Periodontitis is a chronic inflammatory condition with infectious origin that affects the tissues supporting the teeth. Increasing epidemiological evidence suggests that periodontitis is a risk factor for ischemic stroke with associated adverse outcomes. However, the underlying mechanism of this association remains incompletely elucidated. We used a C57BL/6J mice model of ischemic stroke induced by transitory occlusion of the middle cerebral artery in the presence or absence of ligature-induced periodontitis using Porphyromonas gingivalis-soaked ligatures. Stroke severity was evaluated through infarct volume, sensorimotor deficit, blood-brain barrier (BBB) integrity, and markers of systemic and brain inflammation. The direct effect of P gingivalis on BBB endothelial cells was further explored invitro. Mice with P gingivalis-associated periodontitis showed a significant exacerbation of stroke severity: larger infarct volume, more severe sensorimotor deficit, greater BBB disruption, and increased brain neutrophil infiltration compared with sham. Systemic inflammation was also markedly elevated. Intravenous administration of P gingivalis alone, without gingival injury, before transitory occlusion of the middle cerebral artery was sufficient to amplify brain inflammation and stroke lesions. Invitro P gingivalis, through its gingipain proteases, directly impaired BBB integrity by increasing endothelial permeability and disrupting tight-junction proteins. Our findings demonstrate that P gingivalis-associated periodontitis worsens ischemic stroke outcome both indirectly by enhancing systemic and brain inflammation and directly via BBB disruption. These results highlight periodontitis as a modifiable risk factor and potential therapeutic target for improving stroke prognosis.

Introduction: Japanese Encephalitis (JE) is considered one of the leading causes of Acute Encephalitis Syndrome (AES) affecting children and adolescents, particularly in tropical countries. It presents a major challenge for the health sector, particularly in management, due to its unpredictable course and lack of specific treatment. Therefore, adequate data regarding the clinico-epidemiological pattern and the identification of prognostic factors may assist treating physicians in proper triaging and delivering appropriate management. Aim: To study the clinico-epidemiological profile and predictors of adverse outcomes in children with JE at Assam Medical College and Hospital (AMCH), a tertiary care hospital in Dibrugarh, Assam. Materials and Methods: A retrospective cohort study was conducted in the Department of Paediatrics at Assam Medical College and Hospital (AMCH) from April 1, 2018, to September 30, 2019. Data from 146 children were collected, including demographic details, clinical signs and symptoms, laboratory parameters, risk factors, and mortality outcomes. Statistical methods used included Odds Ratio (OR), simple proportion test, Chi-square test, and Relative Risk (RR) estimation with 95% confidence intervals. Results: The most common age group affected was 5-12 years, with a slight male predominance 1.3:1. Among the participants, 31 (21.23%) children were vaccinated against JE. Common clinical presentations included fever (104 cases, 71.23%), seizures (95 cases, 65.06%), vomiting (88 cases, 60.27%), and headache (84 cases, 57.53%). The common complications observed were circulatory shock (31 cases, 21.23%), sepsis (21 cases, 14.38%), dyselectrolytaemia (34 cases, 23.28%), and acute kidney injury (37 cases, 25.34%). Overall mortality was 33 (22.60%). The highest mortality was observed in children with circulatory shock, altered sensorium with a Glasgow Coma Scale (GCS) score of less than 8, and refractory seizures. Of the children, 86 (58.90%) recovered completely, 33 (22.60%) died, and 16 (10.95%) were discharged with neurological sequelae. Conclusion: The case fatality rate was 22.60%. Vaccination coverage was significantly low among the children. The poor prognostic factors included shock, low GCS, the need for multiple anticonvulsants, ionotropes, hypertonic saline infusion, and ventilatory support. Therefore, this study highlights the need for extensive research and increased JE vaccination efforts in the region.

