Search Results (5,180)

The Hippo–Yorkie (Yki) signaling pathway is a conserved regulator of tissue growth, and its dysregulation leads to excessive growth and tumorigenesis. Although several microRNAs (miRNAs) have been implicated in Hippo pathway regulation, how they modulate Yki activity in vivo remains incompletely understood. Here, we identify miR-137 as a suppressor of Yki-driven overgrowth in a Drosophila model. A functional miRNA screen revealed that miR-137 overexpression markedly suppresses Yki-induced eye overgrowth, whereas inhibition of miR-137 enhances eye overgrowth phenotypes. Through bioinformatic prediction and genetic screening, we identified Drep1 as a candidate downstream factor associated with miR-137 function. RNAi-mediated depletion of Drep1 phenocopies the suppressive effects of miR-137, whereas Drep1 overexpression enhances Yki-driven tissue overgrowth and proliferation. Consistent with these phenotypes, miR-137 overexpression or Drep1 depletion reduces the expression of canonical Yki target genes, including Diap1 and Expanded, indicating decreased Yki transcriptional output. Importantly, Drep1 knockdown was associated with reduced Yki immunostaining in a complementary wing-disk context, suggesting a potential link between Drep1 and Yki-associated signaling. Consistent with this, miR-137 also reduced the expression of ICAD, the mammalian homolog of Drep1, providing preliminary evidence that miR-137 may regulate ICAD expression in mammalian cells. Together, these findings support a potential regulatory relationship between miR-137 and Drep1 that modulates Yki-driven eye overgrowth and reveal an additional layer of Hippo pathway regulation in vivo. Full article

Atopic dermatitis (AD) is a chronic inflammatory dermatosis driven by skin barrier impairment and immune dysregulation. This study aimed to investigate the anti-inflammatory and barrier-related effects of the ethanol extract of Bidens bipinnata L. fruits (EEBB) in a calcipotriol (MC903)-induced AD-like dermatitis mouse model and lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. In vivo, repeated topical application of EEBB (60, 180, and 600 μg/day) significantly attenuated MC903-induced AD-like clinical symptoms, skin weight, and erythema index. Notably, EEBB significantly improved skin hydration-related parameters, including relative skin hydration readings and the post-application moisture retention profile, and partially restored filaggrin and loricrin expression in lesional skin, whereas dexamethasone showed limited effects on these hydration-related parameters under the present conditions. Histopathologically, EEBB ameliorated epidermal lesions and reduced inflammatory cell infiltration. Mechanistically, EEBB suppressed the levels of pro-inflammatory (TNF-α, IFN-γ) and Th2 (IL-4, IL-5) cytokines in lesional skin. In vitro, EEBB significantly inhibited the production of nitric oxide (NO) and prostaglandin E₂ (PGE₂), and downregulated inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression in RAW 264.7 cells. These effects were associated with inhibited phosphorylation of JNK and p38 MAPK, with no marked effect on ERK phosphorylation under the present conditions. In conclusion, EEBB effectively alleviated AD-like dermatitis, accompanied by improved skin hydration and restoration of barrier-related protein expression, attenuation of local inflammatory responses, and targeted inhibition of the MAPK signaling pathway. Full article

Chronic liver disease (CLD) constitutes a major global health burden, with high morbidity and mortality, limited treatment options for several etiologies, and an urgent need for novel therapeutic targets. Fibroblast growth factor 1 (FGF1) is a unique member of the FGF family capable of binding all four FGFR subtypes, thereby regulating multiple signaling pathways including PI3K/AKT, Ras/MAPK, and PLCγ, which are involved in metabolism, cell survival, proliferation, and tissue repair. Emerging evidence highlights the multifaceted and context-dependent roles of FGF1 in CLD. In drug-induced liver injury (DILI) caused by anti-tuberculosis drugs, acetaminophen, or doxorubicin, FGF1 confers protection by restoring bile acid homeostasis, reducing oxidative stress, inflammation, and apoptosis. In Metabolic dysfunction-associated steatotic liver disease (MASLD), FGF1 ameliorates hepatic steatosis, oxidative injury, and insulin resistance through downregulation of SREBP1, upregulation of PPARα, and activation of Nrf2-mediated antioxidant responses. Conversely, in primary sclerosing cholangitis (PSC), FGF1 aggravates ductular reaction, biliary senescence, and liver fibrosis via upregulation of SASP and TGF-β1, suggesting that inhibition of the FGF1/FGFR axis may be therapeutic. For alcohol-related liver disease (ALD), although direct experimental evidence is lacking, FGF1 is hypothesized to confer protection given its known activities against oxidative stress, lipid dysregulation, and cell death. Despite its promise, the mitogenic potential of FGF1 raises safety concerns; however, N-terminally modified FGF1 analogs (e.g., FGF1Δ) retain metabolic benefits with reduced proliferative activity. Collectively, FGF1 represents a versatile and disease-dependent regulator in CLD, warranting further mechanistic studies, safety evaluations, and development of targeted analogs as a novel therapeutic strategy for difficult-to-treat liver diseases. Full article

