Search Results (169)

Neuroimmune interactions play a critical role in the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), with microglia acting as key mediators of neuroinflammation. Microglia exhibit dual roles, contributing to both neuroprotection and neurotoxicity depending on their activation state. In AD, amyloid-beta (Aβ) aggregation leads to chronic microglial activation, resulting in excessive pro-inflammatory cytokine release (e.g., TNF-α, IL-1β, IL-6), oxidative stress, and synaptic dysfunction. In PD, α-synuclein aggregation triggers a similar neuroinflammatory cascade, exacerbating dopaminergic neuronal loss in the substantia nigra. Beyond inflammatory responses, microglia regulate synaptic plasticity, phagocytose pathological proteins, and interact with peripheral immune cells, influencing disease progression. Emerging evidence suggests that genetic variants in genes such as TREM2, CD33, and HLA modulate microglial function, thereby altering susceptibility to neurodegeneration. Dysregulated microglial responses, characterized by impaired clearance of protein aggregates and prolonged neuroinflammation, further amplify neuronal damage. Therapeutic strategies targeting microglial activation are under investigation, aiming to balance neuroinflammatory responses and enhance clearance mechanisms. Small-molecule inhibitors, monoclonal antibodies, and modulators of innate immune pathways are being explored to mitigate microglia-driven pathology. Understanding the complex interplay between microglia and neurodegeneration could pave the way for precision medicine approaches, optimizing treatments based on individual immune profiles. Further research is essential to delineate microglial heterogeneity across disease stages and uncover novel targets for therapeutic intervention. Full article

With the global increase in population aging, allergic diseases in older adults are becoming an increasingly relevant clinical and public health challenge. Age-related molecular and cellular alterations significantly affect the pathophysiology, clinical manifestations, diagnosis, and management of major allergic diseases in the elderly. This review focuses on immunosenescence in major allergic conditions, including asthma, chronic urticaria and angioedema, dermatitis, food and drug allergies, and hymenoptera venom hypersensitivity. Particular emphasis is placed on molecular mechanisms underlying immune aging, such as inflammaging, dysregulation of innate and adaptive immune responses, epithelial barrier dysfunction, microbiota alterations, neuro-immune interactions, and age-related comorbidities. Sex-related differences in immune responses are also addressed, together with current diagnostic and therapeutic strategies, including the opportunities and limitations of biologic therapies in aging populations. Despite growing interest in this field, a major limitation remains the paucity of studies specifically targeting geriatric populations, underscoring the need for age- and sex-specific research and dedicated clinical trials. A personalized approach integrating frailty assessment and immune profiling is essential to optimize the management of allergic diseases in older adults. Full article

Background/Objectives: Lithium (Li), silicon (Si), and boron (B) are proposed nutritional trace elements with potential roles in metabolic, neurobiological, endocrine, inflammatory, and bone-related processes. This review provides a critical synthesis of data on Li–Si–B, emphasizing (i) physiological and mechanistic pathways, (ii) human clinical relevance, (iii) shared biological domains, and (iv) safety considerations. Methods: A narrative review was conducted across PubMed, Scopus, and Web of Science from inception to January 2025. Predefined search strings targeted dietary, environmental, and supplemental exposures of lithium, silicon, or boron in relation to metabolism, endocrine function, neurobiology, inflammation, bone health, and the gut microbiome. Inclusion criteria required peer-reviewed studies in English. Data extraction followed a structured template, and evidence was stratified into human, animal, cellular, and ecological tiers. Methodological limitations were critically appraised. Results: Li, Si, and B influence overlapping molecular pathways including oxidative stress modulation, mitochondrial stability, inflammatory signaling, endocrine regulation, and epithelial/gut barrier function. Human evidence remains limited: Li is supported primarily by small trials; Si by bone-related observational studies and biomarker-oriented interventions; and B by metabolic, inflammatory, and cognitive studies of modest sample size. Convergence across elements appears in redox control, barrier function, and neuroimmune interactions, but mechanistic synergism remains hypothetical. Conclusions: Although Li–Si–B display compelling mechanistic potential, current human data are insufficient to justify dietary recommendations or supplementation. Considerable research gaps—including exposure assessment, dose–response characterization, toxicity thresholds, and controlled human trials—must be addressed before translation into public health policy. Full article

