Neuroinflammatory Processes Research Articles

RTMS improves dysphagia by inhibiting NLRP3 inflammasome activation and caspase-1 dependent pyroptosis in PD mice

High incidence, severe consequences, unclear mechanism, and poor treatment effect happened in Parkinson’s disease-related dysphagia. Repetitive transcranial magnetic stimulation is an effective treatment for dysphagia in Parkinson’s disease. However, the therapeutic effect and underlying mechanism of repetitive transcranial magnetic stimulation for dysphagia in Parkinson’s disease are still unknown. Neuroinflammation has been proven to be associated with dysphagia in Parkinson’s disease, and NLRP3 inflammasome activation and pyroptosis are common neuroinflammatory processes. Therefore, we compared swallowing quality, NLRP3 inflammasome activation, and caspase-1 dependent pyroptosis among NS control, repetitive transcranial magnetic stimulation control, sham repetitive transcranial magnetic stimulation control, and L-Dopa control mice by tongue muscle tone detection, immunohistochemistry, immunofluorescence, western blotting, co-immunoprecipitation, and quantitative PCR. The results showed that NLRP3 inflammasome activation and caspase-1-dependent pyroptosis were involved in dysphagia in MPTP-induced Parkinson’s disease mice model. Repetitive transcranial magnetic stimulation and L-dopa inhibited the above two pathways to alleviate dopaminergic neuronal damage and improve the quality of dysphagia. Repetitive transcranial magnetic stimulation (1 Hz, 1 time/3 days, 6 weeks) had the same effect on dysphagia as L-Dopa treatment (25 mg/kg/day, 6 weeks). Finally, we conclude that repetitive transcranial magnetic stimulation will be the preferred option for the treatment of dysphagia in Parkinson’s disease in certain conditions such as motor complications secondary to L-Dopa and L-Dopa non-response dysphagia.

Effects of metal oxide inhalation on the transcription of some hormone receptors in the brain, examined in an in vivo mouse model

Respirable metal oxide nanoparticles in welding fumes pose significant health risks upon inhalation, potentially leading to neurodegenerative diseases. While the exact mechanisms remain unclear, it is evident that metal oxide nanoparticles can disrupt cellular functions, including metabolism and inflammatory responses after crossing the blood–brain barrier (BBB). Our study investigates the impact of manual metal arc welding fumes on hormone receptor transcription in an in vivo mouse model. After collecting samples from six different brain regions at 24 and 96 h upon exposure, we focused on expression levels of estrogen receptors (ERs), thyroid hormone receptors (TRs), and peroxisome proliferator-activated receptors (PPARs) due to their roles in modulating neuroprotective responses and neuroinflammatory processes. Analysis revealed differential susceptibility of brain regions to hormonal disruption induced by welding fumes, with the hypothalamus (HT) and olfactory bulb (OB) showing prominent changes in receptor expression. Considering ERs, 24 h sampling showed an elevation in OB, with later increases in both ERα and ERβ. HT showed significant ERβ change only by 96 h. TRs mirrored ER patterns, with notable changes in OB and less in HT. PPARγ followed TR trends, with early upregulation in HT and downregulation elsewhere. These findings suggest a compensatory response within the CNS aimed at mitigating neuroinflammatory effects, as evidenced by the upregulation of ERβ, TRα, and PPARγ. The coordinated increase in ERs, TRs, and PPARs in the hypothalamus and olfactory bulb also highlights their potential neuroprotective roles in response to welding fume exposure. Our results also support the theory of metal oxide penetration to the CNS via the lungs-blood-BBB pathway, making HT and OB more vulnerable to welding fume exposure.

CD33 Ameliorates Surgery-Induced Spatial Learning and Memory Impairments Through TREM2.

