Search Results (354)

Neuroinflammation is the major contributor to the pathology of neonatal hypoxic–ischemic (HI) brain injury. Our previous studies have demonstrated that microRNA210 (miR210) inhibition with antisense locked nucleic acid (LNA) inhibitor mitigates neuroinflammation and provides neuroprotection after neonatal HI insult. However, the underlying mechanisms remain elusive. In the present study, using miR210 knockout (KO) mice and microglial cultures, we tested the hypothesis that miR210 promotes microglial activation and neuroinflammation through suppressing mitochondrial function in microglia after HI. Neonatal HI brain injury was conducted on postnatal day 9 (P9) wild-type (WT) and miR210 knockout (KO) mouse pups. We found that miR210 KO significantly reduced brain infarct size at 48 h and improved long-term locomotor functions assessed by an open field test three weeks after HI. Moreover, miR210 KO mice exhibited reduced IL1β levels, microglia activation and immune cell infiltration after HI. In addition, in vitro studies of microglia exposed to oxygen–glucose deprivation (OGD) revealed that miR210 inhibition with LNA reduced OGD-induced expression of Il1b and rescued OGD-mediated downregulation of mitochondrial iron–sulfur cluster assembly enzyme (ISCU) and mitochondrial oxidative phosphorylation activity. To validate the link between miR210 and microglia activation, isolated primary murine microglia were transfected with miR210 mimic or negative control. The results showed that miR210 mimic downregulated the expression of mitochondrial ISCU protein abundance and induced the expression of proinflammatory cytokines similar to the effect observed with ISCU silencing RNA. In summary, our results suggest that miR210 is a key regulator of microglial proinflammatory activation through reprogramming mitochondrial function in neonatal HI brain injury. Full article

Hydrogen-rich water (HRW) has shown neuroprotective effects in acute brain injury, but its role in chronic radiation-induced brain injury (RIBI) remains unclear. This study investigated the long-term efficacy of HRW in mitigating cognitive impairment and neuronal damage caused by chronic RIBI. Fifty male Sprague Dawley rats were randomly divided into five groups: control, irradiation (IR), IR with memantine, IR with HRW, and IR with combined treatment. All but the control group received 20 Gy whole-brain X-ray irradiation, followed by daily interventions for 60 days. Behavioral assessments, histopathological analyses, oxidative stress measurements, ¹⁸F-FDG PET/CT imaging, transcriptomic sequencing, RT-qPCR, Western blot, and serum ELISA were performed. HRW significantly improved anxiety-like behavior, memory, and learning performance compared to the IR group. Histological results revealed that HRW reduced neuronal swelling, degeneration, and loss and enhanced dendritic spine density and neurogenesis. PET/CT imaging showed increased hippocampal glucose uptake in the IR group, which was alleviated by HRW treatment. Transcriptomic and molecular analyses indicated that HRW modulated key genes and proteins, including CD44, CD74, SPP1, and Wnt1, potentially through the MIF, Wnt, and SPP1 signaling pathways. Serum CD44 levels were also lower in treated rats, suggesting its potential as a biomarker for chronic RIBI. These findings demonstrate that HRW can alleviate chronic RIBI by preserving neuronal structure, reducing inflammation, and enhancing neuroplasticity, supporting its potential as a therapeutic strategy for radiation-induced cognitive impairment. Full article

β-hydroxybutyrate (BHB) is the most abundant ketone body produced during ketosis, a process initiated by glucose depletion and the β-oxidation of fatty acids in hepatocytes. Traditionally recognized as an alternative energy substrate during fasting, caloric restriction, and starvation, BHB has gained attention for its diverse signaling roles in various physiological processes. This review explores the emerging therapeutic potential of BHB in the context of sarcopenia, metabolic disorders, and neurodegenerative diseases. BHB influences gene expression, lipid metabolism, and inflammation through its inhibition of Class I Histone deacetylases (HDACs) and activation of G-protein-coupled receptors (GPCRs), specifically HCAR2 and FFAR3. These actions lead to enhanced mitochondrial function, reduced oxidative stress, and regulation of inflammatory pathways, with implication for muscle maintenance, neuroprotection, and metabolic regulation. Moreover, BHB’s ability to modulate adipose tissue lipolysis and immune responses highlight its broader potential in managing chronic metabolic conditions and aging. While these findings show BHB as a promising therapeutic agent, further research is required to determine optimal dosing strategies, long-term effects, and its translational potential in clinical settings. Understanding BHB’s mechanisms will facilitate its development as a novel therapeutic strategy for multiple organ systems affected by aging and disease. Full article