Oocyte formation occurs successfully within a meticulously controlled follicular environment characterized by well-documented endocrine, metabolic, and paracrine signals. Yet, the immunological landscape of the follicle and its role in influencing oocyte competency has received less attention in research. Growing research indicates that the ovarian follicle functions as an immunological-active niche necessitating a precise equilibrium between controlled inflammation and targeted immune tolerance. The programmed cell death-1 (PD-1) receptor and its ligand PD-L1 constitute a crucial immune checkpoint pathway, essential for sustaining peripheral immunological tolerance and averting excessive immune activation. Despite their comprehensive research in cancer biology and maternal–fetal interactions, their possible function in the follicular microenvironment remains mostly unexamined. We propose that PD-1/PD-L1 signaling may facilitate the formation of a localized immune-tolerant milieu inside the follicle to safeguard the developing oocyte from inflammatory injury and immune-mediated stress. The disturbance of this suggested equilibrium may lead to a pro-inflammatory follicular environment, compromised granulosa cell function, and modified oocyte maturation, hence affecting fertilization and embryonic developmental potential. In clinical contexts with immunological dysregulation, such as endometriosis, polycystic ovarian syndrome, and unexplained IVF failure, such processes may be especially significant. The purpose of this narrative review is to assimilate the current comprehension of immune regulation in the follicle with the established biology of PD-1/PD-L1 and to investigate a potential correlation between immune checkpoint signaling, oocyte competence, and assisted reproductive outcomes. Considering the follicle as an immune-regulated microenvironment offers a new paradigm for comprehending infertility and identifying novel indicators or therapeutic targets. Full article

Antibiotic-resistant bacteria are widely distributed and threaten public health. Photocatalytic antimicrobial technology can effectively inactivate multidrug-resistant bacteria without readily inducing resistance. We previously showed that oxygen-rich vacancy Bi₂MoO₆ (OBM) exhibits excellent activity against methicillin-resistant Staphylococcus aureus (MRSA), but the underlying molecular mechanisms remain poorly understood. Here, we employed integrated transcriptomics and metabolomics, with qRT-PCR validation, to systematically elucidate the antibacterial mechanism of OBM against MRSA. OBM treatment induced profound transcriptional and metabolic alterations: 231 differentially expressed genes and 206 differentially abundant metabolites were identified. Functional enrichment analysis revealed cooperative involvement in multiple critical pathways, including inhibition of amino acid biosynthesis and protein translation, disruption of cell wall and membrane integrity, induction of oxidative stress, collapse of energy metabolism (suppression of oxidative phosphorylation and impaired ATP synthesis), and imbalance in nucleotide metabolism (down-regulation of DNA helicase and mismatch repair genes, dysregulation of purine/pyrimidine metabolism). These findings demonstrate that OBM photocatalytically inactivates MRSA through a multi-target systemic attack at both the transcriptional and metabolic levels, providing a novel theoretical foundation for the development of photocatalytic materials aimed at controlling MRSA and other drug-resistant bacteria. Full article

