Search Results (70)

Chronic joint disease is a major cause of lameness and reduced performance in sport horses and is characterized by persistent synovial inflammation and protease-mediated matrix degradation. This exploratory prospective pilot study investigated clinical outcomes and synovial biomarker changes following intra-articular administration of an α-2-macroglobulin plasma-derived preparation. Twenty client-owned sport horses were observed in the treatment group (n = 10) or a comparison group (n = 10) and monitored for up to 180 days under field conditions. Clinical outcomes were assessed longitudinally, while synovial fluid was analyzed at baseline and 30 days post-treatment only in treated horses. Mixed-effects analysis showed significant group × time interactions for American Association of Equine Practitioners (AAEP) lameness score, flexion test response, and joint effusion. Treated horses showed early and sustained improvement in clinical scores, whereas minimal changes were observed in the comparison group. At 30 days, treated horses exhibited consistent within-subject reductions in synovial total protein, total nucleated cell count, polynuclear cell percentage, pro-inflammatory cytokines (PGE₂, TNF-α, IL-6, IL-1β), matrix metalloproteinases (MMP-9, MMP-13), sulphated glycosaminoglycans, and neurogenic mediators (NGF, Substance P). These findings indicate a coherent pattern of clinical improvement associated with parallel changes in synovial biomarkers in treated horses. However, as longitudinal biomarker data were not collected in the comparison group, these observations should be interpreted as exploratory and do not establish causality. The observed findings support the rationale for further investigation of protease-targeted approaches in equine joint disease. Full article

Gut microbial metabolites play a crucial role in modulating cognitive function. In a previous animal study, oral administration of Lactiplantibacillus plantarum MWFLp-182 (L. plantarum MWFLp-182) significantly increased inosine levels in both the serum and feces of D-galactose (D-gal)-induced mice, which was accompanied by improved cognitive performance. Building on this finding, we further investigated the neuroprotective mechanisms of inosine derived from L. plantarum MWFLp-182 in alleviating D-gal-induced neuronal damage in HT-22 cells. Reverse transcription-quantitative PCR (RT-qPCR) was used to analyze the addition of inosine (250 μg/mL, 500 μg/mL), which considerably reduces oxidative stress induced by D-gal (20 mg/mL), on the regulation of mRNA expression of the nuclear factor erythroid 2-related factor (Nrf2)/hemeoxygenase 1 (HO-1) signaling pathway factors. Compared to the D-gal group, the inosine-treated group exhibited a 4.3-fold and 8.7-fold increase in HO-1 and Nrf2 levels, respectively. Furthermore, inosine alleviates neuroinflammation by modulating the mRNA expression of the Toll-like receptor 4 (TLR4)/myeloid differentiation primary response protein 88 (MyD88)/nuclear factor kappa B (NF-κB) signaling pathway. Compared to the D-gal group, the inosine-treated group showed reductions of 41.75%, 28.29%, and 32.17% in TLR4, MyD88, and NF-κB levels, respectively. Moreover, immunofluorescence staining revealed that inosine exhibits anti-apoptotic properties by enhancing the levels of neurotrophic factors, including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), while simultaneously lowering the expression of the pro-apoptotic protein bcl-2-associated X (Bax). These findings suggest that inosine, a differentially expressed metabolite identified in a probiotic-intervention mouse model, alleviates D-gal-induced neuronal damage in HT-22 cells by modulating oxidative, inflammatory, and apoptotic pathways, providing mechanistic insights into the neuroprotective effects of this metabolite. Full article

