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2. Wang J, Yu L, Jiang C, Chen M, Ou C, Wang J. Bone marrow mononuclear cells exert long-term neuroprotection in a rat model of ischemic stroke by promoting arteriogenesis and angiogenesis. Brain Behav Immun. 2013 Nov;34:56-66.
- Published
- 2021
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3. Wang J, Yu L, Jiang C, Fu X, Liu X, Wang M, Ou C, Cui X, Zhou C, Wang J. Cerebral ischemia increases bone marrow CD4+ CD25+ FoxP3+ regulatory T cells in mice via signals from sympathetic nervous system. Brain Behav Immun. 2015 Jan; 43:172-83.
- Author
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Pariante C
- Published
- 2021
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4. Cerebral ischemia increases bone marrow CD4+CD25+FoxP3+ regulatory T cells in mice via signals from sympathetic nervous system.
- Author
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Wang J, Yu L, Jiang C, Fu X, Liu X, Wang M, Ou C, Cui X, Zhou C, and Wang J
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- Animals, Bone Marrow Cells metabolism, Brain Ischemia metabolism, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, Dinoprostone metabolism, Forkhead Transcription Factors metabolism, Immune Tolerance immunology, Male, Mice, Receptors, Prostaglandin E, EP4 Subtype metabolism, Sympathetic Nervous System metabolism, T-Lymphocytes, Regulatory metabolism, Bone Marrow Cells immunology, Brain Ischemia immunology, Signal Transduction immunology, Sympathetic Nervous System immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Recent evidence has shown that an increase in CD4(+)CD25(+)FoxP3(+) regulatory T (Treg) cells may contribute to stroke-induced immunosuppression. However, the molecular mechanisms that underlie this increase in Treg cells remain unclear. Here, we used a transient middle cerebral artery occlusion model in mice and specific pathway inhibitors to demonstrate that stroke activates the sympathetic nervous system, which was abolished by 6-OHDA. The consequent activation of β2-adrenergic receptor (AR) signaling increased prostaglandin E2 (PGE2) level in bone marrow. β2-AR antagonist prevented the upregulation of PGE2. PGE2, which acts on prostaglandin E receptor subtype 4 (EP4), upregulated the expression of receptor activator for NF-κB ligand (RANKL) in CD4(+) T cells and mediated the increase in Treg cells in bone marrow. Treatment of MCAO mice with RANKL antagonist OPG inhibited the increase in percent of bone marrow Treg cells. PGE2 also elevated the expression of indoleamine 2,3 dioxygenase in CD11C(+) dendritic cells and promoted the development of functional Treg cells. The effect was neutralized by treatment with indomethacin. Concurrently, stroke reduced production of stromal cell-derived factor-1 (SDF-1) via β3-AR signals in bone marrow but increased the expression of C-X-C chemokine receptor (CXCR) 4 in Treg and other bone marrow cells. Treatment of MCAO mice with β3-AR antagonist SR-59230A reduced the percent of Treg cells in peripheral blood after stroke. The disruption of the CXCR4-SDF-1 axis may facilitate mobilization of Treg cells and other CXCR4(+) cells into peripheral blood. This mechanism could account for the increase in Treg cells, hematopoietic stem cells, and progenitor cells in peripheral blood after stroke. We conclude that cerebral ischemia can increase bone marrow CD4(+)CD25(+)FoxP3(+) regulatory T cells via signals from the sympathetic nervous system., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2015
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5. Metagenomic symphony of the intestinal ecosystem: How the composition affects the mind.
- Author
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Malan-Müller S, Martín-Hernández D, Caso JR, Matthijnssens J, Rodriguez-Urrutia A, Lowry CA, and Leza JC
- Abstract
Mental health disorders and neurodegenerative diseases place a heavy burden on patients and societies, and, although great strides have been made to understand the pathophysiology of these conditions, advancement in drug development is lagging. The importance of gastrointestinal health in maintaining overall health and preventing disease is not a new concept. Hundreds of years ago, healers from various cultures and civilizations recognized the crucial role of the gut in sustaining health. More than a century ago, scientists began exploring the restorative effects of probiotics, marking the early recognition of the importance of gut microbes. The omics era brought more enlightenment and enabled researchers to identify the complexity of the microbial ecosystems we harbour, encompassing bacteria, eukaryotes (including fungi), archaea, viruses, and other microorganisms. The extensive genetic capacity of the microbiota is dynamic and influenced by the environment. The microbiota therefore serves as a significant entity within us, with evolutionarily preserved functions in host metabolism, immunity, development, and behavior. The significant role of the bacterial gut microbiome in mental health and neurodegenerative disorders has been realized and described within the framework of the microbiota-gut-brain axis. However, the bacterial members do not function unaccompanied, but rather in concert, and there is a substantial knowledge gap regarding the involvement of non-bacterial microbiome members in these disorders. In this review, we will explore the current literature that implicates a role for the entire metagenomic ensemble, and how their complex interkingdom relationships could influence CNS functioning in mental health disorders and neurodegenerative diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)
- Published
- 2024
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6. Pathways to maternal health inequities: Structural racism, sleep, and physiological stress.
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Christian LM, Brown RL, Carroll JE, Thayer JF, Lewis TT, Gillespie SL, and Fagundes CP
- Abstract
Racial inequities in health are vast and well-documented, particularly regarding maternal and infant health. Sleep health, including but not limited to duration and quality, is central to overall health and well-being. However, research has not adequately addressed how racism embedded in structures and systems, in addition to individual experiences, may affect maternal health by impacting sleep. In this critical review, we aim to 1) synthesize findings, emphasizing collaborative studies within our group, 2) highlight gaps in knowledge, and 3) propose a theoretical framework and methodological approach for moving the field forward. Specifically, we focus on findings and future directions linking perinatal sleep, cardiovascular and immune function, and racial disparities in maternal health. Because too few studies look beyond individual-level determinants of sleep deficiencies among Black Americans, we assert a critical need for research that bridges multiple levels of analysis (e.g., individual, community, society) and provides recommendations for specific health parameters that researchers in this area can target. Although the need to understand and address perinatal health disparities is clear, the goal of identifying multilevel mechanisms underlying how racism in one's environment and daily life may interact to affect health extends far beyond pregnancy research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)
- Published
- 2024
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7. Molecular mechanisms underlying stress vulnerability and resilience in the chronic mild stress model: New insights from mRNA and miRNAs data combining.
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Cattane N, Mazzelli M, Begni V, Mombelli E, Papp M, Maj C, Riva MA, and Cattaneo A
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- Animals, Rats, Male, Depression metabolism, Depression genetics, Rats, Wistar, Gene Expression Profiling methods, Stress, Psychological metabolism, Stress, Psychological genetics, MicroRNAs metabolism, MicroRNAs genetics, RNA, Messenger metabolism, Resilience, Psychological, Disease Models, Animal, Hippocampus metabolism, Transcriptome
- Abstract
Stress is a major risk factor for the development of psychiatric disorders, including depression. However, its effects are not the same in all the subjects as only a portion of individuals exposed to stress will eventually develop negative mental outcomes, while others can be considered resilient. However, the biological processes underlying the development of a vulnerable or resilient phenotype are still poor understood. In order to cover this, we here used both transcriptomic and miRNomic based approaches in the ventral hippocampus of control (CON) and rats exposed to the chronic mild stress (CMS) paradigm, which were then divided into vulnerable (VULN) or resilient (RES) animals according to the sucrose consumption test. Transcriptomic analyses in VULN rats, compared to both the group of CON and RES animals, revealed the activation of inflammatory/immune-related pathways, specifically involved in antibodies and cytokine production, and the inhibition of pathways involved in protein synthesis. Conversely, transcriptomic data in RES animals suggested the activation of several pathways involved in neurotransmission. We then performed a mRNA-miRNA integration analysis by using miRComb R package, and we found that the most significant mRNA-miRNA pairs were involved in promoting the inflammatory status in VULN animals and, vice versa, by decreasing it in RES rats. Moreover, in VULN animals, the mRNA-miRNA combining analyses revealed the modulation of the olfactory sensory system, a key biological process that has been already found involved in the etiology of stress related disorders such as depression. Overall, our mRNA-miRNA integration-based approach identified distinct biological processes that are relevant for the development of a vulnerable or resilient phenotype in response to the negative effects of CMS exposure, which could allow the identification of novel targets for prevention or treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)
- Published
- 2024
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8. The plasma proteome and prognosis for psychiatric symptoms in psychosis: A focus on function, not factors.
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Westacott LJ and Severance EG
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- Humans, Prognosis, Biomarkers blood, Schizophrenia blood, Psychotic Disorders blood, Proteome metabolism
- Abstract
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
- Published
- 2024
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9. Placenta-specific CYP11A1 overexpression lead to autism-like symptom in offspring with altered steroid hormone biosynthesis in the placenta-brain axis and rescued by vitamin D intervention.
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Yin H, Zhang J, Chen Y, Guo J, Li Q, Dinnyes A, Sun Q, Liu X, He G, Zhu B, Liu Y, Xu P, Xu W, and Xie J
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- Animals, Female, Pregnancy, Mice, Vitamin D metabolism, Male, Autistic Disorder metabolism, Autistic Disorder genetics, Prenatal Exposure Delayed Effects metabolism, Progesterone metabolism, Gene Knock-In Techniques, Placenta metabolism, Cholesterol Side-Chain Cleavage Enzyme metabolism, Cholesterol Side-Chain Cleavage Enzyme genetics, Brain metabolism, Autism Spectrum Disorder metabolism, Autism Spectrum Disorder genetics, Disease Models, Animal
- Abstract
Alterations in steroid hormone regulation have been implicated in the etiology and progression of autism spectrum disorders (ASD), with the enzyme cytochrome P450 family 11 subfamily A member 1 (CYP11A1)-a key catalyst in cholesterol side-chain cleavage, prominently expressed in the adrenal glands, ovaries, testes, and placenta-standing at the forefront of these investigations. The potential link between aberrations in placental Cyp11a1 expression and the resultant neurodevelopmental disorders, along with the mechanisms underpinning such associations, remains inadequately delineated. In this study, we employed a placental trophoblast-specific Cyp11a1 Hipp11 (H11) knock-in murine model to dissect the phenotypic manifestations within the placenta and progeny, thereby elucidating the underlying mechanistic pathways. Behavioral analyses revealed a diminution in social interaction capabilities alongside an augmented anxiety phenotype, as evidenced by open field and elevated plus maze assessments; both phenotypes were ameliorated after vitamin D3 supplementation. Electrophysiological assays underscored the augmented inhibition of paired-pulse facilitation, indicating impaired neuroplasticity in Cyp11a1 H11-modified mice. An elevation in progesterone concentrations was noted, alongside a significant upregulation of Th1-related cytokines (IL-6 and TNFα) across the plasma, placental, and frontal cortex-a pathological state mitigable through vitamin D3 intervention. Western blotting revealed a vitamin D-mediated rectification of vitamin D receptor and PGC-1α expression dysregulations. Immunofluorescence assays revealed microglial activation in the knock-in model, which was reversible upon vitamin D3 treatment. In conclusion, Cyp11a1 overexpression in the placenta recapitulated an autism-like phenotype in murine models, and vitamin D3 administration effectively ameliorated the resultant neurobehavioral and neuroinflammatory derangements. This study substantiates the application of Cyp11a1 as a biomarker in prenatal diagnostics and posits that prenatal vitamin D3 supplementation is a viable prophylactic measure against perturbations in steroid hormone metabolism associated with ASD pathogenesis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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10. A 12-week randomized double-blind clinical trial of eicosapentaenoic acid intervention in episodic migraine.
