Search Results (56,950)

The neonatal heart possesses a unique capacity for reparative healing after myocardial injury, unlike the adult heart. While immune cells, particularly T cells, regulate post-infarction inflammation, their role in age-dependent cardiac repair remains unclear. This study aimed to characterize the temporal activation of T cell subsets and their contribution to immune homeostasis and myocardial repair. Myocardial infarction was induced in mice of different ages, and T cell subsets (CD4+ T cells, CD8+ T cells, and CD4+Foxp3+ T [T-reg] cells) were analyzed using flow cytometry and RNA sequencing. Neonatal hearts exhibited CD4+ T cells, CD8+ T cells, and T-reg cells that gradually increased until seven days post-injury. Transcriptome analysis identified Rcn3 as a neonatal-specific, injury-responsive gene in T-reg cells, with minimal induction in adult and aged hearts, promoting a reparative microenvironment and exerting anti-fibrotic effects via the PI3K/Akt pathway. Under endoplasmic reticulum stress, Rcn3 activated unfolded protein response genes, and Rcn3-conditioned media reduced fibrosis-associated gene expression in adult cardiac fibroblasts. In a conditional knockout mouse model (Lck-cre; Rcn3^fl/fl), Rcn3 deletion in T cells led to impaired cardiac function recovery and increased fibrosis post-injury. These findings suggest that neonatal T-reg cells play a crucial role in cardiac repair, with Rcn3 as a potential therapeutic target for enhancing immune-mediated cardiac repair and limiting pathological remodeling in the adult heart. Full article

Elevated sodium concentrations are commonly observed in tumors and sites of inflammation. Previous studies have shown that high salt levels modulate the phenotype and function of CD4⁺ and CD8⁺ T cells, regulatory T cells, and macrophages. In this study, we performed transcriptomic studies that revealed profound alterations in the neutrophil transcriptome upon high salt exposure, with changes that significantly exceeded those triggered by conventional agonists. By integrating transcriptomic data with functional assays, our findings suggest that high salt-induced neutrophil activation involves mitochondrial ROS production, which subsequently activates p38 MAPK and engages FOS-, Bruton’s tyrosine kinase (BTK)-, and cyclooxygenase 2 (COX2)-dependent pathways. Remarkably, the plasticity of the neutrophil transcriptome in response to high salt was further evidenced by the upregulation of genes typically associated with other cell types, including semenogelin 1 (SEMG1), intercellular adhesion molecule-4 (ICAM4), tripartite motif69 (TRIM69), amphiregulin (AREG), oncostatin (OSM), and transducer of ERBB2-1 (TOB1), suggesting a broader role for neutrophils in different biological processes beyond their participation in innate immunity. Full article

The extracellular matrix (ECM) is a dynamic, tissue-specific network that integrates biochemical and mechanical cues to regulate cell behavior and organ homeostasis. Increasing evidence indicates that dysregulated ECM remodeling is an upstream driver of chronic human diseases rather than a passive consequence of injury. This review summarizes principles of ECM organization, mechanotransduction, and pathological remodeling and highlights translational opportunities for ECM-targeted therapies, biomaterial platforms, and precision diagnostics. We conducted a narrative synthesis of foundational and recent literature covering ECM composition and turnover, stiffness-dependent signaling, and disease-associated remodeling across fibrosis/cardiovascular disease, cancer, and metabolic disorders, together with advances in ECM-based biomaterials, drug delivery, and ECMderived biomarkers and imaging. Across organs, a self-reinforcing cycle of altered matrix composition, excessive crosslinking, and stiffness-dependent mechanotransduction (including integrin–FAK and YAP/TAZ pathways) sustains fibroinflammation, myofibroblast persistence, and progressive tissue dysfunction. In tumors, aligned and crosslinked ECM promotes invasion, immune evasion, and therapy resistance while also shaping perfusion and drug penetration. Translational strategies increasingly focus on modulating ECM synthesis and crosslinking, normalizing rather than ablating matrix architecture, and targeting ECM–cell signaling axes in combination with anti-fibrotic, cytotoxic, or immunotherapeutic regimens. ECM biology provides a unifying framework linking pathogenesis, therapy, and precision diagnostics across chronic diseases. Clinical translation will benefit from standardized quantitative measures of matrix remodeling, mechanism-based biomarkers of ECM turnover, and integrative imaging–omics approaches for patient stratification and treatment monitoring. Full article

