Search Results (2,121)

Homeostasis, which supports and maintains brain function, results from the continuous regulation of thermodynamics within tissue: the balance of heat production, redox oscillations, and vascular convection regulates coherent energy flow within the organ. Neuroinflammation disturbs this balance, creating measurable entropy gradients that precede structural damage to its tissue components. This paper proposes that a thermodynamic unity can be devised that incorporates nanoscale physics, energetic neurophysiology, and systems neuroscience, and can be used to understand and treat neuroinflammatory processes. Using multifactorial modalities such as quantum thermometry, nanoscale calorimetry, and redox oscillometry we define how local entropy production (s_t), relaxation time (τ^R), and coherence lengths (λc) allow quantification of the progressive loss of energetic symmetry within neural tissues. It is these variables that provide the basis for the etiology of thermodynamic biomarkers which on a molecular-redox-to-network scale characterize the transitions governing the onset of the neuroinflammatory process as well as the recovery potential of the organism. The entropic probing of systems (PEP) further allows the translation of these parameters into dynamic patient-specific trajectories that model the behavior of individuals by predicting recurrent bouts of instability through the application of machine learning algorithms to the vectors of entropy flux. The parallel development of the nanothermodynamic intervention, which includes thermoplasmonic heat rebalancing, catalytic redox nanoreacting systems, and adaptive field-oscillation synchronicity, shows by example how the corrections that can be applied to the entropy balance of the cell and system as a whole offer a feasible form of restoration of energy coherence. Such closed loop therapy would not function by the suppression of inflammatory signaling, but rather by the re-establishment of reversible energy relations between mitochondrial, glial, and vascular territories. The combination of these factors allows for correction of neuroinflammation, which can now be viewed from a fresh perspective as a dynamic phase disorder that is diagnosable, predictable, and curable through the physics of coherence rather than the molecular suppression of inflammatory signaling. The significance of this set of ideas is considerable as it introduces a feasible and verifiable structure to what must ultimately become the basis of a new branch of science: predictive energetic medicine. It is anticipated that entropy, as a measurable and modifiable variable in therapeutic “inscription”, will be found to be one of the most significant parameters determining the neurorestoration potential in future medical science. Full article

Developing robust methods to differentiate pluripotent stem cells (PSCs) into specific neuronal subtypes is crucial for advancing neuroscience research, including disease modelling and regenerative medicine. Research in this area has primarily focused on generating and studying excitatory neurons, often in co-culture with primary astrocytes to support maturation. Due to the shared ectodermal lineage of these cell types, any mesoderm derived cells, such as microglia, are absent using traditional methods of culture. To more accurately model the intricate complexity of the brain and its normal neuronal physiology, it is important to incorporate other critical neural subtypes, such as inhibitory interneurons and various glial cells. This review highlights recent progress in using transcription factor-based in vitro differentiation strategies to generate these diverse neural populations. A major advantage of this approach is the ability to rapidly produce highly specific cell types in a controlled manner, allowing for the precise seeding of cells at defined anatomical and physiological ratios. This controlled methodology enables the creation of more accurate and reproducible in vitro models, including two-dimensional (2D) and three-dimensional (3D) cultures and organoids, thereby moving beyond the limitations of random differentiation from neuronal progenitor cells. Despite these advances, key challenges remain, including reproducibility between pluripotent stem cell lines, off-target transcriptional effects of exogenous factors, and incomplete phenotypic maturation of derived cells. Addressing these constraints is essential for translating transcription factor-based approaches into robust and clinically relevant neural models. Full article