Hepatic ischemia–reperfusion injury (HIRI) is a major cause of postoperative liver dysfunction and adverse outcomes in hepatectomy, liver transplantation, and hemorrhagic shock. Among the multiple mechanisms implicated in HIRI, mitochondria are recognized as central organelles that integrate metabolic failure, oxidative stress, inflammation, and cell death. During ischemia, interruption of oxygen and nutrient supply impairs oxidative phosphorylation, depletes ATP, disrupts ionic homeostasis, and renders mitochondria highly vulnerable to subsequent injury. Upon reperfusion, reoxygenation triggers excessive reactive oxygen species production, calcium overload, mitochondrial permeability transition pore opening, and release of damage-associated molecular patterns, thereby amplifying hepatocellular injury and sterile inflammatory responses. As a key component of mitochondrial quality control, mitophagy plays a context-dependent role in HIRI. Appropriate activation of mitophagy facilitates the clearance of damaged mitochondria, limits oxidative stress, restrains inflammasome activation, and preserves hepatocellular homeostasis, whereas insufficient or dysregulated mitophagy contributes to mitochondrial accumulation and aggravates liver injury. This review summarizes mitochondrial alterations during the ischemic and reperfusion phases, outlines the major mitophagy pathways involved in HIRI and discusses recent advances in upstream regulation, disease-specific dysregulation, and mitophagy-targeted interventions. A better understanding of the dynamic and biphasic nature of mitophagy in HIRI may provide a stronger theoretical basis for precision liver-protective strategies and future translational therapies. Full article

Premature coronary artery disease (PCAD) is a growing public health concern, especially in South Asia, where traditional risk factors fail to fully explain the increasing incidence of early-onset myocardial infarction. To explore its molecular underpinnings, we conducted a pilot study analyzing plasma proteins and lipids to identify potential biomarkers and dysregulated pathways associated with PCAD. Label-free quantitative proteomics revealed distinct molecular signatures separating PCAD patients from age- and sex-matched healthy controls. Key alterations included upregulation of GALE, immunoglobulin genes, and KIF20B, suggesting enhanced inflammatory responses and proliferative activity associated with post-myocardial infarction cellular repair. Similarly, down regulations of various proteins linked to multiple functions, such as myocardial infarction, hemoglobinopathy, complement and coagulation cascade, and fatty acid and lipoprotein transport in hepatocytes, were observed. Untargeted lipidomics further revealed significant elevations in several phosphatidylcholine species (PC 42:5, PC 40:3, and PC 42:7), highlighting disruption of highly unsaturated phospholipid metabolism. Overall, these findings indicate that PCAD is a multifactorial disorder involving metabolic, immune, and vascular dysfunction beyond conventional lipid abnormalities, underscoring the need for larger cohort studies to validate these biomarkers and uncover novel therapeutic targets. Full article

Background/Objectives: Non-small cell lung cancer (NSCLC) remains associated with high mortality, frequent late-stage diagnosis, biological heterogeneity, and recurrence after treatment. Although molecular and immunohistochemical biomarkers have transformed treatment selection, there remains a need for accessible, repeatable, and clinically practical circulating biomarkers that may support prognosis and post-treatment monitoring. This review discusses prolactin (PRL) as a candidate supplementary biomarker in NSCLC, with particular emphasis on its biological rationale, potential prognostic relevance, and possible role in personalized risk stratification after systemic therapy. Methods: This narrative review summarizes current evidence on established biomarkers in NSCLC, the physiology and regulation of PRL, PRL/PRLR signaling in cancer biology, mechanisms of PRL dysregulation in lung cancer, and available clinical observations concerning PRL alterations in NSCLC. Particular attention is given to the distinction between prognostic and predictive biomarkers, longitudinal monitoring, pituitary involvement, immune checkpoint inhibitor-related endocrine effects, and biological, pharmacological, and analytical confounders affecting PRL interpretation. Results: Current evidence suggests that PRL may be biologically relevant in NSCLC through its involvement in pathways related to cell proliferation, survival, angiogenesis, invasion, epithelial–mesenchymal transition, immune modulation, and possible therapy resistance. Clinical observations indicate that altered PRL levels may occur in advanced disease, pituitary involvement, systemic inflammation, stress, or during anticancer and supportive treatment. However, PRL lacks cancer specificity and is influenced by multiple confounders, including circadian rhythm, stress, endocrine disorders, macroprolactin, cachexia, medications, and assay variability. Available clinical data remain limited and are largely derived from small studies or case-based evidence. Conclusions: PRL should not currently be considered a standalone diagnostic, predictive, or treatment-selective biomarker in NSCLC. Its most realistic potential role is as a supplementary circulating marker within multimarker prognostic and monitoring models. Prospective validation with standardized sampling, assay procedures, and confounder adjustment is required before clinical implementation. Full article

