Search Results (361)

Background: Heat therapy (HT) and electroacupuncture (EA) are widely utilized pain relief methods, but the analgesic mechanisms of their combined application remain unclear. Methods: In acetic acid (AA)-induced writhing test and complete Freund’s adjuvant (CFA)-induced inflammatory pain tests, mice received one of three treatments: EA at bilateral ST36, HT via a 45 °C heating pad, or the combination (EA + HT). To probe underlying pathways, separate groups were pretreated with caffeine, DPCPX (a selective adenosine A₁ receptor antagonist), or naloxone (an opioid receptor antagonist). Spinal expression of glial fibrillary acidic protein (GFAP) and phosphorylated p38 (p-p38) was examined by Western blot and immunofluorescence. Results: Both EA and HT individually reduced AA-induced writhing, with the combination (EA + HT) exhibiting the greatest analgesic effect. EA’s analgesic effect was reversed by caffeine and DPCPX and partially by naloxone, while HT’s effect was reversed by caffeine and DPCPX but was unaffected by naloxone. AA injection elevated spinal p-p38 and GFAP expression, which were attenuated by either EA or HT, with the most substantial suppression observed in the EA + HT group. In the CFA model, both treatments alleviated mechanical allodynia, while the combined treatment resulted in significantly greater analgesia compared to either treatment alone. Conclusions: EA combined with HT synergistically enhances analgesia in both AA and CFA pain models, accompanied by reduced spinal inflammation and astrocyte activation. EA’s analgesic effects appear to involve adenosine A₁ receptor pathways and, to a lesser extent, opioid receptor mechanisms, whereas HT’s effects involve adenosine A₁ receptor pathways. Full article

Background: Soft tissue sarcomas (STSs) are a rare and heterogeneous group of mesenchymal tumors with limited response to current therapies, particularly in advanced stages. STS tumors were traditionally considered “cold” tumors, characterized by limited immune infiltration and low immunogenicity. However, emerging evidence is challenging this perception, highlighting a potentially critical role for the immune system in STS biology. Objective: Building on our previous findings suggesting impaired natural killer (NK) cell activity in STS patients, we aimed to perform an in-depth characterization of peripheral NK cells in STS. Methods: Peripheral blood samples from STS patients and sex- and age-matched healthy donors were analyzed to assess NK cell degranulation, IFNγ production, and receptor repertoire. Results: Functional assays revealed a notable reduction in both degranulation and IFNγ production in NK cells from STS patients. STS patients also exhibited dysregulated expression of activating and inhibitory NK cell receptors. Principal component analysis (PCA) identified CD27 and NKp44 as critical markers for distinguishing STS patients from healthy donors. Increased CD27 expression represents a shift towards a more regulatory NK cell phenotype, and we found that CD27 expression was negatively correlated with NK cell degranulation and IFNγ production. ROC curve analysis demonstrated strong potential to distinguish between the groups for both CD27 (AUC = 0.85) and NKp44 (AUC = 0.94). Conclusion: In conclusion, STS patients exhibited impaired NK cell function, altered receptor repertoire, and a shift towards a less cytotoxic and more regulatory phenotype. Full article

Background/Objectives: Cell–cell communication (CCC) is a critical process within the tumor microenvironment, governing regulatory interactions between cancer cells and other cellular subpopulations. Aiming to improve the accuracy and completeness of intercellular gene-regulatory network inference, we constructed a novel spatial-resolved gene-regulatory network framework (spGRN). Methods: Firstly, the spatial multi-omics data of colorectal cancer (CRC) patients were analyzed. We precisely located the tumor boundaries and then systematically constructed the spGRN framework to study the network regulation. Subsequently, the key signaling molecules obtained by the spGRN were identified and further validated by the spatial-proteomics dataset. Results: Through the constructed spatial gene regulatory network, we found that in the communication with malignant cells, the highly expressed ligands LIF and LGALS3BP and receptors IL6ST and ITGB1 in fibroblasts can promote tumor proliferation, and the highly expressed ligands S100A8/S100A9 in plasma cells play an important role in regulating inflammatory responses. Further, validation of the key signaling molecules by the spatial-proteomics dataset highlighted the role of these genes in mediating the regulation of boundary-related cells. Furthermore, we applied the spGRN to publicly available single-cell and spatial-transcriptomics datasets from three other cancer types. The results demonstrate that ITGB1 and its target genes FOS/JUN were commonly expressed in all four cancer types, indicating their potential as pan-cancer therapeutic targets. Conclusion: the spGRN was proven to be a useful tool to select signal molecules as potential biomarkers or valuable therapeutic targets. Full article