Background: Glioblastoma (GBM) remains refractory to chemoradiotherapy. Glial populations—microglia/monocyte-derived macrophages, reactive astrocytes, and the oligodendrocyte lineage—shape both treatment resistance and radiation-related brain injury. Scope: We synthesize how myeloid ontogeny and plasticity, astrocytic hubs (IL-6/STAT3, TGF-β, connexin-43/gap junctions), and oligodendrocyte precursor cells (OPCs)–linked programs intersect with DNA-damage responses, hypoxia-driven metabolism, and extracellular vesicle signaling to support tumor fitness while predisposing normal brain to radiotoxicity. Translational implications: Convergent, targetable pathways (IL-6/JAK–STAT3, TGF-β, chemokine trafficking, DDR/senescence) enable co-design of radiosensitization and neuroprotection. Pragmatic levers include myeloid reprogramming (CSF-1R, CCR2), astrocyte-axis modulation (STAT3, TGF-β, Cx43), and brain-penetrant DDR inhibition (e.g., ATM inhibitors), paired with delivery strategies that raise intratumoral exposure while sparing healthy tissue (focused-ultrasound blood–brain barrier opening, myeloid-targeted dendrimers; Tumor Treating Fields as an approved adjunct therapy). Biomarker frameworks (TSPO-PET, macrophage-oriented MRI radiomics, extracellular vesicle liquid biopsy) can support selection and pharmacodynamic readouts alongside neurocognitive endpoints. Outlook: Timing-aware combinations around radiotherapy and hippocampal/white-matter sparing offer a near-term roadmap for “glia-informed” precision radiotherapy. Full article

The enteric nervous system (ENS), frequently referred to as the “second brain,” is integral to maintaining gastrointestinal and systemic homeostasis. The structural and functional homeostasis of the ENS is crucial for both local intestinal processes (digestion, immunity) and systemic physiological equilibrium via the gut–brain axis, directly influencing overall health and disease. In recent years, dietary substances have attracted increasing scholarly attention for their potential to modulate the ENS, attributed to their safety and accessibility. This review commences with a systematic exploration of the anatomical structure of the ENS, including the myenteric and submucosal plexuses, its cellular constituents such as enteric neurons and enteric glial cells, and its core physiological functions, encompassing the regulation of gastrointestinal motility, the secretion–absorption balance, and the maintenance of immune homeostasis. Subsequently, it delineates the classification, distribution, and properties of essential dietary components, encompassing polyphenols, short-chain fatty acids, amino acids and their derivatives, as well as prebiotics and probiotics. Additionally, it examines the mechanisms through which these substances modulate the physiological functions of the ENS, including the regulation of intestinal motility, support for neuronal survival and network integrity, and the maintenance of neuro-immune homeostasis. The review concludes by highlighting current limitations—including reliance on rodent models, unclear human ENS mechanisms, and imprecise interventions—and proposes future directions focused on precision medicine, clinical translation, and advanced tools like single-cell sequencing and targeted delivery systems. Full article

GNAO1 is an alpha subunit of the G-protein complex involved in signal transduction in neurons. The G203R mutation in the GNAO1 gene arises recurrently de novo and causes epileptic encephalopathy and movement disorder. GNAO1 has two main isoforms, GNAO1-A and GNAO1-B, but their functional or expression differences are poorly understood. Molecular functions of GNAO1 are mainly studied in neurons, yet glial cells also express GNAO1 and participate in the pathogenesis of epilepsy. Here, we used human-induced pluripotent stem cell-based models to investigate the localization and expression of GNAO1 isoforms in astrocytes. We showed that in astrocytes, almost 100% of GNAO1 transcripts encoded GNAO1-B with very low GNAO1-A expression. We showed that there were no differences in localization between GNAO1-A and GNAO1-B, both in WT and G203R states. We also showed that GNAO1 localized in astrocytic retraction fibers and migrasomes, structures not previously described in this cell type. We showed that GNAO1-positive retraction fibers of neighboring cells provided cell-to-cell contacts and also provided calcium waves during astrocytic excitation. Overexpression of both GNAO1-A and GNAO1-B tends to lower calcium activity in astrocytes, with GNAO1-A providing the most severe impairment of activity. Our results demonstrate that astrocytes, in addition to neurons, should be used as a model for studying GNAO1-related disorders and that GNAO1 mutations should be evaluated in the context of both the GNAO1-A and GNAO1-B isoforms. Full article