Fetal growth restriction (FGR) remains a significant problem in obstetrics and is a key risk factor for perinatal brain injury. The fetal neuronal vesicles (FNVs) isolated from maternal blood represent an innovative approach—a “fetal brain liquid biopsy”—enabling early diagnostics of neuronal dysfunction in FGR. Western blotting was used to evaluate the protein pattern expression of FNVs isolated from the blood of pregnant women with FGR and uncomplicated pregnancy. Significant changes in the neurotrophic proteins levels (pro-BDNF, pro-NGF) and presynaptic neurotransmission proteins (SYN1, SYP, SYNPO) were identified. New data were obtained on changes in the expression of proteins of sumoylation (SUMO2/3/4) and neddylation (NAE1, UBC12), which differs in early-onset and late-onset FGR. Moreover, increased SUMO2/3/4 levels can be considered as an endogenous neuroprotective response to cerebral hemodynamic reaction in fetuses with late-onset growth restriction. An association has been established between changes in the expression of the studied proteins and intraventricular hemorrhage (IVH) in newborns with late-onset growth restriction. 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

Background: Type 2 diabetes mellitus represents a global health challenge, with chronic hyperglycemia leading to a spectrum of microvascular and macrovascular complications. This narrative review provides a comprehensive and integrated analysis of the nerve growth factor (NGF) axis as a key, yet underrecognized, pathogenic mechanism. Methods: This narrative review was conducted in accordance with scholarly standards for non-systematic syntheses (SANRA). We included both clinical and preclinical studies focusing on NGF/proNGF biology and interventions across major diabetes complications. Discussion: Growing evidence highlights NGF as a pivotal mediator at the crossroads of neuronal, vascular and metabolic pathways. In diabetes, a disrupted balance between mature NGF and its precursor proNGF, favors the detrimental p75NTR pathway, leading to increased cellular stress, inflammation and apoptosis. In this narrative review, we examine how a decline in mature NGF and a relative excess of proNGF contribute to the pathophysiology of diabetic complications across various organ systems. We highlight the dual role of the NGF axis: while NGF-TrkA signaling consistently confers neuroprotective and vasculoprotective benefits, unchecked proNGF-p75NTR activity amplifies tissue damage. Conclusions: Collectively, the evidence identifies NGF as a candidate biomarker for both early tissue distress and therapeutic monitoring. We conclude by outlining key priorities for future research, including the development of standardized assays and the initiation of well-designed clinical trials to translate these promising strategies for early detection and treatment of diabetes-related complications. Full article

Traumatic brain injury (TBI), a leading cause of mortality and disability, recognizes a primary, immediate injury due to external forces, and a secondary phase that includes inflammation that can lead to complications such as the post-traumatic confusional state (PTCS), potentially impacting long-term neurological recovery. An earlier identification of these complications, including PTCS, upon admission to intensive rehabilitation units (IRU) could possibly allow the design of personalized rehabilitation protocols in the immediate post-acute phase of moderate-to-severe TBI. The present study aims to identify potential biomarkers to distinguish between TBI patients with and without PTCS. We analyzed cellular and molecular mechanisms involved in neuroinflammation (IL-6, IL-1β, IL-10 cytokines), neuroendocrine function (norepinephrine, NE, epinephrine, E, dopamine), and neurogenesis (glial cell line-derived neurotrophic factor, GDNF, insuline-like growth factor 1, IGF-1, nerve growth factor, NGF, brain-derived growth factor, BDNF) using enzyme-linked immunosorbent assay (ELISA), comparing results between 29 TBI patients (17 with PTCS and 12 non-confused) and 34 healthy controls (HC), and correlating results with an actigraphy-derived sleep efficiency parameter. In TBI patients compared to HC, serum concentration of (1) pro-inflammatory IL-1β cytokine was significantly increased while that of anti-inflammatory IL-10 cytokine was significantly decreased; (2) NE, E and DA were significantly increased; (3) GDNF, NGF and IGF-1 were significantly increased while that of BDNF was significantly decreased. Importantly, IL-10 serum concentration was significantly lower in PTCS than in non-confused patients, correlating positively with an improved actigraphy-derived sleep efficiency parameter. An anti-inflammatory environment may be associated with better prognosis after TBI. Full article