Background/Objectives: Cefiderocol is a novel siderophore cephalosporin with potent in vitro activity against a broad spectrum of Gram-negative bacteria, including carbapenemase-producing Enterobacterales (CPE). However, the recent emergence of resistance in clinical settings raises important concerns regarding its long-term effectiveness. This study aims to investigate the genomic determinants associated with cefiderocol resistance in CPE isolates of human origin. Methods: Comparative genomic analyses were conducted between cefiderocol-susceptible and -resistant CPE isolates recovered from human clinical and epidemiological samples at a tertiary care hospital. Whole-genome sequencing, variant annotation, structural modelling, and pangenome analysis were performed to characterize resistance mechanisms. Results: A total of 59 isolates (29 resistant and 30 susceptible) were analyzed, predominantly comprising Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae. The most frequent carbapenemase gene among the resistant isolates was bla_NDM, which was also present in a subset of susceptible strains. The resistant isolates exhibited a significantly higher burden of non-synonymous mutations in their siderophore receptor genes, notably within fecR, fecA, fiu, and cirA. Structural modelling predicted deleterious effects for mutations such as fecR:G104S and fecA:A190T. Additionally, porin loss and loop 3 insertions (e.g., GD/TD) in OmpK36, as well as OmpK35 truncations, were more frequent in the resistant isolates, particularly in high-risk clones such as ST395 and ST512. Genes associated with toxin–antitoxin systems (chpB2, pemI) and a hypothetical metalloprotease (group_2577) were uniquely found in the resistant group. Conclusions: Cefiderocol resistance in CPE appears to be multifactorial. NDM-type metallo-β-lactamases and missense mutations in siderophore uptake systems—especially in those encoded by fec, fhu, and cir operons—play a central role. These may be further potentiated by alterations in membrane permeability, such as porin disruption and efflux deregulation. The integration of genomic and structural approaches provides valuable insights into emerging resistance mechanisms and may support the development of diagnostic tools and therapeutic strategies. Full article

Background: The PATHFINDER-CHD Registry is a prospective, multicenter, non-interventional registry across tertiary care centers in Germany. The aim is to analyze real-world data on adults with congenital heart defects (ACHD) or hereditary connective tissue disorders who have manifest heart failure (HF), a history of HF, or are at significant risk of developing HF. This analysis investigates the prevalence and clinical impact of overweight and obesity in this unique population. Methods: As of 1st February, 2025, a total of 1490 ACHD had been enrolled. The mean age was 39.4 ± 12.4 years, and 47.9% were female. Patients were categorized according to Perloff’s functional class and the Munich Heart Failure Classification for Congenital Heart Disease (MUC-HF-Class). Results: The most common congenital heart disease (CHD) in this cohort was Tetralogy of Fallot, transposition of the great arteries, and congenital aortic valve disease. Marfan syndrome was the most common hereditary connective tissue disease. Of the patients, 46.1% were classified as overweight (32.8%) or obese (13.3%), while 4.8% were underweight. The highest prevalence of overweight (47.1%) was observed among patients who had undergone palliative surgery, whereas untreated patients showed the highest proportion of normal weight (57.2%). Cyanotic patients were predominantly of normal weight. Patients with univentricular circulation exhibited significantly lower rates of overweight and obesity (35%; p = 0.001). Overweight and obesity were statistically significantly associated with arterial hypertension, diabetes mellitus, and sleep apnea (all p < 0.001). High BMI was linked to increased use of HF-specific medications, including SGLT2 inhibitors (p = 0.040), diuretics (p = 0.014), and angiotensin receptor blockers (p = 0.005). Conclusions: The data highlight the clinical relevance of overweight and obesity in ACHD with HF, emphasizing the need for individualized prevention and treatment strategies. The registry serves as a critical foundation for the optimization of long-term care in this population. Full article