Protein-protein interactions play key roles in leukocyte extravasation process into the brain and have been attractive therapeutic targets for inhibiting brain inflammation using blocking (or neutralizing) antibodies. These targets include protein-protein interactions between cytokines (or chemokines) and their receptors on leukocytes and between adhesion molecules of leukocyte and brain endothelium. While a number of therapeutics against these targets are currently used in clinic for treatment of brain autoimmune and inflammatory disorders (e.g., multiple sclerosis), they are associated with side effects partly due to the off-target actions (i.e., nonspecific targets). There is a need for novel targets involved in the leukocyte extravasation process that are specific to leukocyte subsets or to individual inflammatory disorder and are amenable for drug development (i.e., druggable). We recently described the blood-brain barrier (BBB) Carta Project as a comprehensive collection of molecular "maps" consisting of multiple experimental omics (including RNA sequencing, proteomics, glycoproteomics, glycomics, and metabolomics) and in silico informatic analyses on a number of mammalian species from hundreds of internal, publicly available, or curated datasets. Utilizing the datasets and tools from the BBB Carta Project, we describe a methodology to identify novel "druggable" targets involving protein-protein interactions between activated leukocytes and brain endothelial cells using a combination of proteomics, bioinformatics, and in silico interactomics. The result is a prioritized list of protein-protein interactions in a network consisting of leukocyte-brain endothelial cell communication and contacts. These interactions can be further pursued for development of therapeutics such as neutralizing antibodies and their validation through preclinical testing. In addition to targeting brain inflammation, the method described here is applicable for peripheral inflammation and provides the opportunity to target important cell-cell interactions and communications that are more specific/selective for inflammatory disorders and improve currently available therapies.

Time-restricted feeding in adult mice improves mood-related behaviors in a sex-dependent manner.

The simultaneous targeting of RXFP1 and RXFP3 improves motor function and reduces brain inflammation, apoptosis and glial scarring following photothrombotic stroke in male mice.

Pyraclostrobin induces brain oxidative stress, apoptosis and inflammation through mitochondrial phosphorylation-induced ROS activation of the p38 MAPK pathway.

Introduction: Rasmussen's encephalitis is a type of autoimmune encephalitis unusual in adults, an inflammatory, chronic and neurodegenerative brain disorder that manifests itself with treatment-resistant neocortical focal motor seizures. The pathophysiology of this disease has involved viral infections and the existence of antibodies, among other possible etiologies. Due to pharmacological resistance to anticonvulsants, management with immunoglobulin, in most patients, demonstrates clinical improvement and decreased progression. However, the only therapeutic management that seems to give accurate results to date is hemispherectomy.Objective was to describe the risk factors, symptoms and treatments of Rasmussen's Encephalitis.Methods: As it is a disease with scarce bibliography and occasionally rare diagnosis, the study was carried out under a cross-sectional, historical, statistical search supported by a comparative review in the various national and international databases.Conclusions: The authors found a certain discrepancy in certain aspects, an element that, together with the magnitude that this pathology can have and its consequences, reflects the need for study and knowledge on the part of professionals and the health team for an accurate diagnosis in time.

NMDAR autoantibodies modify the phenotype of psychosis in severe brain inflammation.

Multistage oral astaxanthin targeted delivery system: Increasing serotonin levels with a dual therapeutic effect for alleviating inflammatory bowel disease and psychiatric disorders.

Epstein-Barr virus (EBV) infection shows the strongest causative association with multiple sclerosis (MS), but its contribution to disease progression and the mechanisms allowing for viral persistence in the MS brain are still elusive. Studies in post-mortem MS brain tissue indicate an ongoing yet ineffective antiviral immune reaction in advanced stages of the disease. EBV has evolved strategies to evade immune recognition and clearance by the host immune system during both the latency and lytic phase of its life cycle. Recent evidence demonstrates that cells expressing EBV latent membrane protein (LMP) 2A exploit the PD-1/PDL1 inhibitory immune checkpoint to escape immune surveillance and maintain a persistent latent infection in the MS brain. This study investigated whether the virus also utilizes this inhibitory mechanism during other phases of the viral life cycle. By using multiple immunostainings on highly inflamed MS brain tissues containing meningeal tertiary lymphoid structures (TLSs), we analyzed PD-L1 expression on EBV-infected cells expressing EBNA2, five EBV lytic gene products, BZLF1, BHRF1, BMRF1, BALF2, and gp350/220, as well as on follicular dendritic cells within the TLSs. This is the first study describing in secondary progressive MS brain tissue the expression and the cellular and tissue distribution of PD-L1 on EBV-infected cells being in different stages of the viral life cycle, and confirms the meningeal TLSs as immune-permissive habitats favoring the maintenance of an intracerebral EBV reservoir.