Chronic pain is a pervasive and debilitating condition that affects millions of individuals worldwide. Unlike acute pain, which serves a protective physiological role, chronic pain persists beyond routine tissue healing and often arises without a discernible peripheral cause. Accumulating evidence indicates that chronic pain is not merely a symptom but a disorder of the central nervous system, underpinned by interacting molecular, neurochemical, and network-level alterations. Molecular neuroimaging using PET and MR spectroscopy has revealed dysregulated excitatory–inhibitory balance (glutamate/GABA), altered monoaminergic and opioidergic signaling, and neuroimmune activation (e.g., TSPO-indexed glial activation) in key pain-related regions such as the insula, anterior cingulate cortex, thalamus, and prefrontal cortex. Converging multimodal imaging—including functional MRI, diffusion MRI, and EEG/MEG—demonstrates aberrant activity and connectivity across the default mode, salience, and sensorimotor networks, alongside structural remodeling in cortical and subcortical circuits. Parallel advances in neuromodulation, including transcranial magnetic stimulation (TMS), transcranial electrical stimulation (tES), deep brain stimulation (DBS), and emerging biomarker-guided closed-loop approaches, provide tools to perturb these maladaptive circuits and to test mechanistic hypotheses in vivo. This review integrates neuroimaging findings with molecular and systems-level mechanistic insights into chronic pain and its modulation, highlighting how imaging markers can link biochemical signatures to neural dynamics and guide precision pain management and individualized therapeutic strategies. Full article

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an immune-mediated neurological disorder driven by dysregulated neuroimmune interactions, yet the molecular architecture linking tumor-associated immune activation, peripheral immunity, and neuronal dysfunction remains insufficiently understood. In this study, we established an integrative computational framework that combines multi-tissue transcriptomic profiling, weighted gene co-expression network analysis, immune deconvolution, and machine learning-based feature prioritization to systematically characterize the regulatory landscape of the disease. Joint analysis of three independent GEO datasets spanning ovarian teratoma tissue and peripheral blood transcriptomes identified 2001 consistently dysregulated mRNAs, defining a shared tumor–immune–neural transcriptional axis. Across multiple feature selection algorithms, ACVR2B and MX1 were reproducibly prioritized as immune-associated candidate genes and were consistently downregulated in anti-NMDAR encephalitis samples, showing negative correlations with neutrophil infiltration. Reconstruction of an integrated mRNA-miRNA-lncRNA regulatory network further highlighted a putative core axis (ENSG00000262580–hsa-miR-22-3p–ACVR2B), proposed as a hypothesis-generating regulatory module linking non-coding RNA regulation to immune-neuronal signaling. Pathway and immune profiling analyses demonstrated convergence of canonical immune signaling pathways, including JAK-STAT and PI3K-Akt, with neuronal communication modules, accompanied by enhanced innate immune signatures. Although limited by reliance on public datasets and small sample size, these findings delineate a systems-level neuroimmune regulatory program in anti-NMDAR encephalitis and provide a scalable, network-based multi-omics framework for investigating immune-mediated neurological and autoimmune disorders and for guiding future experimental validation. Full article