Background/Objective: Bisphenol AF (BPAF), a fluorinated analogue of bisphenol A, is an environmental contaminant associated with hepatotoxicity and metabolic disruption. However, the systematic molecular mechanisms linking early transcriptional events to metabolic dysfunction in the liver remain poorly defined. The aim of this study is to elucidate the association between BPAF exposure and hepatic lipid accumulation by integrating transcriptomics, cellular metabolomics, and targeted phenotypic assays. Methods: We performed RNA-sequencing on livers from mice exposed to BPAF (0.1–10 mg/kg/day, 28 days), and performed non-targeted metabolomics on AML12 murine hepatocytes co-cultured with RAW264.7 macrophages in a Transwell system (0–2500 nM BPAF, 48 h). Key metabolic pathways were identified through integrated bioinformatics and validated using enzymatic assays, qRT-PCR, Western blotting, and phenotypic staining (lipid droplets, ROS). Results: Multi-omics integration revealed significant disruption of PPAR signaling and the tricarboxylic acid (TCA) cycle. A striking dose-dependent accumulation of succinate was observed in exposed cells, concomitant with a significant inhibition of succinate dehydrogenase (SDH) activity (52% reduction at 2500 nM, p < 0.001). Transcriptomic data confirmed the downregulation of mitochondrial fatty acid β-oxidation genes. Phenotypic validation indicated that BPAF exposure is associated with oxidative stress, pro-inflammatory cytokine release (TNF-α, IL-6), and pronounced intracellular lipid droplet accumulation in hepatocytes. Conclusions: This study suggests that BPAF exposure is associated with SDH dysfunction, TCA cycle arrest, and lipid dysregulation. Whether BPAF directly inhibits SDH or acts through upstream mitochondrial targets warrants further structural and kinetic investigation. Full article

Fear is a transdiagnostic construct implicated in multiple psychiatric disorders, reflecting a partial dissociation between clinical phenotypes and underlying neurobiological mechanisms. Converging evidence suggests that aberrant fear processing plays a central role in cognitive and psychopathological models of psychosis. In this narrative review, we synthesize evidence on the neurobiological mechanisms of aberrant fear modulation in schizophrenia from a translational perspective, integrating findings from neuroimaging, preclinical models, pharmacological interventions, and psychotherapy. Schizophrenia is characterized by aberrant emotional processing and inappropriate neural responses to stimuli with reduced or absent objective salience, reflecting impaired discrimination of relevant environmental information. At the system level, evidence implicates dysregulation of cortico-limbic and salience-processing networks in altered fear learning, threat appraisal, and emotional prediction. Neurochemical findings indicate that dopamine–glutamate dysregulation and associated intracellular signaling pathways act as upstream modulatory mechanisms contributing to these network-level abnormalities. Therapeutic interventions, including antipsychotic drugs and psychotherapeutic approaches, partially modulate these systems, although effects remain heterogeneous. Overall, the evidence supports a hierarchical model in which aberrant fear processing in schizophrenia arises from disrupted salience attribution and impaired integration across cognitive, affective, and neurobiological levels. This intermediate dysfunction links molecular alterations to large-scale network disturbances and clinical symptom expression, providing a framework for more mechanism-based therapeutic strategies. Full article

