Search Results (583)

Pediatric asthma is a multifactorial and heterogeneous disease determined by the dynamic interplay of genetic susceptibility, environmental exposures, and immune dysregulation. Recent advances have highlighted the pivotal role of epigenetic mechanisms, in particular, DNA methylation, histone modifications, and non-coding RNAs, in the regulation of inflammatory pathways contributing to asthma phenotypes and endotypes. This review examines the role of respiratory viruses such as respiratory syncytial virus (RSV), rhinovirus (RV), and other bacterial and fungal infections that are mediators of infection-induced epithelial inflammation that drive epithelial homeostatic imbalance and induce persistent epigenetic alterations. These alterations lead to immune dysregulation, remodeling of the airways, and resistance to corticosteroids. A focused analysis of T2-high and T2-low asthma endotypes highlights unique epigenetic landscapes directing cytokines and cellular recruitment and thereby supports phenotype-specific aspects of disease pathogenesis. Additionally, this review also considers the role of miRNAs in the control of post-transcriptional networks that are pivotal in asthma exacerbation and the severity of the disease. We discuss novel and emerging epigenetic therapies, such as DNA methyltransferase inhibitors, histone deacetylase inhibitors, miRNA-based treatments, and immunomodulatory probiotics, that are in preclinical or early clinical development and may support precision medicine in asthma. Collectively, the current findings highlight the translational relevance of including pathogen-related biomarkers and epigenomic data for stratifying pediatric asthma patients and for the personalization of therapeutic regimens. Epigenetic dysregulation has emerged as a novel and potentially transformative approach for mitigating chronic inflammation and long-term morbidity in children with asthma. Full article

The induction of type I interferon (IFN) via intracellular nucleic acid sensors may be useful in preventing viral infections. However, little is known about the effect of natural plant materials on sensor responses. We previously found that cardamom (Elettaria cardamomum (L.) Maton) seed extract (CSWE) enhanced type I IFN expression and prevented influenza virus infection. In this study, we investigated the effect of CSWE on type I IFN responses using intracellular nucleic acid sensor molecules. Human lung epithelial A549 cells were treated with CSWE and transfected with poly(dA:dT) or poly(I:C) using lipofection. CSWE and 1,8-cineole, the major CSWE components, dose-dependently induced type I IFNs and IFN-stimulated genes in both poly(dA:dT)- and poly(I:C)-transfected A549 cells. The type I IFN-enhancing effect of CSWE was dependent on the stimulator of interferon genes (STING), whereas the effect of 1,8-cineole was independent of STING and mediated by the down-regulation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly-ADP-ribose polymerase expression. Our study suggests that CSWE has the potential to act as a beneficial antiviral agent by enhancing homeostatic type I IFN production. Full article

Croatian agricultural legislation acknowledges the significance of radionuclides as pollutants in agricultural lands; however, it lacks specific thresholds or reference values for contamination levels, in contrast to other contaminants. This absence highlights the necessity for a comprehensive assessment of radionuclides across various agricultural systems in Croatia. This study investigates the transfer of radionuclides ¹³⁷Cs and ⁴⁰K from soil to agricultural crops throughout Croatia and estimates the consequent annual ingestion dose for the population. The samples collected comprised food crops and animal feed, with corresponding soil samples analyzed to calculate transfer factors. Activity concentrations of ¹³⁷Cs exhibited regional and crop-type variability, reflecting the uneven distribution of fallout and differing soil properties. Transfer factors were found to range from 0.003 to 0.06 for ¹³⁷Cs and from 0.15 to 3.1 for ⁴⁰K, with the highest uptake occurring in kidney beans. The total estimated annual effective ingestion dose was calculated to be a maximum of 0.748 mSv/year for children aged 2–7, predominantly attributable to ⁴⁰K. Given the homeostatic regulation of potassium in the human body, the dose associated with ¹³⁷Cs poses a more significant radiological concern. These findings underscore the need for radionuclide-specific agricultural legislation in Croatia and offer a baseline for recommending reference values and informing future regulations regarding agricultural soil contamination. Full article

