Search Results (84)

Background: Periodontitis affects approximately 7–11% of the global adult population in its severe forms and has been epidemiologically associated with cardiovascular, cardiometabolic, and neurodegenerative diseases. Low-grade chronic inflammation represents the unifying mechanism; however, an integrative framework connecting the oral cavity, the gut, and the brain into a single mechanistic continuum is lacking. Objective: This narrative review, conducted with structured (but non-systematic) elements and PRISMA-2020 style reporting used solely as a transparency tool, synthesizes current evidence on the oral–gut–brain axis. A comprehensive literature search was conducted in PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar (2000–March 2026), yielding 159 included studies after structured screening and eligibility assessment. The review focuses on: the molecular mechanisms by which periodontal dysbiosis may disrupt intestinal homeostasis and contribute to neuroinflammation; the role of salivary and intestinal biomarkers as monitoring tools for the entire axis; and emerging pharmacological opportunities targeting this tripartite pathway. Results: Periodontal pathogens, particularly Porphyromonas gingivalis (P. gingivalis) and Fusobacterium nucleatum, have been detected ectopically in the gut and are associated with reduced tight junction protein expression and altered Firmicutes/Bacteroidetes ratios in preclinical and observational studies. These perturbations have been associated with increased blood–brain barrier (BBB) permeability, microglial activation, and amyloid-beta (Aβ) accumulation, although causal directionality in humans remains to be established. Salivary biomarkers (MMP-8, IL-1β, IL-6, BDNF) and intestinal biomarkers (short-chain fatty acids, calprotectin) reflect systemic inflammatory burden and offer potential for non-invasive screening. Conclusions: The oral–gut–brain axis provides a plausible unifying framework for understanding comorbidity among periodontal, cardiometabolic, and neurodegenerative diseases; however, current evidence is predominantly associative, and mechanistic extrapolation from preclinical models requires validation in longitudinal human studies. Salivary biomarkers may serve as candidate first-line tools for systemic risk assessment, and pharmacological interventions targeting this axis represent promising investigational directions warranting further clinical evaluation. Full article

Background: Brain-derived neurotrophic factor (BDNF) is central to synaptic plasticity and neurodevelopment. Toxic metal exposure is linked to oxidative stress and neuroinflammation, yet its effects on BDNF signaling remain unclear. Objectives: To systematically synthesize evidence from human and experimental studies on the association between environmental or occupational metal exposure and BDNF alterations, and to highlight research gaps with an emphasis on hexavalent chromium (Cr(VI)). Methods: PubMed, Scopus, and ScienceDirect were searched following PRISMA guidelines. Eligible studies included human observational research and animal models reporting quantitative associations between metal exposure (biomarkers/environmental measures) and BDNF outcomes (protein or gene expression). Data were extracted on exposure assessment, BDNF measurement, and neurobehavioral outcomes. Study quality was assessed using NOS (human studies) and SciRAP (experimental studies). Results: Nineteen studies were included. Across metals such as Pb, Hg, Cd, As, Mn, and mixtures, exposure was associated with altered BDNF levels in blood or brain tissue, often alongside oxidative stress markers, inflammatory changes, and cognitive or behavioral impairment in animal models. Most human studies reported decreased circulating BDNF with higher exposure, while experimental evidence suggested context-dependent regulation across exposure windows and brain regions. Conclusions: The available evidence supports a biologically plausible link between metal exposure and BDNF dysregulation. No eligible studies evaluated BDNF in relation to Cr(VI), indicating a major research gap. Future studies should integrate neurotrophic biomarkers with exposome-oriented designs to clarify chromium-related neurotoxicity and support Adverse Outcome Pathway (AOP)-informed frameworks. Full article

