Search Results (159)

Background/Objectives: Preterm newborns (NBs) are at increased risk of motor developmental impairments. Evidence on inflammatory and neurotrophic biomarkers measured in the neonatal period as predictors of motor outcomes is scarce and heterogeneous. This systematic review synthesised data on inflammatory biomarkers and neurotrophic factors in Preterm NB as predictors of motor development (MD) up to 24 months of corrected age. Methods: MEDLINE, SciELO, Web of Science and Embase were searched for longitudinal observational studies of Preterm NB (World Health Organization definition) that measured one or more inflammatory biomarkers and/or neurotrophic factors in blood, urine or saliva and applied validated neurodevelopmental scales up to 24 months. Non-original reports, populations outside scope and studies with incomplete data were excluded. Methodological quality of primary studies was assessed with the Newcastle–Ottawa Scale (NOS). The protocol was registered in PROSPERO (CRD42022365839). Results: Of 1475 records, eight studies met the eligibility criteria. Higher neonatal concentrations of interleukin-6 (IL-6), interleukin-8 (IL-8), tumour necrosis factor-alpha (TNF-α) and C-reactive protein (CRP) were generally associated with poorer motor performance, although null findings occurred in some cohorts. One study assessing neurotrophic factors reported elevated urinary brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) among infants with below-expected MD. Conclusions: Inflammatory biomarkers show promise as early indicators of adverse MD in Preterm NB, but heterogeneity in populations, biospecimens, sampling windows, assays and outcome scales limits comparability and precludes definition of risk thresholds. Larger, standardised cohorts are needed to clarify the prognostic value of inflammatory and neurotrophic biomarkers and to inform early risk stratification. Full article

Background/Objectives: Mesenchymal stem cells (MSCs) are recognized for their therapeutic potential due to their ability to secrete bioactive molecules. Among these secreted factors, bone morphogenetic protein-2 (BMP-2) is known as a secreted factor that plays a crucial role in bone healing and regeneration. However, MSCs naturally secrete only small amounts of BMP-2. To improve the bone healing capacity of MSCs, it is essential to enhance the secretion of BMP-2 in MSCs. One approach that can be used to achieve this goal is by genetically engineering MSCs. Incorporating signal peptides (SPs) into the inserted gene sequence can significantly improve protein secretion efficiency. In this proof-of-concept study, we explored the role of SPs in optimizing BMP-2 secretion in umbilical cord-derived MSCs; Methods: Three human-derived SPs, namely glial-derived neurotrophic factor (GDNF), chemotactic antibacterial glycoprotein 7 (CAP7), and platelet-derived growth factor subunit B (PDGFB), were selected. Transfection of MSCs was performed using polyethylenimine, Lipofectamine 2000^®, and Lipofectamine 3000^®. Transfection efficiency confirmed based on Green Fluorescence Protein expression. BMP-2 secretion levels were quantified using an ELISA assay; Results: Lipofectamine 3000^® achieved the highest transfection efficiency, reaching approximately 10%. BMP-2 secretion levels varied significantly depending on the SPs used, with PDGFB yielding the highest BMP-2 concentration (279.21 ± 6.91 pg/mL), followed by GDNF (265.65 ± 11.49 pg/mL) and CAP7 (233.72 ± 32.33 pg/mL); Conclusions: These findings demonstrate that SP selection critically influences BMP-2 secretion efficiency in genetically engineered MSCs and underscore its potential to enhance the therapeutic applicability of MSC-based strategies for bone healing. Full article

Progressive supranuclear palsy (PSP) is a condition classified as atypical parkinsonism. Pathologically, it is a four-repeat tauopathy; clinically, it is a disease comprising oculomotor dysfunction, postural instability, akinesia, and cognitive/language disorders. Its pathogenesis is not fully recognized; however, neuroinflammation is considered to likely be a significant aspect, though it is not known whether inflammation is a cause or consequence of neurodegeneration. In this study, the authors analyzed the association between inflammatory/neurotrophic factors and parameters linked to quality of life, based on examinations of 10 controls and 11 patients with PSP. They found a negative correlation between mPSPRS (Modified Progressive Supranuclear Palsy Rating Scale) and the glial cell-line-derived neurotrophic factor levels (GDNF) (r = −0.772727, p = 0.003) in the serum, a less pronounced negative correlation between progressive supranuclear palsy–quality of life parameter (PSP-QoL) and GDNF (r = −0.68390, p = 0.011) in the serum, and no correlations were observed in the analyses of inflammatory factors. The obtained results show the association between lower levels of GDNF and more pronounced clinical deterioration. Further analysis in the field based on larger groups of patients is required. Full article

