Search Results (1,095)

Necroptosis and dysfunction of ovarian granulosa cells are major contributors to follicular atresia and reduced fertility in cattle, processes that are closely associated with endoplasmic reticulum stress (ERS). Ginseng polysaccharides (GPSs) are known to reduce ER stress, display anti-inflammatory properties, and modulate reproductive function; however, whether GPS can protect against granulosa cell injury and the underlying mechanisms remain unclear. To address this gap, this study aimed to investigate the protective effects of GPS on ERS-induced bovine granulosa cell damage and to elucidate the associated mechanisms. An ERS model was established in bovine granulosa cells using tunicamycin (Tm), and cellular responses were evaluated via flow cytometry, ELISA, and EdU assays. Further, a mouse model was used to validate the protective effects of GPS against Tm-induced ovarian injury. The results showed that 40 μg/mL of GPS significantly alleviated ERS-induced granulosa cell damage, inhibited necroptosis, and mitigated ERS. Moreover, using the PI3K/Akt pathway inhibitor LY294002, we demonstrated that the inhibitor antagonized the effects of GPS, indicating that GPS promotes granulosa cell proliferation and restores estrogen secretion via activating the PI3K/Akt pathway. In vivo experiments further confirmed that GPS effectively attenuates ERS-induced ovarian damage in mice. Collectively, these findings reveal that GPS improves granulosa cell function and ovarian tissue integrity by modulating the ERS network and the PI3K/Akt pathway, yielding a theoretical basis for preventing follicular atresia and enhancing reproductive efficiency in cattle. Full article

Background: Durvalumab consolidation following radiochemotherapy is now the standard treatment for unresectable stage III non-small cell lung cancer (NSCLC). [¹⁸F]FDG PET/CT offers valuable insights not just for staging but also for tumor characterization via radiomics, which can potentially predict histology, immunophenotype, and prognosis. Methods: We conducted a retrospective analysis of [¹⁸F]FDG PET/CT scans from stage IIIA–IIIB NSCLC patients treated at the Clinical Centre, University of Pécs. All biopsy samples were classified histologically (squamous vs. adenocarcinoma) and tested for PD-L1. Lung tumors were segmented using MEDISO InterViewTM FUSION software (version 3.12.002.0000). with an SUVmax threshold of four. Imaging features were extracted and compared based on histology, PD-L1 status, and neutrophil-to-lymphocyte ratio (NLR)-based prognosis groups. Statistical analyses were performed with Jamovi (v2.6.44), using Shapiro–Wilk, t-test/ANOVA, Mann–Whitney/Kruskal–Wallis, or Chi-square tests as appropriate. Results: Fifty-six patients were included (38 PD-L1-positive, 18 -negative). Among PD-L1-positive cases, poor versus good NLR prognosis groups differed in maximum diameter (p = 0.046), short-zone emphasis (p = 0.026), and zone-length non-uniformity (p = 0.027). Focusing on PD-L1-positive squamous carcinoma, maximum diameter, metabolic tumor volume, busyness, and coarseness showed significant differences (all p < 0.05). SUVmax, mean SUV, SUVpeak, and complexity were higher in squamous than in adenocarcinoma subtypes. PD-L1-positive and -negative squamous tumors differed in zone percentage (p = 0.039) and long-zone high gray-level emphasis (p = 0.024), while no significant differences were observed among adenocarcinomas. Conclusions: [¹⁸F]FDG PET/CT radiomics showed potential for differentiating NSCLC histological subtypes and for identifying PD-L1-associated imaging patterns in squamous cell carcinoma. In addition, certain metabolic features were associated with NLR-based prognostic groups in PD-L1-positive patients. Full article