Background/Objectives: Alzheimer’s disease (AD) is characterized by progressive neurodegeneration driven by interconnected mechanisms, including oxidative stress, mitochondrial dysfunction, neuroinflammation, synaptic impairment, and abnormal protein aggregation. MicroRNAs (miRNAs) have emerged as post-transcriptional regulators of these complex pathways; however, efficient delivery remains a major limitation. Small extracellular vesicles (sEVs) have been proposed as biologically compatible carriers for miRNA delivery. Methods: In this study, milk-derived sEVs were isolated, characterized, and loaded with microRNA-137-5p (miR-137-5p). Their effects were evaluated in an amyloid-β (Aβ)-induced in vitro AD model using SH-SY5Y human neuroblastoma cells. Oxidative stress markers, including reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), lactate dehydrogenase (LDH), and glutathione peroxidase 1 (GPX1), were assessed. Inflammation- and neuroprotection-related gene expression analyses included intercellular adhesion molecule 1 (ICAM1), tumor necrosis factor alpha (TNF-α), and brain-derived neurotrophic factor (BDNF). Cytoskeletal injury was evaluated using neurofilament light chain (NfL). Mitochondrial stress markers included cytochrome c (Cyt-c), 8-hydroxy-2′-deoxyguanosine (8-OHdG), PTEN-induced kinase 1 (PINK1), dynamin-1-like protein (DNM1L), and mitochondrial transcription factor A (TFAM). Synaptic and extracellular matrix-associated proteins, including complexin-2 (CPLX2), SPARC-related modular calcium-binding protein 1 (SMOC1), and receptor tyrosine kinase-like orphan receptor 1 (ROR1), as well as AD-related biomarkers, including total tau, phosphorylated tau at threonine 181 (pTau-181), phosphorylated tau at threonine 217 (pTau-217), and amyloid-β 1–40 (Aβ1–40), were evaluated using molecular and biochemical approaches. Results: Aβ exposure was associated with increased oxidative stress, inflammatory activation, mitochondrial and cytoskeletal alterations, synaptic-related disturbances, and elevations in tau- and amyloid-associated proteins. Treatment with unloaded sEVs was associated with partial modulation of several parameters, whereas miR-137-5p-loaded sEVs were consistently associated with normalization of multiple pathological markers toward control levels. Conclusions: These findings indicate that miR-137-5p-enriched sEVs may represent a useful experimental platform for multi-target modulation of AD-related cellular alterations. Further mechanistic and in vivo studies are required to clarify translational relevance. Full article

(1) Background: The increasing environmental concentration of polystyrene nanoplastics (PS-NPs) may pose a risk of human exposure and health threats. Previous studies have demonstrated that exposure to PS-NPs poses a threat to neural synaptic plasticity, yet the underlying mechanisms remain unclear. (2) Methods: Hippocampal astrocytes and neurons were co-cultured, exposed to PS-NPs at concentrations of 10, 50, and 100 μg/mL, and cytotoxicity was assessed. We investigated PS-NP-induced impairment of synaptic plasticity by regulating the brain-derived neurotrophic factor (BDNF). (3) Results: Calmodulin-dependent protein kinase II (CaMKII) is a central molecular organizer of synaptic plasticity, learning, and memory, and its activity is intrinsically linked to intracellular calcium ion concentration. Our research indicates that PS-NPs may interfere with calcium ion signaling and CaMKIIα activity, thereby reducing CaMKIIα activity. This subsequently downregulates the expression of cAMP response element-binding protein (CREB), modulates BDNF expression, and impacts synaptic plasticity. (4) Conclusions: In summary, this study primarily focused on the effects of PS-NPs exposure on hippocampal synaptic plasticity. Full article