Nipah virus (NiV) poses a significant threat owing to its high mortality and the lack of approved therapeutics. Targeting the conserved heptad repeat 1 (HR1) domain of the viral fusion (F) protein constitutes a promising antiviral strategy. Also, lipopeptides derived from the human parainfluenza virus 3 (HPIV3) heptad repeat 2 (HR2) regions inhibit NiV fusion by blocking formation of the critical six-helix bundle (6-HB); however, their efficacy has been impeded by the controversial use of PEGylation. To resolve these limitations, we employed our proprietary heptad repeat 2 C-terminal fragment (HR2-CF) peptide displacement strategy that eliminates PEG and overcomes the resultant steric hindrance. The lead dePEGylated lipopeptide, VQ-P1-C16, exhibited antiviral activity comparable to that of PEGylated lipopeptide, VIKI-PEG4-C16. Further introducing Glu (E) or Lys (K) mutations yielded VQ-P1-EK3-C16, which exhibited ultra-potent pseudotyped henipavirus inhibition at pM concentrations and increased fusion inhibition. Meanwhile, it protected newborn mice from pseudotyped NiV-Malaysia and NiV-Bangladesh infection in lungs and brains. Structural simulations and mechanistic studies demonstrated that VQ-P1-EK3-C16 adopts a helical conformation, exhibits high affinity for NiV-HR1, and inhibits NiV 6-HB formation. Moreover, VQ-P1-EK3-C16 showed significantly increased solubility, improved thermal stability, strengthened resistance to proteases, and extended serum half-life. These findings establish VQ-P1-EK3-C16 as a highly potent, stable, and safe fusion inhibitor with promising potential for the clinical development of therapeutics against NiV and related henipaviruses.

BackgroundEvidence suggest an association between periodontal disease (PerioD) and Alzheimer's disease (AD), with PerioD‐associated microbial ecosystems driving oral and systemic inflammation that may activate or accelerate neuroinflammation, a hallmark of AD. Social determinants of health (SDoH) are critical factors influencing both oral health and AD risk yet are often overlooked, and rarely investigated together. This study aims to characterize and compare the oral microbiome of age‐ and education‐matched individuals at high risk for AD by virtue of family history, with and without PerioD, and to investigate the relationships between PerioD‐associated microbiome features, SDoH, systemic inflammation and brain inflammation, and AD biomarkers (in cerebrospinal fluid [CSF]).MethodThis two‐year NINDS‐funded study collects oral microbiome samples, blood, and CSF annually in a cognitively normal, racially diverse cohort (n = 165). Metagenomic sequencing will be used to investigate cross‐kingdom microbial communities and their association with inflammatory and systemic markers. Surveys and interviews investigate behaviors and SDoH influencing PerioD and AD risk.ResultTo date, 55 participants have been recruited. Participants are 62 years of age on average, predominantly white (70%), female (63.3%), with Stage 1–2 periodontitis (85.7%). Preliminary analyses found no significant relationships between bleeding on probing, behavioral factors, SDoH variables, and Montreal Cognitive Assessment (MoCA) scores, which was expected given the small sample size. As recruitment continues, we anticipate identifying associations between oral microbiome features, inflammatory markers, AD biomarkers and cognitive outcomes. SDoH, such as access to dental care and oral hygiene behaviors, may mediate these relationships, offering insights into the interplay between periodontal disease, systemic inflammation, and AD risk.ConclusionBy leveraging longitudinal data and exploring upstream sociocultural factors, this research addresses critical gaps in understanding PerioD's contribution to AD risk. Findings will provide novel insights into the interplay between the oral microbiome, systemic inflammation, brain inflammation, and AD risk.

