Search Results (1,642)

Type 2 diabetes mellitus (T2DM) is a chronic disease that has become a serious health problem worldwide. Moreover, increased systemic and cerebrovascular inflammation is one of the major pathophysiological features of T2DM, and a growing body of evidence emphasizes T2DM with memory and executive function decline. Bioactive sphingolipids regulate a cell’s survival, inflammatory response, as well as glucose and insulin signaling/metabolism. Moreover, current research on the role of sphingosine kinases (SPHKs) and sphingosine-1-phosphate receptors (S1PRs) in T2DM is not fully understood, and the results obtained often differ. The aim of the present study was to evaluate the effect of metformin (anti-diabetic agent, MET) on the brain’s sphingosine-1-phosphate-related signaling and ultrastructure in diabetic mice. Our results revealed elevated mRNA levels of genes encoding sphingosine kinase 2 (SPHK2) and sphingosine-1-phosphate receptor 3 (S1PR3), which was accompanied by downregulation of sphingosine-1-phosphate receptor 1 (S1PR1) in the hippocampus of diabetic mice. Simultaneously, upregulation of genes encoding pro-inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) was observed. Administration of MET significantly reversed changes in mRNA levels in the hippocampus and reduced Sphk2, Il6, and Tnf, with concomitant upregulation of S1pr1 gene expression. Ultrastructural analysis of diabetic mice hippocampus revealed morphological alterations in neurons, neuropil, and capillaries that were manifested as mitochondria swelling, blurred synaptic structure, and thickened basal membrane of capillaries. The use of MET partially reversed those changes. Our research emphasizes the important role of insulin sensitivity modulation by metformin in the regulation of SPHKs and S1PRs and inflammatory gene expression in a murine model of T2DM. Full article

Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and progressive cognitive decline. Recent evidence has highlighted the role of blood–brain barrier (BBB) dysfunction in the early stages of AD pathology. Objective: We sought to explore the histological structure and physiological function of the blood–brain barrier, and to identify the shared pathological mechanisms between BBB disruption and Alzheimer’s disease progression. Methods: This narrative review was conducted through a comprehensive search of peer-reviewed literature from 1997 to 2024, using databases such as PubMed, Elsevier, Scopus, and Google Scholar. Results: Multiple histological and cellular components—including endothelial cells, pericytes, astrocytes, and tight junctions—contribute to BBB integrity. The breakdown of this barrier in AD is associated with chronic inflammation, oxidative stress, vascular injury, pericyte degeneration, astrocyte polarity loss, and dysfunction of nutrient transport systems like Glucose Transporter Type 1 (GLUT1). These alterations promote neuroinflammation, amyloid-β (Aβ) accumulation, and progressive neuronal damage. Conclusions: BBB dysfunction is not merely a consequence of AD but may act as an early and active driver of its pathogenesis. Understanding the mechanisms of BBB breakdown can lead to early diagnostic markers and novel therapeutic strategies aimed at preserving or restoring barrier integrity in Alzheimer’s disease. Full article

The deposition of amyloid beta (Aβ) in the human brain is a hallmark of Alzheimer’s disease (AD). Aβ has been shown to exert a wide range of effects on neurons in cell and animal models. Here, we take advantage of differentiated neurons from iPSC-derived neural stem cells of human donors to examine its effects on human neurons. Specifically, we employed two types of neurons from genetically distinct donors: one male carrying APO E2/E2 (M E2/E2) and one female carrying APO E3/E3 (F E3/E3). Genome-wide RNA-sequencing analysis identified 64 and 44 genes that were induced by Aβ in M E2/E2 and F E3/E3 neurons, respectively. GO and pathway analyses showed that Aβ-induced genes in F E3/E3 neurons do not constitute any statistically significant pathways whereas Aβ-induced genes in M E2/E2 neurons constitute a complex network of activated pathways. These pathways include those promoting inflammatory responses, such as IL1β, IL4, and TNF, and those promoting cell migration and movement, such as chemotaxis, migration of cells, and cell movement. These results strongly suggest that the effects of Aβ on neurons are highly dependent on their genetic background and that Aβ can promote strong responses in inflammation and cell migration in some, but not all, neurons. Full article

