Spinal muscular atrophy is a devastating motor neuron disease characterized by severe cases of fatal muscle weakness. It is one of the most common genetic causes of mortality among infants aged less than 2 years. Biomarker research is currently receiving more attention, and new candidate biomarkers are constantly being discovered. This review initially discusses the evaluation methods commonly used in clinical practice while briefly outlining their respective pros and cons. We also describe recent advancements in research and the clinical significance of molecular biomarkers for spinal muscular atrophy, which are classified as either specific or non-specific biomarkers. This review provides new insights into the pathogenesis of spinal muscular atrophy, the mechanism of biomarkers in response to drug-modified therapies, the selection of biomarker candidates, and would promote the development of future research. Furthermore, the successful utilization of biomarkers may facilitate the implementation of gene-targeting treatments for patients with spinal muscular atrophy.

Decellularized extracellular matrix derived from specific organs represents a promising platform for organoid development, offering distinct advantages in tissue engineering. This matrix maintains the complex three-dimensional network of biological macromolecules secreted by tissue-specific cells, including collagen, glycoproteins, and proteoglycans. This extracellular matrix orchestrates cellular behaviors, such as proliferation, migration, and differentiation, while maintaining optimal tissue homeostasis. The organ-specific composition of decellularized extracellular matrix preserves native biological cues, including growth factors and cytokines, as well as mechanical properties, facilitating natural cell-matrix interactions and promoting appropriate stem cell development. These characteristics make organ-derived decellularized extracellular matrix an ideal scaffold for organoid construction. The implementation of decellularized extracellular matrix enhances the physiological relevance of organoid models, which is particularly valuable in drug development, personalized medicine, and the study of complex organ microenvironments. This advancement significantly improves the translational potential of organoid technology for organ transplantation while providing robust research tools. Consequently, decellularized extracellular matrix-based organoid models offer superior platforms for preclinical therapeutic evaluation. This review examines recent progress in decellularized extracellular matrix-based organoid development, beginning with current application strategies and proceeding to an analysis of existing decellularized extracellular matrix-derived organoid models.

Vascular cognitive impairment (VCI) is a syndrome characterized by cognitive decline resulting from insufficient perfusion to the entire brain or specific brain regions. The lack of a clear understanding of the mechanisms linking cerebrovascular disease to cognitive impairment has impeded the development of targeted treatments for VCI. Increasing evidence indicates that exercise may offer significant benefits for patients with VCI. This study explores how neuroinflammatory mechanisms mediate the effects of exercise on VCI, focusing on the broader biological processes involved. Exercise plays a crucial role in mitigating vascular risk factors, reducing oxidative stress, and promoting neurogenesis. Furthermore, exercise influences neuroinflammatory mediators and central immune cells via various signaling pathways. Different types and intensities of exercise, including resistance and endurance training, have been shown to differentially modulate neuroinflammation during the progression of VCI. This paper summarizes the current mechanisms of action and proposes exercise interventions targeting neuroinflammatory pathways, along with biomarker studies, to enhance our understanding of VCI pathogenesis and inform clinical practice. A more in-depth understanding of the inflammatory mechanisms underlying VCI may facilitate the development of targeted therapeutic interventions.

Opioid use disorder (OUD) causes major public health morbidity and mortality. Although standard-of-care treatment with medications for OUD (MOUDs) is available, there are few biological markers of the clinical process of recovery. Neurobiological aspects of recovery can include normalization of brain white matter (WM) microstructure, which is sensitive to cytokine signaling. Here, we determined whether blood-based cytokines can be markers of change in WM microstructure following MOUD.

Inpatient individuals with heroin use disorder (iHUDs) (n = 21) with methadone or buprenorphine MOUD underwent magnetic resonance imaging (MRI) scans with diffusion tensor imaging (DTI) and provided ratings of drug cue-induced craving, arousal, and valence earlier in treatment (MRI1) and ≈14 weeks thereafter (MRI2). Healthy control participants (HCs) (n = 24) also underwent 2 MRI scans during a similar time interval. At MRI2, participants provided a peripheral blood sample for multiplex quantification of serum cytokines. We analyzed the correlation of a multitarget biomarker score (from a principal component analysis of 19 cytokines that differed significantly between iHUDs and HCs) with treatment-related change in DTI metrics (ΔDTI; MRI2 - MRI1).

The cytokine biomarker score was negatively correlated with ΔDTI metrics in frontal, frontoparietal, and corticolimbic WM tracts in iHUDs but not in HCs. Also, serum levels of specific cytokines in the cytokine biomarker score, including the interleukin-related oncostatin M (OSM), similarly correlated with ΔDTI metrics in iHUDs but not in HCs. Serum levels of other specific cytokines were negatively correlated with changes in cue-induced craving and arousal in the iHUDs.

Specific serum cytokines, studied alone or as a group, may serve as accessible biomarkers of WM microstructure changes and potential recovery in iHUDs undergoing treatment with MOUD.

Adult learning, memory, and social interaction partially depend on neurogenesis in two regions: the hippocampus and the subventricular zone. There is evidence that the immune system is important for these processes in pathological situations, but there is no review of its role in non-pathological or near-physiological conditions. Although further research is warranted in this area, some conclusions can be drawn. Intrusive LyC6hi monocytes and autoreactive CD4+ T cells have a positive impact on neurogenesis and behavior, but the latter are deleterious if specific to external antigens. Mildly activated microglia play a crucial role in promoting these processes, by eliminating apoptotic neuronal progenitors and producing low levels of interleukins, which increase if the cells are activated, leading to inhibition of neurogenesis. Chemokines are poorly studied, but progenitor cells and neurons express their receptors, which appear important for migration and maturation. The few works that jointly analyzed neurogenesis and behavior showed congruent effects of immune cells and cytokines. In conclusion, the immune system components -mostly local- seem of utmost importance for the control of behavior under non-pathological conditions.