Pediatric seronegative immune-mediated cerebellar ataxia (IMCA) remains a poorly defined and often under-recognized diagnosis, particularly in young children, where symptoms are frequently misattributed to self-limited post-infectious processes. We report the case of a 2.5-year-old girl who presented with acute-onset ataxia (mSARA score: 14). Cerebrospinal fluid analysis revealed pleocytosis and positive oligoclonal bands, while serial brain imaging and extensive autoantibody panels were unremarkable. However, indirect immunohistochemistry (TIIF/IHC) demonstrated a positive intracellular signal in cerebellar Purkinje cells, supporting the diagnosis of isolated seronegative IMCA. The patient showed sustained clinical improvement with prolonged corticosteroid therapy (mSARA score: 1). To date, only a few similar cases have been reported in the literature. It remains unclear whether these presentations fall within the spectrum of autoimmune encephalitis (AIE) or represent a distinct pediatric phenotype, potentially expanding the age range of primary autoimmune cerebellar ataxia previously described in adults. We recommend incorporating TIIF/IHC into the diagnostic workup of both isolated and combined pediatric cerebellar ataxia syndromes to support diagnosis and guide individualized treatment. Additionally, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are emerging as promising biomarkers in this context and warrant further investigation. Full article

Ischemic stroke remains one of the most catastrophic diseases in neurology, in which, due to a disturbance in the cerebral blood flow, the brain is acutely deprived of its oxygen and glucose oligomer, which in turn rapidly leads to energetic collapse and progressive cellular death. There is now increasing evidence that this type of stroke is not simply a type of ‘oxidative stress’ but rather a programmable loss-of-redox homeostasis, within which electron flow and the balance of oxidants/reductants are cumulatively displaced at the level of the single molecule and at the level of the cellular area. The advances being made in cryo-electron microscopy, lipidomics, and spatial omics are coupled with the introduction of a redox code produced by the interaction of the couples NADH/NAD⁺, NADPH/NADP⁺, GSH/GSSG, BH₄/BH₂, and NO/SNO, which determine the end results of the fates of the neurons, glia, endothelium, and pericytes. Within the mitochondria, pathophysiological events, including reverse electron transport, succinate overflow, and permeability transition, are found to be the first events after reperfusion, while signals intercommunicating via ER–mitochondria contact, peroxisomes, and nanotunnels control injury propagation. At the level of the tissue, events such as the constriction of the pericytes, the degradation of the glycocalyx, and the formation of neutrophil extracellular traps underlie microvascular failure (at least), despite the effective recanalization of the vessels. Systemic influences such as microbiome products, oxidized lipids, and free mitochondrial DNA in cells determine the redox imbalance, but this generally occurs outside the brain. We aim to synthesize how the progressive stages of ischemic injury evolve from the cessation of flow to the collapse of the cell structure. Within seconds of injury, there is reverse electron transport (RET) through mitochondrial complex I, with bursts of superoxide (O₂•⁻) and hydrogen peroxide (H₂O₂) being produced, which depletes the stores of superoxide dismutase, catalase, and glutathione peroxidase. Accumulated succinate and iron-induced lipid peroxidation trigger ferroptosis, while xanthine oxidase and NOX2/NOX4, as well as uncoupled eNOS/nNOS, lead to oxidative and nitrosative stress. These cascades compromise the function of neuronal mitochondria, the glial antioxidant capacity, and endothelial–pericyte integrity, leading to the degradation of the glycocalyx with microvascular constriction. Stroke, therefore, represents a continuum of redox disequilibrium, a coordinated biochemical failure linking the mitochondrial metabolism with membrane integrity and vascular homeostasis. Full article