Cerebral ischemia/reperfusion (I/R) injury remains a significant contributor to adult neurological morbidity, primarily due to exacerbated neuroinflammation and cell apoptosis. These processes amplify brain damage through the release of various pro-inflammatory cytokines and pro-apoptotic mediators. Although long non-coding RNAs (lncRNAs) are increasingly recognized for their involvement in regulating diverse biological pathways, their precise role in cerebral I/R injury has not been fully elucidated. In the current study, transcriptomic profiling was conducted using a rat model of focal cerebral I/R, leading to the identification of lncRNA-1810026B05Rik—also referred to as CHASERR—as a novel lncRNA responsive to ischemic conditions. The elevated expression of this lncRNA was observed in mouse brain tissues subjected to middle cerebral artery occlusion followed by reperfusion (MCAO/R), as well as in primary cortical neurons derived from rats exposed to oxygen-glucose deprivation and subsequent reoxygenation (OGD/R). The results suggested that lncRNA-1810026B05RiK mediates the activation of the nuclear factor-kappaB (NF-κB) signaling pathway by physically binding to NF-kappa-B inhibitor alpha (IκBα) and promoting its phosphorylation, thus leading to neuroinflammation and neuronal apoptosis during cerebral ischemia/reperfusion. In addition, lncRNA-1810026B05Rik knockdown acts as an NF-κB inhibitor in the OGD/R and MCAO/R pathological processes, suggesting that lncRNA-1810026B05Rik downregulation exerts a protective effect on cerebral I/R injury. In summary, the lncRNA-1810026B05Rik has been identified as a critical regulator of neuronal apoptosis and inflammation through the activation of the NF-κB signaling cascade. This discovery uncovers a previously unrecognized role of 1810026B05Rik in the molecular mechanisms underlying ischemic stroke, offering valuable insights into disease pathology. Moreover, its involvement highlights its potential as a novel therapeutic target, paving the way for innovative treatment strategies for stroke patients. Full article

Human amniotic epithelial cell-derived exosomes (hAECs-Exos) are nanoscale extracellular vesicles with neuroprotective, regenerative, and anti-inflammatory properties, presenting a promising cell-free therapeutic approach for ischemic stroke. This study investigated the protective effects of hAECs-Exos against ischemic injury and explored the underlying molecular mechanisms. An optimized oxygen-glucose deprivation/reoxygenation (OGD/R) model was established in murine hippocampal HT22 neurons and BV2 microglial cells to simulate ischemic conditions. hAECs-Exos were successfully isolated and characterized via transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. Confocal microscopy confirmed efficient exosome uptake by both cell types. Functional analyses revealed that hAECs-Exos significantly improved cell viability, suppressed pro-inflammatory cytokine release, alleviated oxidative stress, and modulated apoptosis-related proteins. RNA sequencing identified Forkhead box protein M1 (FoxM1) as a significantly upregulated transcription factor following hAECs-Exos treatment. Further experiments demonstrated that knockdown of FoxM1 in hAECs abolished the beneficial effects of exosomes on the viability of HT22 and BV2 cells and on the suppression of inflammation, oxidative stress, and apoptosis. These findings indicate that hAECs-Exos confer neuroprotection through FoxM1-dependent mechanisms. Together, our results highlight the therapeutic potential of hAECs-Exos as a safe, effective, and clinically translatable strategy for ischemic stroke treatment, warranting future validation in vivo and rescue experiments to fully elucidate FoxM1’s causal role. Full article

Inflammatory bowel disease (IBD) demonstrates chronic relapsing inflammation extending beyond adaptive immunity dysfunction. “Trained immunity”—the reprogramming of innate immune memory in myeloid cells and hematopoietic progenitors—maintains intestinal inflammation; however, the mechanism by which gut microbiome orchestration determines protective versus pathological outcomes remains unclear. Microbial metabolites demonstrate context-dependent dual effects along the gut–bone marrow axis. Short-chain fatty acids typically induce tolerogenic immune memory, whereas metabolites like succinate and polyamines exhibit dual roles: promoting inflammation in certain contexts while enhancing barrier integrity in others, influenced by cell-specific receptors and microenvironmental factors. Interventions include precision probiotics and postbiotics delivering specific metabolites, fecal microbiota transplantation addressing dysbiotic trained immunity, targeted metabolite supplementation, and pharmacologic reprogramming of pathological myeloid training states. Patient stratification based on microbiome composition and host genetics enhances therapeutic precision. Future research requires integration of non-coding RNAs regulating trained immunity, microbiome–immune–neuronal axis interactions, and host genetic variants modulating microbiome–immunity crosstalk. Priorities include developing companion diagnostics, establishing regulatory frameworks for microbiome therapeutics, and defining mechanistic switches for personalized interventions. Full article

