Search Results (30,229)

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impaired social interaction, communication deficits, and repetitive behaviors. Recent research highlights the role of the gut microbiota in ASD pathophysiology, particularly through the microbiota–gut–brain axis. The microbiota may influence neurodevelopment via multiple signaling pathways, including the GABAergic and serotonergic systems, as well as the mTOR signaling pathway. This analytical review examines current evidence on microbiota alterations in ASD and evaluates microbiota-targeted strategies for diagnosis and treatment, focusing on fecal microbiota transplantation (FMT), probiotics, and diet-based therapeutic approaches. The review also provides a critical appraisal of the microbiota–gut–brain axis in the context of autism spectrum disorder. Full article

Ionizing radiation induces reactive oxygen species (ROS) and inflammatory signaling that contribute to both therapeutic efficacy and normal tissue toxicity. While the effects of high-dose radiation are well characterized, responses to low-dose-rate radiation (LDRR) remain inconsistent and are not adequately explained by conventional linear dose–response models. To address this gap, we conducted a narrative review of recent experimental studies across multiple biological systems, including body fluids, joint microenvironments, and reproductive tissues, focusing on redox and immune-related responses under LDRR conditions (dose rates: 0.39–3.49 mGy/h). Literature was identified through PubMed/MEDLINE, Web of Science, and Google Scholar, with emphasis on studies published between 2015 and 2026. These studies demonstrate that LDRR elicits nonlinear, dose-dependent effects that vary across biological compartments and involve coordinated changes in oxidative stress, immune signaling, and metabolic regulation. Based on this synthesis, we propose a unifying framework of nonlinear redox–immune coupling, in which oxidative stress functions as a threshold-dependent regulator and immune responses follow a biphasic trajectory characterized by activation at lower dose rates and attenuation or adaptation at higher levels. These responses are strongly influenced by the local microenvironment, resulting in compartment-specific variability. This integrated perspective supports a shift from dose-centric to systems-level interpretations of radiation biology and provides a basis for improving biomarker development, risk assessment, and therapeutic strategies in chronic low-dose radiation exposure settings. Future research priorities include time-resolved mechanistic studies to define compartment-specific redox thresholds, validation of candidate biomarkers under identical multi-compartment experimental conditions (e.g., GSH/GSSG ratio, 8-OHdG, circulating cytokine panels including IL-10/TNF-α ratio), and integration of subject-specific biological variables (e.g., age, sex, and baseline redox capacity) into predictive models of LDRR response. Full article

Clonal hematopoiesis of indeterminate potential (CHIP) and the gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) are both linked to NLRP3-mediated cardiovascular inflammation, but their interaction has not previously been explored. This work proposes the CHIDT axis (clonal hematopoiesis–dysbiosis–TMAO), a feed-forward mechanism in which TET2 loss-of-function CHIP- and TMAO-generating Gram-negative gut dysbiosis mutually enhance cardiovascular risk. The model proceeds in three nodes. CHIP-associated intestinal immune dysregulation promotes luminal expansion of Gammaproteobacteria, which produce both trimethylamine via CntA/CntB-mediated L-carnitine oxidation and ADP-heptose as an obligate LPS biosynthetic intermediate. TMAO amplifies NLRP3 inflammasome activation through the SIRT3 → SOD2 → mtROS pathway. The evidence base of the CHIDT model is strongest for TET2-CHIP; the proposed extension to DNMT3A-CHIP rests on indirect, associative data and requires dedicated experimental confirmation before it can be considered established. TXNIP cascade, with predicted disproportionate potency in macrophages epigenetically primed by TET2 haploinsufficiency. High concentrations of TMAO have also been shown to suppress TET2 expression in endothelial cells through CYTB promoter hypermethylation, inducing NLRP3–GSDMD-dependent pyroptosis, although it remains unclear whether physiological TMAO levels can trigger this effect. Concurrently, ADP-heptose activates the ALPK1–TIFA–NF-κB pathway in bone marrow progenitors, favoring the expansion of mutant hematopoietic stem and progenitor cells. The model identifies three potential therapeutic strategies: NLRP3 inhibition, microbial TMA lyase inhibition, and microbiome-targeted reduction in Gram-negative bacteria. None has been tested in CHIP carriers stratified by plasma TMAO. Further studies in preclinical models and human cohorts integrating CHIP genotyping and TMAO quantification are needed to validate the CHIDT axis as a target for precision cardiovascular prevention. Full article