Neurodevelopmental disorders (NDDs), including autism spectrum disorder, intellectual disability, and attention deficit hyperactivity disorder, are increasingly recognized as disorders of early brain construction arising from defects in neural stem and progenitor cell (NSPC) proliferation. NSPCs are responsible for generating the diverse neuronal and glial lineages that establish cortical architecture and neural circuitry; thus, their expansion must be tightly coordinated by intrinsic cell cycle regulators and extrinsic niche-derived cues. Disruption of these mechanisms—through genetic mutations, epigenetic dysregulation, or environmental insults—can perturb the balance between NSPC self-renewal and differentiation, resulting in aberrant brain size and connectivity. Recent advances using animal models and human pluripotent stem cell-derived brain organoids have identified key signaling pathways, including Notch, Wnt, SHH, and PI3K–mTOR, as central hubs integrating proliferative cues, while transcriptional and chromatin regulators such as PAX6, CHD8, SETD5, and ANKRD11 govern gene expression essential for proper NSPC cycling. Furthermore, prenatal exposure to teratogens such as Zika virus infection, valproic acid, or metabolic stress in phenylketonuria can recapitulate proliferation defects and microcephaly, underscoring the vulnerability of NSPCs to environmental perturbation. This review summarizes emerging insights into the molecular and cellular mechanisms by which defective NSPC proliferation contributes to NDD pathogenesis, highlighting convergence among genetic and environmental factors on cell cycle control. A deeper understanding of these pathways may uncover shared therapeutic targets to restore neurodevelopmental trajectories and mitigate disease burden. Full article

Neuroinflammation and oxidative stress are key drivers of various ocular diseases. Experimental hypoxia, modeled using cobalt chloride (CoCl₂), induces hypoxia-inducible factor 1-alpha (HIF-1α) stabilization, mitochondrial dysfunction, and excessive reactive oxygen species (ROS) production, primarily via the NADPH oxidase 2 (Nox2)–voltage-gated proton channel Hv1 axis. Although Botulinum neurotoxin type A (BoNT/A) is classically recognized for SNAP-25 cleavage, recent studies suggest broader anti-inflammatory and neuroprotective effects. We evaluated BoNT/A in R28 retinal precursor cells and ex vivo retinal explants subjected to CoCl₂-induced hypoxic stress. BoNT/A pretreatment attenuated CoCl₂-induced upregulation of HIF-1α, Hv1, Nox2, NOD-like receptor protein 3 (NLRP3), COX2, and nuclear factor kappa B (NF-κB), while enhancing protective mediators including suppressor of cytokine signaling 3 (SOCS3), Growth Associated Protein 43 (Gap43), and Syntaxin12. Brn3a expression and retinal architecture were preserved, apoptotic cell death reduced, and glial activation suppressed. Moreover, BoNT/A decreased mitochondrial ROS accumulation, restored voltage-dependent anion channel 1 (VDAC1) distribution, and partially stabilized intracellular pH. These findings indicate that BoNT/A mitigates oxidative stress and inflammation in hypoxia-driven retinal injury, at least in part, via modulation of the Nox2–Hv1–ROS axis, and support its potential as a therapeutic candidate for ocular disorders associated with hypoxia and neuroinflammation. Full article

Major Depressive Disorder (MDD) remains a leading cause of disability worldwide, perpetuated by an incomplete understanding of its pathophysiology and the limited efficacy of conventional antidepressants. Historically, research has focused on neuron-centric models, particularly the monoamine hypothesis. However, the field is now recognizing the critical role of glial cells such as astrocytes, microglia, and oligodendrocytes, establishing them as key contributors to the molecular basis of depression. Rather than serving solely supportive roles, these cells actively modulate neuroinflammation, synaptic plasticity, neurotransmitter homeostasis, and metabolic regulation, processes disrupted in MDD. We discuss how stress-induced epigenetic modifications such as histone acetylation, methylation, and DNA methylation are linked to alterations in astrocytic glutamate transport, microglial inflammatory states, and oligodendrocyte-mediated myelination. Special emphasis is placed on the concept of glial transcriptional plasticity, whereby environmental adversity induces durable and cell type specific gene expression changes that underlie neuroinflammation, excitatory–inhibitory imbalance, and white matter deficits observed in MDD. By integrating findings from postmortem human tissue, single-cell omics, and stress-based animal models, this review highlights converging molecular mechanisms linking stress to glial dysfunction. We further outline how targeting glial transcriptional regulators may provide new therapeutic avenues beyond conventional monoaminergic approaches. Full article