- Author
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You ZB and Cao P
- Subjects
- Humans, Double-Blind Method, Female, Adult, Male, Treatment Outcome, Middle Aged, Eicosapentaenoic Acid administration & dosage, Eicosapentaenoic Acid therapeutic use, Migraine Disorders drug therapy
- Abstract
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
- Published
- 2024
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11. Specific and cumulative infection burden and mild cognitive impairment and dementia: A population-based study.
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Shi R, Yu S, Larbi A, Pin Ng T, and Lu Y
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- Humans, Female, Male, Aged, Risk Factors, Middle Aged, Aged, 80 and over, Cohort Studies, Infections epidemiology, Infections immunology, Cognitive Dysfunction epidemiology, Cognitive Dysfunction immunology, Dementia epidemiology, Dementia immunology
- Abstract
Infection by pathogenic microbes is widely hypothesized to be a risk factor for the development of neurocognitive disorders and dementia, but evidence remains limited. We analyzed the association of seropositivity to 11 common pathogens and cumulative infection burden with neurocognitive disorder (mild cognitive impairment and dementia) in a population-based cohort of 475 older individuals (mean age = 67.6 y) followed up over 3-5 years for the risk of MCI-dementia. Specific seropositivities showed a preponderance of positive trends of association with MCI-dementia, including for Plasmodium, H. pylori, and RSV (p < 0.05), as well as Chickungunya, HSV-2, CMV and EBV (p > 0.05), while HSV-1 and HHV-6 showed equivocal or no associations, and Dengue and VZV showed negative associations (p < 0.05) with MCI-dementia. High infection burden (5 + cumulated infections) was significantly associated with an increased MCI-dementia risk in comparison with low infection burden (1-3 cumulative infections), adjusted for age, sex, and education. Intriguingly, for a majority (8 of 11) of pathogens, levels of antibody titers were significantly lower in those with MCI-dementia compared to cognitive normal individuals. Based on our observations, we postulate that individuals who are unable to mount strong immunological responses to infection by diverse microorganisms, and therefore more vulnerable to infection by greater numbers of different microbial pathogens or repeated infections to the same pathogen in the course of their lifetime are more likely to develop MCI or dementia. This hypothesis should be tested in more studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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12. Sleep-wake behavior and responses to sleep deprivation and immune challenge of protein kinase RNA-activated knockout mice.
- Author
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Valencia-Sanchez S, Davis M, Martensen J, Hoeffer C, Link C, and Opp MR
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- Animals, Male, Mice, Lipopolysaccharides pharmacology, Electroencephalography, Body Temperature physiology, Sleep, REM physiology, Sleep Deprivation immunology, Sleep Deprivation metabolism, Mice, Knockout, Wakefulness physiology, eIF-2 Kinase metabolism, Mice, Inbred C57BL, Sleep physiology
- Abstract
Protein Kinase RNA-activated (PKR) is an enzyme that plays a role in many systemic processes, including modulation of inflammation, and is implicated in neurodegenerative diseases, such as Alzheimer's disease (AD). PKR phosphorylation results in the production of several cytokines involved in the regulation / modulation of sleep, including interleukin-1β, tumor necrosis factor-α and interferon-γ. We hypothesized targeting PKR would alter spontaneous sleep of mice, attenuate responses to sleep deprivation, and inhibit responses to immune challenge. To test these hypotheses, we determined the sleep-wake phenotype of mice lacking PKR (knockout; PKR
-/- ) during undisturbed baseline conditions; in responses to six hours of sleep deprivation; and after immune challenge with lipopolysaccharide (LPS). Adult male mice (C57BL/6J, n = 7; PKR-/- , n = 7) were surgically instrumented with EEG recording electrodes and an intraperitoneal microchip to record core body temperature. During undisturbed baseline conditions, PKR-/- mice spent more time in non-rapid eye movement sleep (NREMS) and rapid-eye movement sleep (REMS), and less time awake at the beginning of the dark period of the light:dark cycle. Delta power during NREMS, a measure of sleep depth, was less in PKR-/- mice during the dark period, and core body temperatures were lower during the light period. Both mouse strains responded to sleep deprivation with increased NREMS and REMS, although these changes did not differ substantively between strains. The initial increase in delta power during NREMS after sleep deprivation was greater in PKR-/- mice, suggesting a faster buildup of sleep pressure with prolonged waking. Immune challenge with LPS increased NREMS and inhibited REMS to the same extent in both mouse strains, whereas the initial LPS-induced suppression of delta power during NREMS was greater in PKR-/- mice. Because sleep regulatory and immune responsive systems in brain are redundant and overlapping, other mediators and signaling pathways in addition to PKR are involved in the responses to acute sleep deprivation and LPS immune challenge., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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13. Author reply: Improving the validity of studies on the relationship between social health and immunity of older adults.
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van der Velpen IF, Yaqub A, Vernooij MW, Perry M, Vernooij-Dassen MJF, Ghanbari M, Arfan Ikram M, and Melis RJF
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- Humans, Aged, Immunity physiology, Reproducibility of Results, Aging immunology, Aging psychology
- Abstract
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
- Published
- 2024
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14. Prenatal exposure to common infections and newborn DNA methylation: A prospective, population-based study.
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Suleri A, Salontaji K, Luo M, Neumann A, Mulder RH, Tiemeier H, Felix JF, Marioni RE, Bergink V, and Cecil CAM
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- Humans, Female, Pregnancy, Infant, Newborn, Male, Prospective Studies, Adolescent, Pregnancy Complications, Infectious genetics, Pregnancy Complications, Infectious epidemiology, Genome-Wide Association Study, Adult, Infections genetics, Infections epidemiology, Prenatal Exposure Delayed Effects genetics, DNA Methylation, Epigenesis, Genetic, Fetal Blood metabolism
- Abstract
Background: Infections during pregnancy have been robustly associated with adverse mental and physical health outcomes in offspring, yet the underlying molecular pathways remain largely unknown. Here, we examined whether exposure to common infections in utero associates with DNA methylation (DNAm) patterns at birth and whether this in turn relates to offspring health outcomes in the general population., Methods: Using data from 2,367 children from the Dutch population-based Generation R Study, we first performed an epigenome-wide association study to identify differentially methylated sites and regions at birth associated with prenatal infection exposure. We also examined the influence of infection timing by using self-reported cumulative infection scores for each trimester. Second, we sought to develop an aggregate methylation profile score (MPS) based on cord blood DNAm as an epigenetic proxy of prenatal infection exposure and tested whether this MPS prospectively associates with offspring health outcomes, including psychiatric symptoms, BMI, and asthma at ages 13-16 years. Third, we investigated whether prenatal infection exposure associates with offspring epigenetic age acceleration - a marker of biological aging. Across all analysis steps, we tested whether our findings replicate in 864 participants from an independent population-based cohort (ALSPAC, UK)., Results: We observed no differentially methylated sites or regions in cord blood in relation to prenatal infection exposure, after multiple testing correction. 33 DNAm sites showed suggestive associations (p < 5e10 - 5; of which one was also nominally associated in ALSPAC), indicating potential links to genes associated with immune, neurodevelopmental, and cardiovascular pathways. While the MPS of prenatal infections associated with maternal reports of infections in the internal hold out sample in the Generation R Study (R
2 incremental = 0.049), it did not replicate in ALSPAC (R2 incremental = 0.001), and it did not prospectively associate with offspring health outcomes in either cohort. Moreover, we observed no association between prenatal exposure to infections and epigenetic age acceleration across cohorts and clocks., Conclusion: In contrast to prior studies, which reported DNAm differences in offspring exposed to severe infections in utero, we do not find evidence for associations between self-reported clinically evident common infections during pregnancy and DNAm or epigenetic aging in cord blood within the general pediatric population. Future studies are needed to establish whether associations exist but are too subtle to be statistically meaningful with present sample sizes, whether they replicate in a cohort with a more similar infection score as our discovery cohort, whether they occur in different tissues than cord blood, and whether other biological pathways may be more relevant for mediating the effect of prenatal common infection exposure on downstream offspring health outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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15. Early intensive rehabilitation reverses locomotor disruption, decrease brain inflammation and induces neuroplasticity following experimental Cerebral Palsy.
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Sanches E, Ho D, van de Looij Y, Aebi Toulotte A, Baud L, Bouteldja F, Barraud Q, Araneda R, Bleyenheuft Y, Brochard S, Kathe C, Courtine G, and Sizonenko S
- Subjects
- Animals, Rats, Female, Male, Brain metabolism, Brain physiopathology, Pregnancy, Recovery of Function physiology, Encephalitis metabolism, Encephalitis physiopathology, Encephalitis rehabilitation, Gait physiology, Physical Conditioning, Animal physiology, Physical Conditioning, Animal methods, Neuroinflammatory Diseases metabolism, Neuroinflammatory Diseases physiopathology, Cerebral Palsy rehabilitation, Cerebral Palsy physiopathology, Neuronal Plasticity physiology, Rats, Wistar, Locomotion physiology, Disease Models, Animal
- Abstract
Background: Cerebral Palsy (CP) is a major cause of motor and cognitive disability in children due to injury to the developing brain. Early intensive sensorimotor rehabilitation has been shown to change brain structure and reduce CP symptoms severity. We combined environmental enrichment (EE) and treadmill training (TT) to observe the effects of a one-week program of sensorimotor stimulation (EETT) in animals exposed to a CP model and explored possible mechanisms involved in the functional recovery., Methods: Pregnant Wistar rats were injected with Lipopolysaccharide (LPS - 200 µg/kg) intraperitoneally at embryonic days 18 and 19. At P0, pups of both sexes were exposed to 20' anoxia at 37 °C. From P2 to P21, hindlimbs were restricted for 16 h/day during the dark cycle. EETT lasted from P21 to P27. TT - 15 min/day at 7 cm/s. EE - 7 days in enriched cages with sensorimotor stimulus. Functional 3D kinematic gait analysis and locomotion were analyzed. At P28, brains were collected for ex-vivo MRI and histological assessment. Neurotrophins and key proteins involved in CNS function were assessed by western blotting., Results: CP model caused gross and skilled locomotor disruption and altered CNS neurochemistry. EETT reversed locomotor dysfunction with minor effects over gait kinematics. EETT also decreased brain inflammation and glial activation, preserved myelination, upregulated BDNF signaling and modulated the expression of proteins involved in excitatory synaptic function in the brain and spinal cord., Conclusions: Using this translational approach based on intensive sensorimotor rehabilitation, we highlight pathways engaged in the early developmental processes improving neurological recovery observed in CP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)
- Published
- 2024
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16. Reproducible gut microbial signatures in bipolar and schizophrenia spectrum disorders: A metagenome-wide study.