Adipose stem cells (ASCs) are a subset of mesenchymal stem cells with validated immunomodulatory and regenerative capabilities that make them attractive tools for treating neurodegenerative disorders, such as multiple sclerosis (MS). Several studies conducted on experimental autoimmune encephalomyelitis (EAE), the animal model of MS, have clearly shown a therapeutic effect of ASCs. However, controversial data on their efficacy were obtained from I- and II-phase clinical trials in MS patients, highlighting standardization issues and limited data on long-term safety. In this context, ASC-derived extracellular vesicles from (ASC-EVs) represent a safer, more reproducible alternative for EAE and MS treatment. Moreover, their physical characteristics lend themselves to a non-invasive, efficient, and easy handling of intranasal delivery. Using an in vitro setting, we first verified ASC-EVs’ ability to cross the human nasal epithelium under an inflammatory milieu. Magnetic resonance corroborated these data in vivo in intranasally treated MOG35-55-induced EAE mice, showing a preferential accumulation of ASC-EVs in brain-inflamed lesions compared to a stochastic distribution in healthy control mice. Moreover, intranasal treatment of ASC-EVs at the EAE onset led to a long-term therapeutic effect using two different experimental protocols. A marked reduction in T cell infiltration, demyelination, axonal damage, and cytokine production were correlated to EAE amelioration in ASC-EV-treated mice compared to control mice, highlighting the immunomodulatory and neuroprotective roles exerted by ASC-EVs during EAE progression. Overall, our study paves the way for promising clinical applications of self-administered ASC-EV intranasal treatment in CNS disorders, including MS. Full article

This narrative review examines the effects of caffeine on brain health in older adults, with particular attention to its potential for dependence—an often-overlooked issue in geriatric care. Caffeine acts on central adenosine, dopamine, and glutamate systems, producing both stimulating and rewarding effects that can foster tolerance and habitual use. Age-related pharmacokinetic and pharmacodynamic changes prolong caffeine’s half-life and increase physiological sensitivity in the elderly. While moderate consumption may enhance alertness, attention, and possibly offer neuroprotective effects—especially in Parkinson’s disease and Lewy body dementia—excessive or prolonged use may lead to anxiety, sleep disturbances, and cognitive or motor impairment. Chronic exposure induces neuroadaptive changes, such as adenosine receptor down-regulation, resulting in tolerance and withdrawal symptoms, including headache, irritability, and fatigue. These symptoms, often mistaken for typical aging complaints, may reflect a substance use disorder yet remain under-recognized due to caffeine’s cultural acceptance. The review explores caffeine’s mixed role in neurological disorders, being beneficial in some and potentially harmful in others, such as restless legs syndrome and frontotemporal dementia. Given the variability in individual responses and the underestimated risk of dependence, personalized caffeine intake guidelines are warranted. Future research should focus on the long-term cognitive effects and the clinical significance of caffeine use disorder in older populations. Full article

The renin–angiotensin–aldosterone system (RAAS) plays a central role in cardiovascular and renal homeostasis and is increasingly recognized for its broad immunomodulatory effects. Pharmacological RAAS inhibition, primarily via angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), has demonstrated therapeutic value beyond its use in hypertension and heart failure, extending to autoimmune, infectious, oncologic, and neurodegenerative conditions. ACEIs and ARBs modulate both innate and adaptive immune responses through Ang II-dependent and -independent mechanisms, influencing macrophage polarization, T-cell differentiation, cytokine expression, and antigen presentation. Notably, ACEIs exhibit Ang II-independent effects by enhancing antigen processing and regulating amyloid-β metabolism, offering potential neuroprotective benefits in Alzheimer’s disease. ARBs, particularly telmisartan and candesartan, provide additional anti-inflammatory effects via PPARγ activation. In cancer, RAAS inhibition affects tumor growth, angiogenesis, and immune surveillance, with ACEIs and ARBs showing distinct yet complementary impacts on tumor microenvironment modulation and chemotherapy cardioprotection. Moreover, ACEIs have shown promise in autoimmune myocarditis, colitis, and diabetic nephropathy by attenuating inflammatory cytokines. While clinical evidence supports the use of centrally acting ACEIs to treat early cognitive decline, further investigation is warranted to determine the long-term outcomes across disease contexts. These findings highlight the evolving role of RAAS inhibitors as immunomodulatory agents with promising implications across multiple systemic pathologies. Full article

