Its involvement in hypothalamic and extrahypothalamic circuits suggests a broad role in homeostatic regulation. Dysfunctions in the orexinergic system are implicated in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and multiple sclerosis, particularly through mechanisms involving sleep disturbances and neuroinflammation. This study examines how orexin influences neural circuits related to arousal, motivation, and motor control. It also explores how physical activity stimulates orexin release, enhancing neuroplasticity and cognitive resilience. In addition, orexin’s role in reward-related feeding, genetic susceptibility to obesity, and brown adipose tissue thermogenesis is discussed. Overall, the orexinergic system represents a vital neurochemical link between physical activity, metabolism, and cognitive health. Although many of its mechanisms remain to be clarified, its central role in integrating energy balance and behavioral responses makes it a promising target for future therapeutic strategies. Full article

Background/Objectives: Dysglycemia including pre-diabetes mellitus (Pre-DM) and type 2 diabetes mellitus (T2DM) is associated with insulin resistance. This study aimed to support personalized early diagnosis of dysglycemia by proposing optimal, sex- and age-specific cutoff values for Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and Homeostatic Model Assessment of Beta-Cell Function (HOMA-β) in Koreans aged ≥65 years. Methods: This study analyzed 3862 older Koreans from the 8th Korea National Health and Nutrition Examination Survey data (2019–2021), excluding those with prior diabetes or medication. The participants were classified into normal and dysglycemia groups, based on fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c). Sex- and age-specific optimal cutoff values were determined using Youden’s Index (YI) and area under the curve (AUC). Results: For T2DM, the optimal HOMA-IR cutoff was 2.25 for men and 2.03 for women, with strong discriminative performance (AUCs: 0.828 and 0.823, respectively). Stratifying cutoff values further by sex and age improved the diagnostic accuracy (AUC > 0.83 in most subgroups), underscoring the value of tailored thresholds. For pre-DM, the HOMA-IR cutoff was 1.73 in men and 1.85 in women (AUCs: 0.682 and 0.665, respectively). Age- and sex-specific cutoffs modestly improved AUCs, particularly in men (up to 0.7), although the improvement was less consistent among women. HOMA-β showed no significant association with dysglycemia, and no meaningful cutoff values were identified. Conclusions: HOMA-IR is a promising marker for the early identification of dysglycemia in older adults when interpreted through a personalized lens. Applying sex- and age-specific cutoff values enhances diagnostic precision and supports a more individualized approach to metabolic risk assessment. Further longitudinal studies are warranted to validate these personalized thresholds and to optimize early detection strategies in diverse populations. Full article