Women exhibit a higher prevalence of depression, anxiety, stress-related disorders, and autoimmune conditions compared to men, yet the biological mechanisms underlying this sex difference remain incompletely understood. Growing evidence identifies neuroinflammation as a central mediator of psychiatric vulnerability in women, shaped by interactions between sex hormones, immune activation, and neural circuit regulation. Throughout the female lifespan, fluctuations in estrogen and progesterone, such as those occurring during puberty, the menstrual cycle, pregnancy, postpartum, and perimenopause, modulate microglial activity, cytokine release, and neuroimmune signaling. These hormonal transitions create windows of heightened sensitivity in key brain regions involved in affect regulation, including the amygdala, hippocampus, and prefrontal cortex. Parallel variations in systemic inflammation, mitochondrial function, and hypothalamic–pituitary–adrenal (HPA) axis responsivity amplify stress reactivity and autonomic imbalance, contributing to increased risk for mood and anxiety disorders in women. Emerging data also highlight sex-specific interactions between the immune system and monoaminergic neurotransmission, gut–brain pathways, endothelial function, and neuroplasticity. This review synthesizes current neuroscientific evidence on the sex-dependent neuroinflammatory mechanisms that bridge hormonal dynamics, brain function, and psychiatric outcomes in women. We identify critical periods of vulnerability, summarize converging molecular pathways, and discuss novel therapeutic targets including anti-inflammatory strategies, estrogen-modulating treatments, lifestyle interventions, and biomarkers for personalized psychiatry. Understanding neuroinflammation as a sex-specific process offers a transformative perspective for improving diagnosis, prevention, and treatment of psychiatric disorders in women. Full article

Diseases of the pancreas—such as pancreatic ductal adenocarcinoma (PDAC) and pancreatitis—have long been a challenge to treat. The study of lymphatics within the pancreas can provide some additional insights and offer new therapeutic targets. Here, we explore the development of pancreatic lymphatics and their connections to the nervous system and individual disease states, as well as the potential for therapeutic interventions. Lymphangiogenesis pathways in PDAC, driven by VEGF-C and other mediators, have been extensively explored, but specific therapeutic interventions are lacking. Furthermore, due to the emergence of PDAC with pancreatitis, insights could improve treatment in both settings. The role of neuroimmune interactions and control, as in other organ sites, appears as critical to both lymphatic and immune processes. With a better understanding of the lymphatic environment within the pancreas, we can develop more effective treatments for patients. Full article

Mutual interaction between the nervous and immune systems underpins many pathophysiological processes. Transient Receptor Potential Melastatin 2 (TRPM2) channels are abundantly expressed in both systems, acting as a critical interface of neuroimmune interaction. TRPM2 channels in immune cells participate in innate immunity and immune inflammation by acting as an oxidative stress and metabolic sensor. TRPM2 in neurons functions not only as an oxidative sensor but also a temperature sensor and a pain transducer critical to neuronal death, temperature sensing, thermoregulation, and chronic pain. Cooperation between immune and neuronal TRPM2 influences the outcome of neuroimmune interaction and many diseases such as infection, inflammation, ischemic stroke, pain, and neurodegenerative diseases. Improved understanding of neuronal and immune TRPM2 interaction is essential for therapeutic interventions for the treatment of diseases mediated by TRPM2 channels. Full article

Chronic pain is increasingly regarded as a condition of glia–neuronal dysregulation driven by persistent neuroinflammatory signaling. Following injury to nerves or tissues, glial cells, including astrocytes or satellite glial cells, undergo changes in their phenotype, thereby amplifying painful stimuli mediated by cytokines, chemokines, or ATP signaling. In response to injuries, activated microglia release several mediators such as BDNF, IL-1β, or TNF-α, thereby disrupting chloride homeostasis and inducing disinhibition in the dorsal horn, and sustaining maladaptive neuroimmune activity. Dysfunction of astrocytes, characterized by impaired glutamate clearance via excitatory amino acid transporter 2 and elevated C-X-C motif chemokine ligand 1 (CXCL1) and ATP release, drives neuronal sensitization, loss of neuroprotective metabolic support, and persistence of pain. In peripheral ganglia, connexin–43–mediated satellite glial cell coupling leads to hyperexcitability, resulting in neuropathic and orofacial pain and contributing to peripheral neuroinflammation. Presently, there is no unified framework for glial cell types, and the molecular mechanisms underlying microglial, astrocyte, and satellite glial cell contributions to the transition to chronic pain from acute pain are not completely elucidated. This review synthesizes current evidence on cellular and molecular mechanisms linking glial reactivity to pain chronification through sustained neuroinflammatory remodeling and impaired neuroprotection. It evaluates therapeutic strategies, including purinergic receptor P2X4 and toll-like receptor 4 antagonists, to metabolic reprogramming, exosome therapy, and neuromodulation, aimed at restoring homeostatic glial function and re-establishing neuroprotective glia–neuron interactions. A deeper understanding of the temporal and spatial dynamics of glial activation may enable personalized, non-opioid interventions that not only achieve durable analgesia but also prevent progressive neuroinflammatory damage and support long-term functional recovery. Full article