The development of the nervous system is a highly complex process orchestrated by a multitude of factors, including various immune elements. These immune components play a dual role, not only regulating the immune response but also actively influencing brain development under both physiological and pathological conditions. The brain's immune barrier includes microglia in the brain parenchyma, which act as resident macrophages, astrocytes that support neuronal function and contribute to the inflammatory response, as well as circulating immune cells that reside at the brain's borders, including the choroid plexus, meninges, and perivascular spaces. Cytokines-soluble signaling molecules released by immune cells-play a crucial role in mediating communication between immune cells and the developing nervous system. Cytokines regulate processes such as neurogenesis, synaptic pruning, and inflammation, helping to shape the neural environment. Dysregulation of these immune cells, astrocytes, or cytokine signaling can lead to alterations in neurodevelopment, potentially contributing to neurodevelopmental abnormalities. This article reviews the central role of microglia, astrocytes, cytokines, and other immune factors in neurodevelopment, and explores how neuroinflammation can lead to the onset of neurodevelopmental disorders, shedding new light on their pathogenesis.

Background/Objectives: 5-(3',4'-dihydroxyphenyl)-γ-valerolactone (γ-VL), recently identified as a predominant microbial metabolite derived from proanthocyanidins, offers benefits such as reducing inflammation, oxidative stress, and supporting brain health. Its effects on neuroinflammation and microglial activation remain largely unexplored. Curcumin, a bioactive component isolated from Curcuma longa L., is well known for its ability to reduce microglial activation and pro-inflammatory mediator production and release. While the individual effects of γ-VL and curcumin are well documented, their potential combined effects remain unexplored. This research sought to investigate the possible synergistic effects of γ-VL and curcumin in reducing microglial activation. Methods: Primary rat cortical microglia were pre-treated with γ-VL and curcumin, alone or in combination, before stimulation with LPS. An MTT assay was used to evaluate cell viability, while pro-inflammatory mediators were assessed by real-time PCR and ELISA. Nitric oxide production was evaluated with the Griess assay. SynergyFinder Plus software analyzed potential synergistic effects. Results: The combination of low micromolar concentrations of γ-VL and curcumin synergistically reduced LPS-induced microglial activation. Specifically, the combination exhibited a significantly greater ability to inhibit the production and release of pro-inflammatory factors (such as IL-1β, TNF-α, and NO) compared to each compound individually. Mechanistically, the anti-inflammatory activity was attributed to the downregulation of NLRP3 expression, and the reduction in microglial activation was linked to the modulation of the NOX2/Nrf2 signaling pathway. Conclusions: The combination of low micromolar concentrations of γ-VL and curcumin produces synergistic anti-inflammatory effects in microglia by targeting key inflammatory pathways, indicating its potential utility as a treatment strategy for neurodegenerative diseases involving microglial activation.

Extracellular vesicles (EVs) are small capsular bodies released by cells, mediating responses in intercellular communication. The role of EVs in Aβ pathology spreading in the Alzheimer's disease (AD) brain has been evidenced, although whether this occurs due to the co-transportation of Aβ peptides or contribution of other factors, such as EV-associated transcripts, remains uncertain. In vitro studies of miRNA cargo in neuron-derived extracellular vesicles (NDEVs) show that Aβ hyperexpression alters the transcriptomic profile; however, it is not clear to what extent this causes changes at the organ level. By utilizing datasets from published studies, we generated competing endogenous RNA (ceRNA) networks for miRNAs co-expressed in NDEVs and the brain in different stages of pathology, using both an APP overexpressing neuronal model (in vitro) and brain cortices from 6- and 9-month-old APP/PSEN1 mice (in vivo). Networks integrating information from mRNAs, lncRNAs, and circRNAs showed two candidate lncRNAs (Kcnq1ot1 and Gm42969) and a circRNA (Pum1), while enrichment analyses detected that NDEVs miRNAs signal to other CNS cells and that this signal can be disrupted by Aβ pathology, contributing to the loss of long-term potentiation seen in early AD.

The central nervous system (CNS) has a unique set of macrophages that seed the tissue early during embryonic development. Microglia reside in the parenchyma, and border-associated macrophages are present in border regions, including the meninges, perivascular spaces, and choroid plexus. CNS-resident macrophages support brain homeostasis during development and steady state. In the diseased brain, however, the immune landscape is altered, with phenotypic and transcriptional changes in resident macrophages and the invasion of blood-borne monocytes, which differentiate into monocyte-derived macrophages upon entering the CNS. In this review, we focus on the fate and function of the macrophage compartment in health, neurodegenerative conditions such as amyloidosis, and neuroinflammation as observed in multiple sclerosis and infection. We discuss our current understanding that monocyte-derived macrophages contribute to neuropathology whereas native macrophages play a neuroprotective role in disease.

Plants from the Rhus genus are renowned for their medicinal properties, including anti-inflammatory effects; however, the mechanisms underlying these effects remain poorly understood. This systematic review, conducted following PRISMA guidelines, evaluated the anti-inflammatory effects of Rhus plants and explored their potential pharmacological mechanisms. A total of 35 articles were included, with the majority demonstrating a low-risk bias, as assessed using the SYRCLE tool. Rhus verniciflua, Rhus chinensis, Rhus coriaria, Rhus succedanea, Rhus tripartite, Rhus crenata, and Rhus trilobata were analyzed in the reviewed articles. In vitro studies consistently demonstrated the ability of Rhus plants to reduce key inflammatory mediators such as TNF-α, IL-1β, and IL-6. In vivo studies confirmed these effects in murine models of inflammation, with doses mostly of 400 and 800 mg/kg body weight, with no reports of toxicity. Fifty-four distinct inflammatory mediators were assessed in vivo; no pattern of mediators was identified that could elucidate the anti-inflammatory mechanisms of the action of Rhus in acute or chronic inflammation. The clinical trial reported anti-inflammatory effects in humans at 1000 mg/kg for 6 weeks. The review data on the Rhus-mediated reduction in inflammatory mediators were integrated and visualized using the Reactome bioinformatics database, which suggested that the mechanism of action of Rhus involves the inhibition of inflammasome signaling. These findings support the potential of Rhus plants as a basis for developing anti-inflammatory therapies. Further research is needed to optimize dosage regimens and fully explore their pharmacological applications.