Background: Crystalline glucosamine sulfate (cGS) claims to be a stabilized form of glucosamine sulfate with a defined crystalline structure intended to enhance chemical stability. It is proposed to offer pharmacokinetic advantages over regular glucosamine sulfate (rGS) which is stabilized with potassium or sodium chloride. However, comparative human bioavailability data are limited. Since both forms dissociate in gastric fluid into constituent ions, the impact of cGS formulation on absorption remains uncertain. This pilot study aimed to compare the bioavailability of cGS and rGS using a randomized, double-blind, crossover design. Methods: Ten healthy adults received a single 1500 mg oral dose of either cGS or rGS with a 7-day washout between interventions. Capillary blood samples were collected over 24 h. Glucosamine and its metabolite concentrations were quantified by Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS), and pharmacokinetic parameters—including maximum concentration (C_max), time to reach C_max (T_max), and area under the curve (AUC)—were calculated. Results: Mean AUC_0–24, C_max, T_max, and T_½ values for glucosamine and glucosamine-6-sulfate (GlcN-6-S) were comparable between cGS and rGS. Although the AUC_0–24 for glucosamine was modestly higher with rGS (18,300 ng·h/mL) than with cGS (12,900 ng·h/mL), the difference was not statistically significant (p = 0.136). GlcN-6-S exposure was also similar between formulations (rGS: 50,700 ng·h/mL; cGS: 50,600 ng·h/mL), with a geometric mean ratio of 1.39, a delayed T_max (6–8 h) and longer half-life, consistent with its role as a downstream metabolite. N-acetylglucosamine levels remained stable, indicating potential homeostatic regulation. Conclusions: This pilot study found no significant pharmacokinetic advantage of cGS over rGS. These preliminary findings challenge claims of cGS’ pharmacokinetic superiority, although the small sample size limits definitive conclusions. Larger, adequately powered studies are needed to confirm these results. Full article

The insular cortex has emerged as a key region implicated in a wide array of cognitive, emotional, and sensory processes. The anterior part of the insula (AIC) is central to emotional awareness, decision-making, and interoception, while the posterior insula (PIC) is more associated with somatosensory processing. The insula acts as a functional hub within the salience network and integrates homeostatic, affective, and cognitive information; thus, its role in different mental disorders seems to be prominent. Altered structure and connectivity of the insular cortex are evident in several psychiatric conditions. In schizophrenia, reductions in insular volume—especially on the left—correlate with hallucinations, emotional dysregulation, and cognitive deficits. Bipolar and major depressive disorders exhibit AIC volume loss and aberrant connectivity patterns linked to impaired affect regulation and interoceptive awareness. Anxiety disorders show functional hyperactivity of the insula, especially in response to fear-inducing stimuli, though findings on structural changes are mixed. Overall, growing evidence underscores the insular cortex’s central role in psychiatric pathophysiology and highlights its potential as a target for future diagnostic and therapeutic strategies. Full article

