Search Results (575)

Background: Sleep disorders, particularly insomnia, represent a major public health concern, while currently available hypnotic drugs are often limited by adverse effects and poor long-term tolerability. Methods: In this study, we investigated the sleep-promoting effects of a mixture of Hypericum perforatum L. and Melissa officinalis L. extract (HME) and its underlying mechanisms in male ICR and C57BL/6 mice. In a pentobarbital-induced sleep model in mice, sleep onset latency and total sleep time were measured. Pharmacological studies using various antagonists and agonists were conducted to elucidate receptor-mediated mechanisms. Immunohistochemical and immunofluorescence analyses were performed to assess neuronal activity, and cortical mRNA expression was evaluated by quantitative analysis. HPLC analysis was used to identify the major constituents of HME, and their pharmacological profiles were functionally evaluated. Results: HME significantly reduced sleep onset latency and prolonged total sleep time. These hypnotic effects were shown to be mediated through adenosine and melatonin receptor signaling pathways. Immunohistochemical and immunofluorescence analyses showed that HME suppressed neuronal activity in wake-promoting cholinergic and orexinergic neurons of the basal forebrain and lateral hypothalamus, while enhancing activation of sleep-promoting GABAergic neurons in the ventrolateral preoptic nucleus. At the molecular level, HME increased cortical mRNA expression levels of adenosine A₁ receptor, adenosine A_2A receptor, melatonin receptor ₁, and melatonin receptor ₂. From the HPLC analysis, rosmarinic acid and hyperoside were identified as the major constituents of HME. Functional evaluation of these compounds revealed complementary pharmacological profiles, with hyperoside primarily acting through adenosine receptors and rosmarinic acid engaging both adenosine and melatonin receptor pathways. Conclusion: These findings suggest that HME enhances both sleep initiation and maintenance through adenosine and melatonin receptor signaling pathways, thereby supporting its potential as a multitarget therapeutic agent for improving sleep quality. Full article

Background: Uterine sarcomas are rare, heterogeneous malignancies with distinct pathological behaviors. This study aimed to identify clinicopathological characteristics, prognostic risk factors, and potential therapeutic targets to enhance clinical management. Methods: A retrospective analysis was conducted on 148 patients with uterine sarcoma treated at Peking University People’s Hospital between 1996 and 2025. Clinical outcomes, pathological subtypes, and immunohistochemical profiles were assessed. Additionally, bioinformatics analyses from RNA bulk sequencing of GEO datasets (GSE87581, GSE85383, GSE222045 and GSE64763) were performed to elucidate molecular characteristics across subtypes. Results: The most prevalent subtypes were uterine leiomyosarcoma (uLMS; 38.5%) and low-grade endometrial stromal sarcoma (LG-ESS; 29.7%). The 5-year recurrence rate was 50.5%, with frequent metastases to the pelvis and lungs. LG-ESS demonstrated the most favorable 5-year survival rate (90.3%), significantly higher than that of uLMS (61.8%) and undifferentiated uterine sarcoma (50.0%). Multivariate analysis identified histological subtype, stage, and coagulative necrosis as independent prognostic factors for overall and progression-free survival. Transcriptomic profiling revealed immunosuppression (CSF1R/CSF3R expression) in high-grade ESS, while uLMS exhibited activation of cell cycle and homologous recombination pathways. Conclusions: Histological subtype, stage, and coagulative necrosis were critical prognostic factors in uterine sarcoma. The findings suggest that vigilant pulmonary surveillance and further investigation into tailored therapeutic strategies may be warranted-including endocrine therapy for hormone-receptor-positive tumors, immunotherapy for high-grade ESS, and PARP inhibitors for uLMS. However, these hypotheses require thorough preclinical and clinical validation. Additionally, caution should be exercised to avoid overtreatment of chemotherapy in early-stage uLMS. Full article

COVID-19 remains a challenge to the global healthcare despite the end of the pandemic, including due to the significant involvement of children in the epidemic process. During the pandemic period, an increase in the incidence of Sudden Unexpected Infant Death (SUID) and Sudden Infant Death Syndrome (SIDS) was observed. Currently, their rates remain elevated compared to the prepandemic period. The pathogenetic mechanisms underlying the fulminant course of infection in infants leading to fatal outcomes remain insufficiently understood. In this study, we report for the first time the results of histological and immunohistochemical examination of the lungs in a case of COVID-19-associated SUID in a 2-month-old infant. The absence of similar studies in the available literature limits opportunities for analyzing the pathogenesis of SUID. Our data allow a detailed characterization of the histological changes in the lungs, the localization and range of SARS-CoV-2 nucleocapsid protein expression, the identification of molecular mechanisms underlying apoptosis in the pulmonary microvascular endothelium, and the elucidation of the role of endothelial dysfunction. Particular attention in this article is devoted to the role of cytokines (IL-6, TNF-α, and IFN-γ) in the pathogenesis of hyperacute viral infection. The obtained data demonstrate substantial differences between the observed changes and the classic presentation of COVID-19 in older children. These findings offer prospects for improving prevention strategies and developing targeted therapy for fulminant forms of COVID-19, while also contributing to the understanding of SIDS pathogenesis. Full article