Instant Cascara (IC), a beverage obtained from dried coffee cherry pulp, represents a sustainable hydration option rich in bioactive phytochemicals, such as caffeine, chlorogenic acids, and melanoidins, which may provide effects beyond basic nutrition. This study evaluated the impact of three weeks of IC consumption on somatic and visceral sensitivity, and on neural and immune markers in the colon of male and female healthy Wistar rats. Behavioral tests showed that IC increased locomotor activity and somatic sensitivity in females (p < 0.05). Although control females were more sensitive to visceral pain than males (p < 0.05), IC intake did not significantly alter pain sensitivity in either sex. Histological and immunohistochemical analyses in the colonic myenteric plexus revealed higher enteric glial cell density and glia-to-neuron ratio (p < 0.01), but lower calcitonin gene-related peptide (CGRP)-positive fiber density (p < 0.001) in IC-treated compared to control females. Macrophages decreased in IC-treated compared with control males in the colon wall (p < 0.05), whereas their number increased in IC-treated females compared to IC-treated males (p > 0.0001). Visceral pain responses are associated with complex sex-dependent neuroimmune changes in the colon. Interestingly, IC effects appear mild under healthy conditions, possibly due to compensatory mechanisms exerted by its different phytochemicals. Further investigation is needed to determine the effects of IC in pathological situations involving visceral hypersensitivity, such as brain–gut axis disorders. Full article

The central nervous system is highly vulnerable to oxygen deprivation during the neonatal period, leading to long-term neurological damage. Growth hormone (GH) has shown neuroprotective and neuroregenerative effects in response to hypoxic injury. This study investigated GH effects on cell survival, inflammatory, and glial activation markers in the developing cerebellum, as well as its impact on motor coordination and anxiety-like behaviors in adulthood following neonatal hypoxia. Global hypoxia was induced in postnatal day 2 Wistar rats (8% O₂, 2 h), followed by subcutaneous GH treatment (0.1 mg/kg/d) for five days. Neonatal hypoxia triggered a sustained inflammatory response in the developing cerebellum, with increased expression of TLR-4, IL-1β, TNF-α, IL-6, COX-2, iNOS, and pNF-κB, persistent gliosis, myelin disruption, and Purkinje cell loss, leading to impaired adult behavior. GH exhibited a biphasic effect—initially proinflammatory, then anti-inflammatory—ultimately downregulating proinflammatory markers and activating prosurvival pathways (pStat5, pErk1/2, pAkt, Bcl-2, TNF-R2, IGF-1). GH also reduced microglial (Iba-1) and astrocytic (GFAP) hypertrophy, restored MBP and β-III tubulin levels, enhanced Purkinje cell survival, and improved motor coordination and anxiety-like behavior in adulthood. These findings demonstrate that GH modulates the cerebellar inflammatory response and supports its therapeutic potential to counteract neuroinflammation and dysfunction following neonatal hypoxic injury. Full article