Background/Objectives: To study the efficacy and pharmacological mechanism of the dual-target liposome complex AD808 in the treatment of Alzheimer’s disease. Methods: Using APP/PS1 mouse models, the therapeutic efficacy and pharmacological mechanism of AD808 on Alzheimer’s disease were studied through water maze tests, brain tissue staining, immunofluorescence, and ELISA for inflammatory and neurotrophic factors. Results: AD808 exhibited significant pharmacodynamic effects in improving behavioral and cognitive abilities (70% reduction in escape latency) and repairing damaged nerve cells (90% reduction in Aβ plaque) in Alzheimer’s disease mice. The efficacy of the liposome complex AD808 was significantly better than that of ST707 or gh625-Zn₇MT3 alone. AD808 significantly reduced brain inflammation (57.3% and 61.5% reductions in TNF-α and IL-1β, respectively) in AD (Alzheimer’s disease) mouse models and promoted the upregulation of neurotrophic factors and nerve growth factors (142.8% increase in BDNF, 275.9% in GDNF, and 111.3% in NGF-1) in brain homogenates. By activating the PI3K/AKT signaling pathway in brain microglia, AD808 upregulated TREM2 protein expression and removed Aβ amyloid plaques in the brain. Additionally, it promoted the transition of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, regulated the M1/M2 balance, released anti-inflammatory and neurotrophic factors, reduced chronic inflammation, and enhanced neurological repair. Based on these results, the potential pharmacological mechanism of AD808 against Alzheimer’s disease was proposed. Conclusions: As a dual-target liposome complex, AD808 has shown promising therapeutic potential in the treatment of Alzheimer’s disease, providing a new strategy for innovative drug development. Full article

Background/Objectives: Overactive bladder (OAB), common in elderly women, involves urgency, frequency, and nocturia, with complex phenotypes. The use of neurotrophins as non-invasive urinary biomarkers has been previously explored. The objective of this study was to assess the diagnostic and therapeutic utility of urinary biomarkers in a Canadian population of aging female OAB patients. Methods: We conducted a single-center prospective study of aging female patients diagnosed with OAB and age-matched healthy controls, where we conducted pre- and post-treatment assessments using a combination of clinical questionnaires, voiding diaries, and urinary biomarkers nerve growth factor (NGF), proform of NGF (proNGF), brain-derived neurotrophic factor (BDNF), proform of BDNF (proBDNF), and neurotrophin receptor p75 extracellular domain (p75^ECD)) quantified using ELISA. Baseline and post-treatment urinary biomarker levels in OAB patients were compared with those of controls. Results: OAB patients and controls at baseline displayed significant differences in neurotrophin levels and in their ratios of mature/precursors. In the post-treatment OAB cohort, only NGF and proNGF exhibited significant improvement correlating with clinical symptom relief. Biomarkers in non-responders remained unchanged, suggesting heterogeneity in therapeutic response. Conclusions: Urinary neurotrophins show promise as non-invasive diagnostic markers of OAB and monitoring treatment response in aging female patients. While this study focused on patients broadly diagnosed with OAB, future research should aim to classify OAB subtypes—such as those based on urodynamic studies or underlying pathophysiology—to better understand how urinary neurotrophins can differentiate between mechanisms like detrusor overactivity, detrusor underactivity, or bladder outlet obstruction. This will enhance their relevance in guiding personalized treatment strategies and predicting outcomes. Full article

Synovial inflammation is recognised as a pathological driver of osteoarthritis (OA), a degenerative joint disease involving cartilage degradation and joint pain. Since extracellular vesicles (EVs) have emerged as key mediators of cellular cross-talk, this study characterised synovial fluid EVs (SFEVs) in OA patients with varying disease severity and determined their functional effects on OA articular chondrocytes. Synovial fluid and articular cartilage were collected from patients undergoing knee surgery. SFEVs were isolated via ultracentrifugation and characterised by nanoparticle tracking analysis, ExoView, and Luminex analysis of protein cargo. Patients were stratified into mild/moderate- and severe-OA groups based on Oxford Knee Score and EQ5D. Chondrocytes were treated with SFEVs, and transcriptomic and secretome responses were analysed using RNA sequencing, Luminex, and ELISA. SFEVs from patients with severe OA were more abundant, smaller and exhibited increased tetraspanin expression. Synovial fluid and SFEVs induced distinct transcriptomic changes in chondrocytes. SFEVs from patients with severe OA promoted a pro-inflammatory and catabolic chondrocyte phenotype, with upregulation of CRTAC1, COL6A3, TNC, and CXCL5, greater secretion of IL-6, MMP1, MMP3 and MMP13, and pro-nociceptive mediators (NGF and Substance P). These findings suggest that SFEVs may contribute to OA progression by exacerbating cartilage damage and promoting pain sensitisation. Full article