Background: Appropriateness of diagnostic test prescriptions represents a critical component of quality care in pediatric allergology, directly influencing diagnostic accuracy, therapeutic decisions, healthcare resource utilization, and patient outcomes. A multidisciplinary expert panel was convened to develop evidence-based clinical recommendations addressing the appropriate use of specialist consultations and diagnostic investigations in children with asthma, allergic rhinoconjunctivitis, and vernal keratoconjunctivitis (VKC). Methods: Clinical questions were formulated using the PICO framework and prioritized through structured expert consensus. Systematic literature reviews were conducted across major databases, and the certainty of evidence was assessed using the GRADE methodology. Results: Specialist evaluation emerged as a key determinant of improved diagnostic precision, optimization of treatment strategies, and reduction of inappropriate therapies. In asthma, spirometry, FeNO measurement, and allergy testing contributed to enhanced diagnostic accuracy and better control. In allergic rhinoconjunctivitis, allergological assessment supported diagnosis and the selection of immunotherapy, with demonstrated benefits on symptoms and quality of life. For VKC, multidisciplinary specialist involvement facilitated early diagnosis, personalized management, and prevention of complications. Conclusions: Although the overall certainty of evidence ranged from moderate to low, consistent clinical benefits supported consensus-based recommendations. Implementation of these recommendations may improve care quality, promote equitable access to diagnostic resources, and reduce unnecessary healthcare utilization. Full article

Background: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and remains associated with poor prognosis despite multimodal treatment. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation and redox imbalance, has recently emerged as a potential therapeutic vulnerability in glioma. This review summarizes current knowledge on the molecular regulation of ferroptosis in glioma and discusses its implications for tumor progression, therapeutic resistance, and translational targeting. Methods: A structured narrative review of the literature was conducted using PubMed/MEDLINE, Scopus, and Web of Science databases. Experimental, translational, and clinically relevant studies investigating ferroptosis-related mechanisms and therapeutic strategies in glioma and GBM were qualitatively analyzed. Results: Ferroptosis in glioma is regulated by interconnected pathways involving iron metabolism, phospholipid remodeling, oxidative stress, and antioxidant defense systems, particularly the SLC7A11–glutathione–GPX4 axis. Additional protective mechanisms mediated by FSP1 and DHODH, together with regulatory networks involving NRF2, ATF4, p53, and hypoxia-related signaling, contribute to adaptive resistance to ferroptosis. Increasing evidence indicates that ferroptosis interacts bidirectionally with the glioma tumor microenvironment and may exert both antitumor and immunosuppressive effects. Preclinical studies further suggest that ferroptosis induction may enhance the efficacy of temozolomide, radiotherapy, and immunotherapy, although clinical translation remains limited by tumor heterogeneity, blood–brain barrier penetration, and resistance mechanisms. Conclusions: Ferroptosis represents a biologically plausible and therapeutically promising target in glioma. Improved understanding of ferroptosis regulation, tumor microenvironment interactions, and biomarker-guided therapeutic strategies may support the future development of more effective treatments for GBM. Full article

Autoimmune and immune-mediated inflammatory diseases (IMIDs) develop when genetically and environmentally susceptible hosts lose stable immune tolerance. The gut ecosystem is increasingly recognized as a biologically active interface in this process. Its bacterial, fungal, and viral components may shape mucosal and systemic immunity through antigenic stimulation, barrier regulation, and metabolite-dependent signaling, although the strength of evidence is uneven: bacteriome data are currently the most mature, whereas mycobiome, virome, and phageome findings remain more disease-specific and emerging. Dysbiosis may influence autoimmunity through overlapping routes, including epithelial barrier failure, altered short-chain fatty acid, bile acid, and tryptophan metabolism, molecular mimicry, and cross-kingdom microbial interactions. Nutrition is central to this network because dietary substrates determine microbial growth, metabolic output, epithelial integrity, and immune-cell differentiation. In this narrative review, we integrate evidence on disease-associated bacteriome, mycobiome, and virome patterns in systemic autoimmune diseases, with emphasis on rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis, spondyloarthritis, vasculitides, and idiopathic inflammatory myopathies. COVID-19 is considered not as a proven causal driver of autoimmunity, but as an example of an environmental and infectious insult capable of perturbing microbiome–barrier–immune communication. Finally, we discuss diet-based and microbiome-targeted approaches, including probiotics, prebiotics, synbiotics, and postbiotics, as adjunctive strategies that may help restore microbial resilience and immune balance. A better understanding of the diet–microbiome–host immunity axis may support more personalized preventive and therapeutic concepts in autoimmune disease. Full article