BackgroundSemaphorin 4D (SEMA4D, CD100) and its receptors Plexin B1, B2 have been identified in multiple transcriptomic/genomic studies as a key signaling pathway associated with reactive gliosis and disease risk in Alzheimer’s Disease (AD), Huntington’s Disease (HD), Multiple Sclerosis, and vascular dementia. Our lab has reported that SEMA4D protein is upregulated in diseased neurons and activates astrocytes via receptor binding, resulting in downregulation of metabolic transporters and release of inflammatory cytokines. In a completed randomized Phase 2 study in HD (NCT02481674), SEMA4D blocking antibody pepinemab prevented metabolic decline in glucose uptake (FDG‐PET) reduced plasma GFAP, biomarkers of astrogliosis, and slowed cognitive decline employing multiple cognitive scales. Mechanistic and clinical studies investigate pepinemab effects on changes associated with reactive gliosis, neuroinflammation, and cognitive decline.MethodEffects of SEMA4D blockade on neuropathology, behavior, and vascular integrity were evaluated in a mouse model of HD (Hu97/18) and an in vitro brain chip model. In the phase 1b/2 SIGNAL‐AD trial (NCT04381468), 50 individuals with mild AD dementia (MMSE 17‐26) were treated for 12 months with pepinemab (40 mg/kg) or placebo, Q4W, IV infusion. Key objectives included safety, cognition, and biomarker assessments.ResultIn preclinical disease models, SEMA4D blocking antibody reduced astrocyte and microglial activation markers, increased synaptic markers, and improved deficits in spatial learning and memory. In a human brain chip model, pepinemab restored α‐synuclein‐induced disruption of vascular integrity. Evaluation of amyloid‐induced damage in the brain chip model is ongoing. In SIGNAL‐AD, pepinemab was well‐tolerated and meaningful improvements in cognitive assessments were observed in the MCI‐early AD subgroup (>70% slowing of cognitive decline in CDR‐SB, iADRS, and ADAS‐Cog13). O‐link proteomic analysis of CSF revealed treatment‐related reductions in biomarkers associated with reactive astrocytes (GFAP), microglia clearance (LILRB4, MARCO), and tau pathology (GAP‐43 and SNAP25).ConclusionGiven the many physiological parallels between glial activation and inflammatory processes in HD and AD, results from these studies suggest that preventing astrocyte activation and reducing brain inflammation and associated vascular disruption with pepinemab treatment could be an attractive alternative or complement to anti‐Aβ antibodies and support the broad application of glial regulators to treat cognitive dysfunction and neurodegenerative disease.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis (NMDARE) is a devastating autoimmune disease associated with the presence of autoantibodies targeting NMDAR1 in the cerebrospinal fluid (CSF) and serum of patients. Besides the critical roles of anti-NMDAR1 autoantibodies, studies have implicated other factors such as brain inflammation in NMDARE. To comprehensively uncover the molecular mechanisms underlying NMDARE, here we performed multi-omics analyses based on human forebrain organoids (hFOs). The transcriptomic and metabolomic analyses showed that hFOs exposed to either monoclonal anti-NMDAR1 IgG antibodies or purified patient CSF-derived IgG antibodies alone led to NMDAR hypofunction that caused a reduction of glutamate content and neuroactivities. Interestingly, hFOs exposed to either patient CSF or IgG-depleted patient CSF led to neuronal hyperexcitability rather than hypo neuroactivities. The following proteomic analysis and electrophysiological assays identified that the activated interleukin (IL)-17 signaling pathway in patient CSF accounted for the neuronal hyperexcitability. Neutralizing IL-17 alleviated the neuronal hyperexcitability in hFOs and seizure-like behaviors in mice exposed to CSF from NMDARE patients. Together, this study indicated that the anti-NMDAR1 antibodies and IL-17 signaling pathway shape NMDARE. Inactivating the IL-17 signaling pathway could be a potential therapeutic strategy for NMDARE treatment.

