Search Results (4,309)

Background: Chronic hypoxemia in cyanotic congenital heart disease triggers well-recognized hematological adaptation; however, whether hypoxemia also drives systemic inflammatory activation remains uncertain. This study aimed to evaluate hematological parameters and inflammatory indices in cyanotic and acyanotic congenital heart disease (CHD) to better characterize the relationship between hypoxemia and systemic inflammatory status. Methods: In this single-center retrospective study, 260 children with congenital heart disease were classified as cyanotic (n = 158) or acyanotic (n = 102). Preoperative clinical data and laboratory parameters were analyzed, including oxygen saturation, hemoglobin, hematocrit, leukocyte indices, C-reactive protein (CRP), and procalcitonin (PCT). Inflammatory indices derived from complete blood counts were calculated, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune–inflammation index (SII). Results: Oxygen saturation was significantly lower in cyanotic patients than in acyanotic patients (75 ± 9% vs. 95 ± 4%, p < 0.001). Consistent with hypoxemia-driven hematological adaptation, hemoglobin and hematocrit levels were significantly higher in the cyanotic group (16.1 ± 2.9 g/dL vs. 13.1 ± 2.0 g/dL and 50.8 ± 9.7% vs. 39.7 ± 5.5%, respectively; p < 0.001). In contrast, inflammatory indices (NLR, PLR, and SII) were similar between cyanotic and acyanotic patients, and no significant associations were observed between oxygen saturation and these inflammatory indices. Conclusions: While cyanotic congenital heart disease demonstrates marked hematological adaptation secondary to chronic hypoxemia, systemic inflammatory indices appear similar in cyanotic and acyanotic patients. These findings suggest a relative dissociation between hypoxemia-driven hematological responses and the evaluated systemic inflammatory indices, indicating that inflammatory burden in congenital heart disease may not be solely explained by cyanosis and may reflect additional underlying mechanisms not captured by these markers. Full article

Background/Objectives: Plant-derived phytochemicals are being increasingly explored for their ability to treat various illnesses, especially those affecting the vasculature. High mobility group box 1 (HMGB1) acts as a crucial mediator during the late phase of sepsis, promoting the secretion of pro-inflammatory cytokines and thereby fueling inflammation and systemic complications. Higher plasma HMGB1 levels not only hinder accurate diagnosis and prognosis but also worsen disease outcomes in inflammatory states. Picropodophyllotoxin (PPT), a key bioactive ingredient isolated from the root of Podophyllum hexandrum, has shown a range of beneficial effects, including anti-cancer and anti-proliferative actions, across several tumor types. Nevertheless, its possible involvement in HMGB1-driven severe vascular inflammation remains unexplored. The current work aimed to investigate whether PPT could influence lipopolysaccharide (LPS)-induced HMGB1 activity and its related inflammatory signaling in human umbilical vein endothelial cells (HUVECs). Methods: A combination of in vitro and in vivo approaches was used to assess the anti-inflammatory action of PPT. These included measurements of endothelial barrier function, cell survival, leukocyte attachment and migration, levels of cell adhesion molecules, and the release of pro-inflammatory factors. Both cultured human endothelial cells and mouse disease models were used to thoroughly evaluate how PPT affects HMGB1-triggered inflammatory reactions. Results: The findings showed that PPT markedly reduced HMGB1 movement from inside HUVECs to the outside, thereby limiting its release into the environment. Moreover, PPT effectively decreased neutrophil sticking and migration, lowered the appearance of HMGB1 receptors, and prevented the activation of nuclear factor-κB (NF-κB), a master switch in inflammatory signaling. At the same time, PPT treatment strongly lowered tumor necrosis factor-α (TNF-α) production, adding to its anti-inflammatory profile. Conclusions: Taken together, these results indicate that PPT potently inhibits HMGB1-driven inflammatory processes by acting at several levels of the inflammatory cascade, such as HMGB1 movement, receptor binding, NF-κB activation, and subsequent cytokine release. Therefore, PPT stands out as a hopeful therapeutic option for HMGB1-related inflammatory diseases and deserves further exploration in preclinical and clinical studies. Full article