Background and Clinical Significance: Carcinoid heart disease (CHD) is an uncommon valvular manifestation of neuroendocrine tumours, usually affecting right-sided cardiac valves. Left-sided involvement is rare and is generally associated with bronchopulmonary carcinoid, right-to-left shunting, or markedly elevated circulating vasoactive substances. Therapeutic decision-making is particularly challenging in advanced disease when severe tricuspid regurgitation occurs in patients at prohibitive surgical risk. Case Presentation: We report the case of a 61-year-old male patient with progressive dyspnoea, abdominal distension, lower-limb oedema, facial flushing, and 15 kg of unintentional weight loss. Transthoracic and transoesophageal echocardiography demonstrated torrential tricuspid regurgitation caused by thickened, retracted, and immobile leaflets, with additional mitral and aortic valve involvement, raising strong suspicion of CHD. An agitated-saline contrast study demonstrated delayed right-to-left shunting without patent foramen ovale, suggesting an extracardiac, likely intrapulmonary, shunt. Somatostatin receptor PET/CT identified a pancreatic lesion with metastatic disease, and bone marrow biopsy confirmed neuroendocrine tumour infiltration. Owing to prohibitive surgical risk, as reflected by a Tricuspid Regurgitation Impact Score (TRI-SCORE) with an estimated in-hospital mortality of 65%, unfavourable tricuspid anatomy for repair, and refractory venous congestion, heterotopic bicaval valve implantation was performed (TricValve system -P&F). Discussion: This case highlights the role of echocardiography in recognising the characteristic phenotype of CHD, detecting occult right-to-left shunting, and supporting selection of a palliative transcatheter intervention. It also illustrates the value of a multimodality diagnostic strategy integrating echocardiography, functional oncological imaging, and histopathology in tumour-related cardiac disease. Conclusions: In selected inoperable patients with advanced carcinoid-related tricuspid regurgitation, heterotopic bicaval valve implantation may represent a feasible strategy for reducing venous congestion and improving functional status. Full article

Acute exacerbation of interstitial lung disease (AE-ILD) represents sudden, severe deterioration in patients with pre-existing ILD and is associated with high morbidity and mortality. Our work presents a case series of AE-ILD in patients with idiopathic pulmonary fibrosis (IPF), idiopathic non-specific interstitial pneumonia (iNSIP), and connective tissue disease-associated ILD (CTD-ILD) managed at our institution and provides a narrative review of AE-ILD. Across cases, AE-ILD manifested as rapid progression of dyspnea and extensive ground-glass opacities (GGOs) on imaging, often triggered by infections or immune-mediated processes. Despite treatment, all cases were fatal, confirming that mortality remains high in AE-ILD. In our literature review, we focus on dysregulated innate immunity, an altered microbiome, potential microaspiration, surgical procedures, and autoantibody-mediated inflammation as triggers, as well as the risk factors for and prevalence of AE-ILD. We also examine pharmacological and non-pharmacological interventions, with particular emphasis on the role of antifibrotic agents as a key protective factor. Evidence for and against corticosteroid use in AE-IPF and non-IPF AE-ILD is discussed, highlighting the radically different treatment approach for AE in melanoma differentiation-associated gene 5 (MDA5)-positive dermatomyositis (DM)-associated ILD compared to AE-IPF. Our findings underscore the heterogeneous presentation and poor prognosis of AE-ILD, emphasizing the urgent need for standardized diagnostic criteria, risk stratification, and prospective studies with larger cohorts to establish evidence-based therapeutic strategies. Full article

