Search Results (1,289)

Background: Aging exerts a progressive and multifaceted impact on the microcirculatory system, undermining the structural and molecular integrity that sustains endothelial stability across both peripheral and cerebral vascular territories. A sustained shift toward oxidative imbalance, chronic low-grade inflammation, and progressive endothelial exhaustion converges to destabilize microvascular networks, linking peripheral artery disease (PAD) with heightened susceptibility to cerebral microvascular dysfunction and neurovascular decline. As redox homeostasis deteriorates, endothelial cells progressively lose barrier-selective properties, intercellular communication with pericytes weakens, and pro-thrombotic tendencies subtly emerge, creating a permissive environment for early neurovascular injury and impaired cerebrovascular resilience. Methods: This narrative review integrates mechanistic evidence derived from experimental, clinical, and translational studies examining the interplay between oxidative stress, inflammatory signaling cascades, endothelial senescence, and blood–brain barrier (BBB) disruption across peripheral and cerebral microvascular systems. A comparative framework was applied to PAD and cerebral microcirculatory pathology to identify convergent molecular drivers and systemic mechanisms underlying endothelial deterioration. Results: Accumulating evidence demonstrates that oxidative stress disrupts endothelial mitochondrial function, compromises tight junction architecture, and accelerates angiogenic failure. Concurrent inflammatory activation amplifies these alterations through cytokine-mediated endothelial activation, enhanced leukocyte adhesion, and promotion of a pro-thrombotic microenvironment. Progressive endothelial senescence consolidates these insults into a persistent state of microvascular dysfunction characterized by diminished nitric oxide bioavailability, capillary rarefaction, and compromised barrier integrity. Notably, these pathological features are shared between PAD and the aging cerebral circulation, reinforcing the concept of a unified systemic microvascular aging phenotype. Conclusions: Microvascular failure in the aging brain should be understood as an extension of systemic endothelial deterioration driven by oxidative stress, chronic inflammation, and senescence-associated vascular exhaustion. Recognizing the shared molecular architecture linking peripheral and cerebral microcirculatory dysfunction offers a strategic framework for developing targeted therapeutic interventions aimed at restoring endothelial resilience, stabilizing BBB integrity, and preserving neurovascular homeostasis in aging populations. Full article

The present study aimed to evaluate whether the inclusion of curcumin as a performance enhancer in finishing cattle has positive effects on animal production, the ruminal environment, hematological and biochemical markers, as well as meat quality. Sixteen castrated Holstein steers, 8 months of age, with an average body weight of 247 ± 3.89 kg were divided into two groups: Control, consisting of animals that consumed 144 mg of monensin/animal/day (n = 8); Treatment, consisting of animals that consumed 552 mg of curcumin/animal/day (n = 8). Animals were fed a diet containing 44% roughage (corn silage) and 56% concentrate for 105 days. During this period, body weight measurements were recorded, and blood samples were collected for the determination of hematological, biochemical, and immunological variables. At the end of the experimental period, animals were slaughtered and meat samples were collected for evaluation. No differences were observed between groups for animal performance, feed intake, or feed efficiency. A lower leukocyte count (lymphocyte and granulocyte) and a higher platelet count were observed in animals that consumed curcumin. These animals also exhibited higher cholesterol levels, along with lower circulating glucose concentrations compared to the control group. In the ruminal environment, higher bacterial activity and greater protozoal counts were observed in the treatment group, but no effects on ruminal short-chain fatty acids were observed. Higher activity of the enzymes glutathione S-transferase in serum and superoxide dismutase in meat was observed, combined with lower lipid peroxidation in serum and meat. Meat from steers fed curcumin showed greater yellow color intensity, higher water-holding capacity, and a higher proportion of monounsaturated fatty acids compared to the control group. These results suggest that curcumin can be used as a performance enhancer, similar to monensin, when thinking about performance, but beyond that, curcumin triggered anti-inflammatory and antioxidant action. Full article