Alzheimer’s disease and related neurodegenerative disorders are associated with progressive cognitive decline, primarily driven by cholinergic dysfunction and impaired synaptic signaling. Hericium erinaceus, also known as lion’s mane mushroom, has been reported to promote neuronal differentiation and synaptic plasticity. In this study, a standardized H. erinaceus extract powder (HEP) was prepared from fruiting bodies and quantified using hericene A as a marker compound. The neuroprotective effects of HEP were then evaluated in both cellular and animal models of scopolamine-induced cognitive dysfunction. Pretreatment of SH-SY5Y human neuroblastoma cells with HEP (5–25 μg/mL) significantly improved cell viability and reduced scopolamine-induced apoptosis, while enhancing the activation of neuroplasticity-related signaling proteins, including brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), and extracellular signal-regulated kinase (ERK). In vivo, oral administration of HEP (300 mg/kg) to scopolamine-treated ICR mice markedly improved cognitive performance, increasing the recognition index to 63.8% compared with 41.6% in the scopolamine group, and enhancing spontaneous alternation in the Y-maze test to 59.6%. These cognitive improvements were accompanied by preserved hippocampal neuronal structure and increased BDNF immunoreactivity. Additionally, HEP improved cholinergic function by restoring serum acetylcholine levels and reducing acetylcholinesterase activity. Collectively, these findings suggest that standardized HEP exerts neuroprotective and cognition-enhancing effects via modulation of cholinergic markers and activation of BDNF-mediated neuroplasticity, highlighting its potential as a functional food ingredient or nutraceutical for preventing cognitive decline related to cholinergic dysfunction. Full article

Non-invasive brain stimulation (NIBS) techniques—including repetitive transcranial magnetic stimulation (rTMS), theta-burst stimulation (TBS), paired associative stimulation (PAS), transcranial direct current stimulation (tDCS), and transcranial alternating current stimulation (tACS)—have emerged as valuable tools for modulating neural activity and promoting plasticity. Traditionally, their effects have been interpreted within a binary framework of long-term potentiation (LTP)-like and long-term depression (LTD)-like plasticity, largely inferred from changes in motor evoked potentials (MEPs). However, existing models do not fully capture the complexity of the biological processes engaged by these techniques and despite extensive clinical application, the cellular and molecular mechanisms underlying NIBS remain only partially understood. This systematic review, conducted in accordance with the PRISMA 2020 guidelines, synthesizes evidence from in vivo, in vitro, and ex vivo studies to delineate how NIBS influences neurotransmission through intracellular signaling, gene expression, and protein synthesis at the cellular level. Emphasis is placed on the roles of classical synaptic models, grounded in Ca²⁺-dependent glutamatergic signaling and receptor phosphorylation dynamics, as well as broader forms of plasticity involving BDNF–TrkB signaling, epigenetic modifications, neuroimmune and glial interactions, anti-inflammatory pathways, and apoptosis- and survival-related cascades. By integrating findings in humans with those in animal and cellular models, we identify both shared and technique-specific molecular mechanisms underlying NIBS-induced effects, highlighting emerging evidence for multi-pathway, non-binary plasticity mechanisms. Understanding these convergent pathways provides a mechanistic foundation for refining stimulation paradigms and improving their translational relevance for treatment of neurological and psychiatric disorders. Full article

Background: As a non-weight-bearing full-body exercise, swimming may reduce inflammation and boost anti-inflammatory agents to decrease the risk of cardiovascular, neurological, and rheumatological disorders. This systematic review examines the current evidence on the role of swimming exercise in modulating immune responses through inflammatory pathways. Methods: First, the PubMed and Scopus databases were searched through December 2024 for studies on swimming and inflammation. The initial search using keywords yielded 509 articles; 102 met the inclusion criteria after screening for relevance, language, and full-text availability. Results: This study suggests that regular swimming reduces neuroinflammation by enhancing BDNF, CREB, and PI3K/Akt signaling while suppressing both mRNA and protein levels of NF-κB, TNF-α, and IL-6 in the brain. In metabolic tissues, it activates SIRT1 and PGC-1α, improving mitochondrial biogenesis and antioxidant defense. Swimming also upregulates PPAR-α and eNOS while downregulating iNOS, leading to reduced vascular inflammation, oxidative stress, and fibrosis in renal and cardiac tissues. Moreover, the enhanced production of IL-10 and the decreasing levels of IL-1β and CRP contribute to systemic anti-inflammatory effects. Conclusions: Consequently, the available evidence suggests that swimming can be a low-impact, full-body exercise with potential therapeutic options in managing inflammation-related conditions such as cardiovascular disease, diabetes, and obesity. Future studies should focus on human clinical trials, investigate mechanisms, and assess longer time frames. Full article