Neuroinflammation is implicated in the onset of postoperative cognitive dysfunction (POCD), with CD33 and triggering receptor expressed on myeloid cells 2 (TREM2) playing crucial roles in immune response modulation and neuroinflammatory processes. A total of 96 aged male C57/BL6 mice (9-12 months) were randomly assigned to one of four groups, each receiving an siRNA injection into the lateral ventricle. Subsequently, the mice underwent partial hepatectomy under general anesthesia. To assess cognitive function, the Morris water maze tests were conducted both pre- and post-surgery. Following behavioral assessments, hippocampal tissues were swiftly harvested. The regulation of CD33 and TREM2 expression was achieved through siRNA in the BV2 microglia cell line. Expression levels of CD33 and TREM2 were evaluated both in vitro and in vivo using quantitative RT-PCR and western blot analyses. This study explored the impact of CD33 and TREM2 on POCD in aged mice and revealed that surgery and anesthesia increased CD33 expression, leading to spatial learning and memory impairments. Inhibiting CD33 expression via siRNA administration ameliorated cognitive deficits and mitigated the neuroinflammatory response triggered by surgery. Additionally, CD33 inhibition reversed the surgery-induced decrease in synaptic-related proteins, highlighting its role in preserving synaptic integrity. Moreover, our experiments suggest that CD33 may influence neuroinflammation and cognitive function through mechanisms involving TREM2. This is evidenced by the suppression of pro-inflammatory cytokines following CD33 knockdown in microglia and the reversal of these effects when both CD33 and TREM2 are concurrently knocked down. These findings imply that CD33 might promote neuroinflammation by inhibiting TREM2. This study highlights the potential of targeting CD33 as a promising therapeutic strategy for preventing and treating POCD. It provides valuable insights into the intricate mechanisms underlying cognitive dysfunction following surgical procedures.

Notopterygium incisum roots extract (NRE) alleviates neuroinflammation pathology in Alzheimer’s disease through TLR4-NF-κB pathway

Ethnopharmacological relevanceNotopterygium incisum Ting ex H. T. Chang, also called ‘Qianghuo’, is a distinct umbelliferae plant in China. The rhizomes and roots of Notopterygium incisum have long been used to treat headaches, colds, analgesia and rheumatoid arthritis. It is a main traditional Chinese medicine in Qianghuo Yufeng Decoction, which was used to treat diseases such as liver and kidney insufficiency, mental paralysis and dementia. Aim of this studyAs the most common dementia, Alzheimer's disease (AD) has a complicated pathogenesis. So far, there is no effective drug to prevent its pathological process. Previous research has shown that Notopterygium incisum root extract (NRE) may inhibit the release of Aβ and the activation of tau in mice with AD. However, the effect of NRE on the pathological process of neuroinflammation is still unclear. Materials and methodsWe determined the pro-inflammatory cytokines levels in BV2 cells exposed to LPS/Aβ42 after treated with NRE. APP/PS1 and LPS-induced C57BL/6 neuroinflammatory mice were given NRE for 8 weeks and 5 days respectively to detect the pathological changes of neuroinflammation. ResultsThe findings showed that NRE had a notable inhibitory effect on the levels of TNF-α and IL-1β in BV2 cells induced by LPS/Aβ42. The results of in vivo experiments show that following NRE treatment, there was a notable decrease in the number of activated microglia in the hippocampus of APP/PS1 mice as indicated by immunofluorescence results. Sholl analysis showed that microglia branches increased in NRE group, indicating that M1 microglia activation was inhibited. In the mice model injected with LPS in the tail vein, PCR and Western Blot results confirmed the anti-inflammatory effect of NRE, Nissl staining showed the protective effect of NRE on neurons, and immunofluorescence results also indicated that the activation of M1 microglia was inhibited. ConclusionThese results suggest that long term oral administration of NRE may inhibit neuroinflammation in the progression of AD.

Neurological Manifestations Following Traumatic Brain Injury: Role of Behavioral, Neuroinflammation, Excitotoxicity, Nrf-2 and Nitric Oxide.

