Search Results (269)

Hydrogen-rich water (HRW) has shown neuroprotective effects in acute brain injury, but its role in chronic radiation-induced brain injury (RIBI) remains unclear. This study investigated the long-term efficacy of HRW in mitigating cognitive impairment and neuronal damage caused by chronic RIBI. Fifty male Sprague Dawley rats were randomly divided into five groups: control, irradiation (IR), IR with memantine, IR with HRW, and IR with combined treatment. All but the control group received 20 Gy whole-brain X-ray irradiation, followed by daily interventions for 60 days. Behavioral assessments, histopathological analyses, oxidative stress measurements, ¹⁸F-FDG PET/CT imaging, transcriptomic sequencing, RT-qPCR, Western blot, and serum ELISA were performed. HRW significantly improved anxiety-like behavior, memory, and learning performance compared to the IR group. Histological results revealed that HRW reduced neuronal swelling, degeneration, and loss and enhanced dendritic spine density and neurogenesis. PET/CT imaging showed increased hippocampal glucose uptake in the IR group, which was alleviated by HRW treatment. Transcriptomic and molecular analyses indicated that HRW modulated key genes and proteins, including CD44, CD74, SPP1, and Wnt1, potentially through the MIF, Wnt, and SPP1 signaling pathways. Serum CD44 levels were also lower in treated rats, suggesting its potential as a biomarker for chronic RIBI. These findings demonstrate that HRW can alleviate chronic RIBI by preserving neuronal structure, reducing inflammation, and enhancing neuroplasticity, supporting its potential as a therapeutic strategy for radiation-induced cognitive impairment. Full article

Triple-negative breast cancer (TNBC) is a clinically and molecularly heterogeneous subtype defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. In this study, tumor specimens from 104 TNBC patients were analyzed to characterize molecular and clinicopathological features and to assess the expression and therapeutic potential of four key surface markers: epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM), tissue factor (TF), and trophoblast cell surface antigen (TROP2). Multiplex immunofluorescence (mIF) demonstrated elevated EGFR and TROP2 expression in the majority of samples. Significant positive correlations were observed between EGFR and TF, as well as between TROP2 and both TF and EpCAM. Expression analyses revealed increased EGFR and TF levels with advancing tumor stage, whereas EpCAM expression declined in advanced-stage tumors. TROP2 and TF expression were significantly elevated in higher-grade tumors. Additionally, EGFR and EpCAM levels were significantly higher in patients with elevated Ki-67 indices. Binding specificity assays using single-chain variable fragment (scFv-SNAP) fusion proteins confirmed robust targeting efficacy, particularly for EGFR and TROP2. These findings underscore the therapeutic relevance of EGFR and TROP2 as potential biomarkers and targets in TNBC. Full article

MET exon 14 skipping mutations have emerged as significant driver alterations in non-small-cell lung cancer (NSCLC), contributing to tumor progression. This study examines the immune microenvironment in NSCLC patients with these mutations and its prognostic implications. We performed multiplex immunofluorescence (mIF) staining on formalin-fixed paraffin-embedded (FFPE) tissue samples from nine NSCLC patients, including four recurrent/metastatic and five non-recurrent/non-metastatic patients. Two panels assessed immune cell markers (CD8, CD4, CD20, CD68, and FoxP3) and immune checkpoints (PD-L1, LAG3, and TIM3). Immune cell infiltration and checkpoint expression were analyzed using HALO^TM software (version 3.6.4134.464). Nearest neighbor analysis was conducted to assess the proximity of immune cells to tumor cells. Univariate Cox regression analysis assessed factors associated with disease-free survival (DFS). CD8+TIM3+ and CD8+LAG3+ cells were predominantly located in the tumor parenchyma of recurrent/metastatic patients but localized to the stroma in non-recurrent/non-metastatic patients. Non-recurrent/non-metastatic patients exhibited a higher density of tertiary lymphoid structures and closer proximity of CD20+ B cells, CD8+TIM3+, and CD8+LAG3+ cells to tumor cells compared to recurrent/metastatic patients, though the differences were not statistically significant. Cox regression analysis suggested a potential association between higher densities of CD8+TIM3+ cells and improved DFS (HR = 0.89), though these findings did not reach statistical significance. Our findings suggest that differences in immune microenvironmental factors, particularly those related to immune checkpoint expression (TIM3 and LAG3), may influence clinical outcomes in NSCLC patients with MET exon 14 skipping mutations. Further studies are needed to validate these observations and explore potential therapeutic implications. Full article