Background: Mounting evidence suggests that the phytocannabinoid cannabidiol (CBD) holds promise as an antidepressant agent in conditions underlined by inflammation. Full-spectrum CBD extracts might provide greater behavioral efficacy than CBD-only isolates and might require lower doses to achieve the same outcomes due to the presence of other cannabinoids, terpenes, and flavonoids. However, investigations in this area remain limited. Methods: We evaluated the behavioral response to the administration for 7 days of 15 and 30 mg/kg of a CBD isolate and a full-spectrum CBD product in a rat model of subchronic lipopolysaccharide (LPS, 0.5 mg/kg/day/7 days, intraperitoneal)-induced depressive-like and sickness behavior. The forced swim test was used to assess depressive-like behavior, the open field test (OFT) to assess locomotion, and the elevated plus maze to assess anxiety-like behavior. Results: The full-spectrum CBD extract at both doses, but not the CBD isolate, reversed the LPS-induced depressive-like behavior in the forced swim test. Moreover, the full-spectrum CBD extract at the higher dose but not the CBD isolate restored the subchronic LPS-induced hypolocomotion in the OFT. Repeated administration of both formulations elicited an anxiogenic-like trend in the elevated plus maze. Conclusion: Full-spectrum CBD products might have greater therapeutic efficacy in resolving inflammation-induced depressive and sickness behavior compared to a CBD-only isolate.

Proinflammatory and neuroendocrine mediators are implicated in disease aetiopathogenesis. Stress increases concentrations of immune-neuroendocrine biomarkers through a complex network of brain-body signalling pathways. Suboptimal sleep further modulates these processes by altering major effector systems that sensitise the brain to stress. Given the ubiquitous, impactful nature of material deprivation, we tested for a synergistic association of financial stress and suboptimal sleep with these molecular processes.

With data drawn from the English Longitudinal Study of Ageing (ELSA), associations were tested on 4,940 participants (∼66 ± 9.4 years) across four-years (2008-2012). Through analytical triangulation, we tested whether financial stress (>60% insufficient resources) and suboptimal sleep (≤5 / ≥9  h) were independently and interactively associated with immune-neuroendocrine profiles, derived from a latent profile analysis (LPA) of C-reactive protein, fibrinogen, white blood cell counts, hair cortisol, and insulin-like growth factor-1.

A three-class LPA model offered the greatest parsimony. After adjustment for genetic predisposition, sociodemographics, lifestyle, and health, financial stress was associated with short-sleep cross-sectionally (RRR = 1.45; 95% CI = 1.18-1.79; p < 0.001) and longitudinally (RRR = 1.31; 95% CI = 1.02-1.68; p = 0.035), and it increased risk of belonging to the high-risk inflammatory profile by 42% (95% CI = 1.12-1.80; p = 0.004). Suboptimal sleep was not related to future risk of high-risk profile membership, nor did it moderate financial stress-biomarker profile associations.

Results advance psychoneuroimmunological knowledge by revealing how inflammation and neuroendocrine markers cluster in older cohorts and respond to financial stress over time. Financial stress associations with short-sleep are supported. The null role of suboptimal sleep, as exposure and mediator, in profile membership, provides valuable insight into the dynamic role of sleep in immune-neuroendocrine processes.

Studies have highlighted complex bidirectional relationships between autoimmune diseases and depressive disorders. Given that early mental health interventions have substantial public health implications, this study investigated association between optic neuritis, an autoimmune inflammatory disorder of the optic nerve, and risk of developing depressive disorders. Utilizing extensive national health insurance data encompassing almost the entire Korean population, this cohort study included 11,745 patients with optic neuritis and 58,725 age- and sex- matched controls between 2010 and 2017. The diagnosis of optic neuritis was confirmed using ICD-10 code H46 and patient medical records. The association with depression risk identified by ICD-10 codes F32 and F33 was assessed using Cox proportional hazards regression models after adjusting for demographics, lifestyle variables, and other comorbidities. Newly diagnosed optic neuritis was associated with an increased risk of depression (hazard ratio = 1.349, 95% confidence interval: 1.277-1.426), independent of potential confounding factors. Subgroup analysis revealed a stronger association for individuals under 50 years, males, current smokers, and those without hypertension. This association suggests that autoimmune neuroinflammatory responses impact mental health differently across demographics. These findings underscore the importance of implementing routine depression screening and developing targeted early intervention strategies for patients with optic neuritis, particularly for those with a high-risk of depression.

The link between gut microbiome and eating behaviours, especially palatable food intake, is a growing focus of scientific investigation. The complex ecosystem of microorganisms in the gut influences host metabolism, immune function and neurobehavioural signalling. This review explores the role of neuroinflammation in dysregulations of food-induced reward signalling and the potential causal role of the gut microbiota on these proinflammatory processes. Particular attention is given to eating disorders (ED, specifically anorexia nervosa, binge eating disorder and bulimia nervosa) and potential links with the gut microbiota, food reward alterations and neuroinflammation. Finally, we propose gut microbiota modulation as a promising therapeutic strategy in food reward alterations and ED.

Recent research has highlighted the crucial role of immune regulation in lung function impairment due to exposure to hazardous materials. This study aimed to identify dynamic network biomarkers for lung function damage caused by hexavalent chromium inhalation exposure, using immune-related indicators in blood. An 11-year follow-up longitudinal study was conducted on a population occupationally exposed to hexavalent chromate (Cr [VI]) from 2010 to 2020, consisting of sixty-one subjects with 328 repeat measurements. Quantitative analysis of immune-related indicators, including white blood cells, cytokines, and platelet count, was performed. The concentration of urinary Cr served as an indicator of internal exposure, confirming its association with lung function impairment. Dynamic network analysis revealed that platelet count was connected to neutrophils, IL-8, IL-6, and IL-33 when the exposure time was equal to or longer than 9.2 years (the median exposure time). Notably, the association between platelet count and IL-33 was specific to long-term (≥ 9.2 years) exposure. The areas under the receiver operating characteristic (ROC) curves (AUCs) for platelet count combined with IL-33 to predict lung function impairment in the long-term and short-term Cr [VI]-exposed populations were 80.5 % and 55.4 %, respectively. These findings provide evidence that the combination of platelets and IL-33 holds significant promise as biomarkers for predicting lung function impairment. Moreover, they shed light on the potential mechanism involving immune and hematopoiesis functions in the context of environmental hazardous exposure.