Traumatic brain injury (TBI) disrupts the blood–brain barrier (BBB), resulting in increased permeability, neuronal loss, and cognitive dysfunction. This study investigates the therapeutic potential of thyroid hormone (T4) to reduce BBB dysfunction following moderate fluid percussion injury. T4 injection (intraperitoneal) after TBI restores the levels of pericytes and endothelial cells vital for BBB integrity, reduces edema by downregulating AQP-4 gene expression, and enhances levels of the tight junction protein ZO-1. T4 counteracts the TBI-related increase in MMP-9 and TLR-4, significantly reducing BBB permeability. Furthermore, T4 enhances the neuroprotective functions of astrocytes by promoting the activity of A2 astrocytes. Additionally, T4 treatment increases DHA levels (important for membrane integrity and function), stimulates mitochondrial biogenesis, and leads to a notable improvement in spatial learning and memory retention. These findings suggest that T4 has significant potential to reduce vascular leakage and inflammation after TBI, thereby improving cognitive function and maintaining BBB integrity. Full article

Spinal cord injury (SCI) poses a substantial physical, psychological and social burden. Although many therapies are currently available, it is still impossible to fully restore the lost organic functions of SCI patients. An important event in SCI physiopathology is the development of a neuron-repulsive fibrotic scar at the lesion site, a barrier that hampers neuronal growth and contributes to long-term functional impairment. This neuron-repulsive scar is present in severe spinal cord injuries in humans but is absent in some animals capable of natural regeneration. In humans and other mammals, various immune cells take part in the development and maturation of the glial scar, and cytokines and other molecular factors regulate the associated histologic changes. Pro-inflammatory cytokines and complement system proteins tend to be overexpressed early after SCI, but anti-inflammatory cytokines also participate in the remodelling of the injured tissue by regulating the excessively pro-inflammatory environment. This inflammatory regulation is not entirely successful in humans, and inflammation inhibitor drugs offer promising avenues for SCI treatment. Some non-specific immunosuppressor drugs have already been studied, but targeted modulation therapies may be more efficient and less prone to secondary effects. Continued experimental research and clinical trials are vital to advance findings and develop effective treatments, aiming to overcome the barriers to spinal cord regeneration and improve recovery for SCI patients. Full article

Background: The limited self-repair capacity of nerve tissue requires a new therapeutic approach. Mesenchymal stem cells from the uterine cervix, hUCESC, have shown anti-inflammatory, regenerative, and anti-oxidative stress effects through their secretome, which makes them candidates to evaluate their potential in the context of neuronal damage. In this study, we aimed to determine whether secretome or conditioned medium of hUCESC (hUCESC-CM) has beneficial action in the treatment of PC-12 and HMC3 cells in vitro under conditions of oxidative stress and inflammation. Methods: Differentiated PC-12 cells and HMC3 cells were subjected to oxidative stress and inflammatory conditions in the presence of hUCESC-CM. The expression of factors related to both processes was evaluated by q-RT-PCR. Results: PC-12 cells treated with hUCESC-CM showed a significant increase in the expression of anti-oxidative stress factors (HO-1 and Nrf2) and a significant decrease in the expression of pro-inflammatory factors (IL1β, IL6 and TNFα). In addition, the treatment of HMC3 cells with hUCESC-CM significantly decreased the expression of IL6 and TNFα and enhanced the expression of neuroprotective factors such as BDNF and GDNF. Conclusions: Considering that both oxidative stress and inflammation are interrelated and implicated in several nerve injuries and neurodegenerative disorders, the effects of hUCESC-CM on neuronal cells are very promising. Full article

Globally, Parkinson’s disease (PD) is the neurodegenerative condition with the most rapidly increasing prevalence, and a growing body of evidence associates its pathology with impairments in the gut–brain axis. Traditionally viewed as a disease marked by the loss of dopaminergic neurons, emerging evidence emphasizes that chronic neuroinflammation is a driver of neurodegeneration, with gut-originating inflammation playing a crucial role. Increased intestinal permeability, often called “leaky gut,” allows harmful substances, toxins, and misfolded α-synuclein into the systemic circulation, potentially exacerbating neuroinflammation and spreading α-synuclein pathology to the brain through the vagus nerve or compromised blood–brain barrier (BBB). This review synthesizes current insights into the relationship between gut health and PD, emphasizing the importance of gut permeability in disrupting intestinal barrier function. This paper highlights innovative therapeutic approaches, particularly personalized therapies involving gut microbiome engineering, as promising strategies for restoring gut integrity and improving neurological outcomes. Modulating specific gut bacteria to enhance the synthesis of certain metabolites, notably short-chain fatty acids (SCFAs), represents a promising strategy for reducing inflammatory responses and decelerating neurodegeneration in Parkinson’s disease. Full article

