Search Results (262,184)

Fatty acid-binding protein 7 (FABP7) is a multifunctional lipid chaperone that is enriched in radial glia and astrocytes within the central nervous system (CNS) and is frequently upregulated in glioma. Beyond its established roles in glial development, lipid homeostasis, and circadian regulation, growing evidence positions FABP7 at the intersection of tumor metabolism, neuronal activity, and immune modulation in the brain. In this review, we integrate the physiological functions of FABP7 in glial cells with its tumor-intrinsic and microenvironmental roles in glioma. We summarize how gliomas co-opt FABP7-dependent metabolic, transcriptional, and post-transcriptional programs to promote stemness, lipid remodeling (e.g., altered fatty acid composition, lipid droplet formation, and lipid peroxidation resistance), inflammatory signaling, and invasive growth, including nuclear FABP7-mediated transcriptional activation linked to oncogene status. Furthermore, we discuss the role of FABP7 in shaping the tumor–neuro–immune interface, including regulating immunosuppressive gene networks, pro-tumoral macrophage polarization, resistance to T-cell-induced ferroptosis and immunotherapy, and tumor microtube-mediated integration into neuronal circuits to support glioma progression. Finally, we highlight therapeutic opportunities and challenges, including small-molecule FABP7 inhibitors, brain-directed delivery strategies, chronotherapeutic considerations, and combination approaches with immunotherapy. Collectively, this work positions FABP7-centered metabolic, circadian, and neuro-immune networks as potential vulnerabilities in glioma, linking fundamental glial biology to glioma therapeutics. Full article

Background: Dupilumab, a monoclonal antibody blocking IL-4Rα, has recently demonstrated efficacy in patients with type 2 (T2)-inflamed chronic obstructive pulmonary disease (COPD) in the BOREAS and NOTUS trials. Real-world experience in older patients with predominant chronic bronchitis phenotype remains limited. Methods: We report a single-centre case series of 12 consecutive patients with T2-inflamed COPD treated with dupilumab 300 mg every two weeks under a compassionate-use programme at San Carlo di Nancy Hospital, Rome (first administration: April 2025). Eligibility required ≥2 moderate or ≥1 severe exacerbation in the prior 12 months despite triple inhaled therapy and a blood eosinophil count ≥300 cells/µL. Follow-up ranged from 3 to 12 months, with 6 months pre-specified as the primary analysis timepoint; data at 9 and 12 months are reported as descriptive observations. Endpoints included paired changes in annualised exacerbation rate (AER), CAT score and item-level CAT, and FEV₁, with exploratory univariate Spearman analyses of candidate baseline predictors of response. Results: The cohort was elderly (mean age 73.6 ± 5.2 years, range 65–82), predominantly female (8/12, 67%) and characterised by a chronic bronchitis phenotype with high symptom burden (mean baseline CAT 22.8 ± 7.5; CAT item 2 [phlegm] median 3, IQR 3–4). Severe exacerbations decreased significantly (Wilcoxon p = 0.0156; mean AER 0.75 → 0.19 events/patient-year; 6/12 improved, 0/12 worsened). The mean cumulative function showed a standardised incidence ratio of 0.46 (95% CI 0.19–0.95; p = 0.033) versus the pre-dupilumab rate. Mean FEV₁ increased by +66 mL at 1 month (n = 11, paired Wilcoxon p = 0.025), +78 mL at 3 months (n = 10, p = 0.082) and +120 mL at 6 months (n = 10, p = 0.007). Total CAT decreased from 22.9 to 12.5 at 6 months (Friedman p = 0.0007), with the largest absolute reductions in item 2 (phlegm; Δ = −2.6 at 6 months, p < 0.001) and item 3 (chest tightness; Δ = −2.5 at 6 months, p = 0.002). Higher baseline CAT was associated with greater reduction in severe AER (Spearman ρ = −0.79, p = 0.002). Conclusions: In this elderly real-world cohort with phlegm-driven T2 COPD, dupilumab was associated with a significant decrease in severe exacerbations, a clinically meaningful gain in lung function and a marked improvement in mucus-related symptoms. Further studies are warranted to confirm these findings and to clarify whether the reduction in severe exacerbations translates into a measurable mortality benefit. Full article

