Search Results (563)

 Modern biomedicine frequently contextualizes disease around isolated molecular or organ-specific mechanisms, but numerous chronic diseases, including Alzheimer’s disease, multiple sclerosis, depression, diabetes, and sepsis, share common trajectories of systemic destabilization. An increasing body of evidence indicates that health is not a property of single organs but the emergent property of interdependent feedback networks linking the microbiome, endocannabinoidome, neuroimmune system, and metabolic regulators. We propose the Endocannabinoid–Microbiota–Neuroimmune Super-System (EMN-S) as an evolutionarily conserved conceptual model that describes how these fields of influence reciprocally interact through feedback control. The microbial communities constituting the EMN-S encode environmental and dietary inputs, endocannabinoid signaling serves as an integrative regulator that synchronizes neural and immune activity, and neuroimmune circuits effectuate adaptive behaviors that alter microbiotal and lipid ecosystems. This review formalizes the EMN-S, contending that it is a unitary and cohesive model of physiological resilience, as well as offering a framework for precision feedback therapeutics. We describe how three mechanisms—encoder drift, integrator detuning, and executor overutilization—convert stabilizing negative feedback into runaway feedback cascades that underlie chronic, recurrent, and multisystemic disease. We then specify the EMN-S signature—integrated microbiome, lipidomic, and immune readouts—as an early indicator of resilience collapse and prospective preclinical state. Finally, we recapitulate the potential of AI-driven digital twins to illuminate feedback collapse, predict tipping points, and direct closed-loop intervention and treatments to restore dynamic equilibrium. By anchoring complexity in concrete and measurable feedback principles, the EMN-S shifts focus to investigate pathophysiology as opposed to reductionist lesion models of systemic derangements and embraces a systemic, empirically testable theory of stability.  Full article

Background: Septic shock remains a major cause of mortality in critical care, driven by profound vasoplegia, myocardial depression and refractory circulatory collapse. Conventional therapy occasionally fails to restore adequate perfusion, leading to life-threatening multi-organ failure. Methods: This narrative review examines current evidence on veno-arterial extracorporeal membrane oxygenation (V-A ECMO) as a salvage strategy for refractory septic shock, focusing on the pathophysiological rationale, patient selection, timing of initiation and hemodynamic management. Results: Data from observational studies and registry analyses suggest that V-A ECMO may improve survival in patients with septic cardiomyopathy (SCM), with reported survival rates approaching 40% in selected adult cohorts and over 50% in pediatric populations. Early initiation, phenotype-guided selection and precise hemodynamic titration are critical to optimize outcomes. Conclusions: The role of ECMO in septic shock remains controversial and should be restricted to experienced centers and well-defined phenotypes. Future research must refine selection criteria, standardize support strategies and evaluate long-term functional recovery beyond survival. 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

Background: Depressive disorders are among the most common and disabling psychiatric conditions. A growing body of evidence suggests that dopaminergic dysfunction plays a key role in the pathophysiology of anhedonia, amotivation, and psychomotor slowing. This systematic review aims to determine whether bromocriptine, amantadine, and selegiline improve depressive symptoms compared to placebo or standard antidepressants, and to test the hypothesis that their antidepressant effects are mediated by dopaminergic modulation of motivational and reward circuits. Methods: The review followed PRISMA guidelines and was registered in PROSPERO. Results: Twenty-eight studies met inclusion criteria. Selegiline, particularly in transdermal form, reduced HAM-D scores by approximately 40% from baseline and by 25–30% relative to placebo. Amantadine augmentation achieved ≥50% symptom improvement in 60–70% of treatment-resistant cases. Bromocriptine yielded comparable response rates (~60%) to tricyclic antidepressants. All three agents improved anhedonia and motivational deficits. Conclusions: Findings suggest that bromocriptine, amantadine, and selegiline may represent effective dopaminergic antidepressants, particularly for treatment-resistant or atypical depression. Further large-scale, methodologically rigorous studies are needed to confirm their clinical utility. Full article