This comment focuses on the contribution of experimental brain ischemia to the overwhelming incidence of Alzheimer’s disease in women as presented by Lohkamp et al. in Life 2025, 15, 333. The authors showed that in Alzheimer’s disease and ischemic stroke there are sex-dependent adaptations in the form of cross-links and vice versa. It was emphasized that the high longevity of women in itself does not explain the mechanisms underlying the biological differences between the sexes causing a female predominance in the development of Alzheimer’s disease. Differences were demonstrated between males and females: female APP/PS1 mice had greater amyloid deposition, hyperactivity, lower body weight, and reduced cerebral blood flow, as well as less neuroinflammation, which the authors suggest may have potential neuroprotection. It should be noted that some of the information presented in the article by Lohkamp et al. raises more questions than answers. Therefore, future studies should consider, for example, studies using single-cell technologies that can provide insight into the timing and sequence of cellular dysfunctions across sexes and analyze the continuity of changes over time, starting from short-term observations of a few days and ending with long-term observations of a year or more, to assess the continuity and differentiation of changes. Full article

Hemolytic uremic syndrome (HUS), a thrombotic microangiopathy primarily affecting the kidneys, can also involve the central nervous system (CNS), often leading to significant morbidity and mortality. Neurologic manifestations are among the most severe extra-renal complications, particularly in children and during outbreaks of Shiga toxin-producing Escherichia coli (STEC)-associated HUS (typical (tHUS)). This review explores the clinical spectrum, pathophysiology, diagnostic workup, and age-specific outcomes of neurologic involvement in both typical (tHUS) and atypical (aHUS). Neurologic complications occur in up to 11% of pediatric and over 40% of adult STEC-HUS cases in outbreak settings. Presentations include seizures, encephalopathy, focal deficits, movement disorders, and posterior reversible encephalopathy syndrome (PRES). Magnetic resonance imaging (MRI) commonly reveals basal ganglia or parieto-occipital lesions, though subtle or delayed findings may occur. Laboratory workup typically confirms microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and kidney damage, with additional markers of inflammation or metabolic dysregulation. Eculizumab is the first-line treatment for aHUS with CNS involvement, while its utility in STEC-HUS remains uncertain. Although many children recover fully, those with early CNS involvement are at greater risk of developing epilepsy, cognitive delays, or fine motor deficits. Adults may experience lingering neurocognitive symptoms despite apparent clinical recovery. Differences in presentation and imaging findings between age groups emphasize the need for tailored diagnostic and therapeutic strategies. Comprehensive neurorehabilitation and long-term follow-up are crucial for identifying residual deficits. Continued research into predictive biomarkers, neuroprotective interventions, and standardized treatment protocols is needed for improving outcomes in HUS patients with neurological complications. Full article

Vitamin E has been extensively studied for its neuroprotective properties, with increasing evidence supporting its broader roles in brain health. This scoping review aims to systematically identify, analyze, and synthesize evidence of the existing literature over the last 10 years on tocotrienol and tocopherol supplementation in humans. A systematic search was conducted across PubMed, Scopus, and EBSCOhost yielding 42 eligible articles. Findings suggest that tocopherols, especially α- and γ-forms, are associated with improved cognitive performance, reduced neuroinflammation, and preservation of synaptic proteins. Despite tocotrienol’s lower plasma bioavailability, tocotrienol availability in selective brain regions has been associated with structural protection, particularly in white matter. Both compounds exhibit complementary effects, suggesting a potential advantage of combined supplementation. However, heterogeneity in study designs, subject characteristics, dosage, duration, and assessment methods limit direct comparisons and generalizability of findings. Based on our review’s findings, further research such as dose-optimization, long-term exposures, and delivery methods on human studies should be performed. This review highlights the multifaceted roles of vitamin E in brain health and underscores the urgent need for well-designed studies to clarify the distinct and synergistic effects of tocopherols and tocotrienols, particularly in human populations. Full article

Recent advances in cannabinoid-based therapies identified the natural CB2 receptor agonist β-caryophyllene (BCP) as a promising anti-inflammatory and neuroprotective agent. To further explore its therapeutic potential on the management of neurodegenerative disorders, in the present study we investigated the ability of BCP to prevent neuroinflammation and promote neuroprotection by using both in vitro and ex vivo models of β-amyloid induced neurotoxicity. Our data showed that BCP significantly protected human microglial HMC3 cells from Aβ_25-35-induced cytotoxicity, reducing the release of pro-inflammatory cytokines (TNF-α, IL-6) while enhancing IL-10 secretion. These effects were associated with a reduced activation of the NF-κB pathway, which emerged as a central mediator of BCP action. Notably, the use of CB2R- or PPARγ-selective antagonists revealed that the observed NF-κB inhibition by BCP may involve the coordinated activation of both canonical (e.g., CB2R) and non-canonical (e.g., PPARγ) receptors. Moreover, BCP restored the expression of SIRT1, PGC-1α, and BDNF, indicating the involvement of neurotrophic pathways. Clear neuroprotective properties for BCP have been highlighted in Aβ_1-42-treated brain slice preparations, where BCP demonstrated the rescue of both the amyloid-dependent depression of BDNF expression and long-term synaptic potentiation (LTP) impairment. Overall, our results suggest that BCP constitutes an attractive natural molecule for the treatment of Aβ-induced neuroinflammation and synaptic dysfunction, warranting further exploration for its clinical application. Full article