- Author
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Ioannou M, Borkent J, Andreu-Sánchez S, Wu J, Fu J, Sommer IEC, and Haarman BCM
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- Humans, Female, Male, Adult, Middle Aged, Metagenomics methods, Antipsychotic Agents therapeutic use, Antipsychotic Agents pharmacology, Bacteria genetics, Schizophrenia microbiology, Gastrointestinal Microbiome genetics, Bipolar Disorder microbiology, Metagenome
- Abstract
Background: Numerous studies report gut microbiome variations in bipolar disorder (BD) and schizophrenia spectrum disorders (SSD) compared to healthy individuals, though, there is limited consensus on which specific bacteria are associated with these disorders., Methods: In this study, we performed a comprehensive metagenomic shotgun sequencing analysis in 103 Dutch patients with BD/SSD and 128 healthy controls matched for age, sex, body mass index and income, while accounting for diet quality, transit time and technical confounders. To assess the replicability of the findings, we used two validation cohorts (total n = 203), including participants from a distinct population with a different metagenomic isolation protocol., Results: The gut microbiome of the patients had a significantly different β-diversity, but not α-diversity nor neuroactive potential compared to healthy controls. Initially, twenty-six bacterial taxa were identified as differentially abundant in patients. Among these, the previously reported genera Lachnoclostridium and Eggerthella were replicated in the validation cohorts. Employing the CoDaCoRe learning algorithm, we identified two bacterial balances specific to BD/SSD, which demonstrated an area under the receiver operating characteristic curve (AUC) of 0.77 in the test dataset. These balances were replicated in the validation cohorts and showed a positive association with the severity of psychiatric symptoms and antipsychotic use. Last, we showed a positive association between the relative abundance of Klebsiella and Klebsiella pneumoniae with antipsychotic use and between the Anaeromassilibacillus and lithium use., Conclusions: Our findings suggest that microbial balances could be a reproducible method for identifying BD/SSD-specific microbial signatures, with potential diagnostic and prognostic applications. Notably, Lachnoclostridium and Eggerthella emerge as frequently occurring bacteria in BD/SSD. Last, our study reaffirms the previously established link between Klebsiella and antipsychotic medication use and identifies a novel association between Anaeromassilibacillus and lithium use., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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17. Comparative utility of MRI and EEG for early detection of cortical dysmaturation after postnatal systemic inflammation in the neonatal rat.
- Author
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White P, Ranasinghe S, Chen J, Van de Looij Y, Sizonenko S, Prasad J, Berry M, Bennet L, Gunn A, and Dean J
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- Animals, Rats, Female, Male, Motor Cortex physiopathology, Rats, Sprague-Dawley, Electroencephalography methods, Animals, Newborn, Inflammation, Cerebral Cortex diagnostic imaging, Cerebral Cortex physiopathology, Lipopolysaccharides, Magnetic Resonance Imaging methods, Diffusion Tensor Imaging methods
- Abstract
Background: Exposure to postnatal systemic inflammation is associated with increased risk of brain injury in preterm infants, leading to impaired maturation of the cerebral cortex and adverse neurodevelopmental outcomes. However, the optimal method for identifying cortical dysmaturation is unclear. Herein, we compared the utility of electroencephalography (EEG), diffusion tensor imaging (DTI), and neurite orientation dispersion and density imaging (NODDI) at different recovery times after systemic inflammation in newborn rats., Methods: Sprague Dawley rat pups of both sexes received single-daily lipopolysaccharide (LPS; 0.3 mg/kg i.p.; n = 51) or saline (n = 55) injections on postnatal days (P)1, 2, and 3. A subset of these animals were implanted with EEG electrodes. Cortical EEG was recorded for 30 min from unanesthetized, unrestrained pups at P7, P14, and P21, and in separate groups, brain tissues were collected at these ages for ex-vivo MRI analysis (9.4 T) and Golgi-Cox staining (to assess neuronal morphology) in the motor cortex., Results: Postnatal inflammation was associated with reduced cortical pyramidal neuron arborization from P7, P14, and P21. These changes were associated with dysmature EEG features (e.g., persistence of delta waveforms, higher EEG amplitude, reduced spectral edge frequency) at P7 and P14, and higher EEG power in the theta and alpha ranges at P21. By contrast, there were no changes in cortical DTI or NODDI in LPS rats at P7 or P14, while there was an increase in cortical fractional anisotropy (FA) and decrease in orientation dispersion index (ODI) at P21., Conclusions: EEG may be useful for identifying the early evolution of impaired cortical development after early life postnatal systemic inflammation, while DTI and NODDI seem to be more suited to assessing established cortical changes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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18. Short-term high fat diet impairs memory, exacerbates the neuroimmune response, and evokes synaptic degradation via a complement-dependent mechanism in a mouse model of Alzheimer's disease.
- Author
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Mackey-Alfonso SE, Butler MJ, Taylor AM, Williams-Medina AR, Muscat SM, Fu H, and Barrientos RM
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- Animals, Mice, Memory Disorders metabolism, Memory Disorders immunology, Male, Complement System Proteins metabolism, Memory physiology, Neuroinflammatory Diseases metabolism, Neuroinflammatory Diseases immunology, Mice, Inbred C57BL, Brain metabolism, Brain immunology, Hippocampus metabolism, Neuroimmunomodulation physiology, Alzheimer Disease metabolism, Alzheimer Disease immunology, Diet, High-Fat adverse effects, Synapses metabolism, Disease Models, Animal, Microglia metabolism, Mice, Transgenic
- Abstract
Alzheimer's Disease (AD) is a neurodegenerative disease characterized by profound memory impairments, synaptic loss, neuroinflammation, and hallmark pathological markers. High-fat diet (HFD) consumption increases the risk of developing AD even after controlling for metabolic syndrome, pointing to a role of the diet itself in increasing risk. In AD, the complement system, an arm of the immune system which normally tags redundant or damaged synapses for pruning, becomes pathologically overactivated leading to tagging of healthy synapses. While the unhealthy diet to AD link is strong, the underlying mechanisms are not well understood in part due to confounding variables associated with long-term HFD which can independently influence the brain. Therefore, we experimented with a short-term diet regimen to isolate the diet's impact on brain function without causing obesity. This project investigated the effect of short-term HFD on 1) memory, 2) neuroinflammation including complement, 3) AD pathology markers, 4) synaptic markers, and 5) in vitro microglial synaptic phagocytosis in the 3xTg-AD mouse model. Following the consumption of either standard chow or HFD, 3xTg-AD and non-Tg mice were tested for memory impairments. In a separate cohort of mice, levels of hippocampal inflammatory markers, complement proteins, AD pathology markers, and synaptic markers were measured. For the last set of experiments, BV2 microglial phagocytosis of synapses was evaluated. Synaptoneurosomes isolated from the hippocampus of 3xTg-AD mice fed chow or HFD were incubated with equal numbers of BV2 microglia. The number of BV2 microglia that phagocytosed synaptoneurosomes was tracked over time with a live-cell imaging assay. Finally, we incubated BV2 microglia with a complement receptor inhibitor (NIF) and repeated the assay. Behavioral analysis showed 3xTg-AD mice had significantly impaired long-term contextual and cued fear memory compared to non-Tg mice that was further impaired by HFD. HFD significantly increased inflammatory markers and complement expression while decreasing synaptic marker expression only in 3xTg-AD mice, without altering AD pathology markers. Synaptoneurosomes from HFD-fed 3xTg-AD mice were phagocytosed at a significantly higher rate than those from chow-fed mice, suggesting the synapses were altered by HFD. The complement receptor inhibitor blocked this effect in a dose-dependent manner, demonstrating the HFD-mediated increase in phagocytosis was complement dependent. This study indicates HFD consumption increases neuroinflammation and over-activates the complement cascade in 3xTg-AD mice, resulting in poorer memory. The in vitro data point to complement as a potential mechanistic culprit and therapeutic target underlying HFD's influence in increasing cognitive vulnerability to AD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)
- Published
- 2024
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19. Effects of low-dose acetylsalicylic acid on the inflammatory response to experimental sleep restriction in healthy humans.
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Engert LC, Ledderose C, Biniamin C, Birriel P, Buraks O, Chatterton B, Dang R, Daniel S, Eske A, Reed T, Tang A, Bertisch SM, Mullington JM, Junger WG, and Haack M
- Subjects
- Humans, Male, Adult, Female, Double-Blind Method, Middle Aged, Young Adult, Sleep drug effects, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Anti-Inflammatory Agents, Non-Steroidal administration & dosage, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, C-Reactive Protein metabolism, C-Reactive Protein analysis, Aspirin administration & dosage, Aspirin pharmacology, Sleep Deprivation, Inflammation metabolism, Cross-Over Studies
- Abstract
Background: Sleep deficiencies, such as manifested in short sleep duration or insomnia symptoms, are known to increase the risk for multiple disease conditions involving immunopathology. Inflammation is hypothesized to be a mechanism through which deficient sleep acts as a risk factor for these conditions. Thus, one potential way to mitigate negative health consequences associated with deficient sleep is to target inflammation. Few interventional sleep studies investigated whether improving sleep affects inflammatory processes, but results suggest that complementary approaches may be necessary to target inflammation associated with sleep deficiencies. We investigated whether targeting inflammation through low-dose acetylsalicylic acid (ASA, i.e., aspirin) is able to blunt the inflammatory response to experimental sleep restriction., Methods: 46 healthy participants (19F/27M, age range 19-63 years) were studied in a double-blind randomized placebo-controlled crossover trial with three protocols each consisting of a 14-day at-home monitoring phase followed by an 11-day (10-night) in-laboratory stay (sleep restriction/ASA, sleep restriction/placebo, control sleep/placebo). In the sleep restriction/ASA condition, participants took low-dose ASA (81 mg/day) daily in the evening (22:00) during the at-home phase and the subsequent in-laboratory stay. In the sleep restriction/placebo and control sleep/placebo conditions, participants took placebo daily. Each in-laboratory stay started with 2 nights with a sleep opportunity of 8 h/night (23:00-07:00) for adaptation and baseline measurements. Under the two sleep restriction conditions, participants were exposed to 5 nights of sleep restricted to a sleep opportunity of 4 h/night (03:00-07:00) followed by 3 nights of recovery sleep with a sleep opportunity of 8 h/night. Under the control sleep condition, participants had a sleep opportunity of 8 h/night throughout the in-laboratory stay. During each in-laboratory stay, participants had 3 days of intensive monitoring (at baseline, 5th day of sleep restriction/control sleep, and 2nd day of recovery sleep). Variables, including pro-inflammatory immune cell function, C-reactive protein (CRP), and actigraphy-estimated measures of sleep, were analyzed using generalized linear mixed models., Results: Low-dose ASA administration reduced the interleukin (IL)-6 expression in LPS-stimulated monocytes (p<0.05 for condition*day) and reduced serum CRP levels (p<0.01 for condition) after 5 nights of sleep restriction compared to placebo administration in the sleep restriction condition. Low-dose ASA also reduced the amount of cyclooxygenase (COX)-1/COX-2 double positive cells among LPS-stimulated monocytes after 2 nights of recovery sleep following 5 nights of sleep restriction compared to placebo (p<0.05 for condition). Low-dose ASA further decreased wake after sleep onset (WASO) and increased sleep efficiency (SE) during the first 2 nights of recovery sleep (p<0.001 for condition and condition*day). Baseline comparisons revealed no differences between conditions for all of the investigated variables (p>0.05 for condition)., Conclusion: This study shows that inflammatory responses to sleep restriction can be reduced by preemptive administration of low-dose ASA. This finding may open new therapeutic approaches to prevent or control inflammation and its consequences in those experiencing sleep deficiencies., Trial Registration: ClinicalTrials.gov NCT03377543., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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20. B Cell-activating factor (BAFF): A promising trans-nosographic biomarker of inflammation and autoimmunity in bipolar disorder and schizophrenia.