Focal cortical dysplasia (FCD) is a major cause of drug-resistant epilepsy, yet its molecular basis remains poorly understood. Numerous studies have analyzed RNA, protein, and microRNA alterations, but results are often inconsistent across subtypes and methodologies. To address this gap, we conducted a systematic review integrating transcriptomic, proteomic, and microRNA data from 117 human studies of FCD subtypes I–III. Differentially expressed factors were extracted, categorized by subtype, and analyzed using pathway enrichment and network approaches. Our integrative analysis revealed convergent dysregulation of neuroinflammatory, synaptic, cytoskeletal, and metabolic pathways across FCD subtypes. Consistently altered genes, including IL1B, TLR4, BDNF, HMGCR, and ROCK2, together with dysregulated microRNAs such as hsa-miR-21-5p, hsa-miR-155-5p, and hsa-miR-132-3p, were linked to PI3K–Akt–mTOR, Toll-like receptor, and GABAergic signaling, emphasizing shared pathogenic mechanisms. Importantly, we identified overlapping transcript–protein patterns and subtype-specific molecular profiles that may refine diagnosis and inform therapeutic strategies. This review provides the first cross-omics molecular framework of FCD, demonstrating how convergent pathways unify heterogeneous findings and offering a roadmap for biomarker discovery and targeted interventions. Full article

Brain ischemia-reperfusion (I/R) injury, commonly occurring in ischemic stroke and post-cardiac arrest scenarios, results in complex secondary damage involving oxidative stress, inflammation, apoptosis, and blood-brain barrier (BBB) breakdown. Despite decades of research, no pharmacological agent has yet been clinically approved for post-I/R neuroprotection. Natural compounds have recently gained attention for their multimodal therapeutic potential, including antioxidant, anti-inflammatory, anti-apoptotic, and neuroregenerative effects. This review highlights nine promising candidates—resveratrol, curcumin, quercetin, berberine, ginkgolide B, baicalin, naringin, fucoidan, and astaxanthin—that exhibit efficacy in experimental models of I/R injury when administered after the insult. Their chemical structures, pharmacokinetics, and mechanisms of action are described in detail, focusing on key signaling pathways such as nuclear factor erythroid 2-related (Nrf2), nuclear factor kappa B (NF-κB), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), and brain-derived neurotrophic factor (BDNF). Importantly, we outline the selection criteria for these compounds, including demonstrated neuroprotective efficacy, mechanistic clarity, and translational feasibility. While several challenges remain—such as limited bioavailability, BBB penetration, and species-specific metabolism—emerging strategies like nanoparticle delivery, synthetic analogs, and drug combinations offer potential solutions. By emphasizing the therapeutic versatility and mechanistic diversity of these natural agents, this review supports their clinical potential and encourages further preclinical optimization and biomarker-guided human trials. Full article