Spinal cord injury (SCI) remains a major clinical challenge due to the limited regenerative capacity of the central nervous system (CNS). Effective scaffolds for repair must combine mechanical compatibility with host tissue, controlled degradation matching the time course of regeneration, and microarchitectural features that promote neuronal survival. Electrospun nanofibrous scaffolds mimic the structural and mechanical features of the extracellular matrix, providing critical cues for neuronal adhesion and glial modulation in neural regeneration. Here, we fabricated biodegradable poly(lactic acid)/poly(ε-caprolactone) (PLA/PCL) scaffolds using a dichloromethane/tetrahydrofuran (DCM/THF) solvent system to induce surface porosity via solvent-driven phase separation. The DCM/THF solvent system formulation produced nanofibers with porous surfaces and increased area for cell interaction. PLA/PCL scaffolds showed a Young’s modulus of ~26 MPa and sustained degradation, particularly under oxidative conditions simulating the post-injury microenvironment. In vitro, these scaffolds enhanced neuronal density up to fivefold and maintained ~80% viability over 10 days in primary neuron–glia cultures. Morphometric analysis revealed that DCM/THF-based scaffolds supported astrocytes with preserved process complexity and reduced circularity, indicative of a less reactive morphology. In contrast, scaffolds fabricated with 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) displayed reduced bioactivity and promoted morphological features associated with astrocyte reactivity, including cell rounding and process retraction. These findings demonstrate that solvent-driven control of scaffold microarchitecture is a powerful strategy to enhance neuronal integration and modulate glial morphology, positioning DCM/THF-processed PLA/PCL scaffolds as a promising platform for CNS tissue engineering. Full article

Background: Computed tomography (CT)-derived body composition parameters, including skeletal muscle and fat indices, are prognosticators in oncology. Most studies focus on baseline body-composition parameters; however, changes during treatment may provide better prognostic value. Standardized methods for measuring/reporting these parameters remain limited. Methods: This retrospective study included patients who were treated with immunotherapy for non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), or melanoma between 2017 and 2024 and had technically adequate baseline and follow-up CT scans. Body composition was analyzed using a novel, fully automated software (CompoCT) for L3 slice selection and segmentation. Body composition indices (e.g., skeletal muscle index [SMI]) were calculated by dividing the cross-sectional area by the patient’s height squared. Results: The cohort included 376 patients (mean [SD] age 66.4 [11.4] years, 67.3% male, 72.6% NSCLC, 14.6% RCC, and 12.8% melanoma). During a median follow-up of 21 months, 220 (58.5%) died. Baseline body composition parameters were not associated with mortality, except for a weak protective effect of higher SMI (HR = 0.98, p = 0.043). In contrast, longitudinal decreases were strongly associated with increased mortality. Relative decreases in SMI (HR, 1.17; 95% CI, 1.07–1.27) or subcutaneous fat index (SFI) (HR, 1.11; 95% CI, 1.07–1.15) significantly increased mortality risk. Multivariate models showed similar concordance (0.65) and identified older age, NSCLC tumor type, and relative decreases in SMI and SFI (per 5% units) as independent predictors of mortality. Conclusions: Longitudinal decreases in skeletal muscle and subcutaneous fat were independent predictors of mortality in immunotherapy-treated patients. Automated CT-based body composition analysis may support treatment decisions during immunotherapy. Full article