Background/Objectives: Gut-derived tryptophan (Trp) metabolites play important roles in metabolic and cardiovascular regulation. Although animal studies suggest their protective effects against metabolic dysfunction, data in adolescents, particularly those with obesity, remain limited. The objective of this study was to evaluate associations between circulating gut-derived Trp metabolites and markers of cardiometabolic, vascular, and platelet health in adolescents with obesity. Methods: Data were analyzed from 28 adolescents (ages 13–18; mean BMI = 36 ± 6.4 kg/m²). Fasting blood was collected to assess lipid profiles using a clinical analyzer and insulin resistance using the homeostatic model assessment for insulin resistance (HOMA-IR). Gut-derived Trp metabolites were measured by UPLC–mass spectrometry, peak oxygen uptake (VO_{2 peak}) by gas exchange during an incremental cycle ergometer test, and body composition by dual-energy X-ray absorptiometry. Platelet spare respiratory capacity (SRC), endothelial function, and liver fat were measured using high-resolution respirometry, flow-mediated dilation (FMD) of the brachial artery, and magnetic resonance imaging respectively. Results: Indole-3-propionic acid was inversely associated with diastolic blood pressure (rho = −0.39, p = 0.047), total cholesterol (rho = −0.55, p = 0.002), and LDL-C (rho = −0.57, p = 0.0014), independent of sex and obesity severity. Indoxyl sulfate was positively correlated with fasting glucose (rho = 0.47, p = 0.012), and adolescents with impaired fasting glucose had 1.6-fold higher IS levels. Indole-3-acetaldehyde declined with age (rho = −0.50, p = 0.007), and Indole-3-acetic acid and indole were higher in Hispanics vs. non-Hispanics. No significant associations were observed between Trp metabolites and FMD, VO₂ peak, or SRC. Conclusions: Gut-derived Trp metabolites, particularly indole-3-propionic and indoxyl sulfate, are associated with markers of cardiometabolic risk in adolescents with obesity. These findings support their potential relevance in early-onset cardiovascular disease risk. Full article

Background/objectives: The interplay between genetic factors and nutritional patterns is critical in understanding metabolic health. This analysis evaluated the potential reciprocal relationships between the TNF-α -308 G/A gene polymorphism, the Composite Dietary Antioxidant Index (CDAI), and insulin-related variables in Spanish adults with obesity. Methods: A cross-sectional analysis was conducted in 292 adults with obesity. Anthropometric, biochemical, and dietary variables were assessed. TNF-α -308 G/A genotyping was performed. Associations and potential interactions between CDAI and genotype on insulin and homeostatic model assessment for insulin resistance (HOMA-IR) were examined using multivariate regression and two-way ANOVA. Results: Higher CDAI scores were significantly associated with lower insulin levels (p < 0.001) and HOMA-IR (p < 0.001), regardless of genotype. Carriers of the A allele (GA/AA) showed a non-significant trend toward higher insulin levels (p = 0.087) and a steeper decrease in insulin levels with increasing CDAI, with a significant interaction observed between TNF-α genotype and CDAI (interaction p = 0.003). Multivariate analyses confirmed that CDAI and TNF-α genotype were independently associated with insulin and HOMA-IR levels. However, interaction terms were not consistently significant across all models. Conclusions: These findings emphasize the potential of antioxidant-rich diets to help modulate the influence of pro-inflammatory genotypes on insulin resistance, highlighting the relevance of integrating genetic and dietary factors in managing obesity-related metabolic risks. Further studies are warranted to confirm these preliminary findings and to better understand the mechanisms underlying gene–diet interactions in metabolic regulation. Full article

Galectin-3 (Gal-3) is a β-galactoside-binding lectin that mediates diverse signaling events in multiple cell types, including immune cells. It is also a prognostic indicator for multiple clinically important disorders, including cardiovascular disease. Gal-3 binds to cell surface glycans to form lattices that modulate surface receptor signaling and internalization. However, the tissue-specific regulation of Gal-3 surface expression remains poorly understood. Here, we review evidence for the involvement of Gal-3 in cell surface signaling, intranuclear events, and intracellular trafficking. Our focus will be on the O-GlcNAc modification as a regulator of Gal-3 biosynthesis, non-canonical secretion, and recycling. We argue that the nutrient-driven cytoplasmic hexosamine biosynthetic pathway (HBP) and endomembrane transport mechanisms generate unique pools of nucleotide sugars. The differing levels of nucleotide sugars in the cytosol, endoplasmic reticulum (ER), and Golgi apparatus generate differential thresholds for the responsiveness of O-GlcNAc cycling, N- and O-linked glycan synthesis/branching, and glycolipid synthesis. By regulating Gal-3 synthesis and non-canonical secretion, O-GlcNAc cycling may serve as a nexus constraining Gal-3 cell surface expression and lattice formation. This homeostatic feedback mechanism would be critical under conditions where extensive glycan synthesis and branching in the endomembrane system and on the cell surface are maintained by elevated hexosamine synthesis. Thus, O-GlcNAc cycling and Gal-3 synergize to regulate Gal-3 secretion and influence cellular signaling. In humans, Gal-3 serves as an early-stage prognostic indicator for heart disease, kidney disease, viral infection, autoimmune disease, and neurodegenerative disorders. Since O-GlcNAc cycling has also been linked to these pathologic states, exploring the interconnections between O-GlcNAc cycling and Gal-3 expression and synthesis is likely to emerge as an exciting area of research. Full article