Neuroinflammation is a key hallmark of both neurodegenerative and neurospecific autoimmune diseases, including multiple sclerosis (MS), where immune dysregulation contributes to cellular stress, autophagy, and disease progression in Alzheimer’s disease (AD), Parkinson’s disease (PD), and MS. Emerging evidence suggests a shared mechanism behind MS, AD, and PD, driven by chronic interaction between the peripheral immune system and the central nervous system (CNS). While MS was traditionally viewed as a primary autoimmune condition, recent research indicated that all three disorders involve a breakdown of the blood–brain barrier (BBB). This structural failure enables peripheral immune cells and cytokines to enter the brain, causing sustained neuroinflammation and accelerating disease progression. Here, we propose an end-to-end framework for identification of the diagnostic and therapeutic cell-specific protein markers commonly regulated in mild–moderate AD (MMAD), early-stage PD (ESPD), and MS within peripheral blood mononuclear cells (PBMCs). PBMC markers were first identified based on shared differential protein expression, followed by filtering for BBB permeability. Subsequently, sorted cell markers were mapped to disease-specific neural cell types. Our analysis suggests that PBMC-derived cells, including astrocyte- and monocyte-like populations, share overlapping transcriptional signatures and functional similarity with macrophages and neuroglial cells, indicating potential transcriptional similarity or functional convergence. Furthermore, intra- and inter-cellular pathway analysis suggested both shared and disease-specific signaling mechanisms, with kinase–integrin interactions emerging as key regulatory factors. Selected potential seed markers, primarily kinases and immunoglobulins, were further analyzed through evolutionary sequence–structure space to identify druggable structural features. Next, protein moonlighting possibilities were tested to enhance the temporal functional trajectory of the markers for precise therapeutic impact. Hence, the framework provides a robust strategy to identify immune-based disease-specificcandidate diagnostic andpotential therapeutic targets. Full article

Head and neck cancer (HNC), particularly oral squamous cell carcinoma (OSCC), remains a major clinical challenge due to its aggressive behavior, high recurrence rates, and frequent resistance to conventional therapies. Natural compounds, especially curcumin and its derivatives, have gained increasing attention as potential anticancer agents due to their ability to target multiple molecular pathways involved in tumor progression. This review critically evaluates the current preclinical and translational evidence supporting curcumin and its derivatives as monotherapeutic agents in HNC, with particular emphasis on oral cancer. We integrate the available evidence to assess the biological rationale, therapeutic potential, and current limitations of curcumin-based approaches. The molecular mechanisms underlying their antitumor activity are discussed, including modulation of EGFR/ERK and PI3K/Akt signaling pathways, inhibition of NF-κB and STAT3 activation, induction of apoptosis, regulation of oxidative stress, and suppression of epithelial–mesenchymal transition and tumor invasiveness. In addition, we address the impact of curcumin on the tumor microenvironment and its role in overcoming intrinsic cellular resistance mechanisms. The review also highlights advances in drug delivery strategies, such as nanoformulations, that are designed to improve curcumin’s bioavailability and therapeutic efficacy. By critically integrating current evidence, this review highlights both the promise and the challenges associated with curcumin-based monotherapy in HNC, emphasizing the need for more robust and clinically relevant studies to support future translation. Full article

Hepatocellular carcinoma is challenging to detect at an early stage, and its severity increases over time. Recently, the incidence of hepatocellular carcinoma has increased, partly due to lifestyle-related factors such as excessive alcohol intake, sedentary behavior, and diets high in fat, which contribute to the growing prevalence of fatty liver and hepatitis. Various therapeutic strategies are being explored for hepatocellular carcinoma, among which therapies targeting deubiquitinating enzymes (DUBs) have attracted growing attention. Ubiquitination acts as a crucial modulator in the regulation of intracellular signaling across many diseases. E3 ligase recognizes the target protein and transfers ubiquitin, received from the E2 enzyme, to the lysine residues of the substrate, thereby conferring specificity to the ubiquitination process. Once a ubiquitin chain is attached to a target protein by an E3 ligase, the protein is directed to the ubiquitin–proteasome system (UPS) for degradation. In this process, the 26S proteasome complex recognizes the ubiquitin chain and degrades the target protein, thereby serving as a major mechanism for maintaining protein homeostasis. Through this pathway, cells regulate signal transduction, eliminate abnormal proteins, and perform various essential functions. On the other hand, deubiquitinating enzymes (DUBs) recognize the ubiquitin chains on target proteins and remove them by hydrolyzing the isopeptide bonds of ubiquitin, thereby enabling the target proteins to evade degradation by the proteasome system. Furthermore, deubiquitinating enzymes independently remove ubiquitin from proteins and can serve as central regulators in signaling pathways related to hepatocellular carcinoma. Full article

The digestive system is one of the most complex systems in the body, integrating multiple functions, closely linked to and influenced by chemosensory mechanisms, as well as by the presence, composition, and dynamics of the microbiome. Increasing attention has been directed toward plant-derived foods and medicines, which interact with gut microbiota and modulate host physiological responses through microbial metabolism, leading to the formation of bioactive metabolites that influence host signaling pathways and therapeutic response. The review, based on relevant articles from major international databases using specific terms with a focus on microbiome-mediated interactions and molecular mechanisms, highlights the role of microbiome and diagnostic methods through the analysis of specific composition and changes in microbiota, as well as the importance of microbiomes in relation to the treatment of chronic diseases, given their complex influence on drug metabolism. The microbiome influences the response to medications and resistance to therapy, being also involved in the metabolism of plant-derived foods and medicines through complex microbial interactions, while the importance of modern diagnostic approaches supports the use of microbiome analysis to improve diagnosis, monitoring, and personalized medical strategies. Full article