Background/Objective: Osimertinib (OSI) is a third-generation tyrosine kinase inhibitor approved for non-small cell lung cancer (NSCLC) therapy. OSI is administered orally; this route limits the amount of OSI reaching the tumor in the lungs and is associated with serious systemic toxicity. This study aimed to develop a dry powder inhalable formulation to provide tumor-targeted delivery and minimize systemic toxicity. To the best of our knowledge, this is the first study to prepare and evaluate a dry powder inhalation formulation of OSI. Methods: Chitosan-coated PLGA nanoparticles (PLGA-C NPs) encapsulating OSI were prepared using a single emulsion-solvent evaporation technique. PLGA-C NPs were assembled into respirable nanocomposite microparticles (NCMPs) via spray drying with L-leucine as a carrier. PLGA-C NPs were characterized for particle size, zeta-potential, encapsulation efficiency, and in vitro efficacy in A-549 cell line. NCMPs were evaluated for solid-state properties, aerosolization performance, stability and in vitro release. Results: PLGA-C NPs exhibited a particle size of 145.18 ± 3.0 nm, high encapsulation efficiency and a positive zeta potential. In vitro studies demonstrated a 3.6-fold reduction in IC50 compared to free OSI, superior antimigratory effects and enhanced cell cycle arrest. Solid-state characterization of NCMPs demonstrated drug encapsulation in the polymer without chemical interaction. NCMPs exhibited excellent aerosolization (mass median aerodynamic diameter of 1.09 ± 0.23 μm, fine particle fraction of 73.48 ± 8.6%) and sustained drug release (61.76 ± 3.9% at 24 h). Stability studies confirmed the physicochemical stability integrity. Conclusions: These findings suggest that this novel dry powder inhalable OSI formulation may improve therapeutic outcomes while reducing systemic toxicity. Full article

Clinical reports have shown that administration of Nauclea officinalis (Danmu in Chinese, DM) preparations may cause significant gastrointestinal discomfort. This study aimed to systematically evaluate the adverse effects of DM and its primary active constituent, strictosamide, on gastrointestinal motility, intestinal barrier integrity, and gut microbiota homeostasis. Furthermore, we sought to investigate the potential role of the bitter taste receptor (T2R) signaling pathway in mediating these effects. In vitro cell cultures and ex vivo intestinal tissues were employed to assess cell viability and molecular alterations. In vivo studies involved short-term (2 weeks) gavage of DM (0.54 and 1.08 g/kg) and long-term (16 weeks) intervention (0.4, 0.8, and 1.2 g/kg) in rodents. Evaluations included histopathological examination, serum levels of cytokines and oxidative stress markers (ELISA), expression of tight junction proteins (Western blot and qPCR), and 16S rDNA sequencing of cecal microbiota. Mechanistic analyses focused on α-defensin secretion and T2R-associated gene and protein expression. Administration of DM resulted in significant gastrointestinal dysfunction, characterized by delayed intestinal propulsion and increased gastric retention. Dose-dependent histopathological damage, disruption of the intestinal barrier (reduced occludin and claudin-1 expression), and elevated levels of pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β), oxidative stress markers (MDA, SOD, and GSH-Px), and immune mediators (IFN-γ) were observed. Gut microbiota analysis revealed dysbiosis, marked by a decline in beneficial genera (e.g., Mucispirillum, Butyricicoccus, Roseburia) and an increase in potentially pathogenic bacteria (e.g., Citrobacter, Helicobacter). Mechanistically, DM suppressed α-defensin secretion and downregulated the expression of TAS2R108, TAS2R138, and Gα-gustducin both in vitro and in vivo. DM and strictosamide disrupt gut microbiota composition and compromise intestinal barrier function, likely through inhibition of the T2R/α-defensin pathway. These findings provide important mechanistic insights into drug-induced gastrointestinal toxicity and underscore the potential risks associated with prolonged use of DM-containing preparations. Full article