Amyotrophic lateral sclerosis (ALS) is a progressive disease that degeneratively damages both upper and lower motor neurons, eventually resulting in muscular paralysis and death. Although ALS is broad in scope and commonly thought of as a motor neuron disease, more active research sheds light on the that role skeletal muscle plays in the development and progression of the disease. Muscle tissue in ALS patients and in animal models demonstrates severe regenerative deficits, including impaired myogenesis and impaired myoblast fusion. In ALS, muscle stem cells, known as satellite cells, show poor performance in activation, proliferation, and differentiation and thus contribute to ALS muscle wasting. Moreover, the pathological tissue environment that inhibits myoblast fusion is made up of proinflammatory cytokines, oxidative stress, and a lack of trophic signals from the neuromuscular junction, which greatly disrupts homeostatic regulation. It is likely that skeletal muscle is instead a dynamic player, fueling neuromuscular degeneration as opposed to a passive responder to denervation. One must appreciate the cellular and molecular changes that complicate muscle regeneration in ALS for effective treatment to be developed, permitting simultaneous interventions with both muscle and neurons. Full article

Increasing evidence reveals that the deregulation of cellular antioxidant response with advancing age, resulting in the continuing amplification of oxidative stress-induced inflammatory response, is a pre-eminent cause for the onset of aging-related disease states, including blinding diseases. However, several safeguards, like an antioxidant defense system, are genetically in place to maintain redox homeostasis. Nonetheless, if the homeostatic capacity of such systems fails (like in aging), an inflammatory pathway elicited by excessive oxidative stress-evoked aberrant NLRP3 (NOD, LRR- and pyrin domain-containing protein 3) inflammasome activation can become pathogenic and lead to disease states. Among all known inflammasomes, NLRP3 is the most studied and acts as an intracellular sensor to detect danger(s). Upon activation, NLRP3 recruits apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization and facilitates the recruitment of activated Caspase-1 (Cas-1), which results in the release of inflammatory cytokines, IL-1β and IL-18 and the activation of GasderminD, an executor of pyroptosis. NLRP3 inflammasome is tightly regulated in favor of cell health. However, when and how the activation of NLRP3 and its inflammatory components goes awry, leading to cellular derangement, and what regulatory factors are involved in the normal physiological and aging/oxidative conditions will be included in this review. Also, we address the latest findings to highlight the connection between oxidative stress, antioxidants, and NLRP3 activation as this begets aging diseases and explore the cellular pathways that are in place to regulate oxidative-induced inflammations and the pathobiological consequences of dysregulated inflammatory responses and vice versa. Full article