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Boukouaci W, Lajnef M, Wu CL, Bouassida J, Saitoh K, Sugunasabesan S, Richard JR, Apavou M, Lamy A, Henensal A, Nkam I, Hasty L, Sayous R, Bengoufa D, Barau C, Le Corvoisier P, Honnorat J, Maskos U, Yolken R, Leboyer M, and Tamouza R
- Subjects
- Humans, Male, Female, Adult, Middle Aged, Genotype, Autoantibodies blood, B-Cell Activating Factor blood, B-Cell Activating Factor genetics, Bipolar Disorder immunology, Bipolar Disorder genetics, Schizophrenia immunology, Schizophrenia blood, Schizophrenia genetics, Autoimmunity, Biomarkers blood, Inflammation immunology
- Abstract
Immune dysregulation is an important aspect of schizophrenia (SZ) and bipolar disorders (BD) pathophysiology, including not only inflammatory but also autoimmune process reflective of abnormal humoral immune responses. Given that B cell-activating factor (BAFF) is an integral aspect of B lymphocyte regulation, the current study investigated BAFF in SZ and BD. 255 SZ patients, 407 BD patients and 185 healthy controls (HC) were investigated across three aspects of soluble BAFF (sBAFF) by (i) comparing sBAFF circulatory levels across SZ, BD and HC, (ii) determining potential correlations between the circulating levels of sBAFF and the genotype distribution of a functionally relevant polymorphism, namely the TNFSF13B 3'UTR insertion-deletion polymorphism (GCTGT>A), (iii) analyzing relationships between both sBAFF levels and 3'UTR insertion-deletion genotypes and disease risk, patients clinical characteristics and circulating levels of potent inflammatory molecules. In addition, in subsets of patients, we also searched for possible correlations between sBAFF levels and stigma of past infectious events as well as positivity for circulating systemic autoantibodies or those directed against central nervous system (CNS) structures. Studying blood derived serum and DNA, weobserved that circulating sBAFF levels were significantly higher in SZ and BD patients, versus HC (p = 5.3*10
-10 and p = 4.4*10-09 ). Patients experiencing acute episodes, versus stable patients, in between acute episodes, exhibited higher sBAFF levels (p = 0.017).In SZ patients, positive correlations were observed between elevated sBAFF levels and: (i) elevated positive psychotic symptoms (PANSS pos), (ii) history of childhood trauma (physical abuse), and (iii) low scores on global functioning (GAF) (p = 0.024, p = 0.024, and p = 0.041).We also found that the distribution of the BAFF Ins/Del genotypes was significantly correlated with circulating sBAFF levels in SZ and BD patients (p = 0.0004). Elevated sBAFF levels were also correlated with increased levels of pro-inflammatory markers in both SZ and BD cohorts (p < 0.001). Regarding infectious stigma, only patients seropositive, versus seronegative, for herpes simplex virus (HSV)1 immunoglobulin (Ig)G antibodies exhibited a significant association with high sBAFF levels (p = 0.013). In contrast, positivity for systemic or CNS autoantibodies was significantly associated with reduced sBAFF levels, compared to patients without autoantibodies (p = 0.0017). Overall, our findings indicate that BAFF may be a promising trans-nosographic biomarker of inflammation that is likely to offer predictive, diagnostic, and prognostic tools for the management of SZ and BD. The results therefore have practicable clinical utility given the availability of immunotherapeutic treatment options including targeted monoclonal antibodies against BAFF., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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21. Healthy foods, healthy brain? Mediterranean diet is associated with changes in inflammatory pathways affecting brain and behavior in a monkey model.
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Kl H and Md B
- Subjects
- Animals, Behavior, Animal physiology, Humans, Diet, Mediterranean, Brain metabolism, Inflammation metabolism
- Abstract
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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- 2024
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22. Transcriptomic and proteomic profiling of bi-partite and tri-partite murine iPSC-derived neurospheroids under steady-state and inflammatory condition.
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Di Stefano J, Garcia-Pupo L, Di Marco F, Motaln H, Govaerts J, Van Breedam E, Mateiu LM, Van Calster S, Ricciardi L, Quarta A, Verstraelen P, De Vos WH, Rogelj B, Cicalini I, De Laurenzi V, Del Boccio P, FitzGerald U, Vanden Berghe W, Verhoye M, Pieragostino D, and Ponsaerts P
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- Animals, Mice, Astrocytes metabolism, CX3C Chemokine Receptor 1 metabolism, CX3C Chemokine Receptor 1 genetics, Cell Differentiation, Cytokines metabolism, Proteome metabolism, Chemokine CXCL10 metabolism, Receptors, CCR2 metabolism, Receptors, CCR2 genetics, Induced Pluripotent Stem Cells metabolism, Proteomics methods, Inflammation metabolism, Transcriptome, Microglia metabolism, Neurons metabolism
- Abstract
induced-pluripotent stem cell (iPSC)-derived neurospheroid (NSPH) models are an emerging in vitro toolkit to study the influence of inflammatory triggers on neurodegeneration and repair in a 3D neural environment. In contrast to their human counterpart, the absence of murine iPSC-derived NSPHs for profound characterisation and validation studies is a major experimental research gap, even though they offer the only possibility to truly compare or validate in vitro NSPH responses with in vivo brain responses. To contribute to these developments, we here describe the generation and characterisation of 5-week-old CX
3 CR1eGFP+/- CCR2RFP+/- murine (m)iPSC-derived bi-partite (neurons + astrocytes) and tri-partite (neurons + astrocytes + microglia) NSPH models that can be subjected to cellular activation following pro-inflammatory stimulation. First, cytokine analysis demonstrates that both bi-partite and tri-partite NSPHs can be triggered to release IL6 and CXCL10 following three days of stimulation with, respectively, TNFα + IL1β + IFNγ and LPS + IFNγ. Additionally, immunocytochemical analysis for G3BP1 and PABPC1 revealed the development of stress granules in both bi-partite and tri-partite NSPHs after 3 days of stimulation. To further investigate the observed signs of inflammatory response and cellular stress, we performed an untargeted transcriptomic and proteomic analysis of bi- and tri-partite NSPHs under steady-state and inflammatory conditions. Here, using the combined differential gene and protein expression profiles between unstimulated and stimulated NSPHs, Ingenuity Pathway Analysis (IPA) confirms the activation of canonical pathways associated with inflammation and cellular stress in both bi-partite and tri-partite NSPHs. Moreover, our multi-omics analysis suggests a higher level of downstream inflammatory responses, impairment of homeostatic and developmental processes, as well as activation of cell death processes in stimulated tri-partite NSPHs compared to bi-partite NSPHs. Concluding, these results emphasise the advantages of including microglia in NSPH research to study inflammation-induced neurodegeneration in a 3D neural environment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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23. Machine learning-driven diagnosis of multiple sclerosis from whole blood transcriptomics.
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Omrani M, Chiarelli RR, Acquaviva M, Bassani C, Dalla Costa G, Montini F, Preziosa P, Pagani L, Grassivaro F, Guerrieri S, Romeo M, Sangalli F, Colombo B, Moiola L, Zaffaroni M, Pietroboni A, Protti A, Puthenparampil M, Bergamaschi R, Comi G, Rocca MA, Martinelli V, Filippi M, and Farina C
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- Humans, Male, Female, Adult, Middle Aged, Demyelinating Diseases genetics, Demyelinating Diseases blood, Demyelinating Diseases diagnosis, Algorithms, Gene Expression Profiling methods, Machine Learning, Multiple Sclerosis blood, Multiple Sclerosis genetics, Multiple Sclerosis diagnosis, Transcriptome genetics
- Abstract
Multiple sclerosis (MS) is a neurological disorder characterized by immune dysregulation. It begins with a first clinical manifestation, a clinically isolated syndrome (CIS), which evolves to definite MS in case of further clinical and/or neuroradiological episodes. Here we evaluated the diagnostic value of transcriptional alterations in MS and CIS blood by machine learning (ML). Deep sequencing of more than 200 blood RNA samples comprising CIS, MS and healthy subjects, generated transcriptomes that were analyzed by the binary classification workflow to distinguish MS from healthy subjects and the Time-To-Event pipeline to predict CIS conversion to MS along time. To identify optimal classifiers, we performed algorithm benchmarking by nested cross-validation with the train set in both pipelines and then tested models generated with the train set on an independent dataset for final validation. The binary classification model identified a blood transcriptional signature classifying definite MS from healthy subjects with 97% accuracy, indicating that MS is associated with a clear predictive transcriptional signature in blood cells. When analyzing CIS data with ML survival models, prediction power of CIS conversion to MS was about 72% when using paraclinical data and 74.3% when using blood transcriptomes, indicating that blood-based classifiers obtained at the first clinical event can efficiently predict risk of developing MS. Coupling blood transcriptomics with ML approaches enables retrieval of predictive signatures of CIS conversion and MS state, thus introducing early non-invasive approaches to MS diagnosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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24. Predicting psychosocial intervention response from baseline gene expression.
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Ricon-Becker I, West TN, Fredrickson BL, Kaplan DM, Mehl MR, Raison CL, and Cole SW
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- Humans, Male, Female, Adult, Middle Aged, Gene Expression genetics, Cyclic AMP Response Element-Binding Protein metabolism, Cyclic AMP Response Element-Binding Protein genetics, Algorithms, NF-kappa B metabolism, Empathy physiology, Loneliness psychology, Meditation methods, Mindfulness methods, Psychosocial Intervention methods, Stress, Psychological metabolism, Stress, Psychological genetics, Stress, Psychological therapy
- Abstract
To address the challenge of predicting psychological response to a psychosocial intervention we tested the possibility that baseline gene expression profiles might provide information above and beyond baseline psychometric measures. The genomics strategy utilized individual level inferences of transcription factor activity to predict changes in loneliness and affect in response to two well-established meditation interventions. Initial algorithm development analyses focused on three a-priori defined stress-related gene regulation pathways (CREB, GR, and NF-ĸB) as inferred from TELiS promoter-based bioinformatic analysis of basal (pre-intervention) blood samples from a randomized-controlled trial comparing a compassion-based meditation (CM, n = 45) with mindfulness meditation (MM, n = 44). Greater baseline CREB activity (but not GR or NF-ĸB) predicted greater reductions from pre- to post-intervention in loneliness (b = -0.24, p = 0.016) and negative emotions (b = -0.23, p = 0.017) for CM, but not for MM. A second algorithm validation analysis applied the same approach to another randomized controlled trial comparing CM (n = 42) with MM (n = 38) and a health education control condition (n = 41). Similarly, greater baseline CREB activity predicted greater pre- to post-intervention decreases in loneliness (b = -0.24, p = 0.029) and greater increases in satisfaction with life (b = 0.21, p = 0.046) for the CM condition only. Baseline CREB activity was not associated with baseline psychometric measures in either study. Results raise the possibility that pre-intervention gene expression profiles may reflect non-conscious psychobiological states that affect psychological responses to distinct psychosocial interventions, and thereby help personalize intervention selection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)
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- 2024
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25. House dust mite-induced asthma exacerbates Alzheimer's disease changes in the brain of the App NL-G-F mouse model of disease.