Background/Objectives: Neurodegenerative diseases represent a growing global health challenge with limited therapeutic options. Physical exercise has emerged as a promising non-pharmacological intervention with potential neuroprotective effects. This narrative review examines the mechanisms through which exercise induces neuroplasticity and their implications for neurodegenerative disease prevention. Methods: We synthesized evidence from molecular, animal, and human studies on exercise-induced neuroplasticity and neurodegenerative disease prevention through a comprehensive literature review. Results: Exercise enhances neuroplasticity through multiple pathways: (1) neurotrophic signaling (BDNF, IGF-1, VEGF), (2) neuroendocrine regulation, (3) epigenetic modifications, and (4) metabolic pathway optimization. These molecular changes support structural adaptations including hippocampal neurogenesis, enhanced synaptic plasticity, improved cerebrovascular function, and optimized brain network connectivity. Exercise directly impacts pathological features of neurodegenerative diseases by reducing protein aggregation, attenuating excitotoxicity and oxidative stress, and enhancing mitochondrial function. Clinical evidence consistently demonstrates associations between physical activity and reduced neurodegenerative risk, with intervention studies supporting causal benefits on cognitive function and brain structure. Conclusions: Exercise represents a multi-target intervention addressing several pathological mechanisms simultaneously across various neurodegenerative conditions. Its accessibility, minimal side effects, and multiple health benefits position it as a promising preventive strategy. Future research should focus on understanding individual response variability, developing sensitive biomarkers, and creating personalized exercise prescriptions for optimal neuroprotection. Full article

Huntington’s disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms. While traditionally viewed through the lens of neuronal dysfunction, emerging evidence highlights the critical role of endothelial dysfunction in HD pathogenesis. This review provides a comprehensive overview of endothelial dysfunction in HD, drawing on findings from both animal models and human studies. Key features of endothelial dysfunction in HD include impaired angiogenesis, altered cerebral blood flow, compromised neurovascular coupling and cerebrovascular reactivity, and increased blood–brain barrier permeability. Genetic factors such as the mutant huntingtin protein, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), Brain-derived neurotrophic factor (BDNF), and the adenosine A2A receptor (ADORA2A) interact to influence endothelial function in complex ways. Various therapeutic approaches targeting endothelial dysfunction, including antioxidants, nitric oxide enhancers, calcium channel blockers, statins, and metformin, have shown promise in preclinical HD models but face translational challenges, particularly regarding optimal timing of intervention and patient stratification. The implications of these findings suggest that reconceptualizing HD as a neurovascular disorder, rather than purely neuronal, could lead to more effective treatment strategies. Future research priorities should include: (1) developing validated vascular biomarkers for disease progression, (2) advancing neuroimaging techniques to monitor endothelial dysfunction in real-time. These directions will be crucial for bridging the current gap between preclinical promise and clinical success in vascular-targeted HD therapeutics. Full article

Background/Objectives: Brain-derived neurotrophic factor (BDNF) has been investigated as a potential mechanistic marker or therapeutic target to manage symptoms such as fatigue, pain, depression, and sleep disturbances. However, the variability in BDNF response to exercise or physical activity (exercise/PA) and its clinical relevance in symptom management remains unclear. This scoping review assesses existing studies exploring the relationships between exercise/PA, symptoms, and BDNF levels, specifically focusing on fatigue, pain, depression, and sleep disturbances in adults. Methods: Relevant studies indexed in PubMed and CINAHL were identified. Using systematic review software, two reviewers independently screened and evaluated full texts, based on the following criteria: human studies reporting BDNF levels in adults, using exercise/PA interventions, assessing symptoms (pain, fatigue, depression, and/or sleep disturbance) as outcomes, and published in English. Results: Of 950 records, 35 records met the inclusion criteria. While exercise/PA is broadly supported for managing symptoms, 74.3% (n = 26) of studies reported increased BDNF levels, and only 40% (n = 14) showed significant increases following exercise/PA. Only 14% (n = 5) of studies demonstrated a significant relationship between changes in BDNF and symptoms. No significant differences in BDNF levels and symptoms were observed between different types of exercise (e.g., aerobic vs. strength vs. flexibility/stretching) and PA. Conclusions: The current literature provides insufficient evidence to confirm BDNF as a marker for exercise/PA effectiveness on symptoms. Further clinical investigations are needed to validate its potential as a therapeutic target. Full article