Non-thermal millimeter-wave (MMW) irradiation represents a promising non-invasive strategy for cancer therapy, yet its effects in physiologically relevant 3D systems remain poorly defined. Here, we evaluated the biological impact of MMW exposure in 3D non-small-cell lung cancer (NSCLC) spheroids (NCI-H1299, A549) and normal WI-38 fibroblasts under active cooling to suppress bulk heating. We demonstrate that cellular responses are governed primarily by power density (PD), irradiation geometry, and genotype-dependent susceptibility. High-PD pyramidal horn (PH) irradiation (~4.9 mW/cm²) induced rapid apoptosis, metabolic collapse, and near-complete loss of clonogenic survival, whereas lower-PD waveguide (WG) irradiation (~0.6 mW/cm²) produced depth-limited, cumulative cytotoxicity. Surviving cancer cells exhibited robust senescence-associated growth arrest, particularly in p53-deficient NCI-H1299 cells, indicating a dual apoptotic–senescent anti-proliferative response. In contrast, WI-38 fibroblasts showed minimal apoptosis and only transient stress-associated senescence, confirming selective tumor vulnerability. Mechanistic modeling suggests that MMW energy couples to glycan-rich membrane domains, generating localized electromagnetic hotspots that trigger calcium influx, mitochondrial dysfunction, and depth-dependent apoptosis. These findings establish a mechanistic basis for selective, non-thermal MMW-induced cytotoxicity in 3D NSCLC models and support further preclinical development of MMW-based therapeutic strategies. Full article

Early rectal cancer represents a challenging setting in which accurate locoregional staging is essential to guide appropriate treatment. Current diagnostic strategies primarily include magnetic resonance imaging (MRI) and endoscopic ultrasound (EUS). However, both modalities show significant limitations in early-stage disease, particularly in T staging. This diagnostic gap impacts therapeutic decision-making, particularly in patients with lesions suggestive of deep submucosal invasion. In these cases, endoscopic submucosal dissection (ESD) may be insufficient to achieve adequate vertical negative margins, whereas radical surgery is associated with considerable morbidity and potential impairment of quality of life. In this gray zone, endoscopic intermuscular dissection (EID) has recently emerged as a novel therapeutic approach designed to overcome the limitations of standard endoscopic resection. By enabling dissection within the deeper intermuscular plane, it can achieve curative resections while preserving rectal wall integrity. This narrative review aims to explore the current diagnostic gaps in early rectal cancer and to define the potential role of EID within the current therapeutic algorithm. Full article

This review aims to evaluate the potential of endometriosis models, especially patient-derived iPSC models, to gain deeper insights into the disease, thereby advancing our understanding and treatment of endometriosis. This comprehensive narrative review utilized a structured search of the PubMed, Scopus, and Web of Science databases, primarily covering literature published between January 2000 and May 2025. An expansive search strategy was employed to capture the full breadth of the field using keywords such as “endometriosis,” “induced pluripotent stem cells (iPSCs),” “patient-derived organoids,” “disease modeling,” and “epigenetics” without restrictive filtering, ensuring the integration of both foundational theories and emerging biotechnological advances. In total, over 170 peer-reviewed publications were analyzed, ranging from landmark genomic meta-analyses that have identified significant risk loci to state-of-the-art 3D-culture systems for modeling patient-specific endometrial disease. By synthesizing these diverse sources, the review bridges the gap between traditional anatomical classifications and modern molecular modeling to evaluate the potential of iPSC platforms for personalized medicine and therapeutic discovery. Endometriosis is a multifactorial gynecological condition that affects 176 million women worldwide and can significantly impair quality of life. It occurs when endometrium-like tissue grows outside the uterus, responsive to ovarian hormones, causing inflammation, pain, and discomfort, and leading to fibrotic tissue. World Health Organization estimates indicate that 6–10% of women suffer from this disorder, which can cause infertility and increase the risk of developing various types of cancer and autoimmune disorders. The use of patient-derived iPSC models serves to gain deeper insights into the disease by mimicking the endometrial tissue or lesions observed in affected individuals, thereby advancing our understanding and treatment of endometriosis. Full article