Brain tumors, particularly glioblastoma, remain among the most lethal cancers, with limited survival benefits from current genetic and molecular-targeted approaches. Emerging evidence reveals that beyond oncogenes and mutations, neuronal plasticity, long-term potentiation, synaptic remodeling, and neurotransmitter-driven signaling play a pivotal role in shaping tumor progression and therapeutic response. This convergence of neuroscience and oncology has given rise to the field of cancer neuroscience, which explores the bidirectional interactions between neurons and malignant cells. In this review, we summarize fundamental principles of neuronal plasticity, contrasting physiological roles with pathological reprogramming in brain tumors. We highlight how tumor cells exploit synaptic input, particularly glutamatergic signaling, to enhance proliferation, invasion, and integration into neural circuits. We further discuss how neuronal-driven feedback loops contribute to therapy resistance, including chemoresistance, radioresistance, and immune evasion, mediated through pathways such as mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), and calcium influx. The tumor microenvironment, including astrocytes, microglia, and oligodendrocyte-lineage cells, emerges as an active participant in reinforcing this neuron-tumor ecosystem. Finally, this review explores therapeutic opportunities targeting neuronal plasticity, spanning pharmacological interventions, neuromodulation approaches (transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), optogenetics), and computational/artificial intelligence frameworks that model neuron tumor networks to predict personalized therapy. Also, we propose future directions integrating connect omics, neuroinformatics, and brain organoid models to refine translational strategies. Full article

Continuous surveillance of human papillomavirus (HPV) prevalence and genotype distribution in different cervical cytology grades is necessary for cervical cancer prevention and monitoring. This study investigated the distribution of HPV genotypes and associated factors, stratified by cervical cytology grades and human immunodeficiency (HIV) status, among women in the Eastern Cape Province, South Africa. A total of 540 women were recruited from a community health facility and a referral hospital in the OR Tambo District Municipality in Eastern Cape Province. HPV detection and genotyping in cervical cells were performed using the Seegene Allplex^TM and Anyplex^TM II HPV28 assays. HPV prevalence was 60.6% among women with normal cervical cytology, 93.8% among atypical squamous cells of undetermined significance (ASC-US), 100.0% among low-grade squamous intraepithelial lesions (LSILs), 95.2% among atypical squamous cells cannot exclude high-grade lesion (ASC-H), 93.7% among high-grade squamous intraepithelial lesions (HSILs), and 92.5% among women with cervical cancer. HPV types targeted by Gardasil-9^® were detected in 36.0% of women with normal cervical cytology, 83.0% of those with HSIL, and 81.0% of those with cervical cancer. Among women with normal cervical cytology, HPV58, 35, and 68 were the most dominant types, HPV16, 33, and 35 in HSIL, and HPV16, 18, and 35 in cervical cancer. Differences were observed in the prevailing HPV genotype patterns when stratified by HIV infection status. This study highlights the high HPV prevalence, which further increased among women with abnormal cervical cytology. While HPV prevalence did not significantly increase with HIV co-infection, distinct differences were observed in the HPV genotype patterns when stratified by HIV status. The dominance of non-HPV vaccine types in HSIL and cervical cancer cases underscores a critical gap in current prevention strategies. Full article

Gliomas are the most common malignant primary brain tumors in adults. The treatment of high-grade gliomas is very limited due to their diffuse infiltration, high plasticity, and resistance to conventional therapies. Although they were long considered passive massive lesions, they are now regarded as functionally integrated components of neural circuits, as they form authentic electrochemical synapses with neurons. This allows them to mimic neuronal activity to drive tumor growth and invasion. Ultrastructural studies show presynaptic vesicles in neurons and postsynaptic densities in glioma cell membranes, while electrophysiological recordings detect postsynaptic currents in tumor cells. Tumor microtubules (TMs), dynamic cytoplasmic protrusions enriched in AMPA receptors, are the structures responsible for glioma–glioma and glioma–neuron connectivity, also contributing to treatment resistance and tumor network integration. In these connections, neurons release glutamate that mainly activates their AMPA receptors in glioma cells, while gliomas release excess glutamate, causing excitotoxicity, altering the local excitatory-inhibitory balance, and promoting a hyperexcitable and pro-tumorigenic microenvironment. In addition, certain gliomas, such as diffuse midline gliomas, have altered chloride homeostasis, which makes GABAergic signaling depolarizing and growth promoting. Synaptogenic factors, such as neuroligin-3 and BDNF, further enhance glioma proliferation and synapse formation. These synaptic and paracrine interactions contribute to cognitive impairment, epileptogenesis, and resistance to surgical and pharmacological interventions. High functional connectivity within gliomas correlates with shorter patient survival. Therapies such as AMPA receptor antagonists (perampanel), glutamate release modulators (riluzole or sulfasalazine), and chloride cotransporter inhibitors (NKCC1 blockers) aim to improve outcomes for patients. Full article