Inflammatory bowel diseases (IBD) are increasingly recognized as disorders in which epithelial dysfunction and maladaptive regeneration may be as important as immune dysregulation. Tumor necrosis factor (TNF), a key mediator of intestinal inflammation and a therapeutic target, plays a dual role in both immune activation and epithelial repair by regulating progenitor cell expansion, lineage plasticity, and chemokine signaling in the intestinal epithelium. During acute injury, TNF-associated responses are generally considered adaptive, supporting crypt repair, barrier restitution, and secretory remodeling pathways. However, in chronic disease, persistent TNF exposure, potentially reinforced by type I interferons (IFN-I), may contribute to the persistence of epithelial regenerative pathways. IFN-I signaling has been suggested in experimental and translational studies to reinforce chemokine networks and transcriptional imprinting. We propose that this potentially converts physiological repair into a sustained state of what we have termed “regenerative inflammation,” in which epithelial-derived signals may perpetuate immune recruitment and tissue remodeling. Such TNF-IFN-imprinted epithelial states may contribute to sustained pathology in a subset of patients and could be associated with reduced responsiveness to anti-TNF therapy, although direct causal evidence in human disease remains limited. By integrating mechanistic, organoid-based, and clinical observational evidence, we propose that chronic TNF–IFN crosstalk may contribute to a self-sustaining regenerative inflammatory circuit, providing a conceptual framework for disease persistence in IBD and highlighting potential opportunities to target epithelial-immune interactions. Full article

Background: Neutrophil dysregulation drives inflammatory pathologies through mechanisms such as matrix metalloproteinase-9 (MMP-9) release. High-value bioprospecting of agro-industrial residues offers a sustainable strategy to identify novel bioactive compounds. In this study, the immunomodulatory effects of seed oils (SOs) obtained via supercritical fluid extraction from Passiflora edulis and Rubus glaucus byproducts on human neutrophil responses was evaluated. Methods: SO lipid profiles were characterized via GC-MS. Human neutrophils were isolated using Percoll gradients and treated with the SOs (10–50 µg/mL). Cytocompatibility was assessed via MTT and trypan blue assays. MMP-9 activity and ERK1/2/p38 phosphorylation were determined via zymography and Western blotting, respectively. Results of GC-MS revealed matrices rich in unsaturated lipids: R. glaucus SO was dominated by linoleic (50.02%) and α-linolenic (29.84%) acids, whereas P. edulis SO contained linoleic (58.91%) and oleic (19.75%) acids. Both oils were highly biocompatible up to 50 µg/mL. Both SOs significantly increased MMP-9 release; notably, R. glaucus induced a dose-dependent response and a potential priming effect at 10 µg/mL. Interestingly, neither oil induced the phosphorylation of ERK1/2 or p38. Conclusions: Supercritical fluid-extracted SOs from P. edulis and R. glaucus byproducts modulate early neutrophil responses by increasing MMP-9 release through pathways independent of classical MAPK phosphorylation. Further functional and in vivo validation is needed to clarify the precise regulatory roles of these specialized lipid matrices in human inflammation resolution and their potential as bioactive ingredients for nutraceutical or pharmaceutical applications. Full article

Background: The glucocorticoid receptor NR3C1 exhibits antiepileptic properties, but the mechanisms governing its stability during epileptogenesis remain elusive. This study investigated whether the E3 ubiquitin ligase TRIM8 regulates neuronal hyperexcitability and epileptic activity by modulating NR3C1. Methods: We established an in vivo epilepsy model via intrahippocampal kainic acid (KA) injection and an in vitro epileptiform model using Mg²⁺-free artificial cerebrospinal fluid in primary hippocampal neurons. The roles of TRIM8 and NR3C1 were assessed using in vivo and in vitro gain- and loss-of-function approaches, alongside co-immunoprecipitation, Western blotting, immunofluorescence and whole-cell patch-clamp recording. Results: TRIM8 is significantly upregulated in hippocampal and temporal lobe neurons in epileptic mice. TRIM8 was markedly upregulated in the hippocampal neurons of epileptic mice, inversely correlating with NR3C1 levels. Mechanistically, TRIM8 interacted with NR3C1, promoting its polyubiquitination and proteasomal degradation. This TRIM8-mediated NR3C1 reduction enhanced the phosphorylation of AMPA receptor (AMPAR) subunits GluR1 (Ser831) and GluR2 (Ser880) without affecting total receptor expression. In vitro, TRIM8 overexpression exacerbated calcium dysregulation, neuronal injury, and AMPAR phosphorylation; crucially, concurrent NR3C1 overexpression rescued these effects. In vivo, knockdown of TRIM8 significantly reduced seizure frequency, prolonged the latency to the first Stage III seizure, shortened average seizure duration, and decreased total seizure burden in KA-induced epileptic mice. Electrophysiologically, TRIM8 overexpression significantly increased the frequency of spontaneous action potentials and amplitudes of spontaneous excitatory postsynaptic currents under Mg²⁺-free conditions. Furthermore, in vivo knockdown of TRIM8 attenuated KA-induced seizure severity, restored NR3C1 protein stability, and suppressed aberrant AMPAR phosphorylation in the hippocampus. Triple immunofluorescence staining showed that KA-induced epilepsy increased TRIM8 but decreased NR3C1 immunoreactivity in NeuN⁺ hippocampal neurons, and TRIM8 knockdown reversed these changes. Conclusions: TRIM8 acts as a critical driver of epileptiform activity by targeting NR3C1 for degradation, thereby disinhibiting AMPAR phosphorylation and enhancing network hyperexcitability. The TRIM8-NR3C1-AMPAR axis emerges as a previously unrecognized molecular pathway in epileptogenesis, highlighting its potential as a promising therapeutic target for epilepsy. Full article

