Search Results (211)

Parkinson’s disease (PD), a debilitating neurodegenerative disorder, is primarily characterized by motor impairments and concurrent gastrointestinal disturbances. Increasing evidence has highlighted the critical role of the microbiota–gut–brain axis (MGBA) in the pathogenesis of PD. This study investigated the neuroprotective potential of sodium hyaluronate (SH) in a mouse model of PD and its underlying mechanisms via the MGBA. In the oral pre-treatment study, three doses (7.5, 15, and 30 mg/kg/day) were evaluated. The results showed that the high dose (SH-H, 30 mg/kg/day) significantly ameliorated motor disorders and gastrointestinal functional disorders. Therefore, SH-H was selected for subsequent mechanistic investigations. Mechanistically, SH-H restored gut microbiota homeostasis, increased fecal short-chain fatty acid (SCFA) levels, and improved the integrity of the intestinal and blood–brain barrier (BBB). Thus, SH reduced the transfer of lipopolysaccharide (LPS) from the intestine to serum and the substantia nigra (SN), suppressing activation of the LPS-TLR4/MyD88/NF-κB signaling pathway. These effects alleviated neuroinflammation, protected dopaminergic neurons, and reduced the aggregation of α-synuclein (α-syn). In summary, SH attenuated PD-related pathological changes by restoring gut microbiota homeostasis and modulating the MGBA, suggesting that SH may represent a potential therapeutic strategy for PD. Full article

Sleep staging based on PSG is largely confined to clinical settings, while home-based sleep monitoring often faces the challenges of insufficient unimodal information and missing modalities. Aiming to overcome these challenges, this paper proposes a unified multimodal model for sleep staging based on cardiopulmonary signals. First, a heterogeneous multi-scale feature encoder with long and short branches is adopted to adapt to the cross-modal heterogeneity of ECG and THX. It combines a Transformer encoder and a Dilated CNN to complete feature fusion and temporal modeling. Subsequently, the unified model adaptively handles flexible modality combinations by introducing global context via a modal feature alignment strategy, which is built upon a framework consisting of a bimodal global branch and unimodal dedicated branches. On the SHHS dataset, the proposed model achieved Cohen’s kappa coefficients of 0.7547, 0.7121, and 0.7305 for four-stage sleep classification under ECG+THX, ECG-only, and THX-only inputs, respectively, demonstrating consistent improvements over three separately trained individual models. Furthermore, the model exhibits robust generalization performance on the P2018 external dataset and across samples with different severity levels of SDB. This work establishes a reliable algorithmic baseline for unobtrusive, long-term home sleep monitoring with missing modalities. Full article

Maternal stress has been associated with altered embryonic and fetal development, yet the mechanisms by which stress hormones influence early developmental processes remain poorly understood. Early embryogenesis is particularly sensitive because it establishes the vertebrate body plan through tightly regulated events such as somitogenesis. Disruptions during this developmental window may therefore compromise normal morphogenesis and tissue organization. In the present study, we investigated whether elevated acute corticosterone exposure affects somite phenotype and Sonic hedgehog (SHH) signalling during early embryogenesis using the avian chick embryo model. Fertilized specific pathogen-free (SPF) chick eggs were incubated until Hamburger–Hamilton stage 12 (approximately 48 h of incubation) and subsequently injected with 15 µg corticosterone into the yolk sac to mimic acute high-stress conditions for 4 h. Macroscopic examination revealed increased inter-somitic distances between the first five visible pairs of somites in corticosterone-treated embryos compared with controls, suggesting altered somite organization. In addition, histological assessment indicated that corticosterone-treated embryos displayed occasional cells with morphological features consistent with cellular degeneration or cell death. Molecular analysis demonstrated significant downregulation of SHH and GLI1 expression, indicating potential impairment of the SHH signalling axis during somitogenesis. The expression of TGFβ4 was also reduced, whereas HIF2α expression was elevated. These findings suggest a possible association between stress-induced hypoxic responses and altered developmental signalling, warranting further investigation. To the best of our knowledge, this is among the first in vivo studies to examine the relationship between elevated corticosterone exposure and SHH-associated somite development during early embryogenesis. Full article