Background/Objectives: Oral functional decline is associated not only with impaired oral conditions, such as poor oral hygiene, oral dryness, decreased occlusal force, reduced masticatory performance, low tongue pressure, impaired tongue–lip motor function, and dysphagia, but also with deterioration in overall systemic health. Saliva plays a crucial role in maintaining oral function. This study investigated the relationships between conditions related to oral functional decline and salivary biomarkers. Methods: Elderly people residing in the Kyotango area were evaluated using oral function assessments, including the oral hygiene status, salivary flow rate, occlusal force, masticatory performance, tongue pressure, tongue–lip motor function, and swallowing function. Salivary biomarkers were evaluated using an oral environment assessment system (SillHa, Arkray, Kyoto). The biomarkers tested included cariogenic bacteria, acidity, buffering capacity, leukocytes, protein, and ammonia. Statistical analyses were performed using SPSS version 30 (IBM, Armonk, NY, USA). Results: Significant differences and correlations were observed between salivary biomarkers and five of the seven assessment criteria for oral functional decline: a poor oral hygiene status, oral dryness, decreased occlusal force, impaired tongue–lip motor function, and decreased masticatory function. A poor oral hygiene status was associated with the bacterial count and cariogenic bacteria. Oral dryness was associated with the salivary flow rate, acidity, and buffering capacity. Decreased occlusal force was associated with the number of remaining teeth, cariogenic bacteria, acidity, leukocytes, and protein. Impaired tongue–lip motor function was associated with the /pa/, /ta/, and /ka/ sounds and leukocytes. Decreased masticatory function was associated with masticatory performance, cariogenic bacteria, leukocytes, and protein. Conclusions: The present results suggest the potential of salivary biomarker testing using this assessment system as a simple and practical screening tool for identifying oral functional decline. Furthermore, salivary biomarker testing may be useful in oral function assessments. Full article

Hyaluronic acid (HA), a major extracellular matrix component, is used therapeutically to aid healing and deliver drugs to injury sites. Burns create serious clinical and aesthetic problems needing fast skin repair to prevent complications. This study compared 1.8% pharmaceutical-grade HA with panthenol-containing gel (PCG) in deep-burn healing in rats against spontaneous healing. HA slightly accelerated wound closure from day 3 compared to PCG; both induced granulation by day 7 and epithelialization by day 28. HA caused early collagen drop (day 3), later matched PCG levels with abnormal distribution, and both exceeded control by day 28. HA normalized systemic leukocyte counts by day 14 while strongly increasing local leukocyte infiltration in the wound area. HA dual immune effect depends on source and properties; further research is required for clinical use in wound healing. Full article

Micro/nanoplastics (MNPs) are emerging contaminants of concern for maternal and fetal health, yet their effects on the maternal–fetal circulation and serum metabolic homeostasis remain unclear. Here, we investigated the maternal and offspring toxicity of polystyrene microplastics (PS-MPs) and serum metabolomic alterations in dams and offspring. PS-MPs accumulated in multiple tissues, including blood, indicating maternal-to-offspring transfer. Continuous exposure reduced litter size, induced hepatic oxidative stress, and increased IL-6 and TNF-α levels in a dose-dependent manner in both dams and offspring. In dams, PS-MPs also decreased red blood cell and platelet counts and altered leukocyte composition, with increased lymphocyte and decreased neutrophil percentages at the high dose. Untargeted serum metabolomics revealed distinct exposure-related metabolic profiles, including 18 putatively annotated signature metabolites and 26 differentially abundant metabolites. Bilirubin and presqualene diphosphate were exclusively detected in exposed animals, whereas metabolites associated with lipid oxidation and mitochondrial fatty acid β-oxidation were elevated after exposure. RT-qPCR further supported altered expression of genes involved in these pathways. Overall, PS-MPs disrupted hematological homeostasis and metabolic regulation, likely through hepatic lipid peroxidation and systemic inflammation, and serum bilirubin and presqualene diphosphate may serve as candidate biomarkers of exposure. Full article