Chiang Mai, Thailand, experiences seasonal fine particulate matter (PM_2.5) pollution associated with metabolic diseases, but the underlying mechanisms remain unclear. This prospective observational study compared plasma metabolomes of 25 healthy adults in Samoeng District, a highly affected area, between low and high PM_2.5 exposure seasons using proton nuclear magnetic resonance (¹H-NMR) spectroscopy. Twenty-six metabolites differentiating haze and non-haze seasons were identified using PLS-DA (VIP > 1.5). During the haze season, 11 were elevated, whereas 15 were decreased. Among the elevated metabolites, the top five—maleylacetoacetic acid, deoxyribose 5-phosphate, betaine, 3-hydroxyanthranilic acid, and 1-methyladenosine—were associated with inflammation, increased reactive oxygen species, nitric oxide inhibition, and altered amino acid metabolism. The top five decreased metabolites—deoxyguanosine, D-arabitol, glycerophosphocholine, ophthalmic acid, and oxaloacetic acid—were involved in several metabolic pathways, particularly those involved in energy metabolism. A total of 56 metabolic pathways were altered by high PM_2.5 exposure, including pathways related to amino acids, lipids, sugars, nucleotides, vitamins, and energy metabolism. High PM_2.5 exposure disrupts metabolites and pathways, inducing inflammation, oxidative stress, impaired lipid/energy metabolism, insulin resistance, and high blood pressure. These alterations may increase the risk of metabolic and cardiovascular diseases, with dysregulated metabolites serving as potential biomarkers. These findings highlight the molecular impact of air pollution in affected populations and may support preventive strategies and public health policy development in affected regions. Further studies are needed to clarify these findings. Full article

The respiratory system is directly exposed to various environmental factors, and specifically allergens and environmental pollutants, which are ligands/agonists of the aryl hydrocarbon receptor (AhR) and promote chronic lung diseases in humans. AhR, a ligand-activated transcription factor, is involved in the metabolism of xenobiotics, assigning their carcinogenic and toxic effects, and is also involved in normal homeostasis, organogenesis, and immune system function. Exogenous and endogenous AhR ligands are both high-molecular-weight compounds with a planar structure and low-molecular-weight compounds of diverse chemical structures. After entering the cell, the ligands bind to AhR and induce the activation of signaling cascades. The lung immune system responds to pathogens and environmental toxins first with a pro-inflammatory innate immune response, and then with an anti-inflammatory adaptive immune response. An imbalance between these immune systems may have an effect on the course of the disease. Activation of AhR by exogenous or endogenous ligands can affect this balance and lead to dysregulation of the immune response, leading to inflammatory complications in the lungs. Individual features of AhR expression or components of the AhR-dependent signaling pathway may also play a role in the superposition of the functions of these two links of immunity. This review summarizes advances in the comprehension of AhR’s role in immunomodulation and inflammatory responses in the lungs following data in experimental rodent models, in vitro studies utilizing lung structural cells and isolated immune cell lines, and humans. The molecular mechanisms of AhR’s regulation of immunity and inflammation and the potential of AhR as a therapeutic target for inflammatory lung disease are also considered. Full article