Variants in the human PAX4 gene are associated with both monogenic and complex forms of diabetes, yet their pathogenic effects remain difficult to define in models that accurately mimic human islet architecture and neonatal metabolic transitions. Here, we created a porcine PAX4 loss-of-function model using CRISPR/Cas9 cytidine deaminase base editing to introduce a premature stop codon in the PAX4 coding sequence. PAX4 knockout piglets developed severe hyperglycemia within 24 h of birth, followed by rapid postnatal clinical deterioration and uniform death by day 3. Biochemical analysis showed significant diabetic decompensation, including electrolyte imbalances, hyperosmolality, azotemia, dyslipidemia, and metabolic acidosis. Gross and histological examinations revealed notable pancreatic hypoplasia with preservation of exocrine tissue. Single-nucleus RNA sequencing and immunohistochemistry demonstrated an almost complete loss of insulin- and somatostatin-producing β- and δ-cells, respectively, with relative preservation of glucagon-expressing α-cells. Overall, these results establish PAX4 as a crucial factor in pancreatic endocrine development and postnatal glucose regulation in a large-animal model. This platform offers a human-relevant system for studying diabetes-associated PAX4 variants and for testing regenerative and gene-based therapies for insulin-deficient diabetes. Full article

Brucellosis and tuberculosis (TB) are chronic infectious diseases of international public health importance, with developing countries being most affected. The diagnosis of brucellosis and tuberculosis co-infection remains challenging because both diseases present with overlapping nonspecific clinical manifestations, such as prolonged fever, fatigue, and weight loss, and elicit similar cell-mediated immune and inflammatory responses, which can complicate differential diagnosis, particularly in endemic regions. Recently, it has been shown that chronic infections affect cell stress pathways such as oxidative stress and telomere function. The current literature review provides an overview of the relationship between brucellosis and TB at a molecular level, focusing on telomere biology, oxidative stress and the mechanisms of antimicrobial resistance. Due to chronic immune response in brucellosis and TB patients, an increase in reactive oxygen species (ROS) levels is observed, leading to DNA damage and subsequent telomere shortening and alteration of telomerase activity. These alterations might be responsible for immune senescence, weakened defense response and persistent infection. In addition, different methods of drug resistance have been discovered among brucellae and mycobacteria, such as mutation in target sites, efflux systems and intracellular persistence, making their eradication difficult. Finally, the potential role of telomere-related genes and biomarkers of oxidative stress in diagnosis and prognosis is also highlighted. Insights into these interrelated pathways would allow us to have a better understanding of host–pathogen interactions and hence offer a possible means of developing new strategies in the fight against co-infection by finding new biomarkers. Full article

Background: Eggshell membrane peptides (ESMPs) are natural bioactive compounds with reported chondroprotective properties. However, their regulatory effects on canine chondrocytes remain unclear. This study investigated ESMP in an interleukin-1β (IL-1β)-induced inflammatory model of canine chondrocytes. Methods: Chondrocytes were assigned to control (Cont), IL-1β, and ESMP + IL-1β groups. Cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay. NF-κB p65 nuclear translocation was evaluated by immunofluorescence staining. Real-time quantitative PCR (RT-qPCR) and Western blotting (WB) were used to measure mRNA and protein expression levels, respectively. Results: ESMP inhibited IL-1β-induced NF-κB p65 nuclear translocation and reduced the IL-1β-induced increases in interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and matrix metalloproteinase-13 (MMP-13) at both mRNA and protein levels. ESMP also decreased IL-6, nitric oxide (NO), and prostaglandin E₂ (PGE₂) levels in culture supernatants. ESMP reversed the IL-1β-induced reduction in type II collagen α1 chain (COL2A1) and aggrecan (ACAN) expression at both transcriptional and protein levels. Conclusions: ESMP attenuates IL-1β-induced inflammatory responses and extracellular matrix degradation in canine chondrocytes, potentially associated with suppression of NF-κB p65 nuclear translocation. This supports its potential application in promoting joint health in dogs. Full article