Trained immunity refers to the enduring functional reprogramming of innate immune cells after particular stimuli, driven by epigenetic and metabolic alterations that augment non-specific responses upon subsequent exposure. Neutrophils and monocytes/macrophages, as essential innate effectors, are crucial for the induction and control of trained immunity, which is the primary emphasis of this review. Neutrophils, the predominant circulating leukocytes, were historically considered incapable of memory owing to their brief lifespan. Emerging evidence indicates that trained immunity functions at the bone marrow progenitor level, influencing granulopoiesis to produce neutrophils with lasting functional modifications. This research offers new insights into neutrophil functions in infection, cancer, and inflammation. Monocytes and macrophages, characterized by phenotypic plasticity and tissue residence, function as conventional models of trained immunity. They experience direct peripheral reprogramming or emerge as primed descendants of trained bone marrow precursors, performing pro-inflammatory or reparative roles in malignancies, infections, and ischemia lesions. This study comprehensively outlines the regulatory mechanisms of trained immunity in these cells, clarifies their functions in various clinical situations, and examines therapeutic applications. Comprehending these pathways is crucial for elucidating the cellular foundation of innate immunological memory, uncovering its multiple functions in disease, and guiding innovative therapeutics aimed at granulopoiesis and monocyte-macrophage polarization. Full article

Trastuzumab is the first humanised monoclonal antibody (Mab) developed for breast cancer (BC) therapy. The high affinity of Trastuzumab Fab-domain binding to the human epidermal growth factor receptor 2 (HER2) receptor, with a K_d value of <1 nM, is also accompanied by Fc domain interaction with Fc-receptors in natural killer cells and leukocytes, enabling the killing of tumour cells through antibody-directed cellular cytotoxicity (ADCC). Trastuzumab blocks the over-expressed HER2 receptor-mediated dimerization and consequent intracellular signalling, leading to cancerous growth. However, the trastuzumab resistance (TR) became the major problem within 1 year of treatment. The mutation in phosphatidylinositol 3′-kinase (PI3K) pathway, cross-talk with estrogen receptors, over-expression of Mucin 1 (MUC1) protein, insulin-like growth factor I receptor, etc., are key pathways involved in TR. In this review, we have provided a molecular view of TR and the possible remedies for overcoming TR using BC stem cell (BCSC)-based therapy, PI3K pathway inhibitors, MUC1-based treatment, etc. We have also analysed the patents and clinical trials from the pre-TR and post-TR era to rationalise the possible steps to overcome TR. Our analysis implies that Trastuzumab monotherapy no longer applies to HER2+ BC treatment. Further, combination therapy using other antibodies like pertuzumab and protein kinase inhibitors and targeting pathways like the ubiquitin proteasome pathway will be the future option for BC Treatment. Overall, this review provides a detailed summary of the molecular mechanisms involving TR and its potential ways of evasion, based on updated information from published research articles, clinical trial outcomes, and patent data. Full article

Neutrophils constitute the largest fraction of total circulating leukocytes in humans and mediate early innate immune responses. Although they are often considered a uniform population of short-lived immune cells, emerging evidence from single-cell RNA sequencing and high-dimensional flow cytometry has revealed that neutrophils are functionally and phenotypically heterogeneous in both healthy and pathological conditions. However, a critical gap is how molecularly defined neutrophil states translate into distinct spatiotemporal behaviors in vivo. This review summarizes our current understanding of the molecular signatures underlying neutrophil heterogeneity and explores the functional in vivo behaviors in various diseases, including cancer, sepsis, and ischemic stroke. We also discuss the potential of intravital imaging to bridge the gap between static molecular profiling and dynamic cellular behavior, offering a comprehensive view of the functional heterogeneity of neutrophils. Full article