Cleft lip with or without cleft palate (CL/P) is one of the most common congenital craniofacial anomalies worldwide and presents significant functional, esthetic, and psychosocial challenges. Despite advances in multidisciplinary care and surgical reconstruction, complications such as impaired wound healing, scar formation, and growth disturbances warrant the development of novel regenerative and surgical strategies, which heavily rely on animal models at the pre-clinical stage. For the current narrative review, the literature search was performed by combining cleft phenotype terms with modeling-approach terms in six databases and was supplemented by manual review of reference lists from full-text articles. The included articles were summarized based on cleft type and the methods for cleft induction (chemically induced, genetically engineered, and surgically created). Particularly, chemical teratogens such as retinoic acid, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), corticosteroids, and 6-aminonicotinamide have been widely used to induce cleft phenotypes and elucidate environmental influences on palatogenesis, whereas genetic models have clarified the roles of key molecules and signaling pathways, including Sonic hedgehog (SHH), bone morphogenetic protein (BMP), and transforming growth factor-β (TGF-β), in the development of lip and palate. Meanwhile, the surgical models have focused on the alveolar cleft in skeletally mature animals for evaluating novel grafting materials. By comparing the strengths and limitations of existing models, this review highlights opportunities for improving experimental design and translational relevance in future cleft research. Overall, despite a wide range of CL/P animal models available, few replicate clinically relevant defect anatomy and the postnatal craniofacial deformation observed in CL/P patients, underscoring the need for the development of new models. Full article

Buds are continuously renewed sensory organs in which development, adult maintenance, and repair share overlapping molecular circuitry. During embryogenesis, WNT/β-catenin signaling promotes taste placode formation and placodal Shh expression, while SHH refines papilla spacing and restricts neighboring papilla formation. SOX2 functions as a taste-competence and progenitor maintenance factor. In adults, LGR5/LGR6–RSPO–WNT signaling sustains progenitor activity, and gustatory neurons are an important source of RSPO2; available genetic evidence is consistent with a neuron-derived contribution to the LGR5/LGR6 niche, and AAV-Cre-mediated neuron-specific ablation of Rspo2 in the petrosal ganglion led to near-complete loss of circumvallate taste buds. HH signaling from epithelial and neuronal sources further supports SOX2-dependent progenitor homeostasis. Lineage allocation is governed by transcriptional programs that include POU2F3/SKN-1a for sweet, umami, and bitter type II taste receptor cells, and ASCL1 with posterior-field NKX2-2 for type III presynaptic/sour cells. After denervation or irradiation, regeneration depends primarily on LGR5⁺/KRT14⁺ progenitors and may be supplemented, in specific injury contexts, by plasticity of a subset of K8-lineage taste receptor cells that acquire KRT14/SOX2/PCNA progenitor-like features. Key unresolved questions include the direct chromatin targets of taste lineage regulators (which remain to be defined by ChIP-seq in native taste progenitors), the identity of the type I cell selector, the contribution of dedifferentiation across injury models, and the degree to which mouse-derived networks are conserved in human taste biology. Full article

Tooth agenesis is a common developmental anomaly of the human dentition, ranging from hypodontia to oligodontia, yet its marked phenotypic variability remains insufficiently explained. This review synthesizes developmental and molecular evidence on epithelial–mesenchymal interactions during early odontogenesis and proposes a signaling-threshold framework for human tooth agenesis. We focus on the coordinated roles of Wnt/β-catenin, bone morphogenetic protein (BMP), fibroblast growth factor (FGF), and Sonic hedgehog (SHH) pathways and on recurrent disease-associated genes, including MSX1, PAX9, WNT10A, and AXIN2, as quantitative modulators of pathway activity rather than binary determinants of tooth identity. Within this framework, successful tooth initiation may depend on whether integrated signaling output exceeds a field-specific activation threshold within spatially graded developmental regions of the dental arch. Differences in signaling amplitude, duration, and transcriptional responsiveness may therefore account for distal tooth susceptibility, variable penetrance, arch asymmetry, and the broad clinical spectrum from mild hypodontia to severe oligodontia. By integrating molecular genetics with developmental field theory, this model provides a testable systems-level explanation for selective tooth absence and highlights priority directions for future functional and genotype–phenotype studies. Full article