Traumatic Brain Injury (TBI) is attributed to a forceful impact on the brain caused by sharp, penetrating bodies, like bullets and any sharp object. Some popular instances like falls, traffic accidents, physical assaults, and athletic injuries frequently cause TBI. TBI is the primary cause of both mortality and disability among young children and adults. Several individuals experience psychiatric problems, including cognitive dysfunction, depression, post-traumatic stress disorder, and anxiety, after primary injury. Behavioral changes post TBI include cognitive deficits and emotional instability (anxiety, depression, and post-traumatic stress disorder). These alterations are linked to neuroinflammatory processes. On the other hand, the direct impact mitigates inflammation insult by the release of pro-inflammatory cytokines, namely IL-1β, IL-6, and TNF-α, exacerbating neuronal injury and contributing to neurodegeneration. During the excitotoxic phase, activation of glutamate subunits like NMDA enhances the influx of Ca2+ and leads to mitochondrial metabolic impairment and calpain-mediated cytoskeletal disassembly. TBI pathological insult is also linked to transcriptional response suppression Nrf-2, which plays a critical role against TBI-induced oxidative stress. Activation of NRF-2 enhances the expression of anti-oxidant enzymes, providing neuroprotection. A possible explanation for the elevated levels of NO is that the stimulation of NMDA receptors by glutamate leads to the influx of calcium in the postsynaptic region, activating NOS's constitutive isoforms.

Exploring Mechanism of Electroacupuncture in Modulating Neuroinflammation Based on Intestinal Flora and Its Metabolites.

Neuroinflammatory responses play an important role in the pathogenesis of various diseases, particularly those affecting the central nervous system. Inhibition of neuroinflammation is a crucial therapeutic strategy for the management of central nervous system disorders. The intestinal microbial-gut-brain axis serves as a key regulatory pathway that modulates neuroinflammatory processes. Intestinal flora metabolites such as short-chain fatty acids, indoles and their derivatives, lipopolysaccharides, trimethylamine oxide, and secondary bile acids exert direct or indirect effects on neuroinflammation. Studies have shown that electroacupuncture (EA) modulates the composition of the intestinal microbiota and its metabolites, while also suppressing neuroinflammation by targeting the TLR4/NF- κ B, NLRP3/caspase-1, and microglial cell M2-type transformation pathways. This review discusses the mechanisms by which EA regulates neuroinflammation via intestinal microbiota and its metabolites, providing information and a foundation for further investigation of the precise therapeutic mechanisms of EA in neurological disorders.

SARS-CoV-2 S1 subunit produces a protracted priming of the neuroinflammatory, physiological, and behavioral responses to a remote immune challenge: A role for corticosteroids

Long COVID is a major public health consequence of COVID-19 and is characterized by multiple neurological and neuropsychatric symptoms. SARS-CoV-2 antigens (e.g., spike S1 subunit) are found in the circulation of Long COVID patients, have been detected in post-mortem brain of COVID patients, and exhibit neuroinflammatory properties. Considering recent observations of chronic neuroinflammation in Long COVID patients, the present study explores the idea that antigens derived from SARS-CoV-2 might produce a long-term priming or sensitization of neuroinflammatory processes, thereby potentiating the magnitude and/or duration of the neuroinflammatory response to future inflammatory insults. Rats were administered S1 or vehicle intra-cisterna magna and 7d later challenged with vehicle or LPS. The neuroinflammatory, physiological, and behavioral responses to LPS were measured at various time points post-LPS. We found that prior S1 treatment potentiated many of these responses to LPS suggesting that S1 produces a protracted priming of these processes. Further, S1 produced a protracted reduction in basal brain corticosteroids. Considering the anti-inflammatory properties of corticosteroids, these findings suggest that S1 might disinhibit innate immune processes in brain by reducing anti-inflammatory drive, thereby priming neuroinflammatory processes. Given that hypocortisolism is observed in Long COVID, we propose that similar S1-induced innate immune priming processes might play role in the pathophysiology of Long COVID.

PARK7/DJ-1 deficiency impairs microglial activation in response to LPS-induced inflammation