Background: Obesity alters metabolic, inflammatory, and immune responses, and acute exercise may affect these parameters differently according to body composition. This study investigated the acute effects of Spartacus exercise on metabolic, inflammatory, and immune markers in adolescent girls with overweight/obesity and normal weight. Methods: In this non-randomized clinical study, sixteen girls with overweight/obesity (BMI: 31.17 ± 3.85 kg/m²) and fourteen normal-weight girls (BMI: 21.93 ± 0.99 kg/m²) performed an intermittent running test (15 s effort, 15 s passive recovery), starting at 7 km·h⁻¹ with 1 km·h⁻¹ increments every 3 min until exhaustion. Blood samples were collected at rest (T0), immediately post-exercise (T1), and 30 min post-exercise (T2). CRP and ESR were assessed at baseline to characterize participants’ inflammatory status, while glucose and leukocyte subpopulations were evaluated to investigate acute exercise responses. Results: Fasting glucose, lipid profile (TC, TG, HDL-C, LDL-C), inflammatory markers (CRP, ESR), and leukocyte subpopulations were assessed. Significant group effects were observed for all metabolic and inflammatory markers, reflecting higher baseline values in participants with overweight/obesity compared with normal-weight participants (p < 0.05). Significant effects of time were found for glucose and leukocytes (p < 0.001), indicating acute exercise-induced changes, along with significant time × group interactions. Participants with overweight/obesity showed greater and more prolonged increases in glucose, total leukocytes, and neutrophils, whereas normal-weight girls returned to baseline within 30 min. Conclusions: Acute high-intensity intermittent exercise induces transient metabolic and immune responses in adolescents, with amplified and prolonged effects in those with obesity. These findings highlight the importance of considering body composition when prescribing exercise programs. Full article

Cell membrane-coated nanoparticles represent a biomimetic drug delivery approach that integrates biological membrane functions with synthetic nanomaterials. Among the various membrane sources, those derived from blood cells such as red blood cells, platelets, and leukocytes offer distinctive advantages, including immune evasion, prolonged systemic circulation, and selective tissue targeting. These properties collectively enable efficient and biocompatible delivery of therapeutic agents to diseased tissues, minimizing off-target effects and systemic toxicity. This review focuses on blood cell membrane-derived nanocarriers as drug delivery and immune-regenerative platforms, in which membrane-mediated immunomodulation synergizes with therapeutic payloads to address inflammatory or degenerative pathology. We discuss recent advances in blood cell membrane coating technologies, including membrane isolation, nanoparticle core selection, fabrication techniques, and the development of hybrid and engineered membrane systems that enhance therapeutic efficacy through integrated immune regulation and localized drug action. To illustrate these advances, we also compile membrane type-specific nanocarrier systems, summarizing their core nanoparticle designs, coating strategies, therapeutic cargoes, and associated disease models. Challenges related to biological source variability, scalability, safety, and regulatory standardization remain important considerations for clinical translation. In this review we systematically address these issues and discuss emerging solutions and design strategies aimed at advancing blood cell membrane-based nanocarriers toward clinically viable immune-regenerative therapies. Full article

Medication-related osteonecrosis of the jaw (MRONJ) is a devastating complication arising primarily after invasive dentoalveolar procedures in patients treated with antiresorptive, antiangiogenic, or targeted therapies. Although recognized risk factors are established, the distinctive vulnerability of jawbones compared to long bones is not fully understood. This review comprehensively synthesizes recent advances regarding the embryological, anatomical, and physiological disparities that contribute to region-specific susceptibility to MRONJ. Recent evidence suggests that jawbones diverge significantly from long bones in embryonic origin, ossification pathways, vascular architecture, innervation patterns, and regenerative capacities. These differences affect bone metabolism, healing dynamics, response to pharmacologic agents, and local cellular activities, such as enhanced bisphosphonate uptake and specialized microcirculation. Experimental and clinical evidence reveals that mandibular periosteal cells exhibit superior osteogenic and angiogenic potentials, and the jaws respond differently to metabolic challenges, trauma, and medication-induced insults. Furthermore, site-specific pharmacologic and inflammatory interactions, including altered periosteal microcirculation and leukocyte–endothelial interactions, may explain the development of MRONJ, although rare cases of medication-related osteonecrosis have also been reported in long bones. Emerging research demonstrates that immune dysregulation, particularly M1 macrophage polarization with overexpression of matrix metalloproteinase-13 (MMP-13), plays a crucial role in early MRONJ development. Understanding these mechanisms highlights the critical need for region-specific preventive measures and therapeutic strategies targeting the unique biology of jawbones. This comparative perspective offers new translational insights for designing targeted interventions, developing tissue engineering solutions, and improving patient outcomes. Future research should focus on gene expression profiling and cellular responses across skeletal regions to further delineate MRONJ pathogenesis and advance personalized therapies for affected patients. Full article