Endometriosis is the extrauterine engraftment of endometrium-like tissue, causing chronic pain. Complex sensory–vascular–immune interactions, including growth factors, cytokines, and neuropeptides, are implicated in its pathophysiology, but the mechanisms remain unknown. Here, epidermal growth factor (EGF), vascular endothelial growth factor, interleukins (IL-1β, IL-6, IL-8), macrophage migration inhibitory factor (MIF), calcitonin gene-related peptide, and somatostatin were measured in the serum of endometriosis patients with different disease severities, menstruation cycle- and pharmacotherapy-related hormonal status compared with controls. Mediator levels in deep-infiltrating rectosigmoid nodules were also compared with those in non-endometriotic colon tissues. Pain was assessed by the visual analogue scale. Serum EGF was significantly lower in mild endometriosis and in the secretory phase. MIF and IL-6 were higher in stage I–IV endometriosis, with MIF also higher in the secretory phase and in patients not receiving oral contraceptives. Somatostatin was lower in mild endometriosis than that in healthy individuals and the severe endometriosis group. No tissue-level differences were found. A strong positive correlation between serum EGF and somatostatin levels and dysmenorrhea and dysuria was detected in mild cases. It is concluded that certain serum alterations may be related to severity- and hormone status-dependent endometriosis mechanisms, but their diagnostic/prognostic value seems to be limited due to variability and lack of specificity. Full article

Human induced pluripotent stem cells (iPSCs) offer immense potential as a source for cell therapy in spinal cord injury (SCI) and other diseases. The development of hypoimmunogenic, universal cells that could be transplanted to any recipient without requiring a matching donor could significantly enhance their therapeutic potential and accelerate clinical translation. To create off-the-shelf hypoimmunogenic cells, we used CRISPR-Cas9 to delete B2M (HLA class I) and CIITA (master regulator of HLA class II). Double-knockout (DKO) iPSC-derived neural progenitor cells (NPCs) evaded T-cell-mediated immune rejection in vitro and after grafting into the injured spinal cord of athymic rats and humanized mice. However, loss of HLA class I heightened susceptibility to host natural killer (NK) cell attack, limiting graft survival. To counter this negative effect, we engineered DKO NPCs to overexpress macrophage migration inhibitory factor (MIF), an NK cell checkpoint ligand. MIF expression markedly reduced NK cell-mediated cytotoxicity and improved long-term engraftment and integration of NPCs in the animal models for spinal cord injury. These findings demonstrate that MIF overexpression, combined with concurrent B2M and CIITA deletion, generates hiPSC neural derivatives that escape both T- and NK-cell surveillance. This strategy provides a scalable route to universal donor cells for regenerative therapies in SCI and potentially other disorders. Full article

Introduction: Postoperative delirium (POD) remains a major complication in geriatric surgical care, with poorly understood molecular mechanisms. Emerging evidence links cardiac surgery to elevated markers of neurologic injury, even in cognitively intact individuals. While neuroinflammation is the prevailing model, a more detailed characterization of the systemic inflammatory and metabolic response to surgery may offer deeper insights into POD pathogenesis. Methods: We used the 7K SomaLogic proteomic platform to analyze preoperative and postoperative day-one serum samples from 78 patients undergoing cardiac surgery with cardiopulmonary bypass. We compared proteomic profiles within individuals (pre- vs. post-surgery) and between those who developed POD and those who did not. Functional analyses were performed to identify relevant biological pathways. A composite metabo-inflammatory score (MIF) was derived to quantify systemic derangement. We modeled the association between POD and age, sex, baseline cognition, and MIF score. Results: Cardiac surgery with CPB was associated with marked inflammatory responses across all subjects, including increased IL-6, CRP, and serum amyloid A. Compared to controls, POD cases showed greater metabo-inflammatory shifts from baseline (average logFC = 2.56, p < 0.001). Lower baseline cognitive scores (OR = 0.74, p = 0.019) and higher MIF scores (OR = 1.03, p = 0.013) were independently associated with increased POD risk. Conclusions: Cardiac surgery with CPB elicits a significant metabo-inflammatory response in all patients. However, those who develop POD exhibit disproportionately greater dysregulation. Full article