Multiple Sclerosis (MS) therapies effectively modulate peripheral immune responses but largely fail to promote neural repair within the central nervous system. This review evaluates whether psychedelic compounds (PSYs), via 5-HT2A activation, can fill a critical therapeutic gap: the need for agents that simultaneously suppress neuroinflammation and promote regeneration. We dissect the evidence suggesting PSYs can reprogram the neuroimmune milieu by downregulating key pro-inflammatory cytokines (e.g., TNF-α, IL-6) in glial cells while concurrently upregulating crucial neurotrophic factors (e.g., BDNF) that promote synaptic plasticity and oligodendrocyte support. However, we argue that the current evidence, largely derived from non-specific inflammation models, is insufficient to predict clinical efficacy in an autoimmune disease like MS. We critically analyze the significant translational barriers—from cardiovascular and psychiatric risks to profound legal and ethical challenges—that temper the immediate clinical promise. Finally, we propose a forward-looking perspective, suggesting that the true value of PSYs may lie not in their direct clinical use, but in uncovering novel therapeutic pathways. The emergence of non-hallucinogenic, functionally selective 5-HT2A agonists, inspired by psychedelic pharmacology, represents a more viable strategy to harness these mechanisms for MS therapy, demanding rigorous preclinical validation in disease-relevant models. Full article

The bidirectional relationship between the brain and gut microbiota has led to the concept of the microbiota–gut–brain axis. It refers to a system of bilateral communication that integrates neuronal, immunological, and metabolic signals, whose disruption has been linked to the pathogenesis of digestive, metabolic, and neurological disorders, among others. Intestinal dysbiosis (an imbalance in the gut microbiota) can promote a proinflammatory and prothrombotic state, as well as dyslipidaemia and dysglycemia, that increase atherogenic risk and consequently the risk of stroke. Dysbiosis can also lead to neuroinflammatory and neurodegenerative effects, compromising the integrity of the blood–brain barrier and exacerbating brain injury after stroke. Specific bacterial profiles have been associated with varying levels of stroke risk, emphasising the role of gut microbiota-derived vasoactive metabolites such as Trimethylamine N-Oxide (TMAO), phenylacetylglnutamine (PAGln), and short-chain fatty acids (SCFAs), which may serve as biomarkers for stroke risk and severity. Gut microbiota also influences neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF), involved in recovery after stroke. Research has explored the potential to modify the gut microbiota to either prevent stroke (by reducing risk) or improve outcomes (by decreasing severity and sequelae). Current scientific evidence supports the role of gut microbiota as a potential diagnostic and prognostic biomarker, as well as a therapeutic target. Full article

Methamphetamine (METH) is a highly addictive synthetic psychostimulant that can induce severe neurotoxicity, leading to neurodegeneration similar to neurodegenerative diseases. The endocytosis of glial cell line-derived neurotrophic factor (GDNF) and its family receptor alpha 1 (GFRα1), regulated by transmembrane receptor tyrosine kinase (RET), has been shown to resist neurodegeneration. Specifically, the endocytosis of GDNF-GFRα1 mediated by RET is crucial in protecting neurons. Although many molecular mechanisms of METH induced neurotoxicity have been explored, the obstacles to the neuroprotective effect of GDNF in the context of METH induced neurotoxicity are still unclear. In this study, an increase in cell apoptosis and GDNF expression was observed in the hippocampus of METH abusers. METH also induces cell degeneration, cytotoxicity, and GDNF expression and release in hippocampal neuronal (HT-22) cells in a concentration-dependent manner (0.25, 0.5, 1, 2, and 4 mM) and time-dependent manner (3, 6, 12, 24, and 48 h). Meanwhile, after 24 h of exposure to METH (2mM), apoptosis, impaired endocytosis of GDNF-GFRα1, and decreased expression of RET were observed in HT-22 cells and organotypic hippocampal slices of mice. More notably, overexpression of RET weakened METH induced cell degeneration, apoptosis, and disruption of GDNF-GFRα1 endocytosis in HT-22 cells. This study suggests that RET is a key molecule for METH to disrupt GDNF-mediated neuroprotective signaling, and targeting RET-mediated endocytosis of GDNF-GFRα1 may be a potential therapeutic approach for METH induced neurotoxicity and neurodegeneration. Full article

Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease, multiple sclerosis, and amyotrophic lateral sclerosis share converging mechanisms of neuronal dysfunction, including protein aggregation, oxidative stress, and chronic neuroinflammation. Glial cells, once considered passive supporters, are now recognized as central drivers of these processes, offering both pathogenic triggers and therapeutic opportunities. Yet, despite compelling preclinical evidence, the translation of glial-targeted therapies into clinical success has been limited. This review provides a critical synthesis of current knowledge by examining therapeutic strategies through the lens of their translational challenges and failures. This narrative review highlights how interspecies variability of glial phenotypes, shifting neuroprotective versus neurotoxic states, limited biomarker stratification, and delivery barriers have constrained trials, such as anti-triggering receptor expressed on myeloid cells 2 (anti-TREM2) antibodies in AD and glial cell line-derived neurotrophic factor (GDNF) in PD. By analyzing these obstacles across major neurodegenerative disorders, this review argue that the next stage of glial medicine requires precision approaches that integrate stage-specific phenotyping, biomarker-guided patient selection, and innovative delivery platforms. Understanding not only what has been tried but why translation has stalled is essential to chart a roadmap for effective, disease-modifying glial therapies in the aging brain. 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

Schwann cells (SCs) are the primary glial cells of the Peripheral Nervous System (PNS), which insulate and provide protection and nutrients to the axons. Technological and experimental advances in neuroscience, focusing on the biology of SCs, their interactions with other cells, and their role in the pathogenesis of various diseases, have paved the way for exploring new treatment strategies that aim to harness the direct protective or causative properties of SCs in neurological disorders. SCs express cytokines, chemokines, neurotrophic growth factors, matrix metalloproteinases, extracellular matrix proteins, and extracellular vesicles, which promote the inherent potential of the injured neurons to survive and accelerate axonal elongation. The ability of SCs to support the development and functioning of neurons is lost in certain hereditary, autoimmune, metabolic, traumatic, and toxic conditions, suggesting their role in specific neurological diseases. Thus, targeting, modifying, and replacing SC strategies, as well as utilizing SC-derived factors and exosomes, have been considered novel therapeutic opportunities for neuropathological conditions. Preclinical and clinical data have demonstrated that SCs and SC-derived factors can serve as viable cell therapy for reconstructing the local tissue microenvironment and promoting nerve anatomical and functional recovery in both peripheral and central nerve injury repair, as well as in peripheral neuropathies. However, despite the promising successes of genetic engineering of SCs, which are now in preclinical and clinical trials, improving tactics to obtain ‘repair’ SCs and their products from different sources is the key goal for future clinical success. Finally, further development of innovative therapeutic approaches to target and modify SC survival and function in vivo is also urgently needed. Full article

According to the World Health Organization (WHO), a healthy lifestyle is defined as a way of living that lowers the risk of becoming seriously ill or dying prematurely. Physical activity, as a well-known contributor to overall health, plays a vital role in supporting such a lifestyle. Exercise induces complex molecular responses that mediate both acute metabolic stress and long-term physiological adaptations. FGF21 (fibroblast growth factor 21) and GDF15 (growth differentiation factor 15) are recognized as metabolic stress markers, while their receptors play critical roles in cellular signaling. However, the differential gene expression patterns of these molecules in trained and untrained individuals following exhaustive exercise remain poorly understood. This study aimed to examine the transcriptional and protein-level responses in trained and untrained individuals performed a treadmill maximal exercise test to voluntary exhaustion. Blood samples were collected at six time points (pre-exercise, immediately post-exercise, and 0.5 h, 6 h, 24 h, and 48 h post-exercise). Gene expression of FGF21, GDF15, FGFR1 (fibroblast growth factor receptors), FGFR3, FGFR4, KLB (β-klotho), and GFRAL (glial cell line-derived neurotrophic factor receptor alpha-like) was analyzed using RT-qPCR, while plasma protein levels of FGF21 and GDF15 were quantified via ELISA. The results obtained were statistically analyzed by using Shapiro–Wilk, Mann–Whitney U, and Wilcoxon tests in Statistica 13 software. Untrained individuals demonstrated significant post-exercise upregulation of FGFR3, FGFR4, KLB, and GFRAL. FGF21 and GDF15 protein levels were consistently lower in trained individuals (p < 0.01), with no significant correlations between gene and protein expression. Trained individuals showed more stable expression of genes, while untrained individuals exhibited transient upregulation of genes after exercise. Full article