The study of molecular mechanisms underlying late-life depression (LLD) is increasingly important in light of population aging. To date, LLD-related molecular brain changes remain poorly understood. Furthermore, environmental factors such as climate change and geography contribute to LDD risks. One overlooked factor might be deuterium—a stable hydrogen isotope—whose concentration in drinking water can vary geographically (~90–155 ppm) and alter the incidence of mood disorders. Conversely, potential effects of natural variations in deuterium content in drinking water on LLD symptoms and brain gene expression remain unknown. We conducted Illumina gene expression profiling in the hippocampi and prefrontal cortexes of 18-month-old C57BL/6J mice, a model of LLD-like behaviors, compared to 3-month-old controls. Separately, aged mice were allowed to consume deuterium-depleted (DDW, ~90 ppm) or control (~140 ppm) water for 21 days and were studied for LLD-like behaviors and Illumina gene expression of the brain. Naïve old mice displayed ≥2-fold significant changes of 35 genes. Housing on DDW increased their hedonic sensitivity and novelty exploration, reduced helplessness, improved memory, and significantly altered brain expression of Egr1, Per2, Homer1, Gadd45a, and Prdx4, among others. These genes revealed significant alterations in several GO-BP and KEGG pathways implicated in inflammation, cellular stress, synaptic plasticity, emotionality, and regeneration. Additionally, we found that incubation of primary neuronal cultures in DDW-containing buffer ameliorated Ca²⁺ influx and mitochondrial potential in a toxicity model, suggesting the involvement of mitochondrial mechanisms in the effects of decreased deuterium levels. Thus, aging induced profound brain molecular changes that may at least in part contribute to LLD pathophysiology. Reduced deuterium intake exerted modest but significant effects on LLD-related behaviors in aged mice, which can be attributed to, but not limited by ameliorated mitochondrial function and changes in brain gene expression. Full article

Background/Objectives: The pathophysiology of juvenile idiopathic arthritis (JIA), the most widespread rheumatologically illness in juvenile period, is shaped by complex interactions between leukocytes and the cytokines they secrete. The aim of this research was to evaluate the severity of sleep disturbances and depression, which are closely associated with many diseases and can negatively impact the course of the illness, in patients with JIA using Beck Depression Inventory (BDI) and Sleep Disturbance Scale for Children (SDSC) scores and to investigate the relationship between these scores and laboratory findings in patients with JIA. Methods: The research involved 58 children with JIA and 71 healthy children as controls. BDI and SDSC scores of these groups were compared with laboratory findings and correlation analysis were performed. Results: In the JIA group, BDI and SDSC scores, C-reactive protein (CRP), red blood cell distribution width (RDW), erythrocyte sedimentation rate, neutrophil, and leukocyte counts, were higher than in the control group, while vitamin D values were lower. A positive relation was determined between BDI and SDSC scores in the JIA group, but no correlation was found in the control group. In the JIA group, both BDI and SDSC scores were found to be negatively related with leukocyte and neutrophil counts. In the control group, the BDI score was determined to be negatively correlated with CRP, vitamin D and RDW levels. Conclusions: Depression and sleep disorders may interact in patients with JIA, and their causal relationship with leukocyte and neutrophil levels should be investigated. Full article

Treatment-resistant depression (TRD) remains a major clinical challenge, with a substantial proportion of patients with major depressive disorder (MDD) failing to respond to conventional antidepressant therapies. Increasing evidence suggests that dysregulation of immune signaling contributes to the pathophysiology of TRD. While proinflammatory cytokines such as IL-6 and TNF-α have been extensively studied, less is known about the role of chemokines such as interleukin-8 (IL-8). This review aims to synthesize current knowledge on the biological functions of IL-8, its involvement in neuroimmune mechanisms, and its potential as a biomarker and therapeutic target in treatment-resistant depression. Clinical and preclinical studies evaluating IL-8 levels in MDD and TRD patients were discussed with a focus on treatment response, neuroinflammatory pathways, and predictive modeling. Methodological factors affecting IL-8 measurement and interpretation were critically assessed. Even though clinical studies indicate that IL-8 levels may predict treatment response to antidepressants, including ketamine, findings are inconsistent, partly due to methodological variability, small sample sizes, and confounding factors such as comorbid medical conditions. Therefore, future longitudinal and multimodal studies are warranted to validate its utility in psychiatric precision medicine. Full article

The intestinal barrier has recently gained attention as a contributor to the pathophysiology of depression. This narrative review examines the current literature on blood-based markers of intestinal permeability in patients with depression. A structured search of PubMed and EMBASE was performed. Both recent and older studies were included to capture key mechanisms and theoretical foundations. We focused on zonulin, intestinal fatty acid-binding protein (I-FABP), lipopolysaccharides (LPS), LPS-binding protein (LBP), and soluble CD14 (sCD14). While several studies report altered intestinal permeability markers in individuals with depression, results remain inconsistent. Factors such as small sample sizes and variability in measurement procedures complicate interpretation. In some cases, altered biomarker levels were associated with disease severity or response to antidepressant treatment, suggesting a potential role in patient stratification. However, current evidence does not support their routine use in clinical settings. Further research is needed to clarify their value in psychiatric populations. If validated, these markers may help identify inflammation-related depression subtypes and guide more precise treatment strategies. Full article