A new class of plant phosphotransfer proteins belonging to the multistep phosphorelay (MSP) system implicated in phytohormone cytokinin signaling was discovered based on large-scale bioinformatics methods. Unlike the canonical soluble nucleo-cytosolic forms, these proteins were predicted to have transmembrane (TM) domains and, apparently, should be localized on some kind of cell membrane. To date, 94 predicted TM-containing phosphotransmitter (TM-HPt) homologs were found in 62 plant species belonging to different clades, taxa, and groups of embryophytes: bryophytes, gymnosperms, and mono- and dicotyledons. The conserved HPt motif with phosphorylatable histidine was preserved in most of the TM-HPts under study, which allowed us to consider these proteins potentially active in MSP signaling. For the identified TM-HPts, a Bayesian analysis at the DNA level was performed, and a relevant phylogenetic tree was constructed. According to evolutionary relationships, plant TM-HPts were divided into two main groups corresponding to Arabidopsis AHP1-3,5,6, and AHP4 orthologs. Transcriptomic analysis confirmed the expression of most of the investigated TM-HPt-encoding genes. Their moderate-to-low overall transcription rate may be a consequence of inducible and/or tissue-specific expression. Using molecular modeling methods, a variety of potential spatial organizations of several such proteins are demonstrated. The ability of the uncovered TM domains to tether HPts to membranes was supported by molecular dynamic simulation. Possible roles of TM-HPts as modulators of the MSP signaling pathway and corresponding putative mechanisms of their action are suggested. Full article

The molecular fatty acid (FA) profiles of seven certified thermophilic Lactobacillus strains, including the influence of an extracellular source of oleic acid (as Tween 80^TM), were characterised using advanced chromatographic and spectrometric methods. Cyclic and conjugated fatty acids were identified by GC-MS using co-injections with authentic standards, ECL, and diagnostic EI ions, with a secondary confirmation using literature data. Additionally, the molecular-level characterisation of fatty acid profiles of bacterial cells was summarised using the latest analytical approaches, highlighting inconsistencies and differences reported in previous studies. Six saturated fatty acids, two single-branched fatty acids with iso and anteiso structures, one hydroxy fatty acid, nine unsaturated fatty acids with one double bond, two fatty acids with unsaturated double bonds, six fatty acids with conjugated bonds, and three fatty acids with a cyclic part in the carbon chain were identified. Within these fatty acids, we also demonstrated the limitations of molecular chromatographic resolution and structural discrimination, which impacted the effective identification of fatty acids in our research. We confirmed the significant differences in terms of the identification of C18:1,cis-9 and C18:1,cis-11 acids, as well as cycC19:0,cis-10,11, and cycC19:0,cis-9,10 acids. The observations at the molecular–physiological interface related to the lack of growth of L. acidophilus strains and the visibly reduced growth of L. delbrueckii subsp. lactis ATCC 4797 in the MRS without the addition of Tween 80^TM allowed us to confirm that the exclusion of this medium is useful in differentiating the lactobacilli. Full article