Lafora progressive myoclonus epilepsy (LD, OMIM#254780, ORPHA:501) is an ultra-rare and severe autosomal recessive neurological disorder that typically manifests in early adolescence. It is characterized by the accumulation of insoluble forms of aberrant glycogen in the brain and peripheral tissues. Given the urgent need for reliable tools to monitor disease progression, we aimed to identify reliable biomarkers in minimally invasive fluids, which could also provide valuable insights into the natural history of the disease. Plasma-EDTA samples from eleven LD patients and healthy controls were analyzed to identify potential biomarkers of LD using a high-throughput assay. The findings were subsequently validated using specific enzyme-linked immunosorbent assays (ELISAs). Eleven cytokines and growth factors were identified to be significantly reduced in LD patient samples compared to healthy controls. Among these, four mediators [platelet-derived growth factor subunit B (PDGF-BB), epidermal growth factor (EGF), brain derived growth factor (BDNF), and macrophage migration inhibitory factor (MIF)] exhibited the greatest fold change between the groups and were further validated. Given the minimally invasive nature of plasma sampling and the straightforward quantification via ELISA assays, these biomarkers hold strong promise for rapid translation to the clinic, potentially enhancing early diagnosis and longitudinal disease monitoring in LD patients. Full article

The cap-binding protein complex (CBC), comprising Cbp20 and Cbp80, is crucial for gene expression, yet its role in the notorious crop pathogen Botrytis cinerea remains unclear. Immunoprecipitation coupled with LC-MS/MS demonstrated that BcCbp20 interacts with BcCbp80. Yeast two-hybrid, GST pull-down, and Split-luciferase complementation assays confirmed that the conserved RNA recognition motif (RRM, 54–127 aa) of BcCbp20 and the N-terminal MIF4G domain (1–370 aa, 1–577 aa) of BcCbp80 constitute the core interaction regions. Genetic transformation experiments revealed that BcCBP80 exerts a more dominant role than BcCBP20 in regulating hyphal morphology, growth rate, conidiophore development, and conidial yield. Furthermore, BcCBP20 and BcCBP80 differentially regulate sclerotium formation to maintain sclerotial quantity. Based on pathogenicity assays, BcCBP80 associated with infection cushion development, with this phenotypic alteration possibly being among the factors correlated with altered pathogenicity. However, the increased sensitivity of ΔBccbp20 to various stress factors may be the primary reason for the diminished pathogenicity. Taken together, these results indicate that BcCBP20 and BcCBP80 play important roles in multiple aspects of B. cinerea growth, development, stress response, and pathogenicity. Full article

Multimodal medical image fusion plays a critical role in enhancing diagnostic accuracy by integrating complementary information from different imaging modalities. However, existing methods often suffer from issues such as unbalanced feature fusion, structural blurring, loss of fine details, and limited global semantic modeling, particularly in low signal-to-noise modalities like PET. To address these challenges, we propose PPMF-Net, a novel progressive and parallel deep learning framework for PET–MRI image fusion. The network employs a hierarchical multi-path architecture to capture local details, global semantics, and high-frequency information in a coordinated manner. Specifically, it integrates three key modules: (1) a Dynamic Edge-Enhanced Module (DEEM) utilizing inverted residual blocks and channel attention to sharpen edge and texture features, (2) a Nonlinear Interactive Feature Extraction module (NIFE) that combines convolutional operations with element-wise multiplication to enable cross-modal feature coupling, and (3) a Transformer-Enhanced Global Modeling module (TEGM) with hybrid local–global attention to improve long-range dependency and structural consistency. A multi-objective unsupervised loss function is designed to jointly optimize structural fidelity, functional complementarity, and detail clarity. Experimental results on the Harvard MIF dataset demonstrate that PPMF-Net outperforms state-of-the-art methods across multiple metrics—achieving SF: 38.27, SD: 96.55, SCD: 1.62, and MS-SSIM: 1.14—and shows strong generalization and robustness in tasks such as SPECT–MRI and CT–MRI fusion, indicating its promising potential for clinical applications. Full article