Oxidative stress (OS) is a critical regulator of placental development; however, its specific effects on trophoblast biology remain incompletely elucidated. This narrative review synthesizes evidence derived from studies using human placental tissues and trophoblast cell models to delineate how excessive reactive oxygen species (ROS) disrupt molecular and cellular pathways essential for normal placentation. The literature search was restricted to human-based and in vitro investigations. Across these studies, OS was consistently shown to impair mitochondrial function in trophoblasts, resulting in increased mitochondrial ROS generation, loss of mitochondrial membrane potential, and activation of apoptotic signaling cascades. These mitochondrial disturbances were associated with reduced trophoblast proliferation, migration, and invasion, as well as dysregulation of angiogenic balance. Furthermore, several studies reported alterations in mitophagy, involvement of redox-sensitive pathways such as CYP1A1 and KLF9, and the extracellular release of mitochondrial DNA, which was linked to reduced cell viability and increased necrotic cell death. Collectively, the available evidence indicates that OS interferes with key trophoblast-dependent developmental processes, providing mechanistic insight into the pathogenesis of placental dysfunction observed in pregnancy complications such as preeclampsia (PE) and intrauterine growth restriction (IUGR). Elucidation of these pathways may inform the development of targeted therapeutic strategies aimed at preserving placental function and improving adverse pregnancy outcomes. Full article

Objective: The objective was to evaluate the optimal timing of cervical cerclage insertion for perinatal outcomes, such as birthweight, gestational week, and pregnancy prolongation in women with diagnosed cervical insufficiency (CI). Methods: This retrospective study was conducted at the 1st Department of Obstetrics and Gynaecology of the Medical University of Warsaw, over a 10-year period. Maternal and perinatal outcomes were compared between 75 women divided into three groups based on the gestational week (GW) at cerclage insertion: (1) before 18 GW (n = 31), (2) 18–22 GW (n = 31), (3) after 22 GW (n = 13). Only single pregnancies were included in the final analysis in order to maintain the homogeneity of the population. The primary outcomes included the week of delivery and pregnancy prolongation following cervical cerclage insertion. Numerous secondary outcomes were also evaluated, including neonatal mortality, need for NICU hospitalization, Apgar score, birthweight, maternal white blood cell (WBC) count and C-reactive protein (CRP) levels. Results: Birth week was significantly associated with GW at insertion—35.8 ± 3.8 vs. 34.8 ± 5.2 vs. 32 ± 5.7, respectively, p = 0.016. Moreover, statistical difference was also found regarding birthweight of the analysed groups—2723.8 ± 951.6 g vs. 2518.5 ± 1167.9 g vs. 1886.7 ± 1011.2 g, respectively, p < 0.001, and pregnancy prolongation following cerclage insertion 20.4 ± 4.2 vs. 14.7 ± 5.5 vs. 7.3 ± 5.7 weeks, respectively, p < 0.001. Conclusions: Earlier cerclage placement (<18 weeks) is associated with significantly improved perinatal outcomes. However, this association largely reflects the benefit of prophylactic intervention over emergency ‘rescue’ procedures (common in the >22-week group). The sharp decline in outcomes after 22 weeks highlights the risks of advanced cervical dilation, suggesting that clinical management should prioritize risk assessment within the prophylactic window. Full article