Spatial transcriptomics (ST) is emerging as a powerful technology that transforms our understanding of thyroid cancer by offering a spatial context of gene expression within the tumor tissue. In this review, we synthesize the recent applications of ST in thyroid cancer research, with a particular focus on the heterogeneity of the tumor microenvironment, tumor evolution, and cellular interactions. Studies have leveraged the spatial information provided by ST to map distinct cell types and expression patterns of genes and pathways across the different regions of thyroid cancer samples. The spatial context also allows a closer examination of invasion and metastasis, especially through the dysregulation at the tumor leading edge. Additionally, signaling pathways are inferred at a more accurate level through the spatial proximity of ligands and receptors. We also discuss the limitations that need to be overcome, including technical limitations like low resolution and sequencing depth, the need for high-quality samples, and complex data handling processes, and suggest future directions for a wider and more efficient application of ST in advancing personalized treatment of thyroid cancer. Full article

Inflammation contributes to myocardial injury in ST-elevation myocardial infarction (STEMI). Interleukin-6 receptor (IL-6R) inhibition has been shown to mitigate myocardial injury and reduce levels of the prothrombotic and inflammatory mediator, neutrophil extracellular traps (NETs). The enzyme peptidylarginine deiminase 4 (PAD4) is central in NET formation. We hypothesized that PAD4 links IL-6R activation and NET formation. Methods: We conducted thrombus aspiration and peripheral blood sampling in 33 STEMI patients. In thrombi and leukocytes, we quantified the mRNA of IL-6, IL-6R, and PAD4. In peripheral blood, the protein levels of IL-6, IL-6R, PAD4, dsDNA, H3Cit, MPO-DNA, and troponin T were quantified. Results: In thrombi and circulating leukocytes, PAD4 mRNA was associated with IL-6R mRNA (thrombi: β = 0.34, 95% CI [0.16–0.53], p = 0.001, circulating leukocytes: β = 0.92, 95% CI [0.07–1.77], p = 0.036). There were no correlations between PAD4 and IL-6 in thrombi and leukocytes. The protein levels of IL-6R were associated with the NET marker H3Cit (r_s = 0.40, p = 0.02). In thrombi, PAD4 mRNA was associated with high levels of troponin T (β = 1.15 95% CI [0.27–2.04], p = 0.013). Conclusion: We demonstrate an association between PAD4, IL-6R, and troponin release in STEMI patients. Our findings indicate a PAD4-mediated connection between IL-6R and NET formation and highlight PAD4 as a potential treatment target for mitigating inflammation and myocardial injury in STEMI. Full article

Background: The testis, a critical reproductive organ in male animals, is responsible for sperm production and androgen secretion. Testis weight often correlates with reproductive performance, yet the genetic factors influencing testicular traits in chickens remain unclear. Methods: Previous genome-wide association studies (GWAS) have identified key genes affecting testicular traits in Kangle Yellow chickens, along with the associated regulatory pathways and Gene Ontology (GO) terms, through bioinformatic analyses. In this study, we utilized the existing literature, full-length transcriptome data, and proteome analyses to select key candidate genes. Results: We identified 13 associated markers for chicken testicular traits with 262 candidate genes. Nine candidate genes were found to regulate chicken testicular traits referred to integrated analysis, including CDH3, ZFPM1, CFAP52, ST6GAL1, IGF2BP2, SPG7, CDT1, NFAT5, and OPRK1. Physical interactions among these genes were also observed, implicating mechanisms such as cell adhesion molecules and neuroactive ligand–receptor interaction. Conclusions: These findings provide a genetic basis for improving testicular traits in Chinese native chicken breeds. Full article