Background/Objectives: The prevalence of childhood obesity has recently increased, particularly during the COVID-19 pandemic, owing to lifestyle changes as a result of public health regulations and guidelines introduced by governments worldwide. The aim of our study was to evaluate the impact of novel e-Health applications in addressing childhood obesity prior to and during the COVID-19 pandemic. Methods: The study was conducted as part of the four-year European project BigO (Horizon2020, No.727688). A total of 86 children and adolescents with overweight and obesity (mean age ± standard error of the mean: 11.82 ± 0.25 years; 49 males, 37 females; 31 prepubertal, 55 pubertal) were studied prospectively for 1 year prior to the pandemic (non-COVID-19 group, n = 50) and during the pandemic (COVID-19 group, n = 36). Based on the body mass index (BMI), subjects were classified as having morbid obesity (n = 40, 46,51%) obesity (n = 21, 24.42%), overweight (n = 22, 25.58%), and normal ΒΜΙ (n = 3, 3.49%) according to the International Obesity Task Force cut-off points. The data collection system utilized the BigO technology platform, which connects to a smartphone and smartwatch to objectively record each patient’s diet, sleep, and physical activity. Participants used the BigO system continuously for 4 weeks and wore the smartwatch for specific periods during the week. Subsequently, they entered a personalized, multidisciplinary lifestyle intervention program for 4 months and used the system again for 4 weeks. Results: The key finding was a significantly higher improvement rate in BMI category among children and adolescents during the COVID-19 pandemic (58.3%) compared to before the pandemic (36%). Both groups showed significant reductions in BMI, BMI z-score, insulin resistance indices (homeostatic model assessment and quantitative insulin sensitivity check index), blood pressure, gamma-glutamyl transferase, and insulin concentrations, alongside increases in high-density lipoprotein cholesterol (p < 0.01). Notably, the COVID-19 group experienced a significantly greater reduction in BMI z-score at 12 months compared to the non-COVID-19 group (p < 0.05). Conclusions: Our results reveal that the COVID-19 group demonstrated better compliance with lifestyle interventions and experienced more significant improvements in cardiometabolic risk factors. This suggests that the innovative e-Health applications were successful in managing childhood obesity despite the challenges caused by the COVID-19 pandemic. Full article

Aluminum (Al) is one of the most abundant metals on Earth and is well known as an environmental neurotoxic agent in the pathogenesis of Alzheimer’s disease. Aluminum toxicity is associated with oxidative stress, reduction of antioxidant enzymes, and disruption of the balance of cellular metals, such as iron (Fe), calcium (Ca), and copper (Cu), which causes structural and functional changes in the nervous tissue of the brain or peripheral nervous system. The intake of functional foods, rich in antioxidants, such as quercetin, may be beneficial in combating oxidative stress and neurodegenerative changes in the brain. The aim of this study was to provide deeper insight into the cellular and molecular neuroprotective effects of quercetin in regulating amyloid-beta (Aβ) accumulation, tau pathology, and neuroinflammation in the Al/D-galactose-induced rat model (Al/D-gal) of AD. The results showed that quercetin successfully modulated the impaired homeostatic and neuropathological consequences of aluminum chloride and D-galactose administration over 28 days: it directly protected neurons by regulating the level of oxidative stress and antioxidants, reduced Aβ aggregation by inhibiting the activity of acetylcholinesterase (AChE), increased the survival, growth, and differentiation of nerve cells by maintaining the level of brain-derived neurotrophic factor (BDNF), and regulated microglial immunoreactivity and neuroinflammation by reducing the level of proinflammatory cytokines. The multiple effects confirm that quercetin can be applied as an alternative non-pharmaceutical approach in reducing Al-induced neurotoxicity and maintaining adaptive homeostasis, which consequently affects the functioning of the central nervous system and the whole organism. Full article