Myelodysplastic syndromes are clonal hematopoietic neoplasms in which ineffective hematopoiesis arises within the context of chronic inflammation and immune dysregulation. Growing evidence indicates that aging-associated inflammaging and inflammation-driven remodeling of the bone marrow microenvironment are not secondary phenomena, but active forces that shape clonal selection, lineage commitment, and disease evolution. This narrative review integrates recent insights from translational immunology, stem cell biology, multi-omics analyses, and clinical studies to examine the reciprocal interplay between inflammation and myelodysplastic syndrome pathogenesis. Chronic inflammatory stress imposes selective pressure on hematopoietic stem cells, favoring the expansion of mutation-bearing clones characteristic of clonal hematopoiesis and overt disease. As inflammation persists, immune dysfunction, together with stromal alterations, progressively reinforce ineffective hematopoiesis and clonal dominance. Genetic lesions, including TP53 and spliceosome mutations, further amplify inflammatory signaling and reshape the marrow niche, conferring clonal fitness and genomic instability. Clinically, readily accessible peripheral blood inflammatory indices reflect these biological processes and correlate with prognosis and therapeutic response. Collectively, these observations position inflammation as a unifying determinant of myelodysplastic syndrome initiation, progression, and treatment sensitivity. Integrating inflammatory signatures with genomic profiling may refine risk stratification and support the development of therapeutic strategies aimed at restoring marrow homeostasis and limiting inflammation-driven clonal evolution. Full article

Choriogenesis, the final stage of oogenesis in insects, is a highly coordinated developmental process responsible for the formation of the chorion (eggshell), a specialized multilayered extracellular matrix that protects the embryo and mediates essential physiological functions. Despite its fundamental importance for reproductive success and species survival, the mechanisms underlying chorion biogenesis remain incompletely understood across insect taxa. This review provides an updated synthesis and integrated view of choriogenesis, including cellular, molecular, biochemical, and structural perspectives. We examine the role of follicle cells in chorion formation, the regulatory mechanisms governing chorion gene expression, and the biochemical composition of the eggshell, including proteins, lipids, and carbohydrates. In addition, we compare the structural diversity of the chorion across insect taxa, highlighting both conserved multilayered organization and lineage-specific adaptations in surface morphology and internal architecture. Full article

The aim of this review is to provide a narrative analysis of the role of Lactobacillus acidophilus as an active modulating factor in the prevention and treatment of cancer and allergic diseases. The paper discusses the molecular, metabolic, and bionanotechnological mechanisms of Lactobacillus acidophilus’s anticancer and immunomodulatory effects, which define this probiotic as an essential component of modern natural and functional medicine. A narrative review of the scientific literature was conducted, mainly from 2019–2026, focusing on the results of in vitro studies and studies on preclinical in vivo models, which analyzed the effect of live L. acidophilus strains, tyndallized bacteria (paraprobiotics) and cell-free supernatant from L. acidophilus cultures on, among others, immune system signaling pathways, tissue cytokine profile, and the integrity of the gastrointestinal epithelial cell barrier (enterocytes). Results indicate that L. acidophilus exerts significant antiallergic, antiproliferative, and proapoptotic effects against many types of cancer. Among other aspects, the ability of L. acidophilus to stimulate the production of anticancer exopolysaccharides and short-chain fatty acids, which directly influence the functioning of immune cells, is covered. The article thoroughly explains the immunomodulatory effects of L. acidophilus and the ability of this probiotic to regulate cytokine profiles, which helps promote an anti-inflammatory environment crucial for maintaining intestinal homeostasis. The article also discusses the direct interaction of L. acidophilus with immune cells, such as dendritic cells and macrophages, which leads to their activation and subsequent influence on the differentiation of T lymphocytes, which play a key role in the regulation of immune processes and in the development of immune tolerance. L. acidophilus is a universal mediator of immunological and metabolic homeostasis. Its ability to synergize with conventional therapies (chemotherapy, oncolytic virotherapy) and its innovative applications in the creation of postbiotics and paraprobiotics may provide a new approach to the treatment of inflammatory, allergic, and neoplastic diseases. Further clinical studies are necessary to assess the efficacy, safety, and optimal dose of this probiotic, which are essential for the widespread use of L. acidophilus in human therapy. Full article