Traumatic brain injury (TBI) is a common and important cause of morbidity and mortality among pediatric patients, affecting 47–280 per 100,000 children every year. Head trauma can affect the brain not only by the injury itself but also via a neuroinflammatory process, which leads to blood–brain barrier (BBB) disruption, leukocyte infiltration, and edema formation. This process is regulated by several immune mediators, including interleukins (ILs), which are molecules that are currently investigated in both adult and pediatric TBI. In pediatric patients, IL-1β, IL-6, and IL-8 have mainly been investigated, while IL-10 and IL-17 also play a role in the neuroinflammatory cascade. Therefore, the purpose of this review was to examine the role of the aforementioned cytokines in the pathophysiology of pediatric TBI, as well as their role in determining clinical outcome and prognosis. IL-1β is a key pro-inflammatory cytokine in glutamate excitotoxicity post-TBI and in upregulating the expression of additional pro-inflammatory cytokines. Its high levels in cerebrospinal fluid (CSF) are correlated with injury severity and poor outcomes. IL-6 is an anti-inflammatory cytokine, and its concentration rises rapidly after the injury. Current data show that it can be useful in predicting severe TBI (sTBI) in addition to clinical parameters. IL-8 is a cytokine with several pro- and anti-inflammatory properties. On the one hand, it is a potent chemotactic agent, attracting inflammatory cells to the injured area, and it plays a role in BBB disruption. On the other hand, it promotes the survival of cholinergic and hippocampal neurons via the secretion of nerve growth factor (NGF). These cytokines are important in predicting the outcome of pediatric patients with TBI, as well as in predicting several post-TBI conditions such as fatigue and epilepsy, thus improving diagnostic ability and timely treatment. Further research, unraveling the complex mechanisms via which post-TBI neuroinflammation occurs, will lead to targeted therapies and better outcomes overall. Full article

Nuclear receptors (NRs) are ligand-activated transcription factors that mediate diverse cellular processes, including signalling, survival, proliferation, immune response and metabolism, through both genomic and non-genomic mechanisms in response to hormones and metabolic ligands. Given their central role in inter-organ, tissue, and cellular communication, NRs are critical for maintaining homeostasis and have become a major focus in biomedical research and drug discovery due to their association with numerous diseases. Among NRs, the NR4A subfamily (NR4A1/Nur77, NR4A2/Nurr1, and NR4A3/Nor1) responds to various stimuli—such as insulin, growth factors, inflammatory cytokines, and β-adrenergic signals—though their endogenous ligands remain unidentified. Their expression is tissue-dependent, particularly in energy-demanding tissues, where they modulate leukocyte function and promote an anti-inflammatory profile. Like other NRs, NR4As regulate acute and chronic inflammation by suppressing pro-inflammatory transcription factors (e.g., NF-κB) or enhancing their inhibitors, thereby polarising macrophages toward an anti-inflammatory phenotype. This review summarises current knowledge on the role of NR4A receptors in immune responses. Given their well-documented involvement in autoimmune diseases, inflammatory conditions, and cancer, elucidating their contributions to neuro–immune–endocrine crosstalk may uncover their therapeutic potential for immunopathological disorders. Full article