Colorectal cancer (CRC) progression and therapy resistance are driven in part by metabolic reprogramming and the persistence of cancer stem-like cells (CSCs). The seven in absentia homolog 2 (SIAH2)/with-no-lysine kinase 1 (WNK1) signaling axis has emerged as a potential regulator of these processes, yet its functional role in CRC metabolism and tumor–stroma crosstalk remains incompletely understood. Integrated analyses of The Cancer Genome Atlas–Colon Adenocarcinoma (TCGA-COAD) and Gene Expression Omnibus (GEO, GSE17538) datasets revealed significant upregulation of SIAH2 and WNK1 in CRC tissues, with strong positive correlations to glycolysis- and hypoxia-associated genes, including PFKP, LDHA, BPGM, ADH1A, ADH1B, and HIF-1α. Single-cell and clinical profiling further demonstrated preferential enrichment of SIAH2 in undifferentiated, stem-like tumor cell populations. Functional studies across multiple CRC cell lines showed that SIAH2 silencing suppressed proliferation, clonogenic growth, tumor sphere formation, and cell-cycle progression, whereas SIAH2 overexpression exerted opposite effects. Seahorse extracellular flux analyses established that SIAH2 promotes glycolytic capacity and metabolic flexibility. At the protein level, SIAH2 regulated glycolytic enzymes and WNK1/hypoxia-inducible factor-1α (HIF-1α) signaling, effects that were amplified by cancer-associated fibroblast (CAF)-derived conditioned medium. CAF exposure enhanced SIAH2 expression, CSC spheroid growth, and resistance to fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy, whereas SIAH2 depletion effectively abrogated these effects. Collectively, these findings identify the SIAH2/WNK1 axis as a central metabolic regulator linking glycolysis, CSC maintenance, and microenvironment-driven therapy resistance in CRC, highlighting its potential as a therapeutic target. Full article

Background and Objectives: Acute and obstructive pyelonephritis (AOP) management, despite advancements in diagnostic imaging and antimicrobial therapy, is characterized by delayed recognition and increasing antimicrobial resistance. This review aimed to summarize current evidence regarding the clinical characteristics, microbiological spectrum, biomarkers, and imaging findings associated with AOP. Materials and Methods: A systematic review was conducted according to PRISMA guidelines and registered in PROSPERO (CRD420251162736). Literature searches were performed across the PubMed, Scopus, and Web of Science databases for articles published between January 2014 and 31 March 2025 using the term “acute obstructive pyelonephritis”. Inclusion criteria comprised original full-text English-language studies, published in the last 10 years and conducted in adults, reporting clinical, laboratory, microbiological, and imaging characteristics. Exclusion criteria are letters to the editor, expert opinions, case reports, conference or meeting abstracts, reviews, and redundant publications; having unclear or incomplete data; and being performed on cell cultures or on mammals. The quality of included studies was assessed using the Newcastle–Ottawa Scale. Results: Twenty-three studies met the inclusion criteria. AOP predominantly affected elderly patients with comorbidities, especially diabetes mellitus and urinary tract obstruction. Predictors of septic shock included thrombocytopenia, hypoalbuminemia, elevated procalcitonin (>1.12 µg/L), presepsin, and a neutrophil-to-lymphocyte ratio ≥ 8.7. Escherichia coli remained the leading pathogen (60–95%) with extended-spectrum β-lactamase (ESBL) rates between 20 and 70%, followed by Klebsiella pneumoniae. CT demonstrated 71–100% sensitivity for detecting obstructive complications, confirming its superiority over ultrasound, while MRI provided comparable diagnostic accuracy in selected cases. Source control through double-J stenting or percutaneous drainage significantly improved survival. Conclusions: AOP requires prompt recognition and early decompression to prevent sepsis-related mortality. Biomarkers such as procalcitonin, presepsin, and neutrophil to lymphocyte ratio enhance risk stratification, while CT remains the gold-standard imaging modality. The increasing prevalence of ESBL-producing pathogens underscores the need for antimicrobial stewardship and individualized therapeutic strategies guided by local resistance data. Full article

Quiescin sulfhydryl oxidase 1 (QSOX1) is a disulfide bond-forming enzyme with both disulfide isomerase and oxidoreductase activities. It plays an important role in protein folding, stability, and secretion. Growing evidence demonstrates that QSOX1 is upregulated in multiple cancer types and influences key behaviors of cancer cells, including proliferation, migration, invasion, and metastasis. Elevated QSOX1 expression is also associated with tumor malignancy and disease relapse. However, the molecular mechanisms by which QSOX1 drives cancer progression remain incompletely understood. In this review, we summarize current knowledge of QSOX1 expression and regulation in cancer, discuss its functional roles, and highlight key unanswered questions to warrant further investigation. Full article