Parkinson's disease is a common neurodegenerative disease related to both genetic and environmental insults. Epidemiological studies have linked Helicobacter pylori (H. pylori) infection to Parkinson's disease risk, but the underlying mechanisms of this association remain unclear. In this study, we investigated whether chronic infection with a pathogenic H. pylori strain could induce α-synuclein aggregation or neurodegeneration, and whether infection clearance mitigates these effects. We also assessed whether H. pylori infection exacerbates α-synuclein pathology and neuron loss when combined with seeding of α-synuclein pathology. We find that chronic H. pylori infection induces a sustained immune response in the gut and plasma that leads to mild brain inflammation and dopaminergic neuron loss, independent of α-synuclein pathology. These effects are attenuated by eradication of the infection. In mice with α-synuclein pathology induced by pre-formed fibrils, H. pylori does not further exacerbate the extent of pathology or neuronal death. Together, these results suggest that H. pylori infection can lead to neurodegeneration through inflammatory mechanisms independent of α-synuclein aggregation. Our findings offer mechanistic insights into how pathogens could influence the risk and progression of Parkinson's disease.

Sarcocystis calchasi is the causative agent of Pigeon Protozoal Encephalitis, a neurological disease in pigeons. The biphasic disease is characterized by neurological signs in the chronic phase. Parasite stages are generally not associated with inflammatory brain lesions and the parasite has been suggested to modulate the host's immune system. To test this hypothesis, pigeons experimentally infected with S. calchasi were T-cell immunosuppressed beginning from 14 days post infection (dpi) until the end of the experiment (59/60 dpi) and compared with immunocompetent animals. When scored histologically (sum encephalitis score consisting of lympho-histiocytic perivascular cuffs, lymphocytic encephalitis and gliosis), encephalitis was markedly less pronounced in immunosuppressed pigeons than in immunocompetent animals (6.8 ± 4.4s.d. versus 11.2 ± 3.0s.d.). Thus, the alleviation of the disease by immunosuppression supports the hypothesis of an immune-mediated mechanism rather than direct damage by the pathogen. Results from a second infection trial, where the effect of immunosuppression only during early (12-20 dpi) or late phase (30 dpi - end of experiment) was compared, did not show significant differences between both groups and suggest that immunomodulation is triggered during the early stage of parasite development by sporozoites and/or more likely merozoites.

ObjectiveTo analyze the efficacy of combined lamotrigine and levetiracetam therapy in epileptic patients and its impact on hippocampal volume and inflammatory response.MethodsA retrospective analysis was conducted on the clinical data of 120 epileptic patients admitted to our hospital from December 2022 to February 2024. All patients met the inclusion and exclusion criteria. Based on the treatment received, patients were divided into a control group (n=60, treated with lamotrigine) and an observation group (n=60, treated with lamotrigine combined with levetiracetam). Clinical efficacy, bilateral hippocampal volume, inflammatory factors, brain injury markers, and adverse reactions were compared between the two groups.Results① Clinical efficacy: The observation group had higher effective rates in seizure control and EEG epileptiform discharge improvement than the control group (P<0.05). ② Hippocampal volume: No significant differences were observed in bilateral hippocampal volume changes between the two groups before and after treatment (P>0.05). ③ Inflammatory factors: TNF-α, hs-CRP, and IL-6 levels decreased in both groups after treatment, with greater reductions in the observation group (P<0.05). ④ Brain injury markers: S-100β and HMGB-1 levels decreased in both groups after treatment, with greater reductions in the observation group (P<0.05). ⑤ Adverse reactions: The incidence of adverse reactions was comparable between the two groups (P>0.05).ConclusionCompared with lamotrigine monotherapy, lamotrigine combined with levetiracetam further improves treatment efficacy in epileptic patients, reduces inflammatory response and brain injury, and does not increase the risk of adverse reactions.