Micropropagation of Selenicereus hybrids is a key tool for breeding and conservation; however, further refining the balance between high multiplication rates and morphological quality remains a complex challenge within conventional protocols. This study explores targeted signaling modulation using nine bioactive small molecules—including three mammalian glycogen synthase kinase 3 (GSK3) inhibitors (TDZD-9, VP3.15 and VP0.7), three leucine rich repeat kinase 2 (LRRK2) inhibitors (JZ1.24, JZ1.3 and IGS4.75), and three phosphodiesterase (PDE) inhibitors—to complement traditional micropropagation. Explants were evaluated in two distinct contexts: a hormone-free basal medium (BM) and a plant growth regulator-supplemented medium (PIT2) and the response rates, yield, and quality were measured and integrated using a Global Efficiency Index (GEI). Results demonstrate that inhibitor efficacy is strictly context-dependent; while most molecules repressed budding in BM, they acted as response modulators by determining the specific type of morphogenic pathway in PIT2. Notably, the GSK3 inhibitor TDZD-9 reached the highest GEI (0.85) by maximizing productivity, whereas LRRK2 inhibitors effectively preserved architectural integrity. Flow cytometry confirmed cytogenetic stability across all treatments, with a 98.5% plantlet survival rate during acclimatization. In conclusion, the strategic integration of targeted signaling modulators and multi-parametric indices offers a refined and objective framework to enhance the efficiency of mass propagation protocols in pitahaya and other recalcitrant species. Furthermore, our findings provide new evidence of the strong potential of these small molecules as novel tools to improve plant micropropagation beyond traditional plant growth regulators. Full article

Background/Objectives: Inflammation plays a central role in the pathophysiology and prognosis of non-ST-segment elevation myocardial infarction (NSTEMI). This study aimed to investigate the clinical and prognostic significance of the Cumulative Inflammatory Index (IIC) in patients with NSTEMI. Methods: This single-center, retrospective study included 2274 individuals, comprising 1172 patients with NSTEMI and 1102 angiographic controls without acute coronary syndrome or obstructive coronary artery disease. IIC was calculated using mean corpuscular volume, red cell distribution width, neutrophil count, and lymphocyte count. The primary outcome was 360-day all-cause mortality in the NSTEMI cohort. Logistic regression, receiver operating characteristic curve analysis, and DeLong testing were performed. Results: Patients with NSTEMI had significantly higher IIC values than controls [9.08 (4.05–15.03) vs. 1.90 (1.45–2.89), p < 0.001]. Among NSTEMI patients, non-survivors had significantly higher IIC levels than survivors [14.25 (8.56–26.59) vs. 8.57 (3.73–14.06), p < 0.001]. In multivariable logistic regression analysis, IIC remained independently associated with 360-day all-cause mortality after adjustment for age, diabetes mellitus, estimated glomerular filtration rate, hemoglobin, albumin, and C-reactive protein (OR: 1.045, 95% CI: 1.029–1.060; p < 0.001). IIC showed a modestly higher area under the curve among the evaluated indices (AUC: 0.704). Conclusions: IIC was significantly elevated in patients with NSTEMI and was independently associated with 360-day all-cause mortality. IIC may serve as a simple adjunctive marker for risk stratification in patients with NSTEMI. Full article