Fetal bovine serum (FBS) has long been the standard supplement in cell culture media, providing essential growth factors and proteins that support cell growth and differentiation. However, ethical concerns and rising costs associated with FBS have driven researchers to explore alternatives, particularly human platelet lysate (HPL). Among these alternatives, fibrinogen-depleted HPL (FD-HPL) has gained attention due to its reduced thrombogenicity, which minimizes the risk of clot formation in cell cultures and enhances the safety of therapeutic applications. This study investigates two preparation methods for FD-HPL from human platelet concentrates: the calcium chloride method and a mechanical approach. The concentrations of critical growth factors, including vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), insulin-like growth factor (IGF), and keratinocyte growth factor (KGF), were evaluated for both methods. Additionally, the impact of FD-HPL on the proliferation and morphology of umbilical cord-derived mesenchymal stem cells (UC-MSCs) was assessed. The findings revealed that the calcium chloride method produced significantly higher concentrations of all measured growth factors compared to the mechanical method. Moreover, UC-MSCs cultured in calcium chloride-prepared FD-HPL exhibited enhanced cellular characteristics, including increased cell size, elongation, and improved overall morphology compared to those cultured in mechanically processed FD-HPL. These results indicate that the preparation method significantly influences the biological properties of HPL and the effectiveness of UC-MSC culture. The calcium chloride method emerges as a superior technique for producing FD-HPL, offering a promising alternative to FBS in regenerative medicine applications. This study underscores the importance of preparation methods in optimizing HPL for cell culture and therapeutic uses. Full article

Thus far, no manufacturing process able to support industrialization has been reported for the recombinant human brain-derived neurotrophic factor (rhBDNF). Here, we described the setup of a new protocol for its production in Escherichia coli (E. coli) and its purification to homogeneity. A synthetic gene, codifying for the neurotrophin precursor, was inserted into an E. coli expression vector and transformed into BL21 (DE3) strain. The recombinant protein accumulates, at high yields, into inclusion bodies. With the developed strategy, more than 50% of the precursor can be refolded. The protein is successively digested by trypsin and the rhBDNF mature form is finally purified by two additional chromatographic steps If the wild-type precursor can be efficiently obtained by the proposed methodology, its pro-peptide remotion, through enzymatic digestion, is however problematic. To circumvent this difficulty, the precursor hinge region, containing the natural furin recognition site, was engineered to be more specifically cleaved by trypsin. Notwithstanding the substitution of three residues in the pro-region carboxyterminal, the precursor correctly refolds and is efficiently cleaved to generate a biologically active mature rhBDNF. This efficient high-yield process fills the current need of a scalable protocol to produce GMP-grade material and unlocks the rhBDNF employment in future clinical investigations. Full article

We determined the relative expression levels of the receptors TrkA, TrkB, TrkC, and p75^NTR and ligands BDNF, NT-3, NGF, and NT-4 with RNAseq analysis on fetal human inner ear samples, located TrkB and TrkC proteins, and quantified BDNF with in situ hybridization on histological sections between gestational weeks (GW) 9 to 19. Spiral ganglion neurons (SGNs) and satellite glia appear to be the main source of BDNF and synthesis peaks twice at GW10 and GW15–GW17. Tonotopical gradients of BDNF revert between GW8 and GW15 and follow a maturation and innervation density gradient in SGNs. NT-3/TrkC follows the same time course of expression as BDNF/TrkB. Immunostaining reveals that TrkB signaling may act mainly through satellite glia, Schwann cells, and supporting cells of Kölliker’s organ, while TrkC signaling targets SGNs and pillar cells in humans. The NT-4 expression is upregulated when BDNF/NT-3 is downregulated, suggesting a balancing effect for sustained TrkB activation during fetal development. The mission of neurotrophins expects nerve fiber guidance, innervation, maturation, and trophic effects. The data shall serve to provide a better understanding of neurotrophic regulation and action in human development and to assess the transferability of neurotrophic regenerative therapy from animal models. Full article