Background: Traumatic brain injury (TBI) and hypoxic–ischemic encephalopathy (HIE) are major causes of long-term neurological disability in children, with limited options for effective neuronal recovery. Recent research has highlighted the therapeutic potential of nerve growth factor (NGF) in promoting neural repair through mechanisms such as neuroprotection, neurogenesis, and the modulation of neuroinflammation. This review evaluates the current evidence on NGF as a treatment strategy for pediatric brain injury, emphasizing its mechanisms of action and translational clinical applications. Methods: A comprehensive review was conducted using the PubMed, Scopus, and Cochrane CENTRAL databases to identify studies published between 1 January 1978 and 1 March 2025, investigating NGF in the context of brain injury. The inclusion criteria comprised studies assessing neurological outcomes through clinical scales, biochemical markers, neuroimaging, or electrophysiological examinations. Results: Seventeen studies met the inclusion criteria, encompassing both preclinical and clinical research. Preclinical models consistently demonstrated that NGF administration reduces neuroinflammation, enhances neurogenesis, and supports neuronal survival following TBI and HIE. Clinical studies, including case reports of pediatric patients treated with intranasal NGF, reported improvements in motor and cognitive function, neuroimaging findings, and electrophysiological parameters, with no significant adverse effects observed. Conclusions: NGF demonstrates significant promise as a neuroprotective and neuroregenerative agent in pediatric brain injury, with both experimental and early clinical evidence supporting its safety and efficacy. Large-scale controlled clinical trials are warranted to validate these preliminary findings and to determine the optimal dosage regimens and administration schedules for NGF in the treatment of TBI and HIE. Full article

Multiple sclerosis (MS) is a long-term disease that causes inflammation and damage to the nervous system. This study evaluated steroidomic alterations related to MS in 57 female MS patients during the follicular phase and 17 during the luteal phase, as well as in age- and phase-matched controls. The data showed that (1) unconjugated and conjugated steroids were strongly linked between the blood and CSF. (2) MS patients have lower levels of unconjugated steroids compared to controls. However, unchanged levels of conjugated steroids suggest a possible increase in steroid sulfotransferase functioning. (3) MS patients show altered levels of steroids linked to 11β-hydroxylase (CYP11B1) function. While direct enzyme activity was not measured, disrupted cortisol biosynthesis—potentially linked to reduced functioning of both CYP11B1 and 17α-hydroxylase/17,20-lyase—is associated with more severe cases of MS. (4) Reduced levels of 5α/β-steroids and protective GABAergic 3α-hydroxy-5α/β-steroids in MS patients might be linked to the pathophysiology of MS. (5) A potential increase in AKR1C3 function in MS could contribute to inflammation, as this enzyme catalyzes the synthesis of both steroids and prostaglandins. However, direct measurements of enzyme activity are needed to confirm this hypothesis. (6) Lower pregnenolone levels in MS patients might weaken neuroprotection, while higher pregnenolone sulfate levels could support cognitive function. (7) Lower levels of protective pregnenolone, DHEA, and androstenediol were associated with worse MS, suggesting these steroids may help shield against the disease. Full article