Mulberry (Morus alba) twigs and leaves, rich in flavonoids, polyphenols, polysaccharides, and alkaloids with multi-target regulatory properties on glucose/lipid metabolism, were evaluated for their anti-obesity effects using methanol-extracted twigs (MTE) and aqueous-extracted leaves (MLE) in high-fat diet (HFD)-induced obese mice. Both extracts significantly ameliorated obesity-related metabolic dysregulation, as evidenced by attenuated body weight gain, visceral fat accumulation, serum lipid profiles, homeostatic model assessment of insulin resistance (HOMA-IR), and hepatic inflammation compared to HFD controls (p < 0.05). Concurrently, MTE and MLE enhanced systemic antioxidant capacity and elevated high-density lipoprotein cholesterol (HDL-C) levels. Notably, high-dose MTE (MTEH, 1000 mg/kg) markedly reduced perirenal adiposity while increasing brown adipose tissue mass (p < 0.05). Mechanistic investigations revealed that MTEH reshaped gut microbiota composition by suppressing Firmicutes and Enterococcus, while enriching beneficial Faecalibaculum and Bifidobacterium spp. (p < 0.05). Furthermore, cecal short-chain fatty acid (SCFA) profiling demonstrated MTEH and MLEH-mediated metabolic reprogramming, characterized by increased propionic acid and decreased butyric acid, suggesting microbiota-dependent modulation of host energy metabolism. These findings collectively highlight the potential of mulberry extracts as multi-targeted nutraceuticals for obesity intervention via gut microbiota–SCFA axis regulation. Full article

Retinal homeostasis and degeneration are significant contributors to global vision loss, with retinal health primarily assessed by the count and function of photoreceptor cells, the most abundant cells in the retina. Genomic studies have identified topoisomerase II beta (Top2b), an enzyme that untangles DNA supercoils to facilitate gene expression, as a critical transcriptional regulator for retinal health. This review aims to uncover and categorize genes linked to Top2b that are dynamically expressed during retinal degeneration, revealing shared and overlooked regulatory pathways. RNA sequencing data from wild-type and Top2b knockout mice revealed thousands of differentially expressed genes regulated by Top2b. By cross-referencing these genes with retinal degeneration datasets, including RetNet and the Gene Ontology Browser, we identified 44 Top2b-linked genes associated with retinal degeneration. These genes were grouped into fourteen functional categories: ciliary function and trafficking, metabolism, synaptic transmission, transcription factors and regulation, visual cycle, retinoids, and more. Key genes such as Bbs7, Ubb, Rbp4, Cetn2, Pik3r1, and Crx were explored, and their critical pathways for retinal health were outlined. This comprehensive catalog of 44 Top2b-linked retinal homeostatic genes will serve as a valuable resource for researchers. It provides new insights into the regulatory mechanisms underlying retinal homeostasis, setting the framework for the development of targeted therapeutic approaches and early intervention strategies for preventing photoreceptor loss. Full article

Heat stress (HS), an important environmental stressor for healthy poultry farming, has been shown to have a detrimental effect on production performance and induce serious diseases through immune system damage. As the avian peripheral immune system’s primary organ, spleen is subject to complex biological processes in response to HS injury. Histopathological characterization demonstrated that HS resulted in the destruction of the splenic red and white medulla, a decrease in cell density and organ atrophy. These changes directly impaired pathogen clearance and immune surveillance. At the physiological level, the impact of HS is characterized by disrupted metabolic homeostasis through interrupting neuroendocrine function. This, in turn, results in a significant suppression of humoral immune response. The oxidative-inflammatory cascade constitutes the core pathology of this disease. Energy metabolism disorder triggered by mitochondrial dysfunction and redox imbalance form a vicious circle, which promotes apoptosis signaling cascade. Meanwhile, over-activation of intrinsic immune system triggers a series of inflammatory factors, which further amplifies effects of tissue damage. The present prevention and control strategies are centered on synergistic anti-inflammatory and antioxidant interventions with nutrient modulators and plant actives. Nevertheless, it is imperative for future studies to incorporate multi-omics technologies in order to analyze the metabolic mechanisms and patterns of stress and establish a precise intervention strategy based on immune homeostatic regulation. This review systematically investigated the multilevel regulatory mechanisms of HS-induced spleen injury, which provides a theoretical basis for the mechanistic analysis and technological innovation of the prevention and control of HS syndrome in poultry. Full article