In eutherian mammals, embryo implantation is a critical process for a successful pregnancy. In mice, the activation of the leukemia inhibitory factor (LIF) receptor–STAT3 signaling axis induces embryo adhesion and decidualization. The LIF receptor is believed to function as a heterodimer composed of LIFR (encoded by Lifr) and GP130 (encoded by Il6st); however, their distinct expression patterns in the uterine epithelium immediately prior to implantation suggest divergent functional roles. In this study, we generated uterine epithelium-specific Lifr knockout (Lifr eKO) mice and conducted a comprehensive gene expression analysis of the endometrium before implantation. We compared these results with those from uterine epithelium-specific Gp130 knockout (Gp130 eKO) mice. Similarly to Gp130 eKO mice, Lifr eKO mice were completely infertile. We identified 299 genes with expression changes greater than twofold following gene deletion; among these, 31 genes were downregulated and 57 genes were upregulated in both eKO models. Many of the downregulated genes were previously implicated in uterine function. Hub gene analysis identified Erbb2 and c-Fos as key regulators in both models. Further experiments using an ERBB2 inhibitor suggested that LIFR–ERBB2-mediated signaling plays a crucial role in embryo implantation. Full article

Obesity is one of the most pressing global public health challenges of the 21st century, affecting over a billion people worldwide. Poland, like many industrialized countries, is experiencing a rapid increase in obesity prevalence across all age groups. This review provides a comprehensive analysis of the obesity trends in Poland in relation to global patterns, emphasizing the complex interplay of dietary habits, physical inactivity, screen time, socioeconomic determinants, and gut microbiota composition. Special attention is given to the health and economic consequences of obesity and the inefficiencies in Poland’s public health response. The article also discusses novel research directions, including the role of hypothalamic BNC2 neurons and NK2R receptors in appetite regulation and energy expenditure, as well as the cellular heterogeneity of adipose tissue. These discoveries may open new avenues for personalized obesity therapies. The findings underscore the urgent need for coordinated, interdisciplinary strategies at the national and international levels to reduce the burden of obesity and improve long-term health outcomes. Full article

Background: Suppression of Tumorigenicity 2 (ST2), a member of the interleukin-1 receptor family, plays a crucial role in immune regulation. Elevated sST2 levels are associated with poor prognosis in various inflammatory and cardiovascular diseases, including acute heart failure (AHF), sepsis and transplant rejection. Objectives and methods: This study aimed to evaluate the diagnostic and prognostic accuracy of sST2, along with other biomarkers, such as high-sensitivity C-reactive protein (hs-CRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), procalcitonin (PCT) and mid-regional pro-adrenomedullin (MR-proADM), in patients with AHF, sepsis and AHF/sepsis overlap. Results: A cohort of 74 patients was analyzed, and comparison statistics revealed that sST2 levels were significantly higher in the AHF/sepsis group (113.88 ng/mL) compared to the AHF group (42.24 ng/mL, p = 0.024), while no significant difference was observed between sepsis and AHF groups (p = 0.10). Other biomarkers, including hs-CRP and PCT, showed significant differences between the AHF and AHF/sepsis groups. ROC curve analysis identified sST2 as a strong predictor of mortality and readmission, with high AUC values for 30-day readmission (0.821) and mortality (0.87). Conclusions: These findings suggest that combining biomarkers, including sST2, could improve the early diagnosis, risk stratification and management of critically ill patients with overlapping AHF and sepsis. Further studies with larger populations are needed to validate these findings and explore the potential of integrating these biomarkers into clinical practice. Full article