Background/Objectives: Low-grade systemic inflammation, characteristic of heart failure (HF), is a nonspecific inflammatory syndrome that affects the entire body. Macrophage migration inhibitory factor 1 (MIF-1) is a pro-inflammatory cytokine, a key mediator of the innate immune response, and may serve as a potential biomarker of monocyte homing and activation in HF with reduced and mildly reduced ejection fraction (HFrEF, HFmrEF). Methods: We evaluated 70 hemodynamically stable patients with left ventricular EF (LVEF) < 50% by means of echocardiography and blood sampling. Results: We report significant correlations between MIF-1, LVEF (r = −0.33, p = 0.005), LV global longitudinal strain (LVGLS, r = 0.41, p = 0.0004), and tricuspid annular plane systolic excursion (TAPSE, r = −0.37, p = 0.001). MIF-1 levels in HFrEF patients were relatively higher, but not significantly different from those observed in HFmrEF. MIF-1 showed significant associations with TAPSE to systolic pulmonary artery pressure ratio (TAPSE/sPAP, p < 0.0001). Also, patients with TAPSE/sPAP < 0.40 mm/mmHg had significantly higher levels of MIF-1 (p = 0.009). Moreover, ischemic cardiomyopathy (ICM) was more frequent in patients with MIF-1 concentrations above 520 pg/mL (57.1% MIF-1^hi vs. 28.6% MIF-1^lo, p = 0.029). In terms of congestion, MIF-1 showed significant associations with the presence of peripheral edema (p = 0.007), but none was found with self-reported dyspnea (p = 0.307) and New York Heart Association (NYHA) class (p = 0.486). Also, no relationship was reported with N-terminal pro-B-type natriuretic peptide concentrations (NT-proBNP, r = 0.14, p = 0.263). However, the six-minute walk distance was greater in individuals in the MIF-1^lo group when compared to those in the MIF-1^hi group (404.0 ± 127.4 vs. 324.8 ± 124.1 m, p = 0.010). Conclusions: Beyond identifying inflammatory biomarkers related to disease severity, linking MIF-1 to various pathophysiological mechanisms may highlight the active involvement of the monocyte-macrophage system in HF. This system holds notable significance in congestion-related conditions, acting as a major source of reactive oxygen species that perpetuate inflammation. Full article

Glaesserella parasuis (G. parasuis) infection is responsible for Glässer’s disease in pigs. G. parasuis could trigger piglet immunosuppression, but the mechanism of inducing immunosuppression by G. parasuis remains unknown. Macrophage migration inhibitory factor (MIF)/CD74 axis has been shown to participate in inflammation response and immunosuppression, but the function of MIF/CD74 during immunosuppression elicited by G. parasuis has not been fully explored. This experiment explored the efficacy of baicalin on immunosuppression elicited by G. parasuis alleviation through regulating polarization via the MIF/CD74 signaling pathway. Our data indicated that baicalin reduced IL-1β, IL-6, IL-8, IL-18, TNF-α, and COX-2 expression, and regulated MIF/CD74 axis expression in the spleen. Immunohistochemistry analysis showed that baicalin enhanced CD74 protein levels in the spleen of piglets induced by G. parasuis. Baicalin regulated the PI3K/Akt/mTOR signaling pathway and RAF/MEK/ERK signaling activation, modified the expression of the autophagy-related proteins Beclin-1, P62, and LC3B, promoted M2 polarization to M1 polarization, and enhanced CD3, CD4, CD8, and TIM3 levels in the spleen of piglets elicited by G. parasuis. Our study reveals the important functions of the MIF/CD74 axis in G. parasuis-induced immunosuppression and may offer a new therapeutic method to control G. parasuis infection. Full article

Depressive disorder during pregnancy is a common condition, affecting approximately 10–15% of pregnant women, and is associated with adverse pregnancy outcomes such as inadequate prenatal care, substance abuse, and fetal growth restriction. Beyond neurotransmitter disturbances, increasing evidence suggests that infectious agents may play a role in the pathophysiology of depression through immune system modulation. Toxoplasma gondii infection has been linked to various mental disorders in the general population, including depression and anxiety. This study aimed to investigate whether depressive disorder during pregnancy is associated with chronic T. gondii infection by analyzing cytokine levels involved in inflammatory response modulation. Serum levels of TNF, IFN-γ, TGF-β1, IL-6, IL-8, IL-10, and MIF were measured in 79 pregnant women (18–40 years old) during the third trimester of an uncomplicated pregnancy. Participants were divided into four groups: Group I—depressive disorder and T. gondii seropositive (n = 19); Group II—no depressive disorder and T. gondii seropositive (n = 20); Group III—depressive disorder and T. gondii seronegative (n = 20); and Group IV—no depressive disorder and T. gondii seronegative (n = 20). Depressive symptoms were assessed using the Edinburgh Postnatal Depression Scale (EPDS) during routine prenatal visits, and blood samples were collected during standard prenatal examinations. Significant differences in cytokine levels were observed among the study groups. Notably, the group with both depressive disorder and chronic T. gondii infection exhibited a distinct cytokine profile characterized by significantly elevated TNF, IL-6, and IL-10 levels and significantly reduced IL-8 and MIF levels compared to the other groups. These findings suggest that pregnant women with depressive disorder and chronic T. gondii infection exhibit an altered balance of pro- and anti-inflammatory cytokines. This is the first study to investigate the association between serum cytokine levels, depressive disorder, and chronic T. gondii infection in pregnant women. Further research is needed to evaluate the potential of these immunobiomarkers as diagnostic tools or for monitoring therapeutic and prognostic strategies in this context. Full article