Huntington's Disease (HD) is a debilitating neurodegenerative condition characterized by motor, cognitive and psychiatric abnormalities. Immune hyperactivity and dysregulation are common in HD. In addition to the central nervous system, HD patients exhibit systemic innate immune activation and inflammation, which has been shown to contribute to the pathogenic effects of the Huntingtin gene mutation. Upregulation of inflammatory mediators including interferon gamma (IFN-γ) and interleukin (IL)-8 has been observed in animal Huntington's disease models. However, studies on HD patients remain limited.

In this study, serum samples from 58 HD patients and 59 age- and gender-matched healthy control individuals were analysed using a bead-based assay, that enabled simultaneous measurement of 13 cytokines and chemokines. Additionally, publicly available transcriptomic data from brain tissues of HD patients and controls were examined.

Our results confirm that IL-8 protein levels are significantly higher in HD patients compared to non-HD controls, with the highest levels observed in the moderate HD group. In the control group, we found significant positive correlations between IL-8 levels and both IL-17A and IL-10. However, these correlations were not observed in HD patients, where IL-8 levels were notably positively correlated with pro-inflammatory markers including IFNγ and IL-23. Interestingly, IL-17A levels demonstrated a negative correlation with disease parameters, including CAG trinucleotide repeat expansion and disease burden score. Furthermore, cytokines and chemokines such as IFNγ and monocyte chemoattractant protein 1 (MCP-1; CCL2) demonstrated positive correlations with the same disease parameters. In-depth analysis of publicly available bulk RNAseq, and single-nucleus RNA-sequencing (snRNAseq) data from two key HD-affected brain regions- the prefrontal cortex and striatum revealed that IL-8 expression is significantly increased in cortex samples from individuals with HD compared to non-HD controls. Moreover, snRNAseq data in the striatum showed higher IL-8 expression in HD patients than in non-HD controls, with a predominant expression in microglia.

Overall, our findings support an upregulation of IL-8 in patients with HD, evident in both central degenerating brain regions, and peripheral blood samples. We identified unique immunological signatures associated with the severity of HD and provide potential biomarkers that may reflect immune-pathological mechanisms in HD patients.

Multiple sclerosis (MS) is the most prevalent human inflammatory disease of the central nervous system with demyelination and glial scar formation as pathological hallmarks. Glial cells are key drivers of lesion progression in MS with roles in both tissue damage and repair depending on the surrounding microenvironment and the functional state of the individual glial subtype. In this review, we describe recent developments in the context of glial cell diversity in MS summarizing key findings with respect to pathological and maladaptive functions related to disease-associated glial subtypes. A particular focus is on the spatial and temporal dynamics of glial cells including subtypes of microglia, oligodendrocytes, and astrocytes. We contextualize recent high-dimensional findings suggesting that glial cells dynamically change with respect to epigenomic, transcriptomic, and metabolic features across the inflamed rim and during the progression of MS lesions. In summary, detailed knowledge of spatially restricted glial subtype functions is critical for a better understanding of MS pathology and its pathogenesis as well as the development of novel MS therapies targeting specific glial cell types.

Previous observational studies have reported a possible association between major depressive disorder (MDD) and abnormal cortical structure. However, it is unclear whether MDD causes reductions in global cortical thickness (CT) and global area (SA).

We aimed to test the bidirectional causal relationship between MDD and CT and SA using a Mendelian randomization (MR) design and performed exploratory analyses of MDD on CT and SA in different brain regions.

Summary-level data were obtained from two GWAS meta-analysis studies: one screening for single nucleotide polymorphisms (SNPs) predicting the development of MDD (n = 135,458) and the other identifying SNPs predicting the magnitude of cortical thickness (CT) and surface area (SA) (n = 51,665).

The results showed that MDD caused a decrease in CT in the medial orbitofrontal region, a decrease in SA in the paracentral region, and an increase in SA in the lateral occipital region. C-reactive protein, tumor necrosis factor alpha (TNF-α), interleukin-1β, and interleukin-6 did not mediate the reduction. We also found that a reduction in CT in the precentral region and a reduction in SA in the orbitofrontal regions might be associated with a higher risk of MDD.

Our study did not suggest an association between MDD and cortical CT and SA.

Neuroinflammation represents a critical pathway in the brain for the clearance of foreign bodies and the maintenance of homeostasis. When the neuroinflammatory process is dysregulate, such as the over-activation of microglia, which results in the excessive accumulation of free oxygen and inflammatory factors in the brain, among other factors, it can lead to an imbalance in homeostasis and the development of various diseases. Recent research has indicated that the development of numerous neurodegenerative diseases is closely associated with neuroinflammation. The pathogenesis of neuroinflammation in the brain is intricate, involving alterations in numerous genes and proteins, as well as the activation and inhibition of signaling pathways. Furthermore, excessive inflammation can result in neuronal cell apoptosis, which can further exacerbate the extent of the disease. This article presents a summary of recent studies on the relationship between neuronal apoptosis caused by excessive neuroinflammation and neurodegenerative diseases. The aim is to identify the link between the two and to provide new ideas and targets for exploring the pathogenesis, as well as the prevention and treatment of neurodegenerative diseases.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by recurrent inflammatory relapses and neurodegeneration. Myeloid cells play a critical role in shaping the inflammatory environment and influencing disease progression. Here, we demonstrate that activation of the Wnt signaling pathway reprograms myeloid cells into an immunoregulatory phenotype, leading to reduced neuroinflammation and disease severity. Using both experimental autoimmune encephalomyelitis (EAE) and human-derived myeloid cells, we show that Wnt agonist treatment promotes the expression of inhibitory molecules such as PD-L1 and PD-L2, suppressing pro-inflammatory responses. In the chronic and relapsing-remitting EAE models, Wnt activation significantly reduced disease severity, immune cell infiltration into the CNS, and pathogenic T cell responses. Notably, in relapsing-remitting EAE, Wnt treatment prevented new relapses in a PD-L1-dependent manner, highlighting the crucial role of myeloid cell-mediated immune regulation. These findings reveal a previously unrecognized role for Wnt signaling in myeloid cell immunoregulation and suggest that targeting this pathway could provide a novel therapeutic strategy for MS and other autoimmune diseases.