Background: Solriamfetol, a dopamine and norepinephrine reuptake inhibitor widely used in narcolepsy management, has not been thoroughly investigated for its anti-fibrotic and anti-inflammatory properties. Herein, we investigated its potential therapeutic applications and underlying mechanisms in both cellular and murine models of pulmonary fibrosis. Methods: To induce fibrosis, C57BL/6 male mice (six-week-old) were administered bleomycin via the intratracheal route. These animals subsequently received solriamfetol orally once per day at dosages of 3 or 10 mg/kg. Histological and immunohistochemical techniques were employed to evaluate inflammatory cell infiltration, collagen accumulation, and α-smooth muscle actin (α-SMA) expression in bronchoalveolar lavage samples and lung tissue sections. Cytokine levels were measured by ELISA, and gene/protein expression of pro-fibrotic markers, A_2A/A_2B adenosine receptors (ARs), adenylate cyclases (ACs), Epac, K_Ca3.1, and adenosine deaminase (ADA) were assessed via quantitative PCR and Western blot. Electrophysiological recordings evaluated K_Ca3.1 channel activity. Purified ADA and normal human lung fibroblasts (NHLFs) were treated with solriamfetol to assess effects on ADA activity and levels of cAMP and adenosine, respectively. Results: Solriamfetol significantly reduced inflammatory cell infiltration, collagen accumulation, and α-SMA expression in fibrotic lungs. Solriamfetol restored downregulated A_2AAR, A_2BAR, ACs, and Epac, while suppressing ADA expression and activity, resulting in elevated extracellular adenosine and intracellular cAMP. The intervention potentiated Epac signaling and inhibited fibroblast activation. Solriamfetol inhibited the K_Ca3.1 current in fibroblasts and reduced K_Ca3.1 protein expression levels in TGFβ-treated fibroblasts and lung tissues from bleomycin-challenged mice. Notably, these effects were abolished by A_2AAR or A_2BAR antagonists, implying that they occur through AR-mediated pathways. Conclusions: Solriamfetol inhibits ADA and reinforces adenosine–cAMP signaling, suppressing pathological fibroblast activation. These findings suggest its therapeutic utility as a novel anti-fibrotic compound for various fibrotic diseases, including pulmonary fibrosis. Full article

In our previous studies, OptiPrep and Percoll density gradients separated human motile sperm without DNA fragmentation from immotile sperm with DNA damage. Even in normospermia, over half of the sperm were already immotile, and angle-modulated two-dimensional single-cell pulsed-field gel electrophoresis showed that these were at the end stage of fragmentation. We developed sperm-specific dye- and lectin-exclusion assays to evaluate plasma and acrosomal membranes, mitochondrial endogenous reactive oxygen species, and vacuole negative staining. Comprehensive analyses suggested that they corresponded to sperm that had not yet undergone apoptosis and to those that had undergone apoptotic denaturation. In ICSI, injectable motile sperm that fully meet criteria have an oval-shaped head, intact membranes on both the head and tail, and normal oxidative phosphorylation in cylindrical mitochondria, and they lack vacuoles and DNA damage. Conversely, sperm exhibiting apoptotic signs, such as immotility, plasma membrane damage, and DNA fragmentation, are not injectable. We must establish threshold criteria for injectable sperm; multiple impairments in sperm hinder the study of these issues. The topic of functional impairments in human sperm is too extensive to cover in a single review; for the full scope of the issue, technical guidance for DNA fragmentation analyses is presented in our previous review. Full article