Cell motility—the dynamic process encompassing migration, adhesion modulation, cytoskeletal remodeling, and extracellular matrix (ECM) interactions—is fundamental to ocular homeostasis. In glaucoma, disrupted motility of trabecular meshwork (TM) and Schlemm’s canal (SC) cells contributes to impaired aqueous humor outflow and elevated intraocular pressure (IOP), while reactive motility of optic nerve head (ONH) glial cells promotes fibrosis and neurodegeneration. Mechanistically, TM/SC motility is regulated by Rho GTPase and ROCK signaling, focal adhesion dynamics, and ECM interactions, while glial cells respond to mechanical stress and cytokines such as TGF-β₂. Cytoskeletal alterations, ECM stiffening, and endothelial–mesenchymal transition (EndMT) contribute to glaucomatous damage by reducing normal cell motility and tissue remodeling capacity. Aberrant motility at the ONH, including heterogeneous astrocytic reactivity, leads to lamina cribrosa remodeling and retinal ganglion cell degeneration. Therapeutically, ROCK inhibitors improve TM/SC motility and outflow, suppress EndMT, and may confer neuroprotection. Stem cell-based strategies and modulation of TGF-β₂ or mechanotransduction pathways represent emerging approaches to restore physiological motility and regenerative potential. Despite promising advances, challenges remain in ensuring targeted, durable, and safe modulation of cellular dynamics. Understanding and therapeutically harnessing cell motility offers a unifying framework to address both pressure-dependent and neurodegenerative mechanisms in glaucoma. Full article

Although intensified flotation cells have been introduced as fast-kinetic and plug-flow-type flotation machines, there is limited empirical verification and information about their fluid flow patterns and dispersion regimes. The present communication paper investigates this for an Imhoflot^TM G-06 cell operated in an open-circuit mode using an impulse method to measure and model the residence time of a liquid–gas system. For experimental measurements, a concentrated KCl solution was employed, and water conductivity was monitored for 20 min. By fitting several relevant models, such as large and small tanks in series (LSTS), Weller, N-Mixer, and perfect mixer, to the experimental data, it was revealed that the N-Mixer represented the dispersion pattern the best (N = 1.3–1.6). Further, the obtained practical mean retention time (MRT) of 4.11 ± 0.16 min was somewhat aligned with the theoretical value, i.e., 5.0 min per pass, indicating a back-calculated gas hold-up magnitude of 18%–22% in the separator. These results provide an in-depth perception of scale-up procedures and requirements for cell modification. Full article

Background: Cultured human skin explants provide preclinical models to investigate drug delivery and the efficacy of topical treatments for wound healing. However, different culture conditions may affect cell viability, proliferation, and even wound healing. Since animal-derived supplements can influence the investigation of human physiological responses, this study evaluated the effects of non-animal supplements on the ex vivo wound healing process to improve the use of this model for preclinical drug efficacy tests. Methods: In in vitro scratch assays using HaCaT cells and fibroblasts, for media supplemented with normal human serum (NHS), oxygen carriers (OCs) had a positive impact on cell migration, supporting the further evaluation in ex vivo skin culture models. Human skin explants with standardized superficial wounds were cultured in four supplemented media: (i) Dulbecco’s Modified Eagle Medium High Glucose (DMEM) with fetal calf serum (FCS), (ii) DMEM with NHS and OC, (iii) CnT-Prime^TM with NHS and OC, and (iv) EpiLife™ with NHS and an OC. Results: During the 12-day culture, we observed re-epithelialization in all groups with the exception of EpiLife + NHS + OC (with no Ca⁺⁺ supplement). For these samples, starting from day 6, we noticed a loosening of the dermal–epidermal junction and disruption of the upper epidermal layer. Furthermore, an immunohistochemical analysis of extracellular matrix components and remodeling factors, including type I and III collagen, transforming growth factor-β2, and matrix metalloproteinase-9, provided insights into tissue repair dynamics. Conclusions: NHS plus OC is comparable to FCS supplementation and represents a more physiological and ethical alternative. Full article