BackgroundSpecific microglia responses are thought to contribute to the development and progression of neurodegenerative diseases, including Parkinson’s disease (PD). However, the phenotypic acquisition of microglial cells and their role during the underlying neuroinflammatory processes remain largely elusive. Here, according to the multiple-hit hypothesis, which stipulates that PD etiology is determined by a combination of genetics and various environmental risk factors, we investigate microglial transcriptional programs and morphological adaptations under PARK7/DJ-1 deficiency, a genetic cause of PD, during lipopolysaccharide (LPS)-induced inflammation.MethodsUsing a combination of single-cell RNA-sequencing, bulk RNA-sequencing, multicolor flow cytometry and immunofluorescence analyses, we comprehensively compared microglial cell phenotypic characteristics in PARK7/DJ-1 knock-out (KO) with wildtype littermate mice following 6- or 24-h intraperitoneal injection with LPS. For translational perspectives, we conducted corresponding analyses in human PARK7/DJ-1 mutant induced pluripotent stem cell (iPSC)-derived microglia and murine bone marrow-derived macrophages (BMDMs).ResultsBy excluding the contribution of other immune brain resident and peripheral cells, we show that microglia acutely isolated from PARK7/DJ-1 KO mice display a distinct phenotype, specially related to type II interferon and DNA damage response signaling, when compared with wildtype microglia, in response to LPS. We also detected discrete signatures in human PARK7/DJ-1 mutant iPSC-derived microglia and BMDMs from PARK7/DJ-1 KO mice. These specific transcriptional signatures were reflected at the morphological level, with microglia in LPS-treated PARK7/DJ-1 KO mice showing a less amoeboid cell shape compared to wildtype mice, both at 6 and 24 h after acute inflammation, as also observed in BMDMs.ConclusionsTaken together, our results show that, under inflammatory conditions, PARK7/DJ-1 deficiency skews microglia towards a distinct phenotype characterized by downregulation of genes involved in type II interferon signaling and a less prominent amoeboid morphology compared to wildtype microglia. These findings suggest that the underlying oxidative stress associated with the lack of PARK7/DJ-1 affects microglia neuroinflammatory responses, which may play a causative role in PD onset and progression.

MiR-223 accelerates lipid droplets clearance in microglia following spinal cord injury by upregulating ABCA1

BackgroundSpinal cord injury (SCI) is characterized by extensive demyelination and inflammatory responses. Facilitating the clearance of lipid droplets (LDs) within microglia contributes to creating a microenvironment that favors neural recovery and provides essential materials for subsequent remyelination. Therefore, investigating MicroRNAs (miRNAs) that regulate lipid homeostasis after SCI and elucidating their potential mechanisms in promoting LDs clearance in microglia have become focal points of SCI research.MethodsWe established a subacute C5 hemicontusion SCI model in mice and performed transcriptomic sequencing on the injury epicenter to identify differentially expressed genes and associated pathways. Confocal imaging was employed to observe LDs accumulation. Multi-omics analyses were conducted to identify differentially expressed mRNA and miRNA post-SCI. Pathway enrichment analysis and protein-protein interaction network construction were performed using bioinformatics methods, revealing miR-223-Abca1 as a crucial miRNA-mRNA pair in lipid metabolism regulation. BV2 microglia cell lines overexpressing miR-223 were engineered, and immunofluorescence staining, western blot, and other techniques were employed to assess LDs accumulation, relevant targets, and inflammatory factor expression, confirming its role in regulating lipid homeostasis in microglia.ResultsHistopathological results of our hemicontusion SCI model confirmed LDs aggregation at the injury epicenter, predominantly within microglia. Our transcriptomic analysis during the subacute phase of SCI in mice implicated ATP-binding cassette transporter A1 (Abca1) as a pivotal gene in lipid homeostasis, cholesterol efflux and microglial activation. Integrative mRNA-miRNA multi-omics analysis highlighted the crucial role of miR-223 in the neuroinflammation process following SCI, potentially through the regulation of lipid metabolism via Abca1. In vitro experiments using BV2 cells overexpressing miR-223 demonstrated that elevated levels of miR-223 enhance ABCA1 expression in myelin debris and LPS-induced BV2 cells. This promotes myelin debris degradation and LDs clearance, and induces a shift toward an anti-inflammatory M2 phenotype.ConclusionsIn summary, our study unveils the critical regulatory role of miR-223 in lipid homeostasis following SCI. The mechanism by which this occurs involves the upregulation of ABCA1 expression, which facilitates LDs clearance and myelin debris degradation, consequently alleviating the lipid burden, and inhibiting inflammatory polarization of microglia. These findings suggest that strategies to enhance miR-223 expression and target ABCA1, thereby augmenting LDs clearance, may emerge as appealing new clinical targets for SCI treatment.

Lupeol protect against LPS-induced neuroinflammation and amyloid beta in adult mouse hippocampus.