Histone deacetylases (HDACs) are crucial enzymes involved in the regulation of gene expression through chromatin remodeling, impacting numerous cellular processes, including cell proliferation, differentiation, and survival. In recent years, HDACs have emerged as therapeutic targets for neurodegenerative diseases (NDDs), such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, given their role in modulating neuronal plasticity, neuroinflammation, and neuronal survival. HDAC inhibitors (HDACi) are small molecules that prevent the deacetylation of histones, thereby promoting a more relaxed chromatin structure and enhancing gene expression associated with neuroprotective pathways. Preclinical and clinical studies have demonstrated that HDACi can mitigate neurodegeneration, reduce neuroinflammatory markers, and improve cognitive and motor functions, positioning them as promising therapeutic agents for NDDs. Given the complexity and multifactorial nature of NDDs, therapeutic success will likely depend on multi-target drugs as well as new cellular and molecular therapeutic targets. Emerging evidence suggests that HDACi can modulate the function of astrocytes, a glial cell type critically involved in neuroinflammation, synaptic regulation, and the progression of neurodegenerative diseases. Consequently, HDACi targeting astrocytic pathways represent a novel approach in NDDs therapy. By modulating HDAC activity specifically in astrocytes, these inhibitors may attenuate pathological inflammation and promote a neuroprotective environment, offering a complementary strategy to neuron-focused treatments. This review aims to provide an overview of HDACs and HDACi in the context of neurodegeneration, emphasizing their molecular mechanisms, therapeutic potential, and limitations. Additionally, it explores the emerging role of astrocytes as targets for HDACi, proposing that this glial cell type could enhance the efficacy of HDACs-targeted therapies in NDD management. Full article

Astrocytes are the most common type of glial cell in the central nervous system (CNS). They have many different functions that go beyond just supporting other cells. Astrocytes were once thought of as passive parts of the CNS. However, now they are known to be active regulators of homeostasis and active participants in both neurodevelopmental and neurodegenerative processes. This article looks at the both sides of astrocytic function: how they safeguard synaptic integrity, ion and neurotransmitter balance, and blood-brain barrier (BBB) stability, as well as how astrocytes can become activated and participate in the immune response by releasing cytokines, upregulating interferons, and modulating the blood–brain barrier and inflammation disease condition. Astrocytes affect and influence neuronal function through the tripartite synapse, gliotransmission, and the glymphatic system. When someone is suffering from neurological disorders, reactive astrocytes become activated after being triggered by factors such as pro-inflammatory cytokines, chemokines, and inflammatory mediators, these reactive astrocytes, which have higher levels of glial fibrillary acidic protein (GFAP), can cause neuroinflammation, scar formation, and the loss of neurons. This review describes how astrocytes are involved in important CNS illnesses such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and ischemia. It also emphasizes how these cells can change from neuroprotective to neurotoxic states depending on the situation. Researchers look at important biochemical pathways, such as those involving toll-like receptors, GLP-1 receptors, and TREM2, to see if they can change how astrocytes respond. Astrocyte-derived substances, including BDNF, GDNF, and IL-10, are also essential for protecting and repairing neurons. Astrocytes interact with other CNS cells, especially microglia and endothelial cells, thereby altering the neuroimmune environment. Learning about the molecular processes that control astrocytic plasticity opens up new ways to treat glial dysfunction. This review focuses on the importance of astrocytes in the normal and abnormal functioning of the CNS, which has a significant impact on the development of neurotherapeutics that focus on glia. Full article