Major depressive disorder (MDD) was long framed as a single clinical entity arising from a linear stress–monoamine–hypothalamic–pituitary–adrenal (HPA) axis cascade. This view was shaped by forced swim and learned helplessness tests in animals and by short-term symptom-based trials using scales such as the Hamilton Depression Rating Scale (HAM-D) and the Montgomery–Åsberg Depression Rating Scale (MADRS). This “unitary cascade” view has been dismantled by advances in neuroimaging, immune–metabolic profiling, sleep phenotyping, and plasticity markers, which reveal divergent circuit-level, inflammatory, and chronobiological patterns across anxiety-linked, pain-burdened, and cognitively weighted depressive presentations, all characterized by high rates of non-response and relapse. Translationally, face-valid rodent assays that equated immobility with despair have yielded limited bedside benefit, whereas cross-species bridges—electroencephalography (EEG) motifs, rapid eye movement (REM) architecture, effort-based reward tasks, and inflammatory/metabolic panels—are beginning to provide mechanistically grounded, clinically actionable readouts. In current practice, depression care is shifting toward systems psychiatry: inflammation-high and metabolic-high archetypes, anhedonia- and circadian-dominant subgroups, formal treatment-resistant depression (TRD) staging, connectivity-guided neuromodulation, esketamine, selected pharmacogenomic panels, and early digital phenotyping, as endpoints broaden to functioning and durability. A central gap is that heterogeneity is acknowledged but rarely built into trial design or implementation. This perspective advances a plasticity-centered systems psychiatry in which a testable prediction is that manipulating defined prefrontal–striatal and prefrontal–limbic circuits in sex-balanced, chronic-stress models will reproduce human network-defined biotypes and treatment response, and proposes hybrid effectiveness–implementation platforms that embed immune–metabolic and sleep panels, circuit-sensitive tasks, and digital monitoring under a shared, preregistered data standard. Full article

Background/Objectives: Mecasin (KCHO-1) is a standardized multi-herb formulation containing diverse bioactive compounds predicted to engage multiple molecular targets. This study applied an integrative network pharmacology approach to explore how Mecasin may interact with Alzheimer’s disease (AD)-related molecular networks. Methods: Bioactive constituents from 9 herbs were screened through OASIS and PubChem, and their predicted targets were cross-referenced with 8886 AD-associated genes from GeneCards. Overlapping genes were analyzed using protein–protein interaction mapping, Gene Ontology, and KEGG to identify potential Mecasin–AD core nodes and pathways. Co-expression, co-regulation, and molecular docking analyses were performed to further characterize mechanistic relevance. Results: Network integration identified 6 core genes—AKT1, STAT3, IL6, TNF, EGFR, and IL1B—positioned within signaling pathways related to neuronal survival, inflammatory regulation, and cellular stress responses, including FoxO, JAK–STAT, MAPK, and TNF pathways. Molecular docking suggested that several Mecasin compounds may interact with targets such as AKT1 and TNF. Conclusions: These in silico findings indicate that Mecasin, a multi-component formulation containing numerous phytochemicals that generate broad compound–target associations, may interface with interconnected neuroimmune pathways relevant to AD. While exploratory, the results highlight potential multi-target mechanisms that merit further investigation and provide a systems-level framework to inform future experimental validation. Full article