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease characterized by heterogeneous phenotypes and endotypes, necessitating personalized therapeutic strategies. Precision medicine approaches integrating molecular biomarkers may improve treatment selection and disease stratification. In this prospective controlled study, we investigated the tissue-level immunohistochemical effects of oral corticosteroids (OCSs) and topical steroids on the expression of periostin, eotaxin, interleukin-4 (IL-4), transforming growth factor-β (TGF-β), and tumor necrosis factor-α (TNF-α) in nasal polyp tissue. Sixty-five patients eligible for endoscopic sinus surgery (ESS) were enrolled and divided into two groups: Group 1 (n = 42) received topical steroids combined with oral prednisone (40 mg/day for 7 days preoperatively), whereas Group 2 (n = 23) received topical steroids alone. Immunohistochemical analysis demonstrated a significant reduction in periostin and eotaxin expression in both epithelial and stromal compartments following OCS therapy, accompanied by increased TGF-β expression. No significant differences were observed in IL-4 or TNF-α expression. These findings indicate that short-term OCSs selectively modulate molecular pathways associated with eosinophilic inflammation and tissue remodeling in CRSwNP, supporting biomarker-driven precision medicine strategies. Full article

Cutaneous squamous cell carcinoma (cSCC) is a common malignant skin tumor with invasive potential and risk of recurrence. This study investigated the anti-cSCC effects of luteolin in vitro and in vivo and explored the associated molecular mechanisms. The effects of luteolin on A431 cell viability were assessed by CCK-8 assay, and apoptosis was analyzed by Annexin V-FITC/propidium iodide (PI) double staining. qRT-PCR and Western blot analyses were performed to evaluate apoptosis-related factors and the EGFR/PI3K/AKT signaling pathway. Molecular docking was further conducted to explore the potential interactions of luteolin with EGFR/PI3K/AKT signaling-related proteins and apoptosis-associated proteins. In vivo, a two-stage skin carcinogenesis model induced by 7,12-dimethylbenz[a]anthracene (DMBA) and croton oil was used to evaluate the antitumor activity of luteolin. Luteolin significantly inhibited A431 cell viability and promoted apoptosis in a concentration-dependent manner. Moreover, luteolin increased Bax expression and decreased Bcl-2 expression at both the mRNA and protein levels. Mechanistically, luteolin suppressed the phosphorylation of EGFR, PI3K, and AKT. Molecular docking suggested that luteolin could interact with EGFR, PIK3CA, AKT, Bax, and Bcl-2, providing supportive in silico evidence for its potential modulation of EGFR/PI3K/AKT signaling and apoptosis-related proteins. In vivo, luteolin alleviated body weight loss, achieved a tumor nodule inhibition rate of 45.28%, significantly improved spleen and thymus indices (p < 0.05), and ameliorated histopathological damage in skin tissues. In addition, immunohistochemical analysis showed that luteolin reduced Ki-67 expression. These results indicate that luteolin exerts anti-cSCC effects in vitro and in vivo, possibly through modulation of the EGFR/PI3K/AKT signaling pathway and apoptosis-related proteins. Full article

Background/Objectives: Atypical teratoid/rhabdoid tumor (AT/RT) is a rare and aggressive pediatric embryonal tumor of the central nervous system with marked histological and immunophenotypic heterogeneity, which can make diagnosis difficult in some cases. This study aimed to summarize the clinicopathological and molecular features of pediatric AT/RT and to evaluate an HE–IHC dual-path deep learning model as an auxiliary diagnostic approach. Methods: Clinical, histopathological, immunophenotypic, ultrastructural, and fluorescence in situ hybridization (FISH) data were retrospectively collected from 18 children with AT/RT treated at Beijing Children’s Hospital between February 2010 and April 2021. A total of 361 pathological images were used to train and test a ResNet50-based dual-path classification model with transfer learning and feature fusion. An additional independent test set of 175 histological and immunohistochemical images from six newly collected patients was used for supplementary validation. Results: The mean age at diagnosis was 2 years and 3 months. All cases showed loss of INI1 expression, positivity for CK and EMA, and a high Ki-67 index. FISH analysis identified SMARCB1 deletion in 7 of 15 tested cases. In the original image-based test set, the dual-path model achieved an accuracy of 90.91%, compared with 81.82% for the model without transfer learning, 86.36% for the single-path immunohistochemistry model, and 50.00% for the single-path histological model. In the additional independent test set, the trained model correctly classified all 175 images. Conclusions: Pediatric AT/RT shows diverse clinicopathological features and complex SMARCB1 alteration patterns. The HE–IHC dual-path model showed encouraging preliminary performance for auxiliary pathological assessment; however, larger multicenter cohorts with molecular subgroup annotation are needed for further validation before routine clinical application. Full article