Background: Neurotrophins (NTs) are pivotal growth factors in cellular development and survival. Their precise implications in Acute Lymphoblastic Leukemia (ALL) remain unclear. Methods: Pediatric ALL samples (2011–2021) were analyzed from a Southern Brazil cohort. Neurotrophin levels were quantified via ELISA, with survival analysis using Kaplan–Meier curves. Gene expression data were sourced from public genomic repositories and analyzed with R software version 4.0.5. Results: At diagnosis, pro-BDNF, BDNF, and NGF levels were significantly lower than in healthy controls. Reduced pro-BDNF correlated with unfavorable outcomes. NGF and sortilin were highly expressed in healthy samples, while BDNF and p75^NTR were predominant in T-ALL and B-ALL, respectively. Conclusions: Neurotrophins show significant alterations in the tumor microenvironment of pediatric ALL. Further studies are needed to elucidate their precise role and prognostic potential. Full article

Post-COVID syndrome has unveiled intricate connections between inflammation, depressive psychopathology, and cognitive impairment. This study investigates these relationships in 101 COVID-19 survivors, focusing on sex-specific variations. Utilizing path modelling techniques, we analyzed the interplay of a one-month 48-biomarker inflammatory panel, with three-months of depressive symptoms and cognitive performance. The findings indicate that cognitive impairment is influenced by both inflammation and depression in the overall cohort. However, prominent sex-specific differences emerged. In females, a lingering imbalance between pro- and anti-inflammatory responses—likely reflecting the long-lasting immune alterations triggered by COVID-19—significantly affects cognitive functioning and shows a marginal, though not statistically significant, association with depressive symptoms. This suggests that a mixed inflammatory profile may contribute to these outcomes. Conversely, in males, inflammation was inversely associated with depression severity, with protective effects from regulatory mediators (IL-2, IL-4, IL-6, IL-15, LIF, TNF-α, β-NGF) against depression. In males, cognitive impairment appeared to be driven mainly by depressive symptoms, with minimal influence from inflammatory markers. These results highlight distinct sex-specific pathways in immune and inflammatory responses post-COVID-19, potentially shaped by endocrine mechanisms. The findings suggest that persistent inflammation may foster long-term neuropsychiatric sequelae, possibly through its effects on the brain, and underscore the need for sex-tailored therapeutic strategies to address the lasting impact of COVID-19. Full article

The vector of modern obstetrics is aimed at finding ways to predict various placenta-associated complications, including those associated with neuronal dysfunction on in fetal growth restriction (FGR). The technology of fetal neuronal exosome (FNE) isolation from the maternal bloodstream opens up unique opportunities for detecting early signs of fetal brain damage. Using this method, FNEs were isolated from the blood of pregnant women with and without early-onset FGR, and the expression of a number of proteins in their composition was assessed (Western blotting). Significant changes in the level of proteins involved in neurogenesis (pro-BDNF (brain-derived neurotrophic factor), pro-NGF (nerve growth factor), TAG1/Contactin2) and presynaptic transmission (Synapsin 1, Synaptophysin) were revealed. The preliminary data on the expression of FNE proteins that perform post-translational modifications—sumoylation (SUMO 1, UBC9) and neddylation (NEDD8, UBC12)—were obtained. A relationship was established between altered protein expression and neonatal outcomes in newborns with growth restriction. Our study opens up new possibilities for non-invasive prenatal monitoring of fetal neurodevelopment disorders and possibilities of their correction in placenta-associated diseases. Full article