P2X receptors are a family of ATP-gated ion channels widely distributed in various tissues, especially in neuronal cells and hematopoietic cells. ATP activates P2X receptors, causing the opening of an ionic channel with preferential permeability to the passage of mono- and divalent cations. High concentrations of ATP stimulate the P2X7 subtype through prolonged activation, which opens pores and causes inflammation, proalgesic effects, and cell death. Peptides, including antimicrobials (antimicrobial peptides), are present in several organisms, such as amphibians, mammals, fish, arachnids, and plants, where they act as the first line of defense. Thus, these peptides have the capacity to eliminate a wide spectrum of microorganisms, such as bacteria, fungi, and some viruses. In general, the mechanism of action of antimicrobial peptides involves interactions with the lipid bilayer of the cell membrane, which can lead to an increase in the internal liquid content of liposomes. However, many peptides can act on ion channels, such as those of the P2X family, especially the P2X7 receptor. We investigated the action of peptides that directly modulate P2X7 receptors, such as beta-amyloid, LL-37/hCap18, Pep19-2.5, rCRAMP, ADESG, and polymyxin B. Additionally, we evaluated peptides that modulate the activity of P2X family receptor subtypes. In this review, we intend to describe the relationships between peptides with distinct characteristics and how they modulate the functionality of P2X receptors. Full article

Autism spectrum disorder (ASD) is a neurodevelopmental condition marked by social/communication deficits and behavioral abnormalities, with neuronal apoptosis and immune-inflammatory dysregulation implicated in its pathogenesis. Marine-derived polysaccharides, particularly those from Enteromorpha prolifera (PEPs), exhibit neuroprotective and anti-inflammatory properties—yet their therapeutic potential for ASD remains unexplored. Major monosaccharide components of PEPs were identified as rhamnose, xylose, glucose, glucuronic acid, galactose, and ribose through ion chromatography analysis. Infrared spectroscopy confirmed PEPs as pyranose-type polysaccharides with α-glycosidic bonds and uronic acids, while gel permeation chromatography showed a predominant molecular weight of 3.813 kDa (83.919%). To explore the therapeutic potential of PEPs in ASD, a comprehensive method combining network pharmacology, molecular docking, and in vitro validation was conducted. A total of 235 ASD-related target proteins were predicted, with enrichment analyses indicating significant involvement in pathways such as neuroactive ligand–receptor interaction and the MAPK signaling pathway. In vitro assays using valproic acid (VPA)-induced HT22 neuronal cells showed that PEPs significantly attenuated apoptosis. Western blot analysis further confirmed the downregulation of HSP90AA1, cleaved CASP3/pro-CASP3, p-NF-κB1/NF-κB1, p-AKT1/AKT, and p-mTOR/mTOR, as well as the upregulation of IκBα after PEPs treatment. These findings suggest that PEPs exert neuroprotective effects through the modulation of apoptosis and inflammation-related signaling pathways, supporting their potential as a promising candidate for further study in ASD. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the pathological aggregation of α-synuclein (α-syn), the loss of dopaminergic neurons, and the appearance of both motor and non-motor symptoms. Emerging evidence suggests a bidirectional influence of the microbiota–gut–brain axis in PD pathogenesis, where gut dysbiosis contributes to increased intestinal barrier permeability, immune activation, chronic inflammation, oxidative stress, α-syn misfolding, and neurotransmitter imbalance. These findings are increasing interest in probiotics as microbiota-targeted interventions that restore intestinal and systemic homeostasis. Lactiplantibacillus plantarum, a probiotic species with remarkable environmental adaptability and genomic plasticity, has emerged as a promising candidate for PD management. Preclinical studies demonstrate that specific Lpb. plantarum strains, such as PS128 or CCFM405, can beneficially modulate gut microbial communities, reinforce barrier integrity, regulate bile acid metabolism, attenuate neuroinflammatory responses, and improve motor deficits in PD-like mice. In addition, Lpb. plantarum DP189 or SG5 interventions can significantly reduce α-syn aggregation in the brain via suppression of oxidative stress, modulation of neuroinflammatory responses, and activation of neurotrophic factors. Recent evidence even suggests that Lpb. plantarum-derived extracellular vesicles may possess anti-PD activity by influencing host gene expression, neuronal function, and immune modulation. Although robust clinical data are still limited, preliminary clinical trials indicate that supplementation with PS128 or certain Lpb. plantarum-contained consortiums can alleviate constipation, improve gastrointestinal function, reduce systemic inflammation, and even ameliorate motor symptoms when used alongside standard dopaminergic therapies. In this review, we provide an integrated overview of preclinical, clinical, and mechanistic insights, and evaluate the translational potential of Lpb. plantarum as a safe and diet-based strategy to target the microbiota-gut–brain axis in PD. Full article