Major Depressive Disorder (MDD) poses a significant global health burden, characterized by a complex and heterogeneous pathophysiology insufficiently targeted by conventional single-treatment approaches. This review presents an integrative framework incorporating network pharmacology, artificial intelligence (AI), and multi-omics technologies to advance a systems-level understanding and management of MDD. Its central contribution lies in moving beyond reductionist methods by embracing a holistic perspective that accounts for dynamic interactions within biological networks. The primary objective is to demonstrate how AI-powered integration of multi-omics data—spanning genomics, proteomics, and metabolomics—can enable the construction of predictive network models. These models are designed to uncover fundamental disease mechanisms, identify clinically relevant biotypes, and reveal novel therapeutic targets tailored to specific pathological contexts. Methodologically, the review examines the microbiota–gut–brain (MGB) axis as an illustrative case study, detailing its pathogenic roles through neuroimmune alterations, metabolic dysfunction, and disrupted neuro-plasticity. Furthermore, we propose a translational roadmap that includes AI-assisted biomarker discovery, computational drug repurposing, and patient-specific “digital twin” models to advance precision psychiatry. Our analysis confirms that this integrated framework offers a coherent route toward mechanism-based personalized therapies and helps bridge the gap between computational biology and clinical practice. Nevertheless, important challenges remain, particularly pertaining to data heterogeneity, model interpretability, and clinical implementation. In conclusion, we stress that future success will require integrating prospective longitudinal multi-omics cohorts, high-resolution digital phenotyping, and ethically aligned, explainable AI (XAI) systems. These concerted efforts are essential to realize the full potential of precision psychiatry for MDD. 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

The liver is intricately innervated by sympathetic, parasympathetic, and sensory fibres, forming a dynamic neurovascular and neuroimmune network that regulates hepatic function and contributes to disease pathogenesis. While traditionally underexplored, hepatic innervation is now recognised as a key modulator of metabolic homeostasis, immune surveillance, and vascular tone. Historically, the liver was not considered a major target of neural regulation, but recent advances in neurology and imaging have revealed complex and dynamic interactions between neural circuits and hepatic functions. This review provides a comprehensive overview of liver innervation, detailing its anatomical organisation and functional roles in both physiological and pathological contexts. We investigate the role of liver innervation in shaping immune responses, particularly in the context of metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, and autoimmune liver diseases, including autoimmune hepatitis and primary biliary cholangitis. Special attention is given to the neuroimmune crosstalk that governs inflammation, fibrosis, malignancy, and tissue remodelling. Furthermore, we examine how neural inputs influence hepatic blood flow, sinusoidal endothelial function, and portal hypertension, highlighting the interplay between neural and vascular systems. We highlight neuromodulatory approaches, including vagus nerve stimulation and other agents to modulate liver inflammation, vascular dysfunction, and immune dysregulation. Finally, we discuss emerging research models, including liver organoids, Artificial Intelligence-based digital twins and biomaterials as innovative platforms designed to study neural-liver interactions and test new therapeutic strategies. By integrating neuromorphology, immunology, and hepatology, this review aims to advance our understanding of liver innervation as a central player in hepatic health and disease and to identify novel targets for therapeutic intervention. Full article

The cannabinoid receptor type 2 (CB₂) is increasingly recognized as a crucial regulator of neuroimmune balance in the brain. In addition to its well-established role in immunity, the CB₂ receptor has been identified in specific populations of neurons and glial cells throughout various brain regions, and its expression is dynamically increased during inflammatory and neuropathological conditions, positioning it as a potential non-psychoactive target for modifying neurological diseases. The expression of the CB₂ gene (CNR2) is finely tuned by epigenetic processes, including promoter CpG methylation, histone modifications, and non-coding RNAs, which regulate receptor availability and signaling preferences in response to stress, inflammation, and environmental factors. CB₂ signaling interacts with TRP channels (such as TRPV1), nuclear receptors (PPARγ), and orphan G Protein-Coupled Receptors (GPCRs, including GPR55 and GPR18) within the endocannabinoidome (eCBome), influencing microglial characteristics, cytokine production, and synaptic activity. We review how these interconnected mechanisms affect neurodegenerative and neuropsychiatric disorders, underscore the species- and cell-type-specificities that pose challenges for translation, and explore emerging strategies, including selective agonists, positive allosteric modulators, and biased ligands, that leverage the signaling adaptability of the CB₂ receptor while reducing central effects mediated by the CB₁ receptor. This focus on the neuro-centric perspective repositions the CB₂ receptor as an epigenetically informed, context-dependent hub within the eCBome, making it a promising candidate for precision therapies in conditions featuring neuroinflammation. Full article