Peripheral nerve regeneration depends on close interaction between neurons and Schwann cells (SCs). After nerve injury, SCs produce growth factors and cytokines that are crucial for axon re-growth. Previous studies revealed the supernatant of SCs exposed to nuclear magnetic resonance therapy (NMRT) treatment to increase survival and neurite formation of rat dorsal root ganglion (DRG) neurons in vitro. The aim of this study was to identify factors involved in transferring the observed NMRT-induced effects to SCs and consequently to DRG neurons. Conditioned media of NMRT-treated (CM NMRT) and untreated SCs (CM CTRL) were tested by beta-nerve growth factor (ßNGF) ELISA and multiplex cytokine panels to profile secreted factors. The expression of nociceptive transient receptor potential vanilloid 1 (TRPV1) channels was assessed and the intracellular calcium response in DRG neurons to high-potassium solution, capsaicin or adenosine triphosphate was measured mimicking noxious stimuli. NMRT induced the secretion of ßNGF and pro-regenerative-signaling factors. Blocking antibody experiments confirmed ßNGF as the main factor responsible for neurotrophic/neuritogenic effects of CM NMRT. The TRPV1 expression or sensitivity to specific stimuli was not altered, whereas the viability of cultured DRG neurons was increased. Positive effects of CM NMRT supernatant on DRG neurons are primarily mediated by increased ßNGF levels. Full article

Many routes may lead to the transition from a healthy to a diseased phenotype. However, there are not so many routes to travel in the opposite direction; that is, therapy for different diseases. The following pressing question thus remains: what are the pathogenic routes and how can be they counteracted for therapeutic purposes? Human cells contain >500 protein kinases and nearly 200 protein phosphatases, acting on thousands of proteins, including cell growth factors. We herein discuss neurotrophins with pathogenic or metabotrophic abilities, particularly brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), pro-NGF, neurotrophin-3 (NT-3), and their receptor Trk (tyrosine receptor kinase; pronounced “track”). Indeed, we introduced the word trackins, standing for Trk-targeting drugs, that play an agonistic or antagonistic role in the function of TrkB^BDNF, TrkC^NT−3, TrkA^NGF, and TrkA^pro-NGF receptors. Based on our own published results, supported by those of other authors, we aim to update and enlarge our trackins concept, focusing on (1) agonistic trackins as possible drugs for (1a) neurotrophin-deficiency cardiometabolic disorders (hypertension, atherosclerosis, type 2 diabetes mellitus, metabolic syndrome, obesity, diabetic erectile dysfunction and atrial fibrillation) and (1b) neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis), and (2) antagonistic trackins, particularly TrkA^NGF inhibitors for prostate and breast cancer, pain, and arrhythmogenic right-ventricular dysplasia. Altogether, the druggability of TrkA^NGF, TrkA^pro-NGF, TrkB^BDNF, and TrkC^NT−3 receptors via trackins requires a further translational pursuit. This could provide rewards for our patients. Full article

Nerve growth factor (NGF) is a neurotrophic peptide largely revealed for its ability to regulate the growth and survival of peripheral sensory, sympathetic, and central cholinergic neurons. The pro-survival and regenerative properties of neurotrophic factors propose a therapeutic potential in a wide range of brain diseases, and NGF, in particular, has appeared as an encouraging potential treatment. In this review, a summary of clinical studies regarding NGF and its therapeutic effects published to date, with a specific interest in the pediatric context, will be attempted. NGF has been studied in neurological disorders such as hypoxic–ischemic encephalopathy, traumatic brain injury, neurobehavioral and neurodevelopmental diseases, congenital malformations, cerebral infections, and in oncological and ocular diseases. The potential of NGF to support neuronal survival, repair, and plasticity in these contexts is highlighted. Emerging therapeutic strategies for NGF delivery, including intranasal administration as well as advanced nanotechnology-based methods, are discussed. These techniques aim to enhance NGF bioavailability and target specificity, optimizing therapeutic outcomes while minimizing systemic side effects. By synthesizing current research, this review underscores the promise and challenges of NGF-based therapies in pediatric neurology, advocating for continued innovation in delivery methods to fully harness NGF’s therapeutic potential. Full article