Background: Liver inflammation and fibrosis are directly associated with non-alcoholic fatty liver disease (NAFLD). Dysregulation of the potent pro-inflammatory cytokine interleukin-1 beta (IL-1β), inducible nitric oxide synthase (iNOS), and tissue leukocyte infiltration (CD45 +ve) are connected with multiorgan injury and fibrosis. We investigated whether the induction of NAFLD can cause dysregulation in the hepatic IL-1β/iNOS and IL-1β/CD45 axes of inflammation and fibrosis, as well as in endogenous metabolites (lipids, glucose, and insulin) and apoptosis, in the presence and absence of the flavonoid quercetin. Methods: The model group of rats was fed with a high-fat and high-carbohydrate diet (HFCD) for 4 weeks. The protective group of rats was given both quercetin (50 mg/kg) and HFCD for 4 weeks. All rats were sacrificed on day 29. Results: NAFLD was induced in rats as demonstrated by dyslipidemia, hyperglycemia, insulin resistance, liver inflammation, and elevation of liver injury enzymes. NAFLD was also associated with the upregulation of hepatic IL-1β, iNOS, CD45, and apoptosis (p53). Biomarkers of fibrosis (TIMP-1 and α-SMA) were also elevated, and fibrosis was confirmed in the model group by increased collagen deposition and elevated stages of fibrosis score (Stage 1 to 2 of Brunt’s NASH classification). All these parameters were significantly (p < 0.01) modulated by quercetin treatment. Additionally, a significant (p < 0.001) correlation between IL-1β and hepatic injury parameters was observed. Conclusions: These findings suggest a potential association between NAFLD and the IL-1β/iNOS and IL-1β/CD45 axes of liver injury and fibrosis, as well as dyslipidemia, glycemia, and apoptosis, with quercetin exhibiting beneficial hepatic pleiotropic effects. Full article

Titanium and its alloys are used in dental and orthopedic implants. However, long-term stability remains a clinical challenge. To overcome this limitation, surface modification has been investigated to improve surface properties. Our previous study demonstrated that the immobilization of secretory leukocyte protease inhibitor (SLPI) on the titanium surface promotes osteoblast adhesion, proliferation, and differentiation in vitro. The current study demonstrated the first in vivo evaluation of SLPI as a bioactive coating for medical implants. Grade 5 titanium screws were coated with 10 µg/mL of recombinant human SLPI (rhSLPI) for 24 h via simple physical adsorption, and the results were preliminarily validated via FE-SEM and ELISA. These SLPI-coated titanium screws (TiSs) were then placed in the tibia of Sprague–Dawley rats for 4 and 8 weeks. The hematological and biochemical parameters (BUN, Creatinine, AST, and Troponin I) demonstrated no acute systemic alterations within the 8-week period across all groups. Moreover, micro-computed tomography (micro-CT) and histological analysis revealed significantly higher bone volume fraction (%BV/TV) at 4 weeks compared to uncoated controls (20.64% ± 2.452% vs. 11.73% ± 0.524%). Finally, the biomechanical stability of implants, assessed using the removal torque test, showed that TiSs showed higher strength compared to Ti at both 4 and 8 weeks. In conclusion, this study represents a novel approach to transitioning rhSLPI-coated titanium evaluation from in vitro models to an in vivo rat model. rhSLPI surface functionalization enhances early-stage osseointegration and improves implant mechanical stability without acute hematological and biochemical alterations. These proof-of-concept findings suggest the potential of SLPI as a bioactive coating strategy. Full article

Platelet-rich plasma (PRP) is widely used as a second-line treatment for chronic tendinopathy that persists despite structured conservative care, yet outcomes and imaging correlates remain heterogeneous. This review outlines PRP biology and preparation, summarises quantitative imaging techniques for monitoring tendon response, and presents the experience of a single centre integrating these methods into routine supraspinatus and lateral elbow PRP workflows. PRP is described as an autologous platelet concentrate with variable leukocyte and fibrin content, with leukocyte-rich formulations commonly selected for chronic tendinopathy. Quantitative approaches—including ultrasound shear-wave elastography and radiomics, MRI T2/T2* mapping, CT-based bone metrics, PET/CT, and optical techniques—offer numerical biomarkers of tendon structure, mechanics, and inflammation but are rarely implemented in PRP trials. At the authors’ centre, leukocyte-rich PRP is injected under ultrasound guidance after failed physiotherapy, and follow-up combines validated questionnaires with grey-level run-length matrix texture analysis of ultrasound and 3.0 T MRI T2 distribution profiling. A pilot ultrasound study in supraspinatus and common extensor tendinosis showed uniform short-term clinical improvement and significant changes in most texture features, with selected parameters correlating with symptom relief. A prospective supraspinatus cohort demonstrated significant six-month clinical gains in both tendinosis and small partial-thickness tears, whereas only the tendinosis group exhibited T2 profile convergence toward asymptomatic patterns. These data indicate that quantitative ultrasound radiomics and whole-length T2 profiling are feasible imaging biomarkers that capture PRP-induced tendon remodelling beyond qualitative imaging and may help tailor PRP protocols to specific tendon phenotypes. Full article