Astrocytes play a crucial role in maintaining neuronal microenvironment homeostasis and regulating synaptic plasticity within the hippocampus. Magnoflorine (MGN), a naturally occurring isoquinoline alkaloid, has demonstrated biological activity in the central nervous system. However, its effects on astroglial cells remain poorly understood. The present study aimed to evaluate the impact of acute and chronic administration of MGN (10 and 20 mg/kg body weight) on the morphology and morphometric parameters of GFAP-positive astrocytes in the CA1 field of the mouse hippocampus. Immunohistochemical and morphometric analyses were performed in the oriens layer (SO), pyramidal layer (SP), radiate layer (SR), and lacunose-molecular layer (SLM). MGN significantly modulated astrocyte density, cell size, and the number of processes in a dose-, time-, and layer-dependent manner. A heterogeneous and layer-specific astroglial response was particularly evident following chronic administration of the tested compound. Together with the observed lack of significant differences in analysed parameters, decreases were mainly detected after administration of the low MGN dose, whereas the 20 mg/kg dose induced primarily increased structural complexity. Thus, the direction of changes was not uniform across all layers. The most prominent changes were detected in the SLM layer. Overall, MGN modulated astrocyte morphology and reactivity in a context-dependent manner. These findings indicate a modulatory influence of MGN on astroglial structural plasticity rather than a uniform directional effect. Although the observed changes may be associated with alterations in astroglia-mediated mechanisms involved in maintaining neuronal homeostasis and responses to stress, their functional significance requires further investigation. Full article

Prenatal exposure to ionizing radiation is a known risk factor for neurodevelopmental deficits; however, the molecular mechanisms linking chronic embryonic insult to abnormal brain development remain poorly understood. This study investigated the long-term consequences of chronic prenatal gamma irradiation throughout gestation in C57BL/6 mice. Behavioural analysis of adult offspring revealed a specific increase in depression-like behaviours, with no significant alterations in anxiety or general exploratory activity. Immunohistochemical assessment demonstrated a significant reduction in adult hippocampal neurogenesis, marked by decreased doublecortin (DCX)-positive newborn neurons in the subgranular zone and fewer NeuN-positive mature neurons in the dentate gyrus hilus. Integrated RNA-seq, qPCR, and Western blot analyses implicated the upregulation of the Mef2c/Egr1 signalling pathway in this neurogenic deficit. Furthermore, miRNA sequencing identified a pronounced decrease in miR-1843a-3p, which was subsequently validated to directly target Mef2c. Collectively, these findings suggest that prenatal gamma irradiation disrupts neurogenic processes and adult brain function, leading to specific behavioral abnormalities. This long-term impairment is associated with, and may be at least partially mediated by, dysregulation of the miR-1843a-3p/Mef2c/Egr1 pathway. Full article

Background: Leptin and adiponectin play a key role in obesity-associated malignancy, particularly in colorectal cancer (CRC). Immunohistochemical (IHC) evaluation of these adipokines may offer valuable prognostic insights in CRC. This study aimed to analyze global publication trends and summarize current knowledge on the potential of these hormones as IHC biomarkers in CRC. Methods: A problem-oriented bibliometric analysis, including publications from 2000 to 2025, was performed across the MEDLINE and Scopus databases. In parallel, a literature review was conducted to present the biological and clinical relevance of these adipokines in CRC. Results and Discussion: A total of 101 publications were identified. Scopus indexed substantially more studies than MEDLINE. The journals Cancer Research, Journal of BUON, Cells, BMC Cancer, and Asian Pacific Journal of Cancer Prevention were identified as the core journals publishing on this topic over the 25-year period. The leading countries were China and the USA. A review of the literature showed that adiponectin is a promising prognostic marker, while leptin appears to be a better indicator of disease progression. Conclusions: IHC research on leptin and adiponectin in CRC is a promising but still underexplored area. Their integration with routine molecular assessment has the potential to improve patient stratification. Full article