Neuroinflammation includes the activation of immune glial cells in the central nervous system, release pro-inflammatory cytokines, which disrupt normal neural function and contribute to various neurological disorders, including Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, and stroke. AD is characterized by various factors including amyloidogenesis, synaptic dysfunction, memory impairment and neuroinflammation. Lipopolysaccharide (LPS) constitutes a vital element of membrane of the gram-negative bacterial cell, triggering vigorous neuroinflammation and facilitating neurodegeneration. Lupeol, a naturally occurring pentacyclic triterpene, has demonstrated several pharmacological properties, notably its anti-inflammatory activity. In this study, we evaluated the anti-inflammatory and anti-Alzheimer activity of lupeol in lipopolysaccharide (LPS)-injected mice model. LPS (250ug/kg) was administered intraperitoneally to C57BL/6 N male mice for 1 week to induce neuroinflammation and cognitive impairment. For biochemical analysis, acetylcholinesterase (AChE) assay, western blotting and confocal microscopy were performed. AChE, western blot and immunofluorescence results showed that lupeol treatment (50 mg/kg) along with LPS administration significantly inhibited the LPS-induced activation of neuroinflammatory mediators and cytokines like nuclear factor (NF-κB), tumor necrosis factor (TNF-α), cyclooxygenase (COX-2) and interleukin (IL-1β). Furthermore, we found that LPS-induced systemic inflammation lead to Alzheimer's symptoms as LPS treatment enhances level of amyloid beta (Aβ), amyloid precursor protein (APP), Beta-site APP cleaving enzyme (BACE-1) and hyperphosphorylated Tau (p-Tau). Lupeol treatment reversed the LPS-induced elevated level of Aβ, APP, BACE-1 and p-Tau in the hippocampus, showing anti-Alzheimer's properties. It is also determined that lupeol prevented LPS-induced synaptic dysfunction via enhanced expression of pre-and post-synaptic markers like SNAP-23, synaptophysin and PSD-95. Overall, our study shows that lupeol prevents memory impairment and synaptic dysfunction via inhibition of neuroinflammatory processes. Hence, we suggest that lupeol might be a useful therapeutic agent in prevention of neuroinflammation-induced neurological disorders like AD.

Associations between Microglia and Astrocytic Proteins and Tau Biomarkers across the Continuum of Alzheimer's Disease.

Recent investigations implicate neuroinflammatory changes, including astrocyte and microglia activation, as crucial in the progression of Alzheimer's disease (AD) Thus, we compared selected proteins reflecting neuroinflammatory processes to establish their connection to AD pathologies. Our study, encompassing 80 subjects with (n = 42) AD, (n = 18) mild cognitive impairment (MCI) and (n = 20) non-demented controls compares the clinical potential of tested molecules. Using antibody-based methods, we assessed concentrations of NGAL, CXCL-11, sTREM1, and sTREM2 in cerebrospinal fluid (CSF). Proinflammatory proteins, NGAL, and CXCL-11 reached a peak in the early stage of the disease and allowed for the identification of patients with MCI. Furthermore, the concentration of the anti-inflammatory molecule sTREM2 was highest in the more advanced stage of the disease and permitted differentiation between AD and non-demented controls. Additionally, sTREM2 was biochemically linked to tau and pTau in the AD group. Notably, NGAL demonstrated superior diagnostic performance compared to classical AD biomarkers in discriminating MCI patients from controls. These findings suggest that proteins secreted mainly through microglia dysfunction might play not only a detrimental but also a protective role in the development of AD pathology.

Inflammatory Markers and Ischemic Stroke: Insights and Implications

Abstract: Cerebral ischemia stands as a significant global cause of both mortality and morbidity among adults, ranking second in mortality rates. Neuroinflammation, a dynamic and intricate process, emerges rapidly after ischemia onset and persists for several days. This cascade begins with the activation of microglia and astrocytes, alongside immune cell infiltration, triggering the release of cytokines and initiating an inflammatory response within the brain. These events ultimately contribute to secondary brain injury, potentially expanding the area of damage beyond the initial affected region. This sustained inflammatory state contributes to blood-brain barrier disruption and cerebral edema, exacerbating neuronal damage and impeding neuroplasticity, ultimately worsening neurological deficits. However, the response of inflammation during ischemia is twofold, potentially offering benefits by clearing cellular debris and facilitating tissue regeneration. This review aims to dissect the roles of both novel and established pro-inflammatory and anti-inflammatory mediators in cerebral ischemia, offering critical insights for the development of effective therapeutic, diagnostic, and prognostic strategies.