Background: Intracavernosal platelet-rich plasma (PRP) is increasingly used for erectile dysfunction (ED), despite the absence of standardized biological characterization and clear dose definitions. This systematic review evaluates the clinical efficacy of PRP in ED while integrating emerging immune-centric mechanistic evidence. Methods: Following PRISMA 2020 guidelines, randomized controlled trials (RCTs) and prospective studies (2020–2025) investigating intracavernosal PRP in adult men with ED were identified across major databases. Validated outcomes included International Index of Erectile Function (IIEF-EF or IIEF-5), Erection Hardness Score (EHS), Sexual Encounter Profile (SEP), and penile Doppler parameters. Preclinical data were narratively integrated to contextualize biological plausibility. Results: Fourteen clinical studies met the inclusion criteria (six RCTs, eight prospective cohorts). Across most studies, PRP produced clinically relevant within-patient improvements, and three RCTs demonstrated minimal clinically important difference (MCID) responder rates compared with placebo. However, other trials showed comparable improvements in placebo arms, underscoring substantial contextual effects. Safety was consistently favourable. Marked heterogeneity in blood volume processed (10–120 mL), injected PRP volume (3–12 mL), preparation systems, and session protocols precluded cross-study comparability. Critically, no study reported platelet dose, leukocyte subsets, peripheral blood mononuclear cell (PBMNC) content, or red blood cell contamination. Preclinical models consistently demonstrate that PRP restores erectile function through angiogenic, neuroprotective, and immunomodulatory mechanisms, including CXCL5-mediated monocyte recruitment and M1-to-M2 macrophage polarization. Conclusions: Intracavernosal PRP shows promising short-term efficacy signals and a favourable short-term safety profile in mild-to-moderate vasculogenic ED, but current evidence is limited by profound biological and methodological heterogeneity. PRP should be reconsidered as an immune-regenerative intervention requiring dose-defined, composition-defined, and mechanistically informed randomized trials. Interpretation of these findings is constrained by the absence of formal risk-of-bias assessment for non-randomized studies, substantial clinical and biological heterogeneity across trials, and the lack of standardized PRP characterization. Full article

A novel ocellatin-P1 isoform was isolated and purified from the skin secretion of the pepper frog Leptodactylus labyrinthicus. The crude skin secretion was fractionated by reversed-phase high-performance liquid chromatography (RP-HPLC) using a C₈ column and the peptide was subsequently purified on a reversed-phase C₁₈ column. Ocellatin-LB3 (as this isoform was named) was chemically sequenced by Edman degradation. This peptide is a linear C-terminally amidated molecule composed of 25 amino acid residues: ¹GLLDTLKGAAKNVVGGLASKVMEKL²⁵-NH₂. Synthetic ocellatin-LB3 was active against Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa and inactive against Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecalis. In addition, the peptide reduced the Trypanosoma cruzi infection in L6 cells. At 64 µM it did not reduce erythrocytes or polymorphonuclear leukocytes, but did reduce mononuclear leukocyte counts, as detected by flow cytometry. No hemolytic activity was observed in red blood cells even at 128 µM. The peptide exhibited limited antiproliferative activity against MCF-7 and HeLa tumor cells at 128 µM. Pre-incubation with the peptide appeared to enhance N-formylmethionine-leucyl-phenylalanine (fMLP)-induced migration, indicating a potential additive or synergistic effect on human neutrophils. The three-dimensional structure of ocellatin-LB3 was investigated by circular dichroism (CD) and nuclear magnetic resonance (NMR). In the presence of sodium dodecyl sulfate (SDS), the peptide adopts an α-helical structure spanning residues Leu³–Lys²⁴, which remains largely preserved even at 95 °C. NMR Hydrogen/Deuterium (H/D) exchange experiments suggest that ocellatin-LB3 adopts a preferential orientation when interacting with SDS micelles. Based on the similarity among ocellatins, and on the physicochemical and structural properties of this peptide, a possible membrane-mediated mode of action is proposed, although this remains to be experimentally validated. Full article