Anti-vascular endothelial growth factor (VEGF) treatment with intravitreal brolucizumab (IVBr) was launched as a novel treatment for neovascular age-related macular degeneration (AMD), but the incidence of intraocular inflammation (IOI) as a specific adverse effect of brolucizumab has been reported. We evaluated the dynamics of inflammatory factors in AMD in patients with or without IOI before and after anti-VEGF treatment with IVBr. We describe three patients who did not develop inflammation after three consecutive administrations of IVBr and three in whom inflammation occurred after the first IVBr treatment. The presence or absence of inflammation was determined by slit-lamp examination and a laser flare meter. Aqueous humor was obtained during anti-VEGF treatment with IVBr. Levels of VEGF, platelet-derived growth factor (PDGF)-AA, monocyte chemoattractant protein 1 (MCP-1), interleukin (IL)-6, IL-8, interferon-inducible 10 kDa protein (IP-10), Fms-related tyrosine kinase 3 ligands (Flt-3L), and fractalkine were measured. Vision worsened in one patient who developed IOI after initial IVBr, so IVBr was discontinued and the patient was switched to intravitreal aflibercept with sub-tenon injection of triamcinolone acetonide. IVBr was continued in the two other patients with IOI. VEGF decreased after IVBr in all patients with and without IOI. On the other hand, at 1 month IL-6, IL-8, MCP-1, IP-10, and Flt-3L were higher in the three patients with IOI compared with baseline and with the three patients without IOI. In two patients with IOI, not only flares but also IL-8, IP-10, and Flt-3L decreased from 1 to 2 months after IVBr despite continued IVBr. This case series might lead to a better understanding of the pathogenesis of IOI after IVBr.

Cognitive impairment is one of the many symptoms reported by individuals suffering from long-COVID and other post-viral infection disorders such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). A common factor among these conditions is a sustained immune response and increased levels of inflammatory cytokines. Tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) are two such cytokines that are elevated in patients diagnosed with long-COVID and ME/CFS. In this study, we characterized the changes in neural functionality, secreted cytokine profiles, and gene expression in co-cultures of human iPSC-derived neurons and primary astrocytes in response to prolonged exposure to TNF-α and IL-6. We found that exposure to TNF-α produced both a concentration-independent and concentration-dependent response in neural activity. Burst duration was significantly reduced within a few days of exposure regardless of concentration (1 pg/mL - 100 ng/mL) but returned to baseline after 7 days. Treatment with low concentrations of TNF-α (e.g., 1 and 25 pg/mL) did not lead to changes in the secreted cytokine profile or gene expression but still resulted in significant changes to electrophysiological features such as interspike interval and burst duration. Conversely, treatment with high concentrations of TNF-α (e.g., 10 and 100 ng/mL) led to reduced spiking activity, which may be correlated to changes in neural health, gene expression, and increases in inflammatory cytokine secretion (e.g., IL-1β, IL-4, and CXCL-10) that were observed at higher TNF-α concentrations. Prolonged exposure to IL-6 led to changes in bursting features, with significant reduction in the number of spikes in bursts across a wide range of treatment concentrations (i.e., 1 pg/mL-10 ng/mL). In combination, the addition of IL-6 appears to counteract the changes to neural function induced by low concentrations of TNF-α, while at high concentrations of TNF-α the addition of IL-6 had little to no effect. Conversely, the changes to electrophysiological features induced by IL-6 were lost when the cultures were co-stimulated with TNF-α regardless of the concentration, suggesting that TNF-α may play a more pronounced role in altering neural function. These results indicate that increased concentrations of key inflammatory cytokines associated with long-COVID can directly impact neural function and may be a component of the cognitive impairment associated with long-COVID and other post-viral infection disorders.

The pathological mechanisms of Parkinson's disease (PD) is complex, and no definitive cure currently exists. This study identified Rutaecarpine (Rut), an alkaloid extracted from natural plants, as a potential therapeutic agent for PD. To elucidate its mechanisms of action and specific effects in PD, network pharmacology, molecular docking, and experimental validation methods were employed. Our findings demonstrated the efficacy of Rut in ameliorating PD symptoms. Network pharmacology analysis indicated that Rut exerts its therapeutic effects through the PPAR signaling pathway and the lipid pathway. Molecular docking results revealed that Rut forms stable protein-ligand complexes with PPARα and PPARγ. Animal experiments showed that Rut improved motor function in PD mice, protected dopaminergic neurons, ameliorated lipid metabolism disorders, and reduced neuroinflammation. This study identified the critical molecular mechanisms and therapeutic targets of Rut in the treatment of PD, providing a theoretical foundation for future investigations into the pharmacodynamics of Rut as a potential anti-PD agent.

Neuroinflammation is closely linked to aging, which damages the structure and function of the brain. It is caused by the intricate interactions of immune cells in the aged brain, such as the dysregulated glial cells and the dysfunctional astrocytes. Aging-associated chronic low inflammation, referred to as neuroinflammaging, shows an upregulated proinflammatory response. Autophagy and senescence play crucial roles as moderators of aging and neuroinflammatory responses. The dysregulated neuroimmune system, dystrophic glial cells, and release of proinflammatory factors alter blood-brain barrier, causing a neuroinflammatory landscape. Chronic inflammation combined with deteriorating neurons exacerbate neurological disorders and decline in cognitive function. This review highlights the neuroinflammaging and mechanism associated with immune cells interplay with central nervous system and aging, cellular senescence, and autophagy regulation in the brain's immune system under neuroinflammatory conditions. Moreover, the roles of microglia and peripheral immune cells in the neuroinflammatory process in the aging brain have also been discussed. Determining treatment targets and comprehending mechanisms that influence immune cells in the aged brain is necessary to decrease neuroinflammation.