Introduction: Rutin is a heterocyclic flavonol glycoside found in plants like apples, citrus fruits and buckwheat, with demonstrated anti-inflammatory properties. However, the molecular mechanisms underlying rutin’s direct effects on microglia, the main immune effector cells in the central nervous system, are not fully understood. The SHH/GLI-1 pathway is a neuronal repair pathway that modulates microglial activity and cell proliferation. Objective: For better compression of the rutin anti-inflammatory effects, this work evaluated the action of rutin on SHH/GLI-1 regulation. Methodology: For this, primary cultures of microglia from postnatal P0–2 days Wistar rats were stimulated with LPS (1 µg/mL) and/or treated with rutin (0.5–1 µM). Microglia morphology was characterized by immunofluorescence for Iba1. Gene expression of cytokines, inflammasome, glial-derived neurotrophic factors (GDNFs), and Sonic Hedgehog and family zinc finger-1 (SHH/GLI) were evaluated by real-time qPCR. Result: The results demonstrated that rutin inhibited the LPS-induced inflammatory response in microglia regulating negatively TNF-alpha, IL-6, and NLR family pyrin domain-containing 3 (NLRP3) mRNA expression. In addition, rutin increased GDNF and SHH-GLI-1 mRNA expression. Furthermore, conditioned medium from rutin-treated microglia showed a protective effect on PC-12 cells against LPS-induced cytotoxicity, reducing cell death as measured by the propidium iodide test and preserving cell morphology. Conclusions: This is the first evidence of the effect of rutin in SHH-GLI-1 signaling, contributing to the understanding of its pharmacological mechanisms and potentially revealing new molecular targets for treatment of neuroinflammatory diseases. Full article

Accurate automatic sleep staging remains challenging due to complex temporal dynamics, inter-subject variability, and the difficulty of effectively integrating heterogeneous physiological signals. Electroencephalogram (EEG) and electrooculogram (EOG) recordings provide complementary information for sleep analysis; however, most existing multimodal approaches rely on simple feature concatenation, which limits their ability to capture structured inter-modality relationships. This paper proposes MFSleepNet, a multimodal sleep staging framework that explicitly models interactions between EEG and EOG signals. The proposed system incorporates a multimodal feature fusion module to enable bidirectional information exchange between modality-specific representations, followed by a gated temporal-channel attention mechanism to adaptively emphasize informative temporal segments and signal channels, facilitating joint representation learning while preserving modality-specific characteristics. Experiments on three public datasets (Sleep-EDF, SHHS, and HSP) under an epoch-level cross-validation protocol show that MFSleepNet consistently outperforms representative single-modality and multimodal baseline methods in terms of overall accuracy, Cohen’s κ, and Macro-F1. Ablation studies further demonstrate the contribution of each functional module. Correlation analysis indicates stage-dependent variations in EEG–EOG relationships, while interaction-based experiments show that explicit feature interaction improves both joint and modality-specific representations. Grad-CAM visualizations provide interpretability of model decisions. External validation on unseen subjects reveals a noticeable performance drop, highlighting the challenges of inter-subject variability and the limited baseline generalization capability of the model. To address this, a lightweight subject-specific adaptation strategy is introduced, which improves performance using a small amount of labeled subject-specific data. Overall, the proposed framework provides an effective and interpretable solution for multimodal sleep staging while emphasizing the importance of structured inter-modality interaction and subject-adaptive modeling in practical applications. Full article

Medulloblastoma (MB) is the most frequent brain malignancy in children, frequently driven by deregulated Sonic Hedgehog (SHH) signaling. We previously identified the antidiabetic drug phenformin (Phen) as a potent Gli1 inhibitor that suppresses SHH-subtype MB growth. Despite its efficacy, systemic administration of Phen is limited by its potential to induce lactic acidosis, primarily through the suppression of hepatic gluconeogenesis. Here, we provide proof-of-concept that phospholipid (liposomes) and non-phospholipid (niosomes) vesicles (<200 nm) can be used to deliver phenformin selectively. Our results show that these vesicle-based delivery systems efficiently entrap Phen (around 50%) and release it into SHH MB cells, reducing proliferation and activating energy stress responses at higher doses. Furthermore, treated cells exhibit marked downregulation of SHH target genes Gli1 and Ptch1. In vivo, phenformin-loaded nanocarriers selectively increased drug accumulation in cerebellar tumors while minimizing systemic and hepatic exposure. Notably, niosomes demonstrated superior brain tumor targeting compared to free drug or liposome administration, as reflected by higher intratumoral concentrations of Phen compared to free drug or liposome administration. Consistent with this targeted delivery, we observed a substantial decline in intratumoral Gli1 and Ptch1 expression, confirming effective SHH pathway modulation. Together, these findings propose a promising nanotechnology-based method to improve phenformin therapeutic index in SHH MB by enhancing tumor specificity and reducing systemic toxicity. Full article