Transgenerational hormesis in healthy aging and antiaging medicine from bench to clinics: Role of food components

Neurodegenerative diseases have multifactorial pathogenesis, mainly involving neuroinflammatory processes. Finding drugs able to treat these diseases, expecially because for most of these diseases there are no effective drugs, and the current drugs cause undesired side effects, represent a crucial point. Most in vivo and in vitro studies have been concentrated on various aspects related to neurons (e.g. neuroprotection), however, there has not been focus on the prevention of early stages involving glial cell activation and neuroinflammation. Recently, it has been demonstrated that nutritional phytochemicals including polyphenols, the main active constituents of the Mediterranean diet, maintain redox balance and neuroprotection through the activation of hormetic vitagene pathway. Recent lipidomics data from our laboratory indicate mushrooms as strong nutritional neuronutrients with strongly activity against neuroinflammation in Meniere’ diseaseas, a model of cochleovestibular neural degeneration, as well as in animal model of traumatic brain injury, or rotenone induced parkinson’s disease. Moreover, Hidrox®, an aqueous extract of olive containing hydroxytyrosol, and Boswellia, acting as Nrf2 activators, promote resilience by enhancing the redox potential, and thus, regulate through hormetic mechanisms, cellular stress response mechanisms., Thus, modulation of cellular stress pathways, in particular vitagenes system, may be an innovative approach for therapeutic intervention in neurodegenerative disorders.

Enviromental endocrine disruptor risks in the central nervous system: Neurotoxic effects of PFOS and glyphosate

Endocrine disruptors (EDs) pose significant risks to human and environmental health, with potential implications for neurotoxicity. This study investigates the synergistic neurotoxic effects of perfluorooctane sulfonate (PFOS) and glyphosate (GLY), two ubiquitous EDs, using SHSY5Y neuronal and C6 astrocytic cell lines. While individual exposures to PFOS and glyphosate at non-toxic concentrations did not induce significant changes, their combination resulted in a marked increase in oxidative stress and neuroinflammatory responses. Specifically, the co-exposure led to elevated levels of interleukin-6, tumor necrosis factor alpha, and interferon gamma, along with reduced interleukin-10 expression, indicative of heightened neuroinflammatory processes. These findings underscore the importance of considering the synergistic interactions of EDs in assessing neurotoxic risks and highlight the urgent need for further research to mitigate the adverse effects of these compounds on neurological health.

Herpes zoster vaccination and new diagnoses of dementia: A quasi-randomized study in Australia.

Increasing evidence suggests that neurotropic herpesviruses could play a role in the development of dementia, possibly through a neuroinflammatory process. Herpes zoster (HZ) vaccination has been reported to lead to a reduced probability of being diagnosed with dementia in several correlational studies and in a prior analysis by our team in Wales. This present study constitutes the first investigation to use a quasi-randomized study design in an electronic health record dataset from a large and diverse nation (Australia) to aim to determine the effect of HZ vaccination on dementia. In Australia, starting on November 1 2016, live-attenuated HZ vaccination was provided for free to individuals aged 70 to 79 years of age through primary care providers. Thus, those whose 80th birthday was just a few days prior to November 1 2016 never became eligible, whereas those whose 80th birthday was just a few days later were eligible. The key advantage of our approach is that one would not expect that these population groups who differ in their age by only a minute degree would, on average, differ in any of their health characteristics and behaviors. We used detailed primary healthcare records with week-of-birth information from 65 general practices across Australia. We analyzed our data using a regression discontinuity approach. Our sample consisted of 101,219 patients. As expected, patients born just before versus shortly after the date-of-birth eligibility threshold (November 2 1936) for HZ vaccination were well-balanced in their past preventive health services uptake and chronic disease diagnoses. There was an abrupt increase of 15.7 (95% CI: [12.2 - 19.3], p < 0.001) percentage points in the probability of ever receiving HZ vaccination between patients born shortly before versus shortly after the eligibility threshold. The eligibility rules of the HZ vaccination program, thus, created comparison groups just on either side of the date-of-birth eligibility threshold who were similar to each other, except for a large difference in their probability of receiving the intervention (HZ vaccination) of interest. Eligibility for HZ vaccination (i.e., being born shortly before versus shortly after November 2 1936) decreased the probability of receiving a new dementia diagnosis over 7.4 years by 2.0 percentage points (95% CI: [0.3 - 3.7], p = 0.021). Being eligible for HZ vaccination did not affect the probability of taking up other preventive health services (including other vaccinations), nor the probability of being diagnosed with other common chronic conditions than dementia. This study provides important evidence on the potential benefits of HZ vaccination for dementia because its quasi-randomized design allows for conclusions that are more likely to be causal than those of the existing associational evidence.