This article presents a conceptual perspective proposing that hypoxia acts as a unifying regulator of plasma membrane phosphohydrolases. We propose that oxygen sensing at the cell surface integrates adenosine and phosphate metabolism to sustain tumour adaptation. Within the oxygen- and nutrient-deprived tumour microenvironment, inorganic phosphate (Pi) and adenosine function as metabolic substrates and signalling mediators that promote cell proliferation, survival, and immune evasion. Stabilisation of hypoxia-inducible factor-1α (HIF-1α) enhances the expression and catalytic activity of specific phosphohydrolases, notably the ectonucleotidases CD39 (NTPDase1) and CD73 (ecto-5′-nucleotidase), which drive adenosine accumulation and immunosuppression. Conversely, the activity of transmembrane prostatic acid phosphatase (TM-PAP), responsible for hydrolysing phosphate esters such as p-nitrophenylphosphate (pNPP) and AMP, is inhibited under hypoxia through oxidative and kinase-dependent mechanisms. Collectively, these mechanisms characterise the plasma membrane as a dynamic metabolic interface, where oxygen sensing coordinates adenosine and phosphate turnover, thereby promoting tumour adaptation across hypoxic environments. We propose that hypoxia orchestrates a dual regulatory loop connecting adenosine accumulation and phosphate turnover at the tumour cell surface, providing a conceptual basis for future mechanistic studies. Full article

Purpose: This study aims to investigate whether two stress keratins, KRT6A or KRT17, label self-renewing stem cells (SCs) in adult mouse Meibomian gland (MG), the palpebral conjunctiva (PC) homeostasis, and to explore the mechanisms regulating their expression. Methods: KRT6A and KRT17 expression in adult mouse MG and PC were examined by single-nucleus RNA sequencing and immunofluorescence (IF). Lineage-tracing experiments were performed using Krt6a-Cre^ERT2 and Krt17-Cre^ERT2 mice carrying the Rosa26R^nTnG or Rosa26R^mTmG reporter. As Hedgehog (Hh) signaling, the histone deacetylase HDAC3, and the transcription factor KLF4 regulate KRT6A and KRT17 in other contexts, IF was conducted to assess the in vivo effects of overexpression of the Hh pathway activator GLI2ΔN, and inducible epithelial deletion of Hdac3 or Klf4 on KRT6A and KRT17 expression in the MG and PC. Results: KRT6A and KRT17 are primarily expressed in the MG central duct and ductules. KRT6A also shows robust expression in PC. Lineage tracing indicated that Krt17 labels self-renewing SCs in the MG, whereas Krt6a labels SCs in the PC. GLI2ΔN overexpression induced ectopic KRT17 expression in MG acini and PC but did not affect KRT6A expression in either MG or PC. Hdac3 deficiency caused expanded expression of KRT6A and KRT17 in MG acini, ectopic KRT17 expression in PC, and increased KRT6A expression in PC basal layer. Klf4 deletion resulted in ectopic KRT17 expression in PC but did not influence KRT6A expression in MG or PC. Conclusions: Krt6a- and Krt17-expressing cells contribute to adult PC and MG homeostasis, respectively. KRT17 expression is enhanced by GLI2ΔN, and suppressed by HDAC3 and KLF4, whereas KRT6A expression is controlled only by HDAC3. These findings provide important biological insight into tissue-specific maintenance mechanisms and may inform future therapeutic strategies for regenerating MG and PC tissues affected by SC exhaustion or dysregulation. Full article