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Sahu B, Nookala S, Floden AM, Ambhore NS, Sathish V, Klug MG, and Combs CK
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- Animals, Female, Mice, Male, Plaque, Amyloid pathology, Plaque, Amyloid metabolism, Amyloid beta-Protein Precursor genetics, Amyloid beta-Protein Precursor metabolism, Bronchoalveolar Lavage Fluid immunology, Cytokines metabolism, Alzheimer Disease metabolism, Alzheimer Disease pathology, Asthma metabolism, Asthma immunology, Disease Models, Animal, Mice, Transgenic, Amyloid beta-Peptides metabolism, Brain metabolism, Brain pathology, Pyroglyphidae immunology, Mice, Inbred C57BL
- Abstract
Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques, neuroinflammation, and neuronal death. Besides aging, various comorbidities increase the risk of AD, including obesity, diabetes, and allergic asthma. Epidemiological studies have reported a 2.17-fold higher risk of dementia in asthmatic patients. However, the molecular mechanism(s) underlying this asthma-associated AD exacerbation is unknown. This study was designed to explore house dust mite (HDM)-induced asthma effects on AD-related brain changes using the App
NL-G-F transgenic mouse model of disease. Male and female 8-9 months old C57BL/6J wild type and AppNL-G-F mice were exposed to no treatment, saline sham, or HDM extract every alternate day for 16 weeks for comparison across genotypes and treatment. Mice were euthanized at the end of the experiment, and broncho-alveolar lavage fluid (BALF), blood, lungs, and brains were collected. BALF was used to quantify immune cell phenotype, cytokine levels, total protein content, lactate dehydrogenase (LDH) activity, and total IgE. Lungs were sectioned and stained with hematoxylin and eosin, Alcian blue, and Masson's trichrome. Serum levels of cytokines and soluble Aβ1-40/42 were quantified. Brains were sectioned and immunostained for Aβ, GFAP, CD68, and collagen IV. Finally, frozen hippocampi and temporal cortices were used to perform Aβ ELISAs and cytokine arrays, respectively. HDM exposure led to increased levels of inflammatory cells, cytokines, total protein content, LDH activity, and total IgE in the BALF, as well as increased pulmonary mucus and collagen staining in both sexes and genotypes. Levels of serum cytokines increased in all HDM-exposed groups. Serum from the AppNL-G-F HDM-induced asthma group also had significantly increased soluble Aβ1-42 levels in both sexes. In agreement with this peripheral change, hippocampi from asthma-induced male and female AppNL-G-F mice demonstrated elevated Aβ plaque load and increased soluble Aβ 1-40/42 and insoluble Aβ 1-40 levels. HDM exposure also increased astrogliosis and microgliosis in both sexes of AppNL-G-F mice, as indicated by GFAP and CD68 immunoreactivity, respectively. Additionally, HDM exposure elevated cortical levels of several cytokines in both sexes and genotypes. Finally, HDM-exposed groups also showed a disturbed blood-brain-barrier (BBB) integrity in the hippocampus of AppNL-G-F mice, as indicated by decreased collagen IV immunoreactivity. HDM exposure was responsible for an asthma-like condition in the lungs that exacerbated Aβ pathology, astrogliosis, microgliosis, and cytokine changes in the brains of male and female AppNL-G-F mice that correlated with reduced BBB integrity. Defining mechanisms of asthma effects on the brain may identify novel therapeutic targets for asthma and AD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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26. Go take a hike: The effects of nature experiences on inflammation.
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Wilson KL and Way BM
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- Humans, Animals, Nature, Stress, Psychological psychology, Stress, Psychological metabolism, Stress, Psychological immunology, Inflammation immunology
- Abstract
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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- 2024
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27. Sex differences in the inflammation-depression link: A systematic review and meta-analysis.
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Jarkas DA, Villeneuve AH, Daneshmend AZB, Villeneuve PJ, and McQuaid RJ
- Subjects
- Female, Humans, Male, Depression blood, Depression immunology, Depression metabolism, Interleukin-1beta blood, Interleukin-1beta metabolism, Interleukin-6 blood, Interleukin-6 metabolism, Tumor Necrosis Factor-alpha blood, Tumor Necrosis Factor-alpha metabolism, Biomarkers blood, Biomarkers metabolism, C-Reactive Protein metabolism, C-Reactive Protein analysis, Depressive Disorder, Major blood, Depressive Disorder, Major immunology, Depressive Disorder, Major metabolism, Inflammation blood, Inflammation metabolism, Sex Factors
- Abstract
Major Depressive Disorder (MDD) is a heterogeneous disorder that affects twice as many women than men. Precluding advances in more tailored and efficacious treatments for depression is the lack of reliable biomarkers. While depression is linked to elevations in inflammatory immune system functioning, this relationship is not evident among all individuals with depression and may vary based on symptom subtypes and/or sex. This systematic review and meta-analysis examined whether inflammatory immune peripheral markers of depression are sex-specific. PRISMA guidelines were followed for the systematic review, and a comprehensive search strategy that identified studies from PubMed and PsycInfo was applied. Studies were included if they reported C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor (TNF)-α and/or IL-1β for males and/or females among depressed and healthy adults. We identified 23 studies that satisfied these inclusion criteria. Random-effects meta-analysis models were fit, and measures of association were summarized between levels of circulating markers of inflammation in depressed and healthy males and females. Sex-based analyses revealed elevated levels of CRP among females with depression (Cohen's d = 0.19) relative to their healthy counterparts (p = 0.02), an effect not apparent among males (Cohen's d = -0.01). Similarly, levels of IL-6 were increased among females with depression compared to healthy controls (Cohen's d = 0.51; p = 0.04), but once again this was not found among males (Cohen's d = 0.16). While TNF-α levels were elevated among individuals with depression compared to controls (p = 0.01), no statistically significant sex differences were found. The meta-analysis for IL-1β resulted in only three articles, and thus, results are presented in the supplemental section. This meta-analysis advances our understanding of the unique involvement of inflammatory biomarkers in depression among men and women, which may help inform more tailored sex-specific treatment approaches in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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28. Modulation of anxiety-like behavior in galactooligosaccharide-fed mice: A potential role for bacterial tryptophan metabolites and reduced microglial reactivity.
- Author
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Spencer KD, Bline H, Chen HJ, Verosky BG, Hilt ME, Jaggers RM, Gur TL, Mathé EA, and Bailey MT
- Subjects
- Animals, Mice, Male, Behavior, Animal drug effects, Prebiotics administration & dosage, Colon metabolism, Tumor Necrosis Factor-alpha metabolism, Chemokine CCL2 metabolism, Anxiety metabolism, Microglia metabolism, Mice, Inbred C57BL, Tryptophan metabolism, Gastrointestinal Microbiome drug effects, Gastrointestinal Microbiome physiology, Prefrontal Cortex metabolism, Oligosaccharides metabolism, Oligosaccharides pharmacology, Oligosaccharides administration & dosage
- Abstract
Prebiotic galactooligosaccharides (GOS) reduce anxiety-like behaviors in mice and humans. However, the biological pathways behind these behavioral changes are not well understood. To begin to study these pathways, we utilized C57BL/6 mice that were fed a standard diet with or without GOS supplementation for 3 weeks prior to testing on the open field. After behavioral testing, colonic contents and serum were collected for bacteriome (16S rRNA gene sequencing, colonic contents only) and metabolome (UPLC-MS, colonic contents and serum data) analyses. As expected, GOS significantly reduced anxiety-like behavior (i.e., increased time in the center) and decreased cytokine gene expression (Tnfa and Ccl2) in the prefrontal cortex. Notably, time in the center of the open field was significantly correlated with serum methyl-indole-3-acetic acid (methyl-IAA). This metabolite is a methylated form of indole-3-acetic acid (IAA) that is derived from bacterial metabolism of tryptophan. Sequencing analyses showed that GOS significantly increased Lachnospiraceae UCG006 and Akkermansia; these taxa are known to metabolize both GOS and tryptophan. To determine the extent to which methyl-IAA can affect anxiety-like behavior, mice were intraperitoneally injected with methyl-IAA. Mice given methyl-IAA had a reduction in anxiety-like behavior in the open field, along with lower Tnfa in the prefrontal cortex. Methyl-IAA was also found to reduce TNF-α (as well as CCL2) production by LPS-stimulated BV2 microglia. Together, these data support a novel pathway through which GOS reduces anxiety-like behaviors in mice and suggests that the bacterial metabolite methyl-IAA reduces microglial cytokine and chemokine production, which in turn reduces anxiety-like behavior., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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29. A rapidly progressive multiple system atrophy-cerebellar variant model presenting marked glial reactions with inflammation and spreading of α-synuclein oligomers and phosphorylated α-synuclein aggregates.