Calcium (Ca2+) is a signal messenger for ion flow in and out of microbial, parasitic, and host defense cells. Manipulation of calcium ion signaling with ion blockers and calcineurin inhibitors may improve host defense while decreasing microbial/parasitic resistance to therapy. Ca2+ release from intracellular storage sites controls many host defense functions (cell integrity, movement, and growth). The transformation of phospholipids in the erythrocyte membrane is associated with changes in deformability. This type of lipid bilayer defense mechanism helps to prevent attack by Plasmodium. Patients with sickle cell disease (SS hemoglobin) do not have this protection and are extremely vulnerable to massive hemolysis from parasitic infestation. Patients with thalassemia major also lack parasite protection. Alteration of Ca2+ ion channels responsive to environmental stimuli (transient receptor potential) results in erythrocyte protection from Plasmodium. Similarly, calcineurin inhibitors (cyclosporine) reduce heart and brain inflammation injury with Trypanosoma and Taenia. Ca2+ channel blockers interfere with malarial life cycles. Several species of parasites are known to invade hepatocytes: Plasmodium, Echinococcus, Schistosoma, Taenia, and Toxoplasma. Ligand-specific membrane channel constituents (inositol triphosphate and sphingosine phospholipid) constitute membrane surface signal messengers. Plasmodium requires Ca2+ for energy to grow and to occupy red blood cells. A cascade of signals proceeds from Ca2+ to two proteins: calmodulin and calcineurin. Inhibitors of calmodulin were found to blunt the population growth of Plasmodium. An inhibitor of calcineurin (cyclosporine) was found to retard population growth of both Plasmodium and Schistosoma. Calcineurin also controls sensitivity and resistance to antibiotics. After exposure to cyclosporine, the liver directs Ca2+ ions into storage sites in the endoplasmic reticulum and mitochondria. Storage of large amounts of Ca2+ would be useful if pathogens began to occupy both red blood cells and liver cells. We present scientific evidence supporting the benefits of calcium channel blockers and calcineurin inhibitors to potentiate current antiparasitic therapies.

Multiple sclerosis (MS) is a chronic autoimmune disease characterized by inflammatory brain lesions, making MRI-based lesion segmentation challenging due to noise, missing data, and limited availability of high-quality labeled images. This paper presents RAUM-GANs, a multi-layer deep learning framework designed to address these challenges and enhance segmentation accuracy. The preprocessing stage comprises three layers: (1) noise reduction using a modified Denoising GAN (DGAN-Net), achieving peak signal-to-noise ratio (PSNR) values up to 42.21 dB across varying noise levels; (2) missing data imputation through advanced GAN-based methods, ensuring clinically reliable reconstruction of incomplete MRI scans; and (3) dataset expansion via a Multi-level Identity GAN (MGAN), which incorporates an identity block to prevent mode collapse, an 8-connected pixel constraint to maintain spatial coherence, and a softened discriminator output to mitigate vanishing gradients. For segmentation, a Residual Attention U-Net (RAU-Net) with identity mapping is employed, yielding precise detection and delineation of MS lesions. Extensive evaluation on the MICCAI MSSEG-2 dataset demonstrates that RAUM-GANs outperform four state-of-the-art methods, achieving a Dice score of 96.6%, Fréchet Inception Distance (FID) of 43.13, and Inception Score (IS) of 14.03. The results highlight the framework’s ability to generate high-quality synthetic MRI data, improve robustness against noise and incomplete information, and deliver superior lesion segmentation performance. RAUM-GANs provides a comprehensive, scalable solution for MS lesion analysis, with potential applicability to other medical imaging domains where data quality and scarcity remain significant barriers.

This study investigated how prolonged aggression in male CD1 mice alters responses to chronic LPS (lipopolysaccharide)-induced inflammation. Experience of aggression induced pathological aggression in 36% of mice. Following LPS, aggressors resolved systemic inflammation within five days—evidenced by normalized locomotor activity, WBC (white blood cells), and lymphocyte counts—while controls remained inflamed. LPS did not alter established aggression or anxiety. Furthermore, aggressors demonstrated accelerated inflammation resolution in the brain, showing a higher proportion of resting microglia and a lower percentage of activated microglia following LPS-induced inflammation compared to control animals. Gene expression analysis revealed a more pronounced inflammatory response in the hypothalamus than in the nucleus accumbens. Aggressive mice exhibited a profile associated with inflammation resolution, indicated by increased expression of the Trem2 gene. These differential immune responses may be modulated by the dopaminergic system. Elevated Drd1 gene expression in the hypothalamus could possibly contribute to the anti-inflammatory signaling, while changes in nucleus accumbens dopaminergic activity, involving D2 receptor activation, appear linked to the development of pathological aggression. Thus, this study demonstrates that prolonged aggression induces persistent changes in behavioral, neuroimmune, and neuroendocrine systems in male CD1 mice. Aggressive animals develop a distinct neuroimmune phenotype characterized by accelerated resolution of both systemic and brain inflammation following LPS challenge.