The overexpression of cyclin-dependent kinase inhibitor p16 (INK4a) is widely recognized as a surrogate marker for high-risk human papillomavirus (HPV) in anogenital malignancies, but its significance in invasive breast carcinoma is complex and remains frequently debated. While historically investigated as a viral proxy, emerging evidence suggests that elevated p16 levels in breast tissue may instead reflect intrinsic cell-cycle dysregulation and retinoblastoma (Rb) pathway disruption, though direct molecular confirmation is lacking in this area of research. This study aims to evaluate the role of p16 as an indicator of tumor aggressiveness for high-risk phenotypes. We conducted a retrospective study of 100 female patients with invasive breast carcinoma. Employing a purposive sampling strategy rather than a consecutive series, we analyzed a targeted cohort consisting predominantly of triple-negative breast cancer (TNBC) and high-grade tumors to evaluate biomarker patterns specifically in advanced disease contexts. Immunohistochemical assessment was performed using a standardized cumulative nuclear and cytoplasmic scoring system, with expression thresholds defined by receiver operating characteristic (ROC) curve analysis optimized for histological grade. p16 overexpression was a predominant characteristic of these aggressive tumors and was identified in 68% of cases. Statistical evaluation revealed a robust and significant correlation between p16 overexpression and the triple-negative molecular subtype, as well as a marked inverse relationship with estrogen receptor (ER) status. Although p16 levels were frequently associated with specific aggressive phenotypes, no statistically significant difference in overall survival was observed between expression groups, a finding attributable to the uniformly high-risk nature of the selected cohort. This study suggests an association between p16 expression levels and aggressive tumor features, although the study design limits causal inferences. A non-significant trend towards p16 overexpression was observed in ductal carcinomas compared to lobular subtypes, while high p16 expression was noted exclusively in G3 tumors within this selected cohort, a finding influenced by the purposive sampling strategy and the ROC-based cutoff definition. Tumor necrosis was more prevalent in p16-overexpressing tumors. Furthermore, p16 levels showed a strong inverse relationship with estrogen receptor (ER) status, as they were significantly elevated in ER-negative and triple-negative tumors compared to luminal phenotypes. Full article

Although sorafenib (SOR) is effective for advanced hepatocellular carcinoma (HCC), significant metabolic heterogeneity limits its therapeutic effect. In this study, we employed high-resolution matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) to profile the spatial lipidomic alterations in 3D HepG2 spheroids following SOR treatment. Interestingly, sphingophospholipid and glycerophospholipid metabolism played crucial roles. In an orthotopic HCC mouse model, immunohistochemical and immunofluorescence staining confirmed that SOR induced immunological and inflammatory changes. Moreover, transcriptomic and Q-PCR analyses showed increased expression of Stat1, Zbp1, Parp14, Irf1, and Tifa along with decreased Eif4e2 in the SOR treatment group compared to the tumor control group. Bio-layer interferometry and molecular docking data also indicated that ZBP1 possessed favorable binding affinities with SOR. Overall, our findings demonstrated that SOR dramatically disrupted sphingolipid metabolism in tumor cell spheroids and, in an orthotopic model, activated the NOD-like receptor signaling pathway, accompanied by altered secretion of inflammatory factors and macrophage polarization. These results suggest that SOR exerts dual effects on tumor cell lipid metabolism and the tumor immune microenvironment. These findings provide a conceptual basis for future exploration of lipid-modulating therapeutic strategies in HCC. Full article

This study aimed to investigate the wound-healing mechanisms of chitosan with a defined molecular weight (MW) and degree of deacetylation (DD), and to explore its potential in hydrogel formulations, optimized for enhanced antibacterial performance. An active molecular chitosan (AMC) was prepared via enzymatic treatment to target a specific MW range with excellent biological activity. The antibacterial, anti-inflammatory, and wound-healing effects of AMC-based hydrogels were evaluated. Given AMC’s antibacterial activity against vancomycin-resistant Staphylococcus aureus (VRSA), its anti-inflammatory effects were also evaluated in full-thickness wounds in BALB/c nude mice. Anti-inflammatory effects were assessed using ELISA and immunohistochemical staining to measure levels of IL-1β, IL-4, IL-6, IL-10, and TNF-α. AMC treatment significantly reduced wound size and suppressed inflammatory cytokine production. These results suggest that hydrogels containing AMC may enhance both antibacterial and anti-inflammatory properties, potentially promoting wound healing. Full article