Background/Objectives: Ischemia with non-obstructive coronary arteries (INOCA) remains an underdiagnosed and undertreated condition due to the extensive diagnostic testing required and heterogeneous pathophysiology of different endotypes, each of which require tailored treatment. This study aimed to explore the effect of intracoronary physiology testing-based endotype-specific medical therapy on quality of life in patients with INOCA. Methods: Intracoronary physiology testing was performed in patients presenting with cardiac symptoms, evidence of significant ischemia on non-invasive testing, and non-obstructive epicardial coronary arteries. Microvascular angina (MVA) was defined as coronary flow reserve ≤ 2.5 and an index of microvascular resistance ≥ 25. Vasospastic angina (VSA) was defined as a >90% vasoconstriction of an epicardial artery during acetylcholine provocation test in the presence of ischemic electrocardiogram changes and chest pain. Quality of life was evaluated using the Seattle Angina Questionnaire 7 (SAQ-7) before the start of new treatment and at the three months follow-up. Results: The total study population consisted of 35 patients (80% women), of whom MVA was observed in 19 (54.3%), VSA in 9 (25.7%), and the combination of MVA and VSA in 3 (8.6%) cases. Four patients (11.4%) had no pathology on intracoronary physiology testing detected. High rates of dyslipidemia (100%), arterial hypertension (85.7%), diabetes (17.1%), and depression and anxiety (34.3%) were documented. In the isolated MVA and VSA groups, adjustment of medical therapy resulted in an improvement in the SAQ-7 summary score at 3 months (p < 0.001 and p = 0.007, respectively). There was no change of SAQ-7 summary score in the mixed endotype group (p = 0.11). Conclusions: Adjustment of medical therapy according to intracoronary physiology testing-based phenotype resulted in improved quality of life as assessed by the SAQ-7. Our findings highlight the importance of invasive testing in patients with clinically suspected INOCA. Full article

Celiac disease (CeD) is an autoimmune disorder where adherence to a lifelong gluten-free diet (GFD) is the only available treatment. While this approach is rather effective, some patients experience ongoing symptoms, and this factor, along with the rigidity of the GFD, may predispose some to disordered eating behaviors, including Avoidant/Restrictive Food Intake Disorder (ARFID). ARFID is characterized by persistent food avoidance that is not driven by body image concerns, resulting in nutritional, psychological, and social impairment. This scoping literature review explores the emerging intersection between ARFID and CeD, examining prevalence, pathophysiology, clinical features, complications, and management strategies. Recent studies report that 14–57% of individuals with CeD may meet the criteria for ARFID, depending on the population and screening tools used. Factors contributing to ARFID in CeD may include ongoing gastrointestinal symptoms, anxiety over gluten exposure, negative conditioned responses to food, social challenges related to GFD adherence, and psychiatric co-morbidities. ARFID in CeD is associated with worsened nutritional deficiencies, anxiety, depression, and impaired social functioning, making the diagnosis of ARFID challenging due to symptom overlap with CeD and other psychiatric conditions. Management requires a multidisciplinary approach, including medical, nutritional, and psychological interventions. Routine screening, early intervention, and integrated care models may improve outcomes and quality of life. Full article

Depression is a prevalent and disabling psychiatric disorder, characterized by persistent disturbances in mood, cognition, and physiological processes, which collectively lead to substantial impairments in daily functioning and quality of life. This review provides a comprehensive overview of the biological mechanisms implicated in the pathophysiology of depression, including neurotransmitter dysregulation, oxidative stress, inflammatory processes, hypothalamic-pituitary-adrenal (HPA) axis dysfunction, mitochondrial impairment, and alterations in the gut-brain axis. Furthermore, it explores the role of diet in both the prevention and management of depression, with particular emphasis on Mediterranean, anti-inflammatory, and ketogenic dietary patterns, while contrasting these with the detrimental impact of a Western dietary pattern. Specific nutrients-such as n-3 polyunsaturated fatty acids (PUFAs), B-complex vitamins, vitamins D and E, zinc, selenium, and polyphenols-are highlighted for their potential roles in modulating neurotransmission, attenuating inflammation, and supporting gut microbiota homeostasis. Despite growing scientific interest in nutrition-based interventions, current evidence on the comparative efficacy of different dietary approaches remains limited. Future research is warranted to elucidate the therapeutic potential of dietary strategies as adjuncts to conventional treatments for depression and to facilitate the development of evidence-based nutritional recommendations for clinical practice. Full article