Brain-derived neurotrophic factor (BDNF) is a neurotrophin involved in the regulation of synaptic plasticity and metabolic processes, including glucose metabolism and insulin sensitivity. In patients with obstructive sleep apnea (OSA), recurrent episodes of intermittent hypoxia may stimulate BDNF expression as a compensatory neuroprotective response. OSA is associated with metabolic disturbances, such as increased insulin resistance and a higher risk of type 2 diabetes. Continuous positive airway pressure (CPAP) therapy may influence both BDNF levels and metabolic outcomes. The aim of this study was to evaluate changes in BDNF concentration and glucose metabolism in patients with OSA, with particular emphasis on the effect of long-term CPAP therapy. Sixty-six adult patients with OSA confirmed by polysomnography were enrolled and divided into severe (s-OSA) and non-severe (ns-OSA) groups. Fasting blood samples were collected to measure glucose, insulin, and BDNF concentrations. Patients with s-OSA were re-evaluated after 12 months of CPAP therapy and further classified as compliant (sc-OSA) or non-compliant (snc-OSA) based on recorded device usage. The same biochemical parameters were assessed after the 12-month follow-up. Baseline BDNF levels were significantly higher in the s-OSA group compared to the ns-OSA group (20.1 ng/mL vs. 8.1 ng/mL, p = 0.02) and correlated with the apnea–hypopnea index (AHI, r = 0.38, p = 0.02). In the nsc-OSA group, BDNF concentrations increased significantly after 12 months (16.2 ng/mL vs. 35.5 ng/mL, p < 0.001), while no significant change was observed in the sc-OSA group (24.4 ng/mL vs. 27.4 ng/mL, p = 0.33). Among sc-OSA patients, a significant improvement in insulin resistance was noted, although no significant changes were observed in fasting glucose or insulin levels. Increased BDNF levels were observed in patients with s-OSA compared to ns-OSA. Compliant CPAP therapy was associated with reduced insulin resistance and no further BDNF increase, in contrast to non-compliance, suggesting a beneficial effect of CPAP on glucose metabolism and BDNF regulation. These findings support the hypothesis that both neurotrophic and metabolic responses in OSA may be modulated by disease severity and therapy adherence. Full article

Sleep is essential for physical and mental health, playing a critical role in memory consolidation, behavioral stability, and the regulation of immune and metabolic functions. The incidence of sleep disorders, particularly sleep deprivation (SD), increases with age and is prevalent in neurodegenerative and psychiatric disorders such as Alzheimer’s disease (AD). Nearly 40% of AD patients experience significant chronic sleep impairments. The clinical distinction between late-life sleep disorders and AD is often challenging due to overlapping symptoms, including cognitive decline and behavioral impairments. Although the exact causal relationship between SD and AD remains complex and multifaceted, strong evidence suggests a bidirectional link, with AD patients frequently exhibiting disrupted sleep architecture, reduced slow-wave activity, and shorter total sleep duration. On a pathophysiological level, SD contributes to neuroinflammation, amyloid-β plaque deposition, and tau tangles, which are key features of AD. Current treatments, such as sedatives and antidepressants, often have limitations, including inconsistent efficacy, dependency risks, and poor long-term outcomes/recurrence, highlighting the need for safer and more effective alternatives. This review examines the interplay between SD and AD and proposes omega (n)-3 fatty acids (FAs) as a potential therapeutic intervention. Preclinical and clinical studies suggest that n-3 supplementation may improve sleep onset/quality, reduce neuroinflammation, support synaptic function, and decrease amyloid-β aggregation, thereby alleviating early AD-related neurological changes. Given their safety profile and neuroprotective effects, n-3 FAs represent a promising strategy for managing the comorbidity of sleep disorders in AD. Full article

Diabetic foot ulcers (DFUs) constitute a severe and debilitating complication of diabetes, imposing a substantial global health burden due to their intricate pathophysiology and impaired wound healing processes. Vitamin D deficiency is highly prevalent among diabetic populations, and accumulating evidence indicates its potential involvement in the pathogenesis and prognosis of DFUs. This review comprehensively explores the diverse roles of vitamin D in DFUs, encompassing its molecular mechanisms such as immunomodulation, promotion of angiogenesis, neuroprotection, and induction of antimicrobial peptides, as well as the metabolic characteristics associated with various vitamin D forms and compromised vitamin D receptor (VDR) signaling pathways. Although robust observational studies have established an association between vitamin D deficiency and adverse outcomes in DFUs, the clinical validation of supplementation efficacy through randomized controlled trials (RCTs) remains constrained by limitations such as small sample sizes, heterogeneity in study protocols, and insufficient long-term follow-up. This highlights the critical need for large-scale, high-quality studies to ascertain optimal treatment regimens and to cater to individualized patient requirements, particularly for individuals with obesity or those with renal impairments. Innovative strategies, such as the topical administration of vitamin D through intelligent delivery systems leveraging advanced biomaterials like nanofibers and hydrogels, exhibit substantial preclinical potential in enhancing stability, achieving targeted controlled release, and augmenting local biological effects, including the induction of antimicrobial peptides. Nevertheless, significant challenges persist in conclusively establishing clinical efficacy, comprehensively elucidating the underlying mechanisms, ensuring the safe translation of novel delivery systems, and developing personalized therapeutic strategies. The future success of these interventions hinges on meticulous research and interdisciplinary collaboration to seamlessly integrate validated vitamin D-based interventions into a comprehensive multidisciplinary management framework for DFUs, thereby holding promise for improving the clinical outcomes of this debilitating condition. Full article