Background: Glioblastoma (GBM) is characterized by high morbidity and mortality due to its localization and often locally invasive growth. Current treatment options for GBM are limited, with conventional therapies achieving a median survival of only 15 months. Mechanotherapy has been proposed as a new therapeutic strategy in oncology. Low-intensity focused ultrasound (LIFU), a form of mechanotherapy, has demonstrated inhibitory effects on GBM. However, its underlying mechanisms remain poorly understood. The present study aimed to evaluate the therapeutic effects of LIFU on GBM and investigate its mechanisms of action. Methods: Cell viability and proliferation were evaluated using cell counting kit-8, EdU and colony formation assays, while the effects of LIFU on GBM cell apoptosis were evaluated by flow cytometry. Transcriptome sequencing, immunofluorescence, reverse transcription-quantitative polymerase chain reaction, Western blot, bioinformatics analysis, dual-luciferase reporter assay and chromatin immunoprecipitation were used to investigate the molecular mechanisms underlying the effects of LIFU on GBM. The therapeutic efficacy of LIFU was further validated in a subcutaneous xenograft tumor model, in which tumor size, survival rate and immunohistochemical changes were monitored. Results: The results of the present study demonstrated that LIFU exerts anti-GBM effects by activating Piezo1 and modulating the downstream ATF3/PPP1r15a pathway to regulate apoptosis. LIFU therapy holds promise as a new treatment strategy for GBM, with the potential to improve patient prognosis. Conclusions: LIFU suppresses GBM progression through the Piezo1/ATF3/PPP1r15a axis by activating endoplasmic reticulum stress. Full article

Annular lichenoid dermatitis of youth (ALDY) is a rare lichenoid dermatosis characterized by distinctive clinical and histopathological features. Its etiopathogenesis remains poorly understood, and previously reported cases have consistently demonstrated polyclonal T-cell receptor (TCR) gene rearrangements. We report a patient with clinical, histopathological, and immunohistochemical findings consistent with ALDY in whom molecular analysis revealed monoclonal T-cell receptor rearrangement within the skin lesions. To our knowledge, this represents the first reported case of ALDY demonstrating T-cell monoclonality. This novel finding expands the current understanding of the molecular spectrum of ALDY and raises the possibility that cases with monoclonal T-cell rearrangement may represent a distinct clinicopathological variant. Based on our findings, we tentatively propose the term monoclonal annular lichenoid dermatitis of youth (MALDY) to describe this potential entity. Further studies are warranted to clarify its clinical significance and relationship to other cutaneous T-cell disorders. Full article

Background and Objectives: Molecular classification has emerged as a key determinant of prognosis in endometrial cancer and has recently been incorporated into the 2023 FIGO staging system. Tumors are categorized into four molecular subgroups—POLE-mutated (POLEmut), p53-abnormal (p53abn), mismatch repair-deficient (dMMR), and no specific molecular profile (NSMP)—each associated with distinct biological behavior and clinical outcomes. However, real-world data evaluating the relationship between molecular classification, FIGO stage distribution, and survival outcomes remain limited. Materials and Methods: This retrospective study included patients diagnosed with endometrial cancer between 2014 and 2022 at Dokuz Eylül University Hospital. Tumor samples were classified according to the ProMisE molecular algorithm using next-generation sequencing for POLE mutations and immunohistochemical evaluation of mismatch repair proteins and p53 expression. Clinicopathological characteristics, recurrence patterns, and survival outcomes were analyzed. Appropriate statistical analyses were performed. Results: A total of 156 patients were included (mean age 60.2 ± 10.0 years). The most common histology was endometrioid carcinoma (51.9%). Molecular subgroup distribution was NSMP (58.3%), dMMR (25%), p53abn (11.5%), and POLEmut (5.1%). Most patients presented with early-stage disease (83.4%). According to the 2023 FIGO molecular staging, 8.3% were classified as stage 2C m-p53abn and 5.8% as Stage 1Am-POLEmut. After a median follow-up of 39.5 months, the overall survival rate was 81.6%. Survival differed significantly across molecular subgroups, with the most favorable outcomes observed in the POLEmut (100%), followed by NSMP (85.2%), dMMR (78.4%), and p53abn (64.7%) (p = 0.011). Lymph node metastasis was significantly more frequent in the p53abn subgroup (p = 0.002), whereas distant metastasis rates did not differ between groups. Conclusions: Molecular classification was associated with differences in FIGO stage distribution and survival outcomes in this retrospective cohort and may provide additional prognostic information beyond traditional clinicopathological factors. The integration of molecular profiling into routine practice and staging systems may enable improved risk assessment and facilitate more personalized therapeutic strategies in endometrial cancer. Full article