Aim: to study the level of immunoglobulin FLC in patients with myocarditis in comparison with non-inflammatory heart diseases, and FLC’s correlation with the severity of CHF. Methods: Ninety-nine patients (41 women, 59.6 ± 14.6 y.o.) were included in the study: 50 patients with myocarditis [confirmed by myocardial biopsy (n = 20) and/or cardiac MRI]; 49 patients with non-inflammatory heart disease. CHF was diagnosed in 66% and 65% of patients, respectively. The levels of FLC were determined using the ‘Cloneus S-FLC-K TIA Kit’ and ‘Cloneus S-FLC-L TIA Kit’ reagents. Results: Elevated FLC levels were found in 56% of patients with myocarditis and in 67% of comparison group patients (p > 0.05). Mean FLC kappa levels were 13.4 [11.7; 16.7] and 16.0 [11.3; 23.7] mg/L, FLC lambda 22.7 [16.7; 32.4] and 24.7 [18.1; 39.1] mg/L, FLC kappa/lambda ratio 0.62 [0.50; 0.73] and 0.65 [0.56; 0.76] in myocarditis and comparison groups, respectively; there were no significant differences between groups. Both groups showed correlations of FLC levels with levels of CRP and leukocytes, as well as with glomerular filtration rate, CHF NYHA class, and left ventricular ejection fraction. Only in patients with myocarditis did we observe a significant correlation between both kappa and lambda FLC and NT-proBNP (r = 0.528, p = 0.004, and r = 0.756, p < 0.001) and high-sensitivity troponin (r = 0.829, p = 0.042) levels. Conclusions: Increased FLC level may be considered an important pathogenetic link reflecting both specific mechanisms of myocarditis and severity of CHF. The determination of FLC can be used as an additional diagnostic marker, as well as one predictor of the decompensated course of myocarditis. Full article

Background: Ischemic stroke remains a leading cause of mortality and long-term disability worldwide. Reperfusion therapies, such as intravenous thrombolysis and mechanical thrombectomy, are crucial for restoring cerebral blood flow but may also trigger ischemia–reperfusion injury and systemic inflammatory activation, associated with poorer clinical outcomes. Methods: We retrospectively analyzed medical records of 8833 patients hospitalized for acute ischemic stroke between January 2014 and May 2025. Of these, 2242 (25.38%) underwent reperfusion therapy (mechanical thrombectomy ± intravenous thrombolysis), and 6591 (74.62%) were treated conservatively. Laboratory parameters, including leukocyte count, C-reactive protein (CRP), and albumin, and composite inflammatory indices (e.g., neutrophil-to-lymphocyte ratio (NLR), systemic immune–inflammation index (SII), systemic-inflammation response index (SIRI), and neutrophil percentage-to-albumin ratio (NPAR)), were assessed at admission. Clinical outcomes included in-hospital mortality and functional scale results (e.g., National Institutes of Health Stroke Scale, modified Rankin score (mRS), Barthel scale, and Glasgow Coma Scale (GCS)). Results: Patients treated with reperfusion therapy had higher inflammatory indices (white blood cells, CRP, NLR, SII, and NPAR) compared to patients treated conservatively. In multiple regression analysis, these indices were significantly determined only by GCS and mRS scores, but age, gender, comorbidities, biochemical determinations, and type of ischemic stroke treatment (reperfusion or conservative) remained non-statistically significant. Conclusions: Patients with acute ischemic stroke undergoing reperfusion therapy exhibited a stronger inflammatory response and higher in-hospital mortality than those treated conservatively. However, multivariate analysis showed that a stronger inflammatory response following reperfusion therapy results more from the severity of the patients’ state than the kind of therapy. Full article

The intra- and intercellular signaling molecule nitric oxide (NO) is produced in endothelial cells by the activity of endothelial NO synthase (eNOS). Upon formation, NO diffuses into the underlying vascular smooth muscle cells, where it activates NO-sensitive guanylyl cyclase (NO-GC) resulting in the production of cyclic guanosine 3′,5′-monophosphate (cGMP) from guanosine 5′-triphosphate (GTP). Inducing vasodilatation, inhibiting platelet aggregation and leukocyte adhesion, and inhibiting the proliferation and migration of vascular smooth muscle cells, the NO-cGMP signaling leads to a number of anti-inflammatory processes. Inflammation-dependent elevated concentrations of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in blood vessels of inflamed dental pulp induce an uncoupling of eNOS and oxidized NO-GC, leading to a disruption of NO-cGMP signaling. Endothelial dysfunction in inflamed dental pulp alters cell–cell and cell–matrix interactions, reducing the regenerative and reparative potential of the dentin–pulp complex in response to carious lesions. In the therapeutic management of caries, it is essential to consider the presence of endothelial dysfunction in the inflamed dental pulp. The utilization of NO-GC stimulators and activators in indirect and direct pulp capping materials may enhance the regeneration and repair potential of inflamed dental pulp. Full article