Traumatic brain injury (TBI), even when mild, has been associated with the presence of depression. Depression is a mood disorder characterized by persistent negative thoughts and sadness and is challenging to treat due to the multiple mechanisms involved in its pathophysiology, including increased nitric oxide (NO) levels. There are no completely safe and effective pharmacological strategies to treat this disorder. Mucuna pruriens (MP) has been shown to possess neuroprotective properties by regulating inflammatory responses and nitric oxide synthase activity. In this study, we evaluated the antidepressant-like effect of MP in male Wistar rats with induced mild traumatic brain injury (mTBI). MP extract (50 mg/kg i.p.) was administered immediately after mTBI and every 24 h for five days. We used the rats’ preference for sucrose consumption to assess the presence of depression-like behavior and analyzed the nitrite and nitrate levels in their cerebral cortex, striatum, midbrain, and nucleus accumbens. Untreated animals with mTBI showed a reduced preference for sucrose than those treated with MP, whose preference for sucrose was similar to that of sham animals. Increased nitrite and nitrate levels were observed in different brain regions in the TBI subjects; however, this increase was not observed in MP-treated animals. MP reduces behavior associated with depression and the brain NO levels in rats with mTBI. Full article

Parkinson’s disease (PD) is a progressive, irreversible neurodegenerative disorder characterized by motor impairments and a wide spectrum of non-motor symptoms, including gastrointestinal dysfunction, sleep disturbances, depression, and cognitive decline. These manifestations arise from disturbances across multiple systems—gastrointestinal, neuroendocrine, immune, enteric, and central nervous systems. Alterations in the gut microbiota may play a causal role in PD onset and frequently accompany disease progression. The gut–brain axis, particularly the vagus nerve, is increasingly recognized as a key communication pathway whose dysregulation contributes to systemic dysfunction and the breakdown of homeostasis, ultimately driving PD pathology. Currently, there is no cure for PD, and existing treatments primarily target symptom relief. Effective management of PD requires a comprehensive approach that integrates multiple pharmacologically active agents aimed at restoring impaired organ functions and, when possible, neutralizing toxic factors that accelerate disease progression. One promising therapeutic avenue lies in functional gut bacteria, which form the basis for developing live biotherapeutic products, postbiotics, and bacterial vesicles. In this review, we summarize current data on the effects of probiotics in PD, drawing on both animal models and clinical studies. We highlight the role of probiotics in modulating PD pathophysiology and discuss their potential as adjunctive therapeutic agents. To provide a broader perspective, we also include sections describing the clinical manifestations of PD, gut microbiota alterations associated with the disease, and the role of artificial intelligence, particularly machine learning, in constructing functional models of PD. Full article

Maternal Immune Activation (MIA) is a phenomenon of pathophysiological stimulation of the maternal immune system during gestation which potentially leads to functional and structural disturbances of fetal neurogenesis. It occurs due to the alteration of paracrine signals between the maternal organism and the developing nervous system of the fetus. Any disturbances in the brain at embryonic and early postnatal stages might compromise its natural developmental trajectory, which could potentially increase the risk of developing neuropsychiatric disorders, such as schizophrenia, autistic spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), major depressive and bipolar disorders, etc. Presumably, all these conditions could initiate the development of age-related cognitive impairment in late ontogenesis, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and others. As the main immune cell population in the CNS, microglia both mediate its proper development and receive pathological stimuli from the maternal organism. This could lead to microglia premature activation and could become a part of the mechanisms of the fetal CNS development alterations. In this review, we discuss the role of prenatal activation of microglia in neuropsychiatric disorders and neurodegenerative disease development. We highlight approaches to modeling MIA, as well as sex differences in the morphological and functional state of microglia in the context of physiological conditions. There is a hypothesis discussed regarding the contribution of these distinctions to neuropsychiatric disorders and neurodegenerative disease incidence, prevalence, and progression in males and females. Full article

N⁶-methyladenosine (m⁶A) is the most prevalent internal modification in eukaryotic messenger RNA (mRNA) and plays a vital role in post-transcriptional gene regulation. In recent years, m⁶A has emerged as a pivotal epitranscriptomic signal involved in neural development, synaptic remodeling, and the molecular pathophysiology of neuropsychiatric disorders. In this review, we summarize the mechanisms underlying the deposition, removal, and recognition of m⁶A by dedicated methyltransferases, demethylases, and RNA-binding proteins. We further explore how these dynamic modifications influence neuronal differentiation and memory formation. Recent studies have linked aberrant m⁶A regulation to psychiatric conditions such as depression, anxiety, schizophrenia, and bipolar disorder. Additionally, we discuss how pharmacological or genetic modulation of m⁶A pathways may promote adaptive neural plasticity and enhance cognitive and emotional resilience. Despite these promising findings, significant challenges remain in achieving spatial and temporal specificity while minimizing off-target effects in the brain. Therefore, we advocate for more in-depth investigations into m⁶A function within developmentally defined neural circuits to better understand its enduring role in maintaining neural homeostasis. Full article