Most wearable biosensors aimed at capturing psychological state target stress biomarkers in the form of physical symptoms that can correlate with dysfunction in the central nervous system (CNS). However, such markers lack the specificity needed for diagnostic or preventative applications. Wearable biochemical sensors (WBSs) have the potential to fill this gap, however, the technology is still in its infancy. Most WBSs proposed thus far target cortisol. Although cortisol detection is demonstrated as a viable method for approximating the extent and severity of psychological stress, the hormone also lacks specificity. Multiplex WBSs that simultaneously target cortisol alongside other viable stress-related biochemical markers (SBMs) can prove to be indispensable for understanding how psychological stress contributes to the pathophysiology of neuropsychiatric illnesses (NPIs) and, thus, lead to the discovery of new biomarkers and more objective clinical tools. However, none target more than one SBM implicated in NPIs. Till this review, cortisol's connection to dysfunctions in the CNS, to other SBMs, and their implication in various NPIs has not been discussed in the context of developing WBS technology. As such, this review is meant to inform the biosensing and neuropsychiatric communities of viable future directions and possible challenges for WBS technology for neuropsychiatric applications.

Parasitic infections can profoundly impact brain function through inflammation within the central nervous system (CNS). Once viewed as an immune-privileged site, the CNS is now recognized as vulnerable to immune disruptions from both local and systemic infections. Recent studies reveal that certain parasites, such as Toxoplasma gondii and Plasmodium falciparum, can invade the CNS or influence it indirectly by triggering neuroinflammation. These processes may disrupt brain homeostasis, influence neurotransmission, and lead to significant behavioral or cognitive changes. This review discusses the pathways by which parasites disrupt CNS function and highlights systemic inflammation as a critical link between peripheral infections and neuroinflammatory conditions, advancing understanding of parasite-associated neurological complications.

The nervous system plays a vital role throughout the entire lifecycle and it may regulate the formation, development and metastasis of tumors. Small cell lung cancer is a typical neuroendocrine tumor, and it is naturally equipped with neurotropism. In this review, we firstly summarize current preclinical and clinical evidence to demonstrate the reciprocal crosstalk among the nervous system, tumor, and tumor microenvironment in various ways, including neurotransmitter-receptor pathways, innervations of nerve fibers, different types of synapse formation by neurons, astrocytes, and cancer cells, neoneurogenesis. Futherly, we emphasize how the nervous system interacts with small cell lung cancer and discuss the limitations of current research methods for examining the interactions. We propose that integrating neuroscience, development biology, and tumor biology can be a promising direction to provide new insights into development and metastasis of small cell lung cancer and raise some novel treatment strategies.

Hippocampal neuroinflammation is present in multiple diseases and disorders that impact motivated behaviour in a sex-specific manner, but whether neuroinflammation alone is sufficient to disrupt this behaviour is unknown. We investigated this question here using mice. First, the application of an endotoxin to primary cultures containing only hippocampal neurons did not affect their activation. However, when the same endotoxin was applied to mixed neuronal/glial cultures it did increase neuronal activation, providing initial indications of how it might be able to effect behavioural change. We next showed neuroinflammatory effects on behaviour directly, demonstrating that intra-hippocampal administration of the same endotoxin increased locomotor activity and accelerated goal-directed learning in both male and female mice. In contrast, lipopolysaccharide-induced hippocampal neuroinflammation caused sex-specific disruptions to the acquisition of instrumental actions and to Pavlovian food-approach memories. Finally, we showed that LPS-induced hippocampal neuroinflammation had a sexually dimorphic effect on neuronal activation: increasing it in females and decreasing it in males.

The central nervous system (CNS) requires specialized blood vessels to support neural function within specific microenvironments. During neurovascular development, endothelial Wnt/β-catenin signaling is required for BBB development within the brain parenchyma, whereas fenestrated blood vessels that lack BBB properties do not require Wnt/β-catenin signaling. Here, we used zebrafish to further characterize this phenotypic heterogeneity of the CNS vasculature. Using transgenic reporters of Wnt/β-catenin transcriptional activity, we found an inverse correlation between activated Wnt/β-catenin signaling in endothelial cells (ECs) versus non-ECs within these distinct microenvironments. Our results indicated that the level of Wnt/β-catenin signaling in non-ECs may regulate Wnt/β-catenin activity in adjacent ECs. To further test this concept, we generated a transgenic Tet-On inducible system to drive constitutively active β-catenin expression in neural progenitor cells (NPCs). We found that dose-dependent activation of Wnt/β-catenin in NPCs caused severe deficiency in CNS angiogenesis and BBB development. Additionally, we discovered a significant increase in the proliferation of microglia and infiltration of peripheral neutrophils indicative of a stereotypical neuroinflammatory response. In conclusion, our results demonstrate the importance of proper Wnt/β-catenin signaling within specific CNS microenvironments and highlights the potentially deleterious consequences of aberrant Wnt activation.

Glycolipid antigens are presented by CD1d on antigen-presenting cells to T cell receptors (TCRs) of natural killer T (NKT) cells, leading to immune responses via cytokine induction. Although various lipid antigens have been found, there are only a limited number of glycolipid antigens having selective cytokine induction. In this study, we identified the glycolipids (α-GalCer nitro-type) that exhibit highly selective induction of Th2 and Th17 type cytokines, with very high binding affinity to CD1d, by introducing nature-inspired nitro-modified fatty acyl groups. The natural nitroalkene moiety of fatty acyl groups in the glycolipids effectively enhances the affinity to CD1d through presumed hydrogen-bonding and NO2-π interactions, leading to the distinctive function in cytokine induction and selectivity.