The transforming growth factor beta (TGF-$\mathsf{\beta }$) gene family is widely distributed across the animal kingdom, playing a crucial role in various cellular processes and maintaining overall health and homeostasis. The present study identified 34 TGF-$\mathsf{\beta }$ family genes based on the genome sequence in Tupaia belangeri, which were classified into the TGF-$\mathsf{\beta }$, bone morphogenetic protein (BMP), growth differentiation factor (GDF), glial cell-derived neurotrophic factor (GDNF), and Activin/Inhibin subfamilies. A phylogenetic analysis revealed the evolutionary relationships among members of the TGF-$\mathsf{\beta }$ family in T. belangeri and their homologous genes in Homo sapiens, Mus musculus, and Pan troglodytes, indicating a high degree of conservation throughout evolution. A chromosomal distribution and collinearity analysis demonstrated the localization of these genes within the genome of T. belangeri and their collinearity with genes from other species. A gene structure and motif analysis further illustrated the conservation and diversity among TGF-$\mathsf{\beta }$ family members. A protein interaction network analysis highlighted the central roles of TGFB1, TGFB3, BMP7, and BMP2 in signal transduction. A functional enrichment analysis underscored the significance of the TGF-$\mathsf{\beta }$ signaling pathway in the biological processes of T. belangeri, particularly in cell proliferation, differentiation, and apoptosis. We assessed the impact of cold acclimation treatment on the expression of TGF-$\mathsf{\beta }$ family proteins in the adipose tissue (white adipose tissue [WAT] and brown adipose tissue [BAT]) of T. belangeri using ELISA technology, finding that protein expression levels in the experimental group were significantly higher than those of in the control group. These results suggested that cold acclimation may enhance the adaptability of T. belangeri to cold environments by modulating the expression of TGF-$\mathsf{\beta }$ family genes. This study offers new insights into the role of the TGF-$\mathsf{\beta }$ family in the cold acclimation adaptation of T. belangeri, providing a scientific foundation for future genetic improvements and strategies for cold acclimation. Full article

Background/Objectives: Degenerative spinal conditions, such as degenerative stenosis, have been linked to metabolic and lifestyle factors, including obesity, smoking, and diabetes. Glial cell line-derived neurotrophic factor (GDNF) plays a crucial role in neuroprotection, but its relationship with these risk factors remains unclear. Methods: This study aims to evaluate the relationship between body mass index (BMI), smoking, diabetes, and GDNF levels in patients with degenerative spine conditions. We measured the GDNF levels in patients with degenerative stenosis and assessed the impact of BMI, smoking status, and the presence of diabetes. Comparisons were made using appropriate statistical analyses to determine the significance of these factors on GDNF levels. Results: A significant inverse relationship was observed between the BMI and GDNF levels (p < 0.01). Patients with a higher BMI exhibited lower GDNF concentrations. Additionally, patients who smoked or had diabetes showed significantly lower GDNF levels compared to non-smokers and those without diabetes (p = 0.03 and p = 0.02, respectively). These findings suggest that both metabolic and lifestyle factors are associated with decreased GDNF, which may accelerate neurodegenerative processes in the spine. Conclusions: Our study demonstrates that increased BMI, smoking, and diabetes are linked to reduced GDNF levels, potentially contributing to the progression of degenerative spine conditions such as stenosis. These findings highlight the need for targeted clinical interventions to manage these risk factors, aiming to preserve GDNF levels and slow the degenerative processes in the spine. Future research should explore therapeutic approaches to modulate GDNF in affected populations. Full article