Extracellular Vesicles as Mediators of Neuroinflammation in Intercellular and Inter-Organ Crosstalk.

Neuroinflammation, crucial in neurological disorders like Alzheimer's disease, multiple sclerosis, and hepatic encephalopathy, involves complex immune responses. Extracellular vesicles (EVs) play a pivotal role in intercellular and inter-organ communication, influencing disease progression. EVs serve as key mediators in the immune system, containing molecules capable of activating molecular pathways that exacerbate neuroinflammatory processes in neurological disorders. However, EVs from mesenchymal stem cells show promise in reducing neuroinflammation and cognitive deficits. EVs can cross CNS barriers, and peripheral immune signals can influence brain function via EV-mediated communication, impacting barrier function and neuroinflammatory responses. Understanding EV interactions within the brain and other organs could unveil novel therapeutic targets for neurological disorders.

Baseline monocyte count predicts symptom improvement during intravenous ketamine therapy in treatment-resistant depression: a single-arm open-label observational study.

Neuroinflammatory processes in depression are associated with treatment resistance to conventional antidepressants. Ketamine is an effective new therapeutic option for treatment-resistant depression (TRD). Its well-established immunomodulatory properties are hypothesized to mediate its antidepressant effect. In this context, higher levels of inflammation may predict a better treatment response. However, conclusive evidence for this hypothesis is lacking. We thus investigated whether standard peripheral inflammatory cell markers and C-reactive protein (CRP) levels could predict symptom improvement during intravenous ketamine therapy in TRD patients. 27 participants with TRD were treated with six weight-adjusted intravenous ketamine infusions (0.5 mg/kg bodyweight) over three weeks. Baseline assessments included CRP, absolute monocyte count (AMC), and absolute neutrophil count (ANC). Depression severity was measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline (D1), after the first (D3) and before the last ketamine infusion (D18). Raters were blinded for the baseline laboratory assessments. 13 participants responded to ketamine treatment, and 8 participants partially responded. Baseline AMC showed a strong negative correlation with MADRS change at D3 (r=-0.57, p=0.002) and at D18 (r =-0.48, p=0.010), indicating that a high baseline AMC was associated with greater symptom improvement. A generalized linear model confirmed the association of baseline AMC with symptom improvement during ketamine treatment when additionally accounting for age, sex, and body mass index. Specifically, baseline AMC demonstrated predictive value to discriminate responders and partial responders from non-responders, but lacked discriminative ability between partial responders and responders. Baseline ANC correlated with the MADRS changes at D3 (r=-0.39, p=0.046), while CRP values did not correlate at all. Our prospective single-arm open-label observational study demonstrated that baseline AMC reliably predicted symptom improvement during intravenous ketamine treatment in TRD patients. AMC could therefore serve as a simple and easily accessible marker for symptom improvement during ketamine therapy in daily clinical practice. Future studies with larger sample sizes and a more detailed longitudinal assessment of AMC subtypes are needed to better understand the specific relationship between monocytes and the neuromodulatory effects of ketamine.