Fast spiking parvalbumin (PV) interneuron is an inhibitory gamma-aminobutyric acid (GABA)ergic interneuron diffused in different brain networks, including the cortex and hippocampus. As a key component of brain networks, PV interneurons collaborate in fundamental brain functions such as learning and memory by regulating excitation and inhibition (E/I) balance and generating gamma oscillations. The unique characteristics of PV interneurons, like their high metabolic demands and long branching axons, make them too vulnerable to stressors. Neuroinflammation is one of the most significant stressors that have an adverse, long-lasting impact on PV interneurons. Neuroinflammation affects PV interneurons through specialized inflammatory pathways triggered by cytokines such as tumor necrosis factor (TNF) and interleukin 6 (IL-6). The crucial cells in neuroinflammation, microglia, also play a significant role. The destructive effect of inflammation on PV interneurons can have comprehensive effects and cause neurological disorders such as schizophrenia, Alzheimer's disease (AD), autism spectrum disorder (ASD), and bipolar disorder. In this article, we provide a comprehensive review of mechanisms in which neuroinflammation leads to PV interneuron hypofunction in these diseases. The integrated knowledge about the role of PV interneurons in cognitive networks of the brain and mechanisms involved in PV interneuron impairment in the pathology of these diseases can help us with better therapeutic interventions.

Acute neuroinflammation, which is notably characterized by a significant elevation in pro-inflammatory cytokines and chemokines, often rapidly develops following a traumatic spinal cord injury and exacerbates damage in the lesion area. This study addresses the limitations inherent in strategies that regulate only a single or a few cytokines, which are often insufficient to counteract the progression of secondary injuries. We explore the use of polydopamine nanoparticles as a broad-spectrum immunomodulator, capable of capturing by adsorption a wide range of cytokines and thereby effectively suppressing neuroinflammation. Leveraging their adhesive properties, these nanoparticles promptly reduce levels of various excessive cytokines, including IL-1α, IL-1β, IL-6, IL-10, IL-17A, IL-18, TNF-α, MCP-1, GRO/KC, M-CSF, MIP-3α, and IFN-γ, primarily through physical adsorption. This reduction in cytokine levels contributes to the subsequent inhibition of pro-inflammatory M1 microglia and A1 astrocyte activation, aiding in the recovery of motor functions in vivo. In summary, polydopamine nanoparticles represent a versatile and effective approach for modulating acute neuroinflammation in spinal cord injuries. By broadly down-regulating cytokines, polydopamine nanoparticles propose an innovative approach for treating spinal cord injuries. STATEMENT OF SIGNIFICANCE: The current study demonstrated the immunomodulatory potential of polydopamine nanoparticles in mitigating neuroinflammation following spinal cord injury. Both in vitro and in vivo analyses revealed significant downregulation of several key cytokines among a panel of 23 cytokines and chemokines. The potential underlying mechanisms governing these interactions were elucidated through comprehensive molecular dynamics simulations for the first time. Consequently, the downregulation of these cytokines and chemokines led to the inhibition of pro-inflammatory M1 microglia and A1 astrocyte activation in both in vitro and in vivo models. This inhibition protected neurons within the microenvironment, resulting in improved locomotor functions. Overall, this study underscores the prominent therapeutic efficacy of polydopamine nanoparticles in alleviating neuroinflammation, highlighting their potential as broad-spectrum regulators in intricate microenvironments.

It is crucial to inhibit the neuroinflammation response as it is a prominent factor contributing to the pathogenesis of neurodegenerative disorders. However, the limited development of neuroinflammation models dramatically hinders the efficiency of nanomedicine discovery. In recent years, the optically transparent zebrafish model provided unique advantages for in vivo imaging of the whole body, allowing the progression of the disease to be visualized. In this study, a lipopolysaccharide (LPS)-mediated zebrafish neuroinflammation model was established to visualize the brain distribution and quickly evaluate the anti-inflammation effect of human ferritin-loaded curcumin (Cur@HFn) nanoparticles. The Cur@HFn drug delivery system was successfully prepared and characterized. The HFn nanocage demonstrated significant brain accumulation and prolonged circulation in a zebrafish larval model. In the LPS-induced zebrafish model, Cur@HFn significantly reduced neutrophil recruitment within the brain region of the LPS-treated zebrafish. Additionally, Cur@HFn mitigated nitric oxide (NO) release and downregulated the mRNA expression levels of proinflammatory cytokines, including TNF-α and IL-1β. Lastly, Cur@HFn significantly reduced the damage of raphe nucleus neurons and alleviated the locomotion deficiency caused by LPS. Overall, our findings highlight that Cur@HFn is a promising drug delivery system for the targeted treatment of brain disorders. This zebrafish neuroinflammation model could be used for high-throughput in vivo drug screening and discovery.

Acupoint catgut embedding (ACE) is a traditional Chinese medicine technique commonly used for managing various disorders, including chronic inflammatory pain and allergic asthma. Despite its growing use, the neuroimmunological mechanisms underlying ACE treatment effects remain unclear.

This study investigated the roles and potential mechanisms of the effects of ACE in treating experimental autoimmune encephalomyelitis (EAE), a frequently used animal model of autoimmune neuroinflammation. The effects of ACE treatment were evaluated by monitoring body weight and EAE severity scores. Behavioral tests, histopathological analysis, ELISA, and flow cytometry were conducted to assess the therapeutic efficacy of ACE. RNA sequencing was performed to uncover ACE-associated transcriptional signatures in the spinal cords of EAE mice.

The results were validated through western blotting, qRT-PCR, and immunofluorescence (IF) staining. In ACE-treated mice, EAE disease severity was significantly ameliorated, along with improvements in anxiety-like behaviors and reduced inflammation and demyelination. The ACE treatment restored immune imbalance in the EAE mice by decreasing Th17 and Th1 cells, while increasing Treg cells in peripheral immune organs and reducing serum inflammatory cytokine levels. RNA sequencing revealed significant suppression of the genes and pathways associated with reactive microglial and astrocytic activation, corroborated by IF studies. Additionally, ACE treatment could suppress the ERK and JNK signaling pathways at both RNA and protein levels.