Background/Objectives: Lumbosacral spinal stenosis (LSS) is a degenerative condition characterized by narrowing of the spinal canal and associated neuropathic pain. While mechanical compression is well-characterized, the molecular mechanisms contributing to symptom severity remain poorly understood. Neurturin (NRTN), a member of the glial cell line-derived neurotrophic factor family, has emerged as a potential mediator of neural plasticity and nociception, but its role in spinal stenosis is largely unexplored. Methods: We analyzed NRTN mRNA and protein expression in ligamentum flavum samples from 96 patients undergoing surgery for LSS and 85 non-degenerative postmortem controls. Quantification was performed using real-time quantitative polymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), Western blotting, and immunohistochemistry. Pain severity Visual Analog Scale (VAS), body mass index (BMI), diabetes, smoking, and alcohol use were assessed as modulators of NRTN expression. Results: NRTN expression was significantly elevated in LSS patients versus controls at both transcript and protein levels (p < 0.05). NRTN levels positively correlated with pain intensity (VAS; ANOVA p = 0.032 for mRNA, p = 0.041 for protein). Multivariate regression identified BMI (β = 0.50, p = 0.015) and diabetes (β = 0.39, p = 0.017) as independent predictors of increased NRTN expression. Alcohol use also showed a positive association (p = 0.046), while smoking showed no significant independent effect. Conclusions: Neurturin is upregulated in ligamentum flavum tissue from LSS patients and correlates with pain severity and metabolic risk factors. These findings suggest NRTN as a potential biomarker and therapeutic target in degenerative spine disease. Further longitudinal and mechanistic studies are warranted to elucidate its role in chronic pain and neuroinflammation. Full article

We recently showed, in a mouse optic nerve crush model, that a sustained cell-based intravitreal administration of ciliary neurotrophic factor (CNTF) and glial cell line-derived neurotrophic factor (GDNF) synergistically slowed the lesion-induced degeneration of retinal ganglion cells (RGCs), resulting in the presence of approximately 35% viable RGCs eight months after the lesion. However, the combinatorial neuroprotective treatment was initiated shortly after the lesion. To mimic a more clinically relevant situation, we co-administered both factors either three or five days after an intraorbital nerve crush when approximately 35% or 57% of the RGCs were degenerated, respectively. Analyses of the retinas at different time points after the lesion consistently revealed the presence of significantly more surviving RGCs in retinas co-treated with CNTF and GDNF than in retinas treated with either factor alone. For example, when the neurotrophic factors were administered five days after the nerve crush and the animals were analyzed two months after the lesion, retinas co-treated with CNTF and GDNF contained approximately 40% of the RGCs present at the start of treatment. In comparison, monotherapy with either CNTF or GDNF protected only about 15% or 10% of the RGCs present at baseline, respectively. The number of regenerating axons in the distal nerve stumps was similar in CNTF- and CNTF/GDNF-treated animals, despite the significantly higher number of rescued RGCs in the latter group. These findings have potential implications for studies aimed at developing neuroprotective treatments for optic neuropathies such as glaucoma. Full article

Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental disorder that significantly impacts learning, daily functioning, and personal development. Astaxanthin (ASTA), a naturally occurring antioxidant, has garnered interest as a potential therapeutic agent for various diseases, particularly in mitigating oxidative stress. This study explores a novel application of ASTA in the context of ADHD, aiming to investigate its therapeutic effects and underlying mechanisms. Spontaneously hypertensive rats (SHRs), widely used ADHD model animals, were treated with ASTA (50/100 mg/kg/day) for three weeks, 5 mg/kg/day atomoxetine (ATO) as the positive, and Wistar Kyoto (WKY) rats as control. Behavioral improvements were assessed using the open field test (OFT) and the Morris water maze (MWM). Biochemical analyses were conducted to evaluate changes in the levels of various neurotrophic factors, while histological examinations were performed to assess neuroprotective effects. Additionally, the role of ASTA in the brain–gut axis was investigated. The behavioral symptoms of hyperactivity, anxiety, and impaired spatial memory in ADHD animals were mitigated by ASTA. This improvement is primarily attributed to the restoration of neurotransmitter levels, particularly dopamine (DA), achieved through the modulation of several critical components within the dopamine system, including dopamine receptor 1 (DR1), dopamine transporter (DAT), tyrosine hydroxylase (TH), and synaptic-associated protein 25 (SNAP-25). Additionally, regulating the serotonin transporter (SERT) and glial cell-derived neurotrophic factor (GDNF) supports the recovery of serotonin levels and facilitates optimal brain development. Furthermore, cerebellar cells were protected, and the structure of the intestinal microbiota was regulated. ASTA can mitigate ADHD symptoms in SHR through the modulation of the dopaminergic system, multiple neurotransmitters, neurotrophic factors, and the neuro-intestinal environment, which establishes ASTA as a promising nutraceutical candidate for adjunctive therapy in pediatric ADHD. Full article