- Author
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Yamaguchi H, Nishimura Y, Matsuse D, Sekiya H, Masaki K, Tanaka T, Saiga T, Harada M, Kira YI, Dickson DW, Fujishima K, Matsuo E, Tanaka KF, Yamasaki R, Isobe N, and Kira JI
- Subjects
- Animals, Humans, Mice, Cerebellum metabolism, Cerebellum pathology, Demyelinating Diseases metabolism, Demyelinating Diseases pathology, Disease Models, Animal, Inflammation metabolism, Mice, Transgenic, Neuroglia metabolism, Oligodendroglia metabolism, Phosphorylation, alpha-Synuclein metabolism, Multiple System Atrophy metabolism, Multiple System Atrophy pathology
- Abstract
Multiple system atrophy (MSA) is a severe α-synucleinopathy facilitated by glial reactions; the cerebellar variant (MSA-C) preferentially involves olivopontocerebellar fibres with conspicuous demyelination. A lack of aggressive models that preferentially involve olivopontocerebellar tracts in adulthood has hindered our understanding of the mechanisms of demyelination and neuroaxonal loss, and thus the development of effective treatments for MSA. We therefore aimed to develop a rapidly progressive mouse model that recaptures MSA-C pathology. We crossed Plp1-tTA and tetO-SNCA*A53T mice to generate Plp1-tTA::tetO-SNCA*A53T bi-transgenic mice, in which human A53T α-synuclein-a mutant protein with enhanced aggregability-was specifically produced in the oligodendrocytes of adult mice using Tet-Off regulation. These bi-transgenic mice expressed mutant α-synuclein from 8 weeks of age, when doxycycline was removed from the diet. All bi-transgenic mice presented rapidly progressive motor deterioration, with wide-based ataxic gait around 22 weeks of age and death around 30 weeks of age. They also had prominent demyelination in the brainstem/cerebellum. Double immunostaining demonstrated that myelin basic protein was markedly decreased in areas in which SM132, an axonal marker, was relatively preserved. Demyelinating lesions exhibited marked ionised calcium-binding adaptor molecule 1-, arginase-1-, and toll-like receptor 2-positive microglial reactivity and glial fibrillary acidic protein-positive astrocytic reactivity. Microarray analysis revealed a strong inflammatory response and cytokine/chemokine production in bi-transgenic mice. Neuronal nuclei-positive neuronal loss and patchy microtubule-associated protein 2-positive dendritic loss became prominent at 30 weeks of age. However, a perceived decrease in tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta in bi-transgenic mice compared with wild-type mice was not significant, even at 30 weeks of age. Wild-type, Plp1-tTA, and tetO-SNCA*A53T mice developed neither motor deficits nor demyelination. In bi-transgenic mice, double immunostaining revealed human α-synuclein accumulation in neurite outgrowth inhibitor A (Nogo-A)-positive oligodendrocytes beginning at 9 weeks of age; its expression was further increased at 10 to 12 weeks, and these increased levels were maintained at 12, 24, and 30 weeks. In an α-synuclein-proximity ligation assay, α-synuclein oligomers first appeared in brainstem oligodendrocytes as early as 9 weeks of age; they then spread to astrocytes, neuropil, and neurons at 12 and 16 weeks of age. α-Synuclein oligomers in the brainstem neuropil were most abundant at 16 weeks of age and decreased thereafter; however, those in Purkinje cells successively increased until 30 weeks of age. Double immunostaining revealed the presence of phosphorylated α-synuclein in Nogo-A-positive oligodendrocytes in the brainstem/cerebellum as early as 9 weeks of age. In quantitative assessments, phosphorylated α-synuclein gradually and successively accumulated at 12, 24, and 30 weeks in bi-transgenic mice. By contrast, no phosphorylated α-synuclein was detected in wild-type, tetO-SNCA*A53T, or Plp1-tTA mice at any age examined. Pronounced demyelination and tubulin polymerisation, promoting protein-positive oligodendrocytic loss, was closely associated with phosphorylated α-synuclein aggregates at 24 and 30 weeks of age. Early inhibition of mutant α-synuclein expression by doxycycline diet at 23 weeks led to fully recovered demyelination; inhibition at 27 weeks led to persistent demyelination with glial reactions, despite resolving phosphorylated α-synuclein aggregates. In conclusion, our bi-transgenic mice exhibited progressively increasing demyelination and neuroaxonal loss in the brainstem/cerebellum, with rapidly progressive motor deterioration in adulthood. These mice showed marked microglial and astrocytic reactions with inflammation that was closely associated with phosphorylated α-synuclein aggregates. These features closely mimic human MSA-C pathology. Notably, our model is the first to suggest that α-synuclein oligomers may spread from oligodendrocytes to neurons in transgenic mice with human α-synuclein expression in oligodendrocytes. This model of MSA is therefore particularly useful for elucidating the in vivo mechanisms of α-synuclein spreading from glia to neurons, and for developing therapies that target glial reactions and/or α-synuclein oligomer spreading and aggregate formation in MSA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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30. Leukocytes: Likely not the immune system's white knights in the wake of early life adversity.
- Author
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Gano A
- Subjects
- Humans, Animals, Stress, Psychological immunology, Leukocytes immunology, Immune System, Adverse Childhood Experiences
- Abstract
Competing Interests: Declaration of competing interest The author declares that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
- Published
- 2024
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31. TLR2 immunotherapy suppresses neuroinflammation, tau spread, and memory loss in rTg4510 mice.
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Kim Y, Ryu SH, Hyun J, Cho YS, and Jung YK
- Subjects
- Animals, Mice, Disease Models, Animal, Hippocampus metabolism, Inflammation metabolism, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Toll-Like Receptor 2 metabolism, Alzheimer Disease metabolism, Immunotherapy methods, Memory Disorders metabolism, Microglia metabolism, Neuroinflammatory Diseases metabolism, Neurons metabolism, tau Proteins metabolism
- Abstract
In Alzheimer's disease, chronic neuroinflammation is accompanied by amyloid and tau pathologies. Especially, aberrant microglial activation is known to precede the regional tau pathology development, but the mechanisms how microglia affect tau spread remain largely unknown. Here, we found that toll-like receptor 2 (TLR2) in microglia recognizes oligomeric tau as a pathogenic ligand and induces inflammatory responses. Knockout of TLR2 reduced tau pathology and microglial activation in rTg4510 tau transgenic mice. Treatment of oligomeric tau induced TLR2 activation and increased inflammatory responses in microglial cells. TLR2 further mediated the tau-induced microglial activation and promoted tau uptake into neurons in neuron-microglia co-culture system and in mouse hippocampus after intracranial tau injection. Importantly, treatment with anti-TLR2 monoclonal antibody Tomaralimab blocked TLR2 activation and inflammatory responses in a dose-dependent manner, and significantly reduced tau spread and memory loss in rTg4510 mice. These results suggest that TLR2 plays a crucial role in tau spread by causing aberrant microglial activation in response to pathological tau, and blocking TLR2 with immunotherapy may ameliorate tau pathogenesis in Alzheimer's disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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32. Improving the validity of studies on the relationship between social health and Immunity of older Adults: Letter to the editor.
- Author
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Pohan RA
- Subjects
- Humans, Aged, Male, Female, Loneliness psychology, Aging immunology, Aging psychology, Social Support, Mental Health, Biomarkers blood, Cross-Sectional Studies, Immunity physiology, Immune System, Sex Factors, Aged, 80 and over, Marital Status
- Abstract
The recent study by Isabelle F. van der Velpen et al., (2024), published in Brain Behavior and Immunity, explores the intricate relationship between social health, marital status, and their effects on immune markers and neurodegeneration in the elderly. It highlights significant gender and marital status differences impacting immune system health and plasma biomarkers. Despite its depth, the study's reliance on self-reported measures for loneliness and social support may not fully capture the complexity of social health, which includes dynamic components like social integration. The use of broad immune indices, such as the Granulocyte to Lymphocyte Ratio and Systemic Immune Inflammation index, limits the detailed understanding of specific immune pathways. The study's cross-sectional design restricts causal inferences, underscoring the need for longitudinal research to establish temporal sequences and causality in the relationship between social health, immune function, and neurodegeneration. Additionally, while the study identifies gender differences, it does not delve into the mechanisms driving these differences, nor does it account for psychosocial factors such as mental health, physical activity, and diet. These findings emphasize the importance of gender-specific health interventions and policies to address social determinants like marital status, which significantly impact long-term health outcomes in older adults., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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33. Rhythmic gamma frequency light flickering ameliorates stress-related behaviors and cognitive deficits by modulating neuroinflammatory response through IL-12-Mediated cytokines production in chronic stress-induced mice.
- Author
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Yao J, Zhang L, Zhang C, Chen X, Bao K, Hou S, Yin Y, Liu K, Wen Q, Huang X, and Song L
- Subjects
- Animals, Mice, Male, Mice, Inbred C57BL, Corticosterone metabolism, Neuroinflammatory Diseases metabolism, Light, Behavior, Animal, Disease Models, Animal, Stress, Psychological metabolism, Cognitive Dysfunction metabolism, Cognitive Dysfunction etiology, Cytokines metabolism, Gamma Rhythm
- Abstract
Chronic stress enhances the risk for psychiatric disorders and induces depression and cognitive impairment. Gamma oscillations are essential for neurocircuit function, emotion, and cognition. However, the influence of gamma entrainment by sensory stimuli on specific aspects of chronic stress-induced responses remains unclear. Mice were subjected to corticosterone (CORT) administration and chronic restraint stress (CRS) for weeks, followed by rhythmic gamma frequency light flickering exposure. Local field potentials (LFPs) were recorded from the V1, CA1, and PFC regions to verify the light flicker on gamma oscillations. Behavioral tests were used to examine stress-related and memory-related behaviors. Golgi staining was performed to observe changes in spine morphology. Synaptosomes were isolated to determine the expression of synapse-related proteins through immunoblotting. RNA sequencing (RNA-seq) was applied to explore specific changes in the transcriptome. Immunofluorescence staining, real-time quantitative polymerase chain reaction (qPCR), and ELISA were used to evaluate microglial activation and cytokine levels. In this study, we demonstrated that rhythmic 40 Hz LF attenuated stress-related behavior and cognitive impairments by ameliorating the microstructural alterations in spine morphology and increasing the expression of GluN2A and GluA1 in chronically stressed mice. Transcriptome analysis revealed that significantly downregulated genes in LF-exposed CRS mice were enriched in neuroimmune-related signaling pathways. Rhythmic 40 Hz LF exposure significantly decreased the number of Iba1-positive microglia in the PFC and hippocampus, and the expression levels of the M1 markers of microglia iNOS and CD68 were reduced significantly in CRS mice. In addition, 40 Hz LF exposure suppressed the secretion of cytokines IL-12, which could regulate the production of IFN-γ and IL-10 in stressed mice. Our results demonstrate that exposure to rhythmic 40 Hz LF induces the neuroimmune response and downregulation of neuroinflammation with attenuated stress-related behaviors and cognitive function in CRS-induced mice. Our findings highlight the importance of sensory-evoked gamma entrainment as a potential therapeutic strategy for stress-related disorders treatment. Abbreviations: CORT, Chronic corticosterone treatment; CRS, Chronic restraint stress; IACUC, Institutional Animal Care and Use Committee; LF, light flickers; FST, Forced swim test; NSFT, Novelty-suppressed feeding test; SPT, Sucrose preference test; NSFT, Novelty-suppressed feeding; qPCR, Quantitative real-time polymerase chain reaction; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; PVDF, polyvinylidene fluoride; PBS, phosphate-buffered saline; PBS-T, phosphate-buffered saline plus 0.1% Tween 20; PVDF, polyvinylidene fluoride; GFAP, Glial fibrillary acidic protein; DAPI, 4',6-Diamid- ino-2-phenylindole; Iba1, Ionized calcium-binding adaptor molecule 1; iNOS, Inducible nitric oxide synthase; IL-10, Interleukin-10; IL6, Interleukin 6; IL-1β, Interleukin 1β; IL-12, Interleukin 12; TNF-α, Tumor necrosis factor alpha; IFN-γ, Interferon-gamma; TLR6 and 9, Toll-like Receptor 6 and 9., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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34. Refining the understanding of EPA's role in episodic migraine: A response to methodological considerations.
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Yang CP, Liu WC, Yang CC, Tsai IJ, and Su KP
- Subjects
- Humans, Migraine Disorders, Eicosapentaenoic Acid analogs & derivatives
- Abstract
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
- Published
- 2024
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35. Mitigating inflammatory response to sleep deficiency through low dose aspirin: A challenge or a chance for behavioural sleep medicine?
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Ballesio A
- Subjects
- Humans, Sleep physiology, Sleep drug effects, Animals, Anti-Inflammatory Agents, Non-Steroidal administration & dosage, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Aspirin administration & dosage, Inflammation, Sleep Deprivation
- Abstract
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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- 2024
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36. Altered brain metabolites in male nonhuman primate offspring exposed to maternal immune activation.