Polyphenols, as natural compounds abundant in plant-derived foods, have been recognised for their human health benefits. This study evaluates the multifunctional properties of Biombalance^TM (BB), a grape seed extract rich in oligomeric procyanidins, in various in vitro and in vivo models. BB was studied to assess (i) its antimicrobial effects in different bacterial species; (ii) its protective effects against oxidative and inflammatory stress in Caco-2 cells; and (iii) its effects in mice, which were fed a standard diet with or without BB at two different doses (BB1X and BB2X) to understand the impacts of BB on microbiota and gut homeostasis. BB selectively inhibited several bacterial species, including Staphylococcus aureus, Helicobacter pylori, and Blautia coccoides. In addition, BB protected Caco-2 cells against hydrogen peroxide (H₂O₂)-induced oxidative damage and lipopolysaccharide (LPS)-induced oxidative and inflammatory stress. In vivo, BB supplementation upregulated the expression of antioxidant and homeostasis genes in the colon, ileum, and liver, accompanied by dose-dependent changes in the gut microbiota composition. Functional predictions indicated favourable modulation of microbial metabolic pathways, including those involved in antioxidant capacity and glutamate degradation. Furthermore, BB positively influenced key gut–brain axis mediators, including GLP-1, the GLP-1 receptor, and NPY. These findings highlight the potential of Biombalance^TM to support health and gut–brain communication and to protect against oxidative and inflammatory stress in the gut. Full article

Infertility affects about 17.5% of couples, with male factors accounting for approximately 50% of cases. Cytoskeletal remodeling is increasingly recognized as a critical component of male reproductive function, particularly in the regulation of testosterone synthesis by Leydig cells. However, the underlying molecular mechanisms remain poorly defined. Rho-associated coiled-coil-containing kinase (ROCK), a key cytoskeletal regulator, influences actin dynamics, impacting intracellular trafficking. In this study, we investigated the roles of ROCK1 and ROCK2 in Leydig cells using the TM3 cell model. Pharmacological inhibition of ROCK activity with Y-27632 impaired actin cytoskeleton organization, reduced the phosphorylation of LIMK, COFILIN, and MLC2, and disrupted the colocalization of F-actin with StAR and cholesterol, thereby decreasing testosterone production. Furthermore, RNA-seq revealed that hCG promotes transcription of steroidogenesis-related genes, while ROCK inhibition reverses this effect. Silencing of ROCK1 via siRNA mimicked the effects of ROCK-i, suppressing steroidogenic gene expression and testosterone synthesis. In contrast, ROCK2 knockdown enhanced testosterone secretion, promoted F-actin remodeling, and increased traffic of cholesterol targeting mitochondria. These opposing effects triggered distinct responses in the SCAP–SREBP2 axis, indicating a feedback mechanism regulating cholesterol homeostasis. Collectively, our findings uncover the isoform-specific roles of ROCK1 and ROCK2 in coordinating cytoskeletal dynamics and steroidogenic activity, providing new insights into the regulation of male reproductive endocrinology and identifying potential therapeutic targets for androgen deficiency and male infertility. Full article

This study examines the thermal modification (TM) of European black alder (Alnus glutinosa) wood boards measuring 1000 × 100 × 32 mm. The TM was carried out in a nitrogen atmosphere under an initial pressure of 4 bar at 160 °C for 60, 120, and 180 min, as well as at 170 °C for 30 and 60 min. The TM process resulted in mass loss and volumetric changes with shrinkage observed across all anatomical directions. Water uptake decreased significantly, with the cell wall’s total water capacity dropping from 35% to a range of 14%–27%. Dimensional stability was improved by between 21% and 61%. The TM wood showed a reduction exceeding 50% in both volumetric swelling and equilibrium moisture content relative to the unmodified specimens. A marked decline in the modulus of rupture was observed, especially in samples treated at 160 °C for 180 min and at 170 °C. Conversely, the modulus of elasticity exhibited a slight upward trend, though the changes were not statistically significant. Brinell hardness revealed a pronounced difference between the tangential and radial orientations, with the tangential surface displaying distinctly lower hardness. Chemical analysis indicated a notable increase in acetone-soluble extractives and reductions in the xylan, mannan, and acetyl groups, reflecting structural alterations in hemicelluloses. Full article