Myostatin (MSTN) is a well-established negative regulator of skeletal muscle growth; however, its role in bone metabolism and osteogenic differentiation remains incompletely understood. In this study, untargeted and targeted metabolomic analyses were performed to investigate the metabolic effects of the MSTN^Del73C mutation during osteogenic differentiation of sheep bone marrow mesenchymal stem cells (BMSCs). Metabolomic profiles were analyzed in wild-type and MSTN^Del73C mutant BMSCs at 0, 7, and 14 days of osteogenic induction. During normal osteogenic differentiation, metabolites related to glycerophospholipid metabolism were repeatedly detected among significantly altered features, accompanied by marked increases in multiple lysophospholipid subclasses, including lysophosphatidylcholine (LPC), lysophosphatidylserine (LPS), and lysophosphatidylinositol (LPI). In contrast, MSTN^Del73C mutation was associated with significant reductions in several LPC and LPI species (p < 0.01 or p < 0.001), suggesting altered lipid metabolic profiles during differentiation. Targeted metabolomic validation further confirmed the altered abundance pattern of LPC 18:2. Collectively, these findings suggest that MSTN mutation is closely associated with metabolic remodeling during osteogenic differentiation and suggest potential involvement of glycerophospholipid-related metabolites involved in MSTN-related regulation of sheep BMSC osteogenesis. Full article

Background: Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms, accounting for approximately 1–3% of all gastrointestinal tumors, with an annual incidence of 1–2 cases per 100,000 population worldwide. They arise from the interstitial cells of Cajal and are most commonly located in the stomach and small intestine. Methods: We report a case of a 39-year-old man admitted with a preliminary diagnosis of an appendiceal inflammatory mass with suspected abscess formation. Results: The patient presented with right iliac fossa pain, fever, signs of pronounced systemic intoxication and laboratory findings consistent with inflammatory syndrome. Abdominal computed tomography revealed a mass in the right iliac region with infiltration of the surrounding adipose tissue, suggestive of an appendiceal infiltrate. Emergency surgical exploration identified a tumor originating from the cecum. Radical resection of the ileocecal region with side-to-side ileo-ascending anastomosis was performed. Histopathological examination confirmed a spindle-cell variant of GIST. The postoperative course was uneventful. Conclusions: This case highlights the diagnostic challenges of atypically localized GISTs, which may clinically and radiologically mimic inflammatory conditions such as appendiceal infiltrate. Conventional imaging modalities may be insufficient for definitive differential diagnosis. Surgical resection remains the cornerstone of treatment, with histopathological and immunohistochemical evaluation establishing the final diagnosis. Early identification and complete tumor excision are essential for optimizing clinical outcomes and long-term prognosis. Adjuvant therapy with tyrosine kinase inhibitors should be considered based on individual recurrence risk. Full article

Lipophilic marine toxins (LMTs) are important toxic risk factors in marine ecosystems and seafood safety, yet the comparative cytotoxicity-associated molecular responses of different LMT classes remain unclear. Here, Neuro-2a cells were exposed to four representative LMTs—dinophysistoxin-1 (DTX1), azaspiracid-3 (AZA3), yessotoxin (YTX), and pectenotoxin-2 (PTX2)—and acute cytotoxicity was evaluated together with integrated transcriptomic, proteomic, and metabolomic analyses. Cell viability assays showed a cytotoxic potency order of DTX1 > AZA3 > YTX > PTX2. Integrated multi-omics analysis revealed that DTX1, the most cytotoxic toxin, caused the broadest molecular perturbations, mainly involving mitochondrial energy metabolism, p53-mediated stress responses, and multilayered metabolic networks. AZA3 and YTX induced intermediate cytotoxicity and showed partially similar perturbation patterns, particularly affecting cytoskeleton-related, immune-related, and metabolism-related processes. In contrast, PTX2, the least cytotoxic toxin, produced more limited responses mainly involving tyrosine metabolism and the cGMP–PKG signaling network. Overall, molecular perturbation patterns generally corresponded to acute cytotoxic potencies, while each toxin exhibited distinct key pathways and functional modules. These findings provide a multi-omics basis for cytotoxic responses of representative LMT classes and guide subsequent functional validation. Full article