These findings confirm the protective role of ACE in mitigating EAE symptoms by modulating microglial and astrocytic activity and regulating inflammatory cytokines.

Background/Objectives: Decompensated cirrhosis is characterized by systemic inflammation and innate and adaptive immune dysfunction. Hepatic encephalopathy (HE) is a prevalent and debilitating condition characterized by cognitive disturbances in which ammonia and inflammation play a synergistic pathogenic role. Extraskeletal functions of vitamin D include immunomodulation, and its deficiency has been implicated in immune dysfunction and different forms of cognitive impairment. The aim was to assess changes in cognitive function and inflammation in decompensated patients with cirrhosis receiving vitamin D supplementation. Methods: Patients with cirrhosis discharged from decompensation in two tertiary hospitals in Spain (from September 2017 to January 2020) were assessed before, at 6 and 12 months after vitamin D supplementation. A comprehensive neuropsychological battery and neuroinflammatory markers were examined. In a subgroup of patients, peripheral immune blood cells were analyzed. Results: Thirty-nine patients were recruited. Of those, 27 completed the 6 months evaluation and were analyzed [age 62.4 ± 11.3 years; 22 men; Model for End-Stage Liver Disease (MELD) 11.7 ± 4.0; prior overt HE 33%; median 25-hydroxyvitamin D (25OHD) plasma level 12.7 µgr/L] and 22 achieved 12 months assessment. At baseline, learning and memory (R = 0.382; p = 0.049) and working memory (R = 0.503; p = 0.047) subtests correlated with plasma 25OHD levels. In addition, processing speed (R = -0.42; p = 0.04), attention (R = -0.48; p = 0.04), Tinnetti balance (R = -0.656; p < 0.001) and Tinnetti score (R = -0.659; p < 0.001) were linked to neuroinflammation marker IL-1β. Patients with lower 25OHD had a greater proportion of TH1cells at baseline and a larger amelioration of IL-1β and IL-6 following supplementation. An improvement in working memory was found after 25OHD replacement (46.7 ± 13 to 50 ± 11; p = 0.047). Conclusions: This study supports that vitamin D supplementation modulates low-grade inflammation in decompensated cirrhosis providing cognitive benefits, particularly in working memory.

Heparan sulfate (HS) is a polysaccharide that is found on the surface of cells and has various biological functions in the body.

The purpose of this study was to predict the pharmacological effects and molecular mechanisms of HS on Alzheimer's disease (AD) and neuroinflammation (NI) through a network pharmacology analysis and to experimentally verify them.

We performed functional enrichment analysis of common genes between HS target genes and AD-NI gene sets and obtained items such as the "Cytokine-Mediated Signaling Pathway", "Positive Regulation Of MAPK Cascade", and "MAPK signaling pathway". To confirm the predicted results, the anti-inflammatory effect of HS was investigated using lipopolysaccharide (LPS)-stimulated BV2 microglia cells. HS inhibited the production of nittic oxide, interleukin (IL)-6, and tumor necrosis factor-α in LPS-stimulated BV2 cells, but not IL-1β. In addition, HS inactivated P38 in the MAPK signaling pathway.

These findings suggest the potential for HS to become a new treatment for AD and NI.

Spinal cord injury (SCI) can lead to severe motor and sensory dysfunction, with a high rate of disability and mortality. Due to the complicated pathological process of SCI, there is no effective clinical treatment strategy at present. Although mesenchymal stem cells (MSCs) are effective in the treatment of SCI, their application is limited by factors such as low survival rate, cell dedifferentiation, tumorigenesis, blood-brain barrier, and immune rejection. Fortunately, there is growing evidence that most of the biological and therapeutic effects of MSCs may be mediated by the release of paracrine factors, which are extracellular vesicles called exosomes. Exosomes are small endosomal vesicles with bilaminar membranes that have recently been recognized as key mediators for communication between cells and tissues through the transfer of proteins, lipids, nucleic acids, cytokines, and growth factors. Mesenchymal stem cell-derived exosomes (MSC-exos) play a critical role in SCI repair by promoting angiogenesis and axonal growth, regulating inflammation and immune response, inhibiting apoptosis, and maintaining the integrity of the blood-spinal cord barrier. Furthermore, they can be used to transport genetic material or drugs to target cells, and their relatively small size allows them to permeate the blood-brain barrier. Studies have demonstrated that some exosomal miRNAs derived from MSCs play a significant role in the treatment of SCI. In this review, we summarize recent research advances in MSC-exos and exosomal miRNAs in SCI therapy to better understand this emerging cell-free therapeutic strategy and discuss the advantages and challenges of MSC-exos in future clinical applications.

Postoperative cognitive dysfunction (POCD), a postsurgical decline in cognitive function, primarily affects older adults and worsens their prognosis. Although elevated interleukin-12p70 (IL-12p70) is closely correlated with slower cognitive decline in older adults, its role in POCD remains unclear. Here, IL-12p70 is identified as a significant mediator of therapeutic effect of electroacupuncture (EA) on POCD. EA at acupoints ST36, GV20, and GV24 significantly enhanced cognitive behaviors of POCD mice. IL-12p70, downregulated in POCD mice but rescued by EA treatment, is the cytokine closely associated with EA's therapeutic effect. Clinically, IL-12p70 is downregulated in older adults' serum post-surgery. Furthermore, IL-12p70 exerts a potent neuroprotective effect in both neuronal cell lines and primary hippocampal neurons. The PI3K-AKT-BCL2 axis enriched by in silico analysis is validated as the signaling mechanism underlying IL-12p70-induced neuroprotection. In vivo, beneficial effects of EA treatment on the activation of PI3K-AKT-BCL2 axis and POCD are reproduced by IL-12p70 administration but attenuated by IL-12p70 knockdown. The findings reveal a novel mechanism underlying the therapeutic effect of EA on POCD, demonstrating that IL-12p70 exerts a neuroprotective effect by activating PI3K-AKT-BCL2 axis in hippocampal neurons. The newly-discovered function and mechanism of IL-12p70 highlight its potential in treating cognitive disorders.