Inflammation underpins pulmonary disease progression during tobacco smoke exposure, which may culminate in irreversible pulmonary disease. While primary smoke poses a notable risk, nearly half of the US population is also susceptible due to frequent exposure to secondhand smoke (SHS). In the present study, we assessed the potential role of VYN202, a novel small molecular bromodomain and extra-terminal inhibitor, as a possible means of attenuating SHS-mediated inflammation. We exposed wild-type mice to an acute time course of room air (RA), SHS via a nose-only delivery system (Scireq Scientific, Montreal, Canada), or to both SHS and 10 mg/kg VYN202 (efficacious dose from prior inflammatory models) via oral gavage three times a week. Specific smoke exposure delivery to mice involved SHS from two cigarettes over 10 min, equilibration in room air for 10 min, followed by exposure to SHS from one cigarette for an additional 10 min, for a total SHS exposure of 20 min per day, five days a week for 30 days. We evaluated leukocyte abundance and the secretion of inflammatory mediators in bronchoalveolar lavage fluid (BALF). We also assessed general morphology via histology staining and the activation of receptor tyrosine kinase (RTK) family members. While standard hematoxylin and eosin (H&E) staining resulted in unchanged morphology, SHS-mediated increases in BALF protein abundance, total cellularity, and percent PMNs were attenuated with concomitant administration of VYN202. We also discovered SHS-induced activation of RTKs that were pro-inflammatory (JAK1, JAK3, ABL1, and ACK1), as well as RTKs related to endothelial and vascular remodeling (VEGFR3, VEGFR2, EphB4, EphB6, and FAK). Furthermore, inflammatory cytokines including GCSF, IFN-γ, IL-12p70, IL-17A, LIX, and TNF-α were all augmented by SHS exposure. Despite SHS exposure, each of these RTKs and cytokines/chemokines was significantly attenuated by VYN202. In summary, inflammatory responses induced by SHS exposure were mitigated by VYN202. These data reveal fascinating potential for the utility of VYN202 in lessening smoke-induced pulmonary exacerbations. Full article

Visceral white spot disease caused by Pseudomonas plecoglossicida severely threatens marine aquaculture, highlighting the need for effective control strategies. To clarify the role of a novel small RNA, sRNA0024, in bacterial pathogenicity, we constructed an sRNA0024 deletion mutant (ΔsRNA0024) and compared its phenotype and virulence with those of the wild-type strain NZBD9. In vitro assays showed that deletion of sRNA0024 did not affect bacterial growth but significantly reduced biofilm formation and adhesion. In vivo infection experiments in orange-spotted grouper (Epinephelus coioides) demonstrated that the ΔsRNA0024 mutant had a 3.8-fold higher 50% lethal dose (LD₅₀), improved host survival, and milder splenic lesions than the wild type. Histopathology and host transcriptome analyses revealed weakened activation of complement–coagulation cascades, neutrophil extracellular traps, leukocyte migration, and inflammatory signaling pathways, indicating a lower-intensity immune response. Bacterial transcriptomics showed that deletion of sRNA0024 was associated with reduced luxR expression and attenuated quorum-sensing–associated virulence traits, supporting a possible role for this small RNA in modulating luxR expression and QS-related host immunopathology. These findings identify sRNA0024 as an important contributor to the virulence of P. plecoglossicida and highlight the sRNA0024–luxR module as a potential antivirulence target for controlling visceral white spot disease in aquaculture. Full article