Study of the neuroprotective properties of the heteroreceptor EPOR/CD131 agonist of peptide structure in tau-proteinopathy modeling

Introduction: Tau proteinopathy is a pathology associated with the activation of post-translational modifications and interactions of pathophysiological cascades of neuroinflammation with hyperphosphorylation of Tau aggregates. Therefore, preference is given to agents that have properties in reducing or slowing down the processes of neuroinflammation and post-translational modifications in the brain. Materials and Methods: The study was conducted on male and female homozygous individuals of a transgenic murine line with overexpression of mutant human Tau gene (P301S) and a background wild mouse line C57Bl/6J. To assess the progression of Tau proteinopathy, behavioral tests were used at two control time points, and the last one measured the level of neuroinflammation markers and tau-proteinopathy. Results and Discussion: In the group of P301S mice treated with ARA-290, an improvement in the phenotypic picture of Tau proteinopathy was demonstrated compared with intact animals. In the Barnes circular maze test, mice showed a decrease in the total distance traveled and the latent time spent on the platform, which indicates a rapid entry into the shelter. In the O-shaped maze test, the group maintained a fairly high level of spontaneous exploratory behavior. In the vertical rod test, the animals recorded the best time indicators that they needed to turn and maintain balance compared to the intact group. A statistically significant decrease in the level of GSK-3β and an increase in CDK5 and PP2A were revealed, which indicates a dephosphorylating effect on Tau protein, as well as markers of neuroinflammation. NF-KB and TNF-α were significantly reduced by 57% and 32%, respectively, compared to the intact group. Conclusion: In the model of transgenic P301S murine line with overexpression of the mutant human Tau gene, the peptide agonist of the EPOR/CD 131 heteroreceptor demonstrated neuroprotective properties, which were confirmed by indicators of behavioral tests and markers of neuroinflammation and tau-proteinopathy.

Frankincense: A neuronutrient to approach Parkinson's disease treatment.

Parkinson's disease (PD), characterized by tremor, slowness of movement, stiffness, and poor balance, is due to a significant loss of dopaminergic neurons in the substantia nigra pars compacta and dopaminergic nerve terminals in the striatum with deficit of dopamine. To date the mechanisms sustaining PD pathogenesis are under investigation; however, a solid body of experimental evidence involves neuroinflammation, mitochondrial dysfunction, oxidative stress, and apoptotic cell death as the crucial factors operating in the pathogenesis of PD. Nutrition is known to modulate neuroinflammatory processes implicated in the pathogenesis and progression of this neurodegenerative disorder. Consistent with this notion, the Burseraceae family, which includes the genera Boswellia and Commiphora, are attracting emerging interest in the treatment of a wide range of pathological conditions, including neuroinflammation and cognitive decline. Bioactive components present in these species have been shown to improve cognitive function and to protect neurons from degeneration in in vitro, animal, as well as clinical research. These effects are mediated through the anti-inflammatory, antiamyloidogenic, anti-apoptotic, and antioxidative properties of bioactive components. Although many studies have exploited possible therapeutic approaches, data from human studies are lacking and their neuroprotective potential makes them a promising option for preventing and treating major neurodegenerative disorders.

Endometriosis, Pain, and Related Psychological Disorders: Unveiling the Interplay among the Microbiome, Inflammation, and Oxidative Stress as a Common Thread.

Endometriosis (EM), a chronic condition in endometrial tissue outside the uterus, affects around 10% of reproductive-age women, significantly affecting fertility. Its prevalence remains elusive due to the surgical confirmation needed for diagnosis. Manifesting with a range of symptoms, including dysmenorrhea, dyschezia, dysuria, dyspareunia, fatigue, and gastrointestinal discomfort, EM significantly impairs quality of life due to severe chronic pelvic pain (CPP). Psychological manifestations, notably depression and anxiety, frequently accompany the physical symptoms, with CPP serving as a key mediator. Pain stems from endometrial lesions, involving oxidative stress, neuroinflammation, angiogenesis, and sensitization processes. Microbial dysbiosis appears to be crucial in the inflammatory mechanisms underlying EM and associated CPP, as well as psychological symptoms. In this scenario, dietary interventions and nutritional supplements could help manage EM symptoms by targeting inflammation, oxidative stress, and the microbiome. Our manuscript starts by delving into the complex relationship between EM pain and psychological comorbidities. It subsequently addresses the emerging roles of the microbiome, inflammation, and oxidative stress as common links among these abovementioned conditions. Furthermore, the review explores how dietary and nutritional interventions may influence the composition and function of the microbiome, reduce inflammation and oxidative stress, alleviate pain, and potentially affect EM-associated psychological disorders.