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with poor prognosis and limited therapeutic options. Although epigenetic dysregulation is a hallmark of HCC, rational combinatorial targeting strategies remain incompletely defined. Here, we identify cooperative oncogenic functions of the chromatin modifiers enhancer of zeste homolog 2 (EZH2) and lysine-specific demethylase 1 (LSD1) in HCC. Analysis of the TCGA-LIHC cohort revealed that co-elevated EZH2 and LSD1 expressions are significantly associated with reduced overall survival. Gene set enrichment analysis demonstrated enrichment of Sonic Hedgehog (SHH) signaling and stress-responsive transcriptional programs in tumors with high EZH2/LSD1 expression. Functionally, dual pharmacological inhibition of EZH2 (GSK126) and LSD1 (SP2509) suppressed HCC cell proliferation, induced G1-phase arrest, and enhanced apoptosis, as evidenced by increased caspase-3/7 activity and decreased pro-caspase levels. Dual inhibition also impaired migration, invasion, tumor sphere formation, and stemness-associated gene expression. Mechanistically, co-targeting disrupted SHH signaling through the suppression of GLI1 expression. Chromatin immunoprecipitation revealed reduced EZH2, LSD1, and STAT3 occupancy at the GLI1 promoter following dual inhibition, leading to the repression of GLI1 and its downstream targets. Collectively, these findings demonstrate that EZH2 and LSD1 cooperatively sustain GLI1-dependent SHH signaling in HCC, and that dual epigenetic inhibition represents a mechanistically defined therapeutic strategy. Full article

With the increasing demand for sleep health monitoring, automatic sleep staging using single-channel electroencephalogram (EEG) signals has become increasingly prominent due to its clinical practicality. Existing methods have achieved notable progress, but they often fail to adequately capture long-term temporal dependencies and struggle to characterize transition phases. We propose SleepLT, an automated sleep staging framework that integrates multi-scale wavelet decomposition (MWD) and multi-head latent Fourier attention (MLFA). The MLFA module incorporates Fourier analysis into self-attention mechanisms and employs a partially weight-sharing bottleneck to optimize Key/Value generation, effectively capturing sleep rhythms. Extensive experiments on SleepEDF-78 and SHHS datasets demonstrate strong and consistent performance, with Macro F1 improvements of 2.1–3.2% over the compared baselines. Visualizations confirm that SleepLT enhances inter-class discriminability between sleep stages, robustly detects salient waveforms, and effectively captures transitions through long-sequence modeling. These results indicate that SleepLT is effective for automatic sleep staging from single-channel EEG, particularly in improving the recognition of ambiguous transitional stages such as N1 and REM. Full article

Background/Objectives: Craniofacial malformations such as orofacial clefts affect ~1 in 700 births; 40–60% lack clear genetic etiology, and many exhibit asymmetry and variable expressivity unexplained by classical Sonic Hedgehog (SHH) morphogen gradient models. We investigated whether integrated molecular modules linking morphogen signaling with metabolic stress responses may better account for craniofacial developmental outcomes. Methods: Sequential UniProt gene set integration identified 186 candidate craniofacial regulators. STRING network analysis revealed modular architecture. Molecular docking profiled 17 compounds against SMO, CK1δ, PINK1, and TIE2 (control). Pathway reconstruction integrated the SHH–CK1δ–HIF1A–HEY1–PINK1 axis with in-silico-predicted CK1δ phosphorylation sites on SMO (S615, T593, S751), HIF1A (Ser247), and GLI1/2/3 transcription factors. A developmental decision tree mapped affinity profiles to node-specific phenotype hypotheses. Results: CK1δ and PINK1 emerged as candidate nodes coupling morphogen signaling with mitochondrial quality control. Cross-docking showed preferential binding to developmental kinases (CK1δ: −8.34 kcal/mol; PINK1: −8.80 kcal/mol) versus TIE2 control (−6.76 kcal/mol; p < 0.001). Pathway reconstruction suggested that CK1δ-mediated Ser247 phosphorylation of HIF1A disrupts ARNT dimerization, redirecting HIF1A toward ARNT-independent HEY1 induction and consequent PINK1 suppression. Based on computed profiles, node-specific associations were proposed as computational hypotheses: SMO perturbation → midline defects; CK1δ → facial asymmetry/clefting; PINK1 → mandibular hypoplasia. Multi-target compounds (e.g., purmorphamine, taladegib) generated composite phenotype predictions consistent with clinical complexity. Conclusions: This strictly in silico study identifies candidate integrated morphogenic modules whose multi-node perturbation may underlie anatomically specific craniofacial malformation patterns. Node–phenotype associations are prioritized computational hypotheses requiring experimental validation; if confirmed, the framework could inform developmental toxicity assessment, therapeutic design, and reclassification of idiopathic craniofacial anomalies. Full article