Temperature changes strongly affect apple development and quality. In this study, we analyze the relationships between the main factors modulating both of the aforementioned processes in the fruits of four apple cultivars. We assessed three-dimensional data concerning the expression profile (fold change) of eight genes related to fruit ripeness regulation (involved in the cell respiration process and sorbitol metabolism as well as encoding cell kinase receptors) and fruit parameters such as fruit weight, ethylene concentration, concentration of soluble solids and acidity, which are affected by seasonal temperature variations (2018–2020). We observed that low temperatures (before the apple ripening phase) promoted an increase in gene activity and improved the fruit quality of the following cultivars: early-flowering/mid-ripening ‘Pink Braeburn’ and ‘Pinokio’, early-flowering/late-ripening ‘Ligol’ and late-flowering/late-ripening ‘Ligolina’. We confirmed the positive effect of low temperatures on the activity of the AAAA1, AALA1, StG and AAXA genes and on the evaluated fruit quality parameters, and we confirmed their dependence on the genotype of the studied cultivars. The obtained results shed light on the complexity of the variability mechanism in fruit features and fruit harvest dates. This knowledge may improve breeding programs for the production of better-quality apples. Full article

After weaning, piglets no longer consume breast milk, and their immune system is not yet fully developed. At this time, if weaned piglets are infected with E. coli, their subsequent growth will be seriously affected. In the present study, 48 healthy 28-day-old weaned piglets (6.65 ± 1.19 kg, Duroc × Landrace × Large White) were randomly divided into an LPS group and control group. Piglets in the LPS group were intraperitoneally injected with an LPS solution (LPS was dissolved in sterile saline to form a solution of 100 μg/mL and injected at a dose of 1 mL per kilogram of body weight) for 13 consecutive days. Piglets in the control group were injected with the same volume of sterile saline. On days 1, 5, 9, and 13 of the experiment, six piglets from each group were randomly selected for dissection, the blood and heart samples were collected, and then cardiac function-related indicators were detected. A portion of the heart tissue was fixed in 4% paraformaldehyde and further used to make paraffin sections; then, hematoxylin–eosin (H&E) staining was performed. Masson staining was used to detect the changes in collagen fibers in the hearts. The other parts of the heart tissues were frozen in liquid nitrogen and stored in a refrigerator at −80 °C for the detection of tissue antioxidant indices. The mRNA expression levels of the toll-like receptor 4 (TLR4) signaling pathway, transforming growth factor-β (TGF-β) signaling pathway, and inflammatory cytokines in heart tissues were detected by real-time PCR. The results showed that catalase (CAT) and superoxide dismutase (SOD) contents in the heart tissue homogenates increased significantly on days 1 and 5 in LPS-induced piglets (p < 0.01, p < 0.05), while total antioxidant capacity (T-AOC) and glutathione peroxidase (GSH-Px) contents decreased significantly on day 5 (p < 0.05). On day 5, the contents of serum cardiac function indicators lactate dehydrogenase (LDH), creatine kinase isoenzymes (CK-MB), and cardiac troponin I (cTn-I) were significantly increased in LPS-induced piglets (p < 0.01). On the 1st and 5th days, the heart tissue showed obvious pathological damage, which was manifested as the disordered arrangement of myocardial fibers, depression of myocardial cells, infiltration of inflammatory factors, congestion of capillaries, and significant increase in cardiac collagen fibers. On the 1st day, the mRNA expression levels of tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) were significantly increased in LPS-induced piglets with heart injury (p < 0.01). On the 5th day, the mRNA expression levels of the TLR4 signaling pathway [TLR4, myeloid differentiation primary response gene 88 (MyD88), nuclear factor kappa-B (NF-κB)], TNF-α, and interleukin 10 (IL-10) were also significantly increased in LPS-induced piglets with heart injury (p < 0.01, p < 0.05). The mRNA expression levels of the TGF-β signaling pathway (TGF-β, Smad2, and Smad4) in cardiac fibrosis-related genes were significantly increased on days 5 and 9 (p < 0.01, p < 0.05). The mRNA expression levels of Smad3 and Smad7 in cardiac fibrosis-related genes were also significantly increased on day 9 (p < 0.01). These results indicate that oxidative stress occurs in the heart tissue of LPS-induced piglets on the 1st and 5th days, leading to cardiac tissue damage. However, on the 9th and 13th days, the degree of heart damage in the piglets was less than that on the 1st and 5th days, which may be due to the tolerance of piglets’ tissues and organs because of multiple same-dose LPS stimulations. Full article