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Maddock RJ, Vlasova RM, Chen S, Iosif AM, Bennett J, Tanase C, Ryan AM, Murai T, Hogrefe CE, Schumann CD, Geschwind DH, Van de Water J, Amaral DG, Lesh TA, Styner MA, Kimberley McAllister A, Carter CS, and Bauman MD
- Subjects
- Animals, Male, Female, Pregnancy, Inositol metabolism, Aspartic Acid metabolism, Aspartic Acid analogs & derivatives, Creatine metabolism, Taurine metabolism, Choline metabolism, Disease Models, Animal, Glutamic Acid metabolism, Glutathione metabolism, Longitudinal Studies, Macaca mulatta, Prenatal Exposure Delayed Effects metabolism, Prenatal Exposure Delayed Effects immunology, Brain metabolism, Poly I-C pharmacology, Prefrontal Cortex metabolism
- Abstract
Converging data show that exposure to maternal immune activation (MIA) in utero alters brain development in animals and increases the risk of neurodevelopmental disorders in humans. A recently developed non-human primate MIA model affords opportunities for studies with uniquely strong translational relevance to human neurodevelopment. The current longitudinal study used 1H-MRS to investigate the developmental trajectory of prefrontal cortex metabolites in male rhesus monkey offspring of dams (n = 14) exposed to a modified form of the inflammatory viral mimic, polyinosinic:polycytidylic acid (Poly IC), in the late first trimester. Brain metabolites in these animals were compared to offspring of dams that received saline (n = 10) or no injection (n = 4). N-acetylaspartate (NAA), glutamate, creatine, choline, myo-inositol, taurine, and glutathione were estimated from PRESS and MEGA-PRESS acquisitions obtained at 6, 12, 24, 36, and 45 months of age. Prior investigations of this cohort reported reduced frontal cortical gray and white matter and subtle cognitive impairments in MIA offspring. We hypothesized that the MIA-induced neurodevelopmental changes would extend to abnormal brain metabolite levels, which would be associated with the observed cognitive impairments. Prefrontal NAA was significantly higher in the MIA offspring across all ages (p < 0.001) and was associated with better performance on the two cognitive measures most sensitive to impairment in the MIA animals (both p < 0.05). Myo-inositol was significantly lower across all ages in MIA offspring but was not associated with cognitive performance. Taurine was elevated in MIA offspring at 36 and 45 months. Glutathione did not differ between groups. MIA exposure in male non-human primates is associated with altered prefrontal cortex metabolites during childhood and adolescence. A positive association between elevated NAA and cognitive performance suggests the hypothesis that elevated NAA throughout these developmental stages reflects a protective or resilience-related process in MIA-exposed offspring. The potential relevance of these findings to human neurodevelopmental disorders is discussed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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37. Communication of inflammation.
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Hennessy MB
- Abstract
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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- 2024
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38. Microglial TREM2 promotes phagocytic clearance of damaged neurons after status epilepticus.
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Bosco DB, Kremen V, Haruwaka K, Zhao S, Wang L, Ebner BA, Zheng J, Xie M, Dheer A, Perry JF, Barath A, Nguyen AT, Worrell GA, and Wu LJ
- Abstract
In the central nervous system, triggering receptor expressed on myeloid cells 2 (TREM2) is exclusively expressed by microglia and is critical for microglial proliferation, migration, and phagocytosis. Microglial TREM2 plays an important role in neurodegenerative diseases, such as Alzheimer's disease and amyotrophic lateral sclerosis. However, little is known about how TREM2 affects microglial function within epileptogenesis. To investigate this, we utilized male TREM2 knockout (KO) mice within the murine intra-amygdala kainic acid seizure model. Electroencephalographic analysis, immunocytochemistry, and RNA sequencing revealed that TREM2 deficiency significantly promoted seizure-induced pathology. We found that TREM2 KO increased both the severity of acute status epilepticus and the number of spontaneous recurrent seizures characteristic of chronic focal epilepsy. Phagocytic clearance of damaged neurons by microglia was also impaired by TREM2 KO and reduced phagocytic activity correlated with increased spontaneous seizures. Analysis of human tissue from patients who underwent surgical resection for drug resistant temporal lobe epilepsy also showed a negative correlation between expression of the microglial phagocytic marker CD68 and focal to bilateral tonic-clonic generalized seizure history. These results indicate that microglial TREM2 and phagocytic activity are important to epileptogenic pathology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)
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- 2024
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39. Upregulation of delta opioid receptor by meningeal interleukin-10 prevents relapsing pain.
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Inyang KE, Sim J, Clark KB, Geron M, Monahan K, Evans C, O'Connell P, Laumet S, Peng B, Ma J, Heijnen CJ, Dantzer R, Scherrer G, Kavelaars A, Bernard M, Aldhamen YA, Folger JK, Bavencoffe A, and Laumet G
- Abstract
Chronic pain often includes periods of transient amelioration and even remission that alternate with severe relapsing pain. While most research on chronic pain has focused on pain development and maintenance, there is a critical unmet need to better understand the mechanisms that underlie pain remission and relapse. We found that interleukin (IL)-10, a pain resolving cytokine, is produced by resident macrophages in the spinal meninges during remission from pain and signaled to IL-10 receptor-expressing sensory neurons. Using unbiased RNA-sequencing, we identified that IL-10 upregulated expression and antinociceptive activity of δ-opioid receptor (δOR) in the dorsal root ganglion. Genetic or pharmacological inhibition of either IL-10 signaling or δOR triggered relapsing pain. Overall, our findings, from electrophysiology, genetic manipulation, flow cytometry, pharmacology, and behavioral approaches, indicate that remission of pain is not simply a return to the naïve state. Instead, remission is an adapted homeostatic state associated with lasting pain vulnerability resulting from persisting neuroimmune interactions within the nociceptive system. Broadly, this sheds light on the elusive mechanisms underlying recurrence a common aspect across various chronic pain conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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40. Pathophysiology, blood biomarkers, and functional deficits after intimate partner violence-related brain injury: Insights from emergency department patients and a new rat model.
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Sun M, Symons GF, Spitz G, O'Brien WT, Baker TL, Fan J, Martins BD, Allen J, Giesler LP, Mychasiuk R, van Donkelaar P, Brand J, Christie B, O'Brien TJ, O'Sullivan MJ, Mitra B, Wellington C, McDonald SJ, and Shultz SR
- Abstract
Intimate partner violence is a serious, but underappreciated, issue that predominantly affects women and often results in concussion (i.e., mild traumatic brain injury). However, concussion in intimate partner violence is unique because it often involves a concomitant strangulation which may exacerbate or alter the physiology and clinical presentation of the brain injury. Therefore, here we conducted human and rodent studies to provide insight into knowledge gaps related to the detection, pathophysiology, and functional consequences of intimate partner violence-related brain injury. We conducted the first study to analyze blood biomarkers and symptoms of brain injury in intimate partner violence patients presenting to an emergency department within 72 h of concussion. Intimate partner violence concussion patients, some of whom had also experienced a concomitant strangulation, had elevated serum neurofilament light and worse brain injury symptoms compared to healthy control, orthopedic trauma, and non-intimate partner violence concussion groups. We also developed the first rat model of non-fatal strangulation and examined the consequences of strangulation and concussion in isolation and in combination on pathophysiology, blood biomarkers, and behavior at 2 h and 1wk post-injury. Rats exposed to combined strangulation and concussion had exacerbated motor and cognitive deficits, neuroinflammation, and serum glial fibrillary acidic protein levels compared with either injury in isolation. Taken together, these rodent findings demonstrate that a concomitant strangulation modifies and exacerbates concussion pathophysiology, biomarkers, and functional consequences. Overall, these findings provide novel insights into intimate partner violence-related brain injury and provides a foundation for future translational studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2024
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41. Inflammatory pain resolution by mouse serum-derived small extracellular vesicles.
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Lin Z, Luo X, Wickman JR, Reddy D, DaCunza JT, Pande R, Tian Y, Kasimoglu EE, Triana V, Lee J, Furdui CM, Pink D, Sacan A, and Ajit SK
- Abstract
Current treatments for chronic pain have limited efficacy and significant side effects, warranting research on alternative strategies for pain management. One approach involves using small extracellular vesicles (sEVs), or exosomes, to transport beneficial biomolecular cargo to aid pain resolution. Exosomes are 30-150 nm sEVs that can be beneficial or harmful depending on their source and cargo composition. We report a comprehensive multi-modal analysis of different aspects of sEV characterization, miRNAs, and protein markers across sEV sources. To investigate the short and long-term effects of mouse serum-derived sEVs in pain modulation, sEVs from naïve control or spared nerve injury (SNI) model male donor mice were injected intrathecally into naïve male recipient mice. These sEVs transiently increased basal mechanical thresholds, an effect mediated by opioid signaling as this outcome was blocked by naltrexone. Mass Spectrometry of sEVs detected endogenous opioid peptide leu-enkephalin. sEVs from naïve female mice have higher levels of leu-enkephalin compared to male and showed stronger effects in male recipients. In investigating the long-term effect of sEVs, we observed that a single prophylactic intrathecal injection of sEVs two weeks prior to induction of the pain model in recipient mice accelerated recovery from inflammatory pain after complete Freund's adjuvant (CFA) injection. Our exploratory studies examining immune cell populations in spinal cord and dorsal root ganglion using ChipCytometry suggested alterations in immune cell populations 14 days post-CFA. Flow cytometry confirmed increases in CD206
+ macrophages in the spinal cord in sEV-treated mice. Collectively, these studies demonstrate multiple mechanisms by which sEVs can attenuate pain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)- Published
- 2024
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42. Sleep loss-induced oncogenic pathways are mediated via the neuron-specific interleukin-1 receptor accessory protein (AcPb).
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Lee Y, English EL, Schwartzmann CM, Liu Y, and Krueger JM
- Abstract
Interleukin-1β (IL1), a pleiotropic cytokine, is involved in sleep regulation, tumor ontogeny, and immune responses. IL1 receptor adaptor proteins, including the IL1 receptor accessory protein (AcP), and its neuron-specific isoform, AcPb, are required for IL1 signaling. The AcPb isoform is resultant from alternate splicing of the AcP transcript. Our previous studies using AcPb null (AcPb
-/- ) mice characterized its participation in sleep regulation and emergent neuronal/glial network properties. Here, we investigated the impact of acute sleep disruption (SD) on brain cancer-related pathways in wild-type (WT) and AcPb-/- mice, employing RNA sequencing methods. In WT mice, SD increased AcPb mRNA levels, but not AcP mRNA, confirming prior similar work in rats. Transcriptome and pathway enrichment analyses demonstrated significant alterations in cancer, immune, and viral disease-related pathways in WT mice after SD, which were attenuated in AcPb-/- mice including multiple upregulated Src phosphorylation-signaling-dependent genes associated with cancer progression and metastasis. Our RNAseq findings, were analyzed within the context of The Cancer Genome Atlas Program (TCGA) data base; revealing an upregulation of sleep- and cancer-linked genes (e.g., IL-17B, IL-17RA, LCN2) across various tumors, including brain tumors, compared to normal tissues. Sleep-linked factors, identified through TCGA analyses, significantly impact patient prognosis and survival, particularly in low-grade glioma (LGG) and glioblastoma multiforme (GBM) patients. Overall, our findings suggest that SD promotes a pro-tumor environment through AcPb-modulated pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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43. Blockage of ATGL-mediated breakdown of lipid droplets in microglia alleviates neuroinflammatory and behavioural responses to lipopolysaccharides.