Three new pyrrole alkaloids, streptopyrroles D–F (1–3), along with four known analogs (4–7) were isolated from Sea Anemone-Associated Streptomyces sp. S1502 via an OSMAC (One Strain Many Compounds)-based strategy. Their structures were elucidated through comprehensive spectroscopic analyses, including HRESIMS and 1D/2D NMR experiments (COSY, HSQC, and HMBC), and further confirmed by X-ray crystallography. Biological evaluation identified streptopyrrole (4) as an anti-MRSA (methicillin-resistant Staphylococcus aureus) agent, while 4 and 6 displayed broad-spectrum cytotoxicity and good selectivity against a panel of human cancer cell lines. Notably, 4 and 6 showed particularly potent activity against the lung cancer cell lines H1299, SW1573, and A549, with IC₅₀ values ranging from 5.43 to 16.24 μM. Further mechanistic investigation revealed that both compounds suppress the proliferation of lung cancer cells by inducing cell cycle arrest at the G0/G1 phase and impair metastatic potential by inhibiting migration and invasion. These findings not only expand the structural diversity of marine-derived pyrrole alkaloids but also reveal the anticancer mechanisms of 4 and 6, highlighting their promise as active candidates for further antitumor drug development, particularly in lung cancer. Full article

Cutaneous viral infections result from the complex interaction between viruses and skin structures, influenced by viral tropism and the host immune response. They can generate lesions ranging from transient rashes to chronic or potentially tumorous formations. Cutaneous manifestations are often the first sign of infection and allow for early recognition. The aim of this review is to analyze the role of viruses in skin pathology, the mechanisms of infection, and the clinical impact. A narrative review of the recent literature was performed, including original articles, systematic reviews, and clinical guidelines on cutaneous viral infections. Data on pathogenic mechanisms, types of lesions, evolution, and therapeutic options were evaluated, covering the main viruses involved in dermatology: herpesviruses, papillomaviruses, poxviruses, and viruses associated with acute rashes. Cutaneous viral infections can be self-limited, recurrent, or chronic, and some can promote malignant transformation of skin cells. The variability of clinical manifestations reflects the virus–host interaction and influences diagnosis and management. Recent advances highlight the development of vaccines and targeted antiviral therapies, which improve prognosis and infection control. Viruses play a major role in the etiology of skin diseases, and their early recognition is essential for preventing complications. Understanding the mechanisms of infection and the cutaneous response contributes to the optimization of therapeutic and preventive strategies, strengthening the modern management of viral cutaneous pathology. Full article

Vitis sp. cv. Koshu is an important Japanese indigenous wine grape cultivar. However, it possesses challenging traits for winemaking, including large berries and low sugar content. To explore the transcriptional profile associated with these characteristics, we conducted a comparative transcriptome analysis of the berry flesh of Koshu and Chardonnay at 10 days after the onset of véraison. A total of 5534 differentially expressed genes were identified, revealing a distinct transcriptional profile in Koshu. The expression patterns in Koshu suggest an altered ripening progression, characterized by the marked downregulation of the ripening marker Grape Ripening-Induced Protein 22-like (GRIP22-like) and the upregulation of photosynthesis-related genes. Despite its large-berry phenotype, cell wall-loosening genes were suppressed in Koshu, leading to the hypothesis that its size may reflect cell division in the early growth stage rather than cell expansion during ripening. Its low-sugar phenotype appears to be associated with multiple factors, including the suppression of key sugar accumulation enzyme genes, such as sucrose synthase 2 (SS2) and sucrose-phosphate synthase 1 (SPS1), the upregulation of Early Response to Dehydration 6-like (ERD6-like) genes, which encode putative vacuolar glucose exporters, and the suppression of cell wall-loosening genes, suggesting a potential biophysical limitation on sugar storage. This study provides the first detailed transcriptomic resource for Koshu berry and identifies key candidate genes for future breeding strategies to improve this unique cultivar. Full article