Integrins and other cell adhesion molecules play a critical role in the migration and homing of leukocytes. This study investigates whether metastatic tumor cells can exploit leukocyte-like rolling and arrest mechanisms during early vascular steps of metastatic dissemination. B16 melanoma cell adhesion to activated bEnd.3 endothelial monolayers or immobilized VCAM-1 were analyzed under defined shear flow using a parallel-plate chamber. Function-blocking antibodies, divalent cation modulation, pertussis toxin, and low-temperature conditions were used as classical controls. B16-BL6 melanoma cells exhibited robust VLA-4-dependent rolling and arrest on activated endothelial monolayers and on immobilized VCAM-1 under physiological shear stresses (0.7–2 dyn/cm²), independent of chemokine-related Gαi signaling. These findings identify a chemokine-independent mechanism of VLA-4-mediated vascular capture by melanoma cells under shear flow, providing a potential mechanistic basis for early steps in metastatic dissemination. Full article

Background and Objectives: Tamoxifen, a cornerstone selective estrogen receptor modulator in breast cancer therapy, is increasingly recognized to be associated with retinal toxicity characterized by mitochondrial dysfunction, oxidative stress, lipid peroxidation, and oxidative DNA injury. By targeting mitochondrial bioenergetic dysfunction and redox disequilibrium, adenosine triphosphate (ATP) emerges as a biologically plausible candidate for retinal cytoprotection. This study aimed to evaluate the protective effect of ATP against tamoxifen-induced retinal toxicity in a rat model. Materials and Methods: Twenty-four male albino Wistar rats were randomly assigned to four groups: healthy control (HG), ATP-alone (ATPG, 4 mg/kg, intraperitoneally), tamoxifen-alone (TAMG, 5 mg/kg, orally), and tamoxifen plus ATP-treated (ATAG; ATP, 4 mg/kg, intraperitoneally; tamoxifen, 5 mg/kg, orally). Treatments were administered once daily for 30 days. Oxidative stress markers (malondialdehyde, total glutathione), antioxidant enzyme activities (superoxide dismutase, catalase), and oxidative DNA damage (8-hydroxy-2′-deoxyguanosine) were assessed in ocular tissues. Retinal histopathological evaluation included hematoxylin–eosin staining with semiquantitative assessment of edema, vascular congestion, polymorphonuclear leukocyte infiltration, and cytoplasmic vacuolization, together with quantitative measurements of retinal layer thicknesses and ganglion cell layer (GCL) cell counts. Results: Tamoxifen administration induced marked oxidative stress, antioxidant depletion, and increased oxidative DNA damage in ocular tissues, accompanied by significant thickening of retinal layers, reduced GCL cell counts, and pronounced disruption of retinal architecture. By comparison, ATP co-administration significantly suppressed lipid peroxidation and restored antioxidant defenses, thereby reducing oxidative DNA damage and preserving retinal structural integrity, as reflected by partial normalization of retinal layer thicknesses, preservation of GCL cell counts, and the presence of only mild residual edema. Conclusions: These findings indicate that ATP attenuates tamoxifen-induced retinal toxicity by supporting mitochondrial energy balance and redox homeostasis. Accordingly, ATP administration may represent a promising protective approach for reducing retinal injury associated with long-term tamoxifen therapy. Full article