Tooth development or odontogenesis is a complex morphogenetic process that requires tightly regulated interactions between the oral epithelium and mesenchyme of neural crest origin. In this narrative review, we compile existing knowledge regarding gene regulatory networks and epigenetic factors throughout tooth development from initiation to eruption. Signaling between the epithelium and mesenchyme is mediated by four conserved pathways—Wnt/β-catenin, bone morphogenetic protein (BMP), fibroblast growth factor (FGF), and Sonic hedgehog (Shh)—which operate iteratively and interact through extensive crosstalk at each developmental stage. Transcription factors, such as PAX9, MSX1, PITX2, and LEF1, interpret these signals to control cell fate decisions and differentiation. Epigenetic modifications, including DNA methylation, histone modifications, and microRNA-mediated regulation, provide additional layers of control that fine-tune gene expression programs. Unlike existing reviews that address these regulatory mechanisms separately, here we integrate signaling pathways, transcription factor networks, epigenetic regulation, human genetic disorders, dental stem cell biology, and recent single-cell transcriptomic insights into a unified framework. We discuss opportunities to apply developmental biology knowledge towards regenerative dentistry goals, including iPSC-derived dental models and spatially resolved multi-omics approaches, while acknowledging the considerable gap between preclinical findings and clinical applications. Full article

The vertebrate respiratory system arose under evolutionary pressures that linked increasing atmospheric oxygen levels to the metabolic demands of mitochondria. This transition—from ancestral gill-based exchange to the highly alveolated mammalian lung—was accompanied by the emergence of a hormonal regulatory axis centered on the glucocorticoid receptor alpha (GRα). Over time, GRα became deeply integrated into the architecture and function of the respiratory system, aligning pulmonary performance with organismal homeostasis across different developmental stages, environmental challenges, and disease states. This review combines evolutionary, embryological, and molecular evidence to explain how GRα shapes respiratory structure and function. We trace the evolution from ancient oxygen-sensing systems to mammalian alveoli and endothelial adaptations, demonstrating how conserved developmental pathways (including WNT, FGF, BMP, and SHH) are repurposed during both organogenesis and repair. Genetic models show that GRα is essential for preparing the lung for postnatal life, coordinating the reciprocal signaling between mesenchyme and epithelium that drives branching, septation, extracellular matrix organization, and the development of functional alveolar units. In the mature lung, GRα maintains the stability of the alveolar–capillary interface and coordinates immune, vascular, and metabolic functions to support efficient gas exchange. Its actions also extend to red blood cell biology and the regulation of stress erythropoiesis, linking pulmonary oxygen management with systemic oxygen delivery. Mechanistically, GRα interacts with circadian and hypoxia pathways and activates mitochondrial programs that enhance energy production and redox homeostasis during stress. By integrating these regulatory layers across developmental and physiological contexts, this review reframes GRα not simply as a stress-response receptor but as a non-redundant system-level integrator of respiratory homeostasis. Understanding this layered control not only explains the benefits of antenatal corticosteroids but also highlights the therapeutic value of phase-specific, precision modulation of the GC–GRα axis—along with strategies that support GC–GR signaling—to reestablishing and maintaining homeostasis in acute and chronic pulmonary disorders. Full article

Non-invasive electrocardiogram (ECG) and respiratory signals are easy to acquire via low-cost sensors, making them promising alternatives for sleep staging. However, existing methods using these signals often yield insufficient accuracy. To address this challenge, we incrementally optimized the sleep staging model by designing a structured experimental workflow: we first preprocessed respiratory and ECG signals, then extracted fused features using an enhanced feature selection technique, which not only reduces redundant features, but also significantly improves the class discriminability of features. The resulting fused features serve as a reliable feature subset for the classifier. In the meantime, we proposed a hybrid optimization algorithm that integrates the snake optimization algorithm (SO) and ant colony optimization algorithm (ACO) for automated hyperparameter optimization of support vector machines (SVMs). Experiments were conducted using two PSG-derived public datasets, the Sleep Heart Health Study (SHHS) and MIT-BIH Polysomnography Database (MIT-BPD), to evaluate the classification performance of multimodal features compared with single-modal features. Results demonstrate that the bimodal staging using SHHS multimodal signals significantly outperformed single-modal ECG-based methods, and the overall accuracy of the SHHS dataset was improved by 12%. The SVM model optimized using the hybrid Snake–ACO algorithm achieved an average accuracy of 89.6% for wake versus sleep classification on the SHHS dataset, representing a 5.1% improvement over traditional grid search methods. Under the subject-independent partitioning experiment, the wake versus sleep classification task maintained good stability with only a 1.8% reduction in accuracy. This study provides novel insights for non-invasive sleep monitoring and clinical decision support. Full article