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Robb JL, Boisjoly F, Machuca-Parra AI, Coursan A, Manceau R, Majeur D, Rodaros D, Bouyakdan K, Greffard K, Bilodeau JF, Forest A, Daneault C, Ruiz M, Laurent C, Arbour N, Layé S, Fioramonti X, Madore C, Fulton S, and Alquier T
- Abstract
Lipid droplets (LD) are triglyceride storing organelles that have emerged as an important component of cellular inflammatory responses. LD lipolysis via adipose triglyceride lipase (ATGL), the enzyme that catalyses the rate-limiting step of triglyceride lipolysis, regulates inflammation in peripheral immune and non-immune cells. ATGL elicits both pro- and anti-inflammatory responses in the periphery in a cell-type dependent manner. The present study determined the impact of ATGL inhibition and microglia-specific ATGL genetic loss-of-function on acute inflammatory and behavioural responses to pro-inflammatory insult. First, we evaluated the impact of lipolysis inhibition on lipopolysaccharide (LPS)-induced expression and secretion of cytokines and phagocytosis in mouse primary microglia cultures. Lipase inhibitors (ORlistat and ATGListatin) and LPS led to LD accumulation in microglia. Pan-lipase inhibition with ORlistat alleviated LPS-induced expression of IL-1β and IL-6. Specific inhibition of ATGL had a similar action on CCL2, IL-1β and IL-6 expression in both neonatal and adult microglia cultures. CCL2 and IL-6 secretion were also reduced by ATGListatin or knockdown of ATGL. ATGListatin increased phagocytosis in neonatal cultures independently from LPS treatment. Second, targeted and untargeted lipid profiling revealed that ATGListatin reduced LPS-induced generation of pro-inflammatory prostanoids and modulated ceramide species in neonatal microglia. Finally, the role of microglial ATGL in neuroinflammation was assessed using a novel microglia-specific and inducible ATGL knockout mouse model. Loss of microglial ATGL in adult male mice dampened LPS-induced expression of IL-6 and IL-1β and microglial density. LPS-induced sickness- and anxiety-like behaviours were also reduced in male mice with loss of ATGL in microglia. Together, our results demonstrate potent anti-inflammatory effects produced by pharmacological or genetic inhibition of ATGL-mediated triglyceride lipolysis and thereby propose that supressing microglial LD lipolysis has beneficial actions in acute neuroinflammatory conditions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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44. Remifentanil-induced inflammation in microglial cells: Activation of the PAK4-mediated NF-κB/NLRP3 pathway and onset of hyperalgesia.
- Author
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Cui C, Wu X, Dong S, Chen B, and Zhang T
- Abstract
Background: The perioperative use of remifentanil is associated with postoperative hyperalgesia, which can impair recovery and extend hospitalization. Recent studies have revealed that microglia-mediated activation of the NLRP3 inflammasome plays a critical role in opioid-induced hyperalgesia, with NF-κB acting as a pivotal activation point for NLRP3. Despite these findings, the specific molecular mechanisms underlying remifentanil-induced postoperative hyperalgesia remain unclear. This study aims to develop a model of remifentanil-induced hyperalgesia and investigate the molecular mechanisms, focusing on the NF-κB/NLRP3 pathway, using both in vitro and in vivo approaches., Method: We established a remifentanil-induced hyperalgesia model and performed proteomic analysis to identify differential protein expression in the spinal cord tissue of rats. NLRP3 or PAK4 antagonists were administered intrathecally in vivo, and mechanical pain thresholds in the hind paws were measured using Von Frey testing. In vitro, we applied NLRP3 or PAK4 inhibitors or used lentivirus infection to silence PAK4, NF-κB, and NLRP3 genes. Protein expression was assessed through immunohistochemistry, immunofluorescence, and Western blotting. Additionally, ELISA was performed to measure IL-1β and IL-18 levels, and RT-qPCR was conducted to evaluate the transcription of target genes., Results: Proteomic analysis revealed that remifentanil upregulates PAK4 protein in spinal cord tissue two hours after the surgery. In addition, remifentanil induces morphological changes in the spinal cord dorsal horn, characterized by increased expression of PAK4, p-p65, NLRP3 and Iba-1 proteins, which in turn leads to elevated IL-1β and IL-18 levels and an inflammatory response. Intrathecal injection of NLRP3 or PAK4 inhibitors mitigates remifentanil-induced hyperalgesia and associated changes. In vitro, downregulation of PAK4 inhibits the increase in PAK4, p-p65, NLRP3 and Caspase-1 induced by LPS. Conversely, the downregulation of NLRP3 does not impact the levels of PAK4 and p-p65 proteins, aligning with the in vivo results and suggesting that PAK4 acts as an upstream signaling molecule of NLRP3., Conclusion: Remifentanil can increase PAK4 expression in spinal cord dorsal horn cells by activating the NF-κB/NLRP3 pathway and mediating microglial activation, thereby contributing to postoperative hyperalgesia., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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45. The role of Kupffer cells in microbiota-brain communication: Sleep and fever signaling in response to lipopolysaccharide.
- Author
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Szentirmai É, Buckley K, and Kapás L
- Abstract
Microbial molecules translocated from the intestinal lumen into the host's internal environment play a role in various physiological functions. Previously, we identified that butyrate, a short-chain fatty acid produced by intestinal bacteria, lipoteichoic acid, a cell wall component of gram-positive bacteria, and lipopolysaccharide (LPS), a cell wall component of gram-negative bacteria, induce sleep when their naturally occurring translocation is mimicked by direct delivery into the portal vein. Our findings suggested that these microbial molecules exert their sleep-promoting effects within the hepatoportal region. In the present experiments, we tested the hypothesis that resident liver macrophages, known as Kupffer cells, play a crucial role in the LPS-responsive, sleep-promoting mechanisms within the hepatoportal region. Intraportal administration of LPS induced increased sleep and fever in control rats. Remarkably, in Kupffer cell-depleted animals, both of these responses were significantly suppressed. These findings highlight the potential role of Kupffer cells in mediating the non-rapid-eye movement sleep-promoting and febrile effects of LPS translocated from the intestinal microbiota into the portal circulation. The strategic location of Kupffer cells within the hepatoportal region, coupled with their ability to rapidly take up LPS and other microbial molecules, together with their high secretory activity of multiple signaling molecules, underlie their key role in the communication between the intestinal microbiota and the brain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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46. Neonatal inflammation impairs developmentally-associated microglia and promotes a highly reactive microglial subset.
- Author
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Dufour A, Heydari-Olya A, Foulon S, Réda C, Mokhtari A, Faivre V, Hua J, Bokobza C, Griffiths AD, Nghe P, Gressens P, Delahaye-Duriez A, and Van Steenwinckel J
- Abstract
Microglia and border-associated macrophages play critical roles in both immunity and neurodevelopment. The disruption of microglial development trajectories by neonatal inflammation is an important issue in research on neurodevelopmental disorders (NDDs), as models have suggested a strong association between inflammation and cognitive deficits. Here, we explored by single-cell RNA sequencing and flow cytometry the impact of neonatal inflammation in a mouse NDD model on the brain myeloid cell subsets. A specific subset of microglia expressing the complement receptor C5ar1 has been identified, in which inflammatory pathways are most strongly activated. Based on transcriptional similarity, this subset appears to originate from the most mature and "homeostatic" microglia at this stage of development and demonstrated hypersensitivity to inflammation. Besides that, Spp1-microglia supporting oligodendrocyte differentiation, primitive and proliferative microglia were reduced by the inflammation. These findings suggest major changes in microglial subsets developmental trajectories and reactivity contributing to NDDs induced by neonatal inflammation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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47. Dietary EPA and DHA enrichment of a high fat diet during doxorubicin-based chemotherapy attenuated neuroinflammatory gene expression in the brain of C57bl/6 ovariectomized mice.
- Author
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Ormiston K, Melink Z, Andridge R, Lustberg M, Courtney DeVries A, Murphy K, Emmers K, Ziouzenkova O, Belury MA, and Orchard TS
- Abstract
Chemotherapy agents in breast cancer are associated with chemotherapy-related cognitive impairments (CRCI). Mechanisms are not fully clear, but alterations of glucose and lipid metabolism, neuroinflammation and neurodegeneration may contribute to CRCI. The aim of this study was to investigate the combined effects of a high fat (HF) diet combined with doxorubicin-based chemotherapy on glucose and lipid metabolism, neuroinflammation, and neurodegeneration in mice. Additionally, we examined the therapeutic potential of dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to attenuate these effects. Female C57Bl/6 mice (n = 42) were fed HF, HFn-3 (2 % kcals as EPA + DHA) or Low Fat (LF) diets for seven weeks, with and without chemotherapy. In this study, two chemotherapy injections led to weight and body fat loss associated with a decrease in insulin resistance measured by HOMA-IR. HOMA-IR was significantly greater in HF versus LF groups; but HOMA-IR in HFn-3 group did not significantly differ from either HF or LF groups. Chemotherapy resulted in higher brain concentrations of the inflammatory chemokine KC/GRO. Compared to LF diet plus chemotherapy, HF diet plus chemotherapy upregulated multiple genes involved in neuroinflammation and neurodegeneration pathways. HFn-3 diet plus chemotherapy attenuated gene expression by downregulating multiple genes involved in neuroinflammation and blood brain barrier regulation, including Mapkapk2, Aqp4, and s100b, and upregulating Kcnb1 and Atxn3, genes involved in reduction of oxidative stress and anxiety, respectively. Overall, a HF diet combined with chemotherapy is associated with neuroinflammatory and neurodegenerative gene expression changes in this mouse model; dietary enrichment of EPA and DHA attenuated these effects. Further studies are needed to understand how diet impacts behavioral outcomes of CRCI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)
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- 2024
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48. Response Letter to "Cumulative infection burden, cognitive impairment and dementia".
- Author
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Lu Y
- Abstract
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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- 2024
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49. Cumulative infection burden, cognitive impairment and dementia.
- Author
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Shen CY, Li CP, Chang HC, and Gau SY
- Abstract
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
- Published
- 2024
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50. Metformin reprograms tryptophan metabolism via gut Microbiome-Derived bile acid metabolites to ameliorate Depression-Like behaviors in mice.
- Author
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Xie X, Li W, Xiong Z, Xu J, Liao T, Sun L, Xu H, Zhang M, Zhou J, Xiong W, Fu Z, Li Z, Han Q, Cui D, and Anthony DC
- Abstract
As an adjunct therapy, metformin enhances the efficacy of conventional antidepressant medications. However, its mode of action remains unclear. Here, metformin was found to ameliorate depression-like behaviors in mice exposed to chronic restraint stress (CRS) by normalizing the dysbiotic gut microbiome. Fecal transplants from metformin-treated mice ameliorated depressive behaviors in stressed mice. Microbiome profiling revealed that Akkermansia muciniphila (A. muciniphila), in particular, was markedly increased in the gut by metformin and that oral administration of this species alone was sufficient to reverse CRS-induced depressive behaviors and normalize aberrant stress-induced 5-hydroxytryptamine (5-HT) metabolism in the brain and gut. Untargeted metabolomic profiling further identified the bile acid metabolites taurocholate and deoxycholic acid as direct A. muciniphila-derived molecules that are, individually, sufficient to rescue the CRS-induced impaired 5-HT metabolism and depression-like behaviors. Thus, we report metformin reprograms 5-HT metabolism via microbiome-brain interactions to mitigate depressive syndromes, providing novel insights into gut microbiota-derived bile acids as potential therapeutic candidates for depressive mood disorders from bench to bedside., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)
- Published
- 2024
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