Protein S-nitrosation, a redox post-translational modification elicited by nitric oxide (NO), is essential for modulating diverse protein functions and signaling pathways. Dysregulation of S-nitrosation is implicated in various pathological processes, including oxygen-glucose deprivation/reperfusion (OGD/R) injury, a widely used model for ischemia-reperfusion diseases. The dynamic changes in S-nitrosothiols (SNOs) during ischemia-reperfusion highlight the need for theranostic strategies to monitor and modulate SNO levels based on pathological progression. However, to date, no theranostic strategies have been reported for addressing dysregulated SNO in disease models, particularly in OGD/R conditions. Here, we report the development of a selective probe P-EHC, which could specifically react with SNOs to release EHC, not only exhibiting turn-on fluorescence with high quantum yield and good water solubility but also demonstrating macrophage migration inhibitory factor (MIF) inhibitory activity. In an OGD/R model of SH-SY5Y cells, we observed elevated SNO levels by using live-cell confocal imaging. Treatment of P-EHC significantly reduced intracellular reactive oxygen species (ROS), lowered total NO_x species, and improved cell viability in the OGD/R model. In summary, the simplicity and versatility of P-EHC suggest its broad applicability for monitoring SNO in various biological models and therapeutic contexts, particularly in ischemia-reperfusion diseases. Full article

Toxoplasmosis is an alarming public health problem that affects more than one-third of the world’s population. In our work, we investigated the antiparasitic effects of catalytically active [BpMP-I and Jararhagin (Jar)] and catalytically inactive [Jararhagin-C (Jar-C)] snake venom metalloproteinases (SVMPs) in human HeLa cells. These toxins impaired the parasite invasion and intracellular growth, and modulated IL-6, IL-8, and MIF cytokines that control the cell susceptibility and response against T. gondii. Furthermore, we verified that the antiprotozoal activities are not restricted to the presence of the proteolytic domain, and the adhesive domains participate in the control of T. gondii infection. Also, by analyzing the structures of Jar and Jar-C through molecular modeling and dynamics, we observed that the adhesive domains in Jar-C are more exposed due to the absence of the proteolytic domain, which could favor the interaction with different targets. Our investigation on the role of SVMP domains in combating T. gondii infection highlights their potential application as biotechnological tools for creating more effective treatments for toxoplasmosis. Full article

The pathogenesis of the central nervous system (CNS) pathology in tick-borne encephalitis (TBE) remains unclear. We attempted to identify mediators of the blood–brain barrier (BBB) disruption in human TBE in paired serum and cerebrospinal fluid (CSF) samples from 100 TBE patients. CSF albumin quotient (Q_alb) was calculated as a measure of BBB impairment. Concentrations of cytokines, cytokine antagonists, adhesion molecules, selectins and matrix metalloproteinases (MMP) were measured with a multiplex bead assay. Single nucleotide polymorphisms (SNP) in genes MIF, TNF, TNFRSF1A, TNFRSF1B, IL-10, TLR3 and TLR4 were studied in patient blood DNA extracts and analyzed for associations with Q_alb and/or cytokine concentrations. The multivariate regression models of Q_alb were built with the soluble mediators as independent variables. The best models obtained included L-selectin, P-selectin, sVCAM, MMP7, MMP8 (or MMP9) and IL-28A as positive and IL-12p70, IL-15, IL-6Rα/IL-6 ratio and TNF-RII/TNFα ratio as negative correlates of Q_alb. The genotype did not associate with Q_alb, but polymorphism rs4149570 (in TNFRSF1A) associated with TNFα and rs1800629 (TNF) with MIF concentration. We confirm the association of the TNFα-dependent response, L-selectin and MMP8/MMP9 with BBB disruption and identify its novel correlates (IL-12, IL-15, IL-28A, MMP7). We detect no genotype associations with BBB function in TBE. Full article