Objective: Ongoing debates focus on the role of human leukocyte antigen (HLA) class II expression in shaping clinical phenotypes of chronic inflammatory airway diseases. This study seeks to clarify the impact of class II HLA on chronic obstructive pulmonary disease (COPD) and asthma–COPD overlap (ACO). Method: The expression levels of HLA-DQ/DR in blood immune cells were analyzed in 116 participants: 41 with COPD, 37 with ACO, 20 with pure asthma, and 18 healthy subjects (HS). Results: In the COPD group, HLA-DR protein expression levels were significantly elevated on blood M2a monocytes (7695 ± 3743 vs. 5391 ± 3153 MFI, p = 0.026), helper T cells (2551 ± 956 vs. 1836 ± 531 MFI, adjusted p = 0.018), cytotoxic T cells (1591 ± 531 vs. 1360 ± 477 MFI, adjusted p = 0.036), and B cells (20,667 ± 7985 vs. 15,694 ± 2003 MFI, adjusted p = 0.031) compared to the HS group. Conversely, no significant changes were observed in the asthma group. In ACO patients, helper T cells showed increased HLA-DR protein expression (2416 ± 914 MFI; adjusted p = 0.016) compared with the HS group. Higher levels of HLA-DR expression correlated with reduced pulmonary function, frequent exacerbations, and more severe symptoms. Following one year of treatment in 14 COPD and 16 ACO patients, HLA-DR protein expression on blood helper T cells, cytotoxic T cells, M2a monocytes, and neutrophils significantly declined (all p < 0.05). In vitro experiments demonstrated that exposure of M2- or M1-polarized THP-1 cells to a stimulus mix containing cigarette smoke extract, house dust mite antigens, and lipopolysaccharide led to up-regulation of HLA-DR expression. This response was linked to increased apoptosis and reduced production of reactive oxygen species. Conclusions: Up-regulation of HLA-DR in COPD and ACO patients may represent a novel biomarker for assessing disease severity and treatment response. Additionally, it could serve as a useful tool to distinguish COPD and ACO from asthma. Full article

Sepsis-induced myocardial dysfunction (SIMD) is a fatal complication with limited therapeutic options. Semicarbazide-sensitive amine oxidase (SSAO) contributes to oxidative stress and leukocyte recruitment, yet its role in SIMD remains unexplored. This study investigates whether hydralazine, a potent SSAO inhibitor, protects against SIMD by evaluating the involvement of SSAO inhibition. Using a murine model of LPS-induced sepsis, hydralazine was administered 30 min post-injection. Over a 7-day observation period, survival rates, cardiac function (assessed by echocardiography), and myocardial injury (evaluated via plasma biomarkers including CK, CK-MB, LDH, and AST, alongside histopathology) were monitored. Additional analyses included measurements of oxidative stress markers (T-AOC, GSH-PX, SOD, MDA, GSH), inflammatory chemokine levels using a Luminex panel, and myocardial SSAO activity via HPLC. The results demonstrated that hydralazine at doses of 5 and 10 mg/kg significantly improved 7-day survival rates from 20% to 90% and enhanced cardiac function in septic mice. It also reduced myocardial injury and histological damage while attenuating systemic inflammation through suppression of chemokine elevation. Furthermore, hydralazine boosted systemic and myocardial antioxidant capacity and normalized the sepsis-induced increase in myocardial SSAO activity, suggesting a potential mechanism for its protective effects. In conclusion, hydralazine shows robust cardioprotection in experimental sepsis by decreasing oxidative stress and inflammatory cell infiltration. The inhibition of SSAO activity may be a pivotal underlying molecular mechanism. Full article

The lipopolysaccharide (LPS)-induced inflammation model is widely used in mammalian studies but remains poorly investigated in a variety of fish species. We reproduce this model in rainbow trout, Oncorhynchus mykiss, a species of high economic value, to validate specific inflammatory biomarkers for reliably assessing the health and immune status of farmed fish. The inflammatory process, together with the effect of preconditioning, was modeled using two consecutive intraperitoneal injections of 300 and 600 µg LPS. We assessed innate immunity biomarkers, including the expression of inflammation-related genes (il1ß, il8), peripheral blood leukocyte profiles, serum bactericidal activity (SBA), and various serum and hepatic biochemical parameters. These parameters comprised the concentration of C-reactive protein (CRP, an acute phase protein), and the activities of antioxidant enzymes (superoxide dismutase, catalase, glutathione-S-transferase) measured at 24 and 96 h post-injection. In trout, LPS-induced effects involved the overexpression of pro-inflammatory interleukins (il1ß, il8), a left shift in white blood cells (characterized by a prevalence of immature neutrophils), and enhanced SBA. In contrast to warm-blooded animals, LPS challenge in trout did not appear to significantly elevate CRP levels or antioxidant enzyme activity. Further investigations in other fish species are needed to determine whether these are traits specific to trout or common to bony fish. Our findings provide a foundation for developing a biomarker panel suitable for the routine assessment of welfare, early detection of infection-associated inflammation in cultured fish, and the screening of the anti-inflammatory and immunostimulant activities of drugs and feed additives. Full article