Background: Gut barrier integrity plays a crucial role in the pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD). Electroacupuncture (EA) at ST-36 can ameliorate inflammatory responses via stimulating the α7 nicotinic acetylcholine receptor (α7nAChR), but whether EA is effective in preserving the intestinal barrier of MAFLD has not been exactly illustrated. This investigation explored potential protection mechanisms of EA at ST-36 targeting the dismantled gut barrier in MAFLD. Methods: C57BL/6 mice were randomly allocated into several subgroups: control (CON), high-fat diet (HFD), HFD with EA, HFD with EA and α7nAChR inhibitor α-BGT, and HFD with EA and intestinal HO-1 knockout (KO). Body weight, liver weight, visceral fat index, and histopathological examination of the liver and the intestine were determined. Serum biological indexes were evaluated through corresponding kits. Furthermore, the expressions of HO-1, α7nAChR, gut barrier-associated proteins, and the molecular mechanisms in intestinal tissues were assessed via Western blot, RT-qPCR, immunohistology, or immunofluorescence examination. Results: EA treatment decreased body weight, liver weight, and visceral fat index gain and mitigated liver function injury and abnormal lipid indexes, exhibiting less severity of hepatic steatosis, fibrosis, and inflammation responses of MAFLD. Lower gut permeability, less intestinal epithelial disruption, and upregulation of tight junction proteins after EA suggested the protective effects in attenuating intestinal epithelial barrier dysfunction. These protective effects were abolished by α-BGT or intestinal HO-1 deletion. Mechanistically, EA markedly enriched α7nAChR and HO-1 expression and mitigated phosphorylated p38 MAPK/NF-κB activation, which was lost in α-BGT or HO-1 KO treatment. Conclusions: The protective effects of EA at ST-36 in the pathogenesis of MAFLD may be attributed to the preserved intestinal barrier, thereby alleviating systemic inflammatory responses and preventing subsequent liver hits, where the α7nAChR-mediated HO-1/p38 MAPK/NF-κB pathway was crucial to maintain homeostasis. Full article

Fibroblast growth factor receptor 1 (FGFR1), also known as KAL2, is a tyrosine kinase receptor, and variants of FGFR1 have been detected in patients with Kallmann syndrome (KS), which is a congenital developmental disorder characterized by central hypogonadism and anosmia. Herein, we report an adult case of KS with a novel variant of FGFR1. A middle-aged male was referred for a compression fracture of a lumbar vertebra. It was shown that he had severe osteoporosis, anosmia, gynecomastia, and a past history of operations for cryptorchidism. Endocrine workup using pituitary and gonadal stimulation tests revealed the presence of both primary and central hypogonadism. Genetic testing revealed a novel variant of FGFR1 (c.2197_2199dup, p.Met733dup). To identify the pathogenicity of the novel variant and the clinical significance for the gonads, we investigated the effects of the FGFR1 variant on the downstream signaling of FGFR1 and gonadal steroidogenesis by using human steroidogenic granulosa cells. It was revealed that the transfection of the variant gene significantly impaired FGFR1 signaling, detected through the downregulation of SPRY2, compared with that of the case of the forced expression of wild-type FGFR1, and that the existence of the variant gene apparently altered the expression of key steroidogenic factors, including StAR and aromatase, in the gonad. The results suggested that the novel variant of FGFR1 detected in the patient with KS was linked to the impairment of FGFR1 signaling, as well as the alteration of gonadal steroidogenesis, leading to the pathogenesis of latent primary hypogonadism. Full article