Background: Neuromyelitis optica spectrum disorder (NMOSD) causes severe optic nerve (ON) inflammation and vision loss. Current treatments remain limited, prompting exploration of new therapeutic strategies. This study evaluated the efficacy of ITRI-E-(S)4046 (ITRI-ES), a dual ROCK1/2 and MYLK4 kinase inhibitor, in a rat model of NMOSD optic neuritis. Methods: NMOSD-like optic neuritis was induced in rats by applying NMOSD patient serum-soaked sponges around the ON. Rats received intravitreal injections of either 0.2% ITRI-ES, phosphate-buffered saline (PBS), or intraperitoneal methylprednisolone (MP). Visual function was assessed using flash visual-evoked potentials (fVEP). Retinal ganglion cell (RGC) survival and apoptosis were quantified using FluoroGold retrograde labeling and TUNEL assay. ON inflammation and demyelination were evaluated via immunohistochemistry and Western blot analysis of aquaporin-4 (AQP4), myelin basic protein (MBP), glial fibrillary acidic protein (GFAP), and inflammatory markers. Results: ITRI-ES significantly preserved visual function, restoring fVEP amplitudes (~36 μV vs. ~21 μV in PBS-treated, p < 0.05) and RGC density (~85% of normal vs. ~37% PBS). RGC apoptosis was reduced (~2.3-fold lower vs. PBS, p < 0.05). PBS-treated rats showed decreased AQP4 and MBP (2.5–2.8-fold vs. sham) and increased GFAP (2.8-fold). ITRI-ES maintained higher AQP4 (~3.5-fold) and MBP (~1.5-fold) levels, suppressed GFAP (~5.5-fold vs. PBS), reduced NF-κB, IL-1β, TNF-α, microglia activation, and macrophage infiltration, and increased anti-inflammatory Arg1 and CD206 markers (~3-fold vs. PBS). Conclusions: ITRI-ES alleviates optic nerve inflammation, preserves retinal integrity, and maintains visual function in NMOSD-associated optic neuritis, underscoring kinase inhibition as a promising therapeutic strategy. Full article

The carotid body is a peripheral chemoreceptor that consists of clusters of chemoreceptive type I cells, glia-like type II cells, afferent and efferent nerves, and sinusoidal capillaries and arterioles. Cells and nerves communicate through reciprocal chemical synapses and electrical coupling that form a “tripartite synapse,” which allows for the process of sensory stimuli within the carotid body involving neurotransmission, autocrine, and paracrine pathways. In this network there are a variety of neurotransmitters and neuromodulators including adenosine 5′-triphosphate (ATP). Carotid body cells and nerve fibre terminals express ATP receptors, i.e., purinergic receptors. Here we used double immunofluorescence associated with laser confocal microscopy to detect the ATP receptor P2X7 and pannexin 1 (an ATP permeable channel) in the human carotid body, as well as the petrosal and cervical sympathetic ganglia. Immunofluorescence for P2X7r and pannexin 1 forms a broad cellular network within the glomeruli of the carotid body, whose pattern corresponds to that of type II cells. Moreover, both P2X7r and pannexin 1 were also detected in nerve profiles. In the petrosal ganglion, the distribution of P2X7r was restricted to satellite glial cells, whereas in the cervical sympathetic ganglion, P2X7r was found in neurons and glial satellite cells. The role of this purinergic receptor in the carotid body, if any, remains to be elucidated, but it probably provides new evidence for gliotransmission. Full article

Obesity causes millions of deaths each year due to metabolic complications, making it a major public health challenge. It results from a chronic imbalance between caloric intake and energy expenditure. Among central structures regulating energy balance, the dorsal vagal complex (DVC) integrates metabolic signals from energy stores and the gastrointestinal tract and coordinates autonomic responses. While historically overshadowed by a focus on neurons, the role of glial cells in regulating energy balance is now well established. Connexin 43 (Cx43) is a well-known protein expressed by astrocytes, playing a key role in glial and neuroglial communication. To investigate the role of astrocytic Cx43 within the DVC, where its expression is remarkably high, we specifically reduced it using an RNA interference approach. Although reduced Cx43 expression led to modified astrocyte and microglia morphology and phenotype, our analyses did not reveal significant changes in the animal’s metabolic phenotype under standard feeding conditions as well as under a high-fat, high-sugar diet. These results suggest that denser astrocytic tiling and hyper-ramified microglia may constitute a buffering system that preserves metabolic and autonomic outputs when a single connexin pathway fails. Full article