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Yonatan E, Shukha ON, Golani I, Abu-Ata S, Awad-Igbaria Y, Khatib N, Ginsberg Y, Palzur E, Beloosesky R, Shamir A. Maternal N-acetylcysteine supplementation in lactation ameliorates metabolic and cognitive deficits in adult offspring exposed to maternal obesity. Neuropharmacology 2025; 271:110390. [PMID: 40023441 DOI: 10.1016/j.neuropharm.2025.110390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 02/26/2025] [Accepted: 02/26/2025] [Indexed: 03/04/2025]
Abstract
Maternal obesity in pregnancy and lactation is linked to metabolic disturbances and neurodevelopmental problems in offspring, increasing the risk of psychiatric disorders in adulthood. We proposed that maternal N-acetyl cysteine (NAC) supplementation during lactation, a critical period for neurodevelopment, potentially protects offspring from developing cognitive impairment in adulthood. Fifteen young female ICR mice were randomly allocated to different experimental groups: high-fat diet (HFD; 60.3% fat before mating, during pregnancy and lactation), HFD-NAC of 300 mg/kg/day during lactation, CD (high-fat diet before mating, during pregnancy, and regular chow control diet of 8.2% fat during lactation), CD-NAC of 300 mg/kg/day during lactation and control group consuming regular chow diet. The serum inflammatory markers of the offspring were evaluated post-weaning, while metabolic markers, microglial density, and cognitive performance were assessed in adulthood using the novel Object Recognition and Morris Water Maze tests. Our results demonstrate maternal obesity during gestation and lactation increased body weight, hepatic steatosis, and microglial cell density in the dentate gyrus (DG) and cortex. Furthermore, these offspring exhibited reduced spatial learning abilities in adulthood, regardless of sex. However, maternal NAC administration during lactation and maternal diet intervention significantly reduced brain microglial density and improved both male and female offspring metabolic profiles. More importantly, NAC supplementation during lactation, regardless of maternal diet, enhanced male offspring's learning ability in adulthood. Our findings indicate that administering NAC to obese mothers during the critical lactation period may offer protection against metabolic disturbances and cognitive deficits in adult offspring previously exposed to maternal obesity.
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Affiliation(s)
- Eden Yonatan
- Psychobiology Research Laboratory, Mazor Mental Health Center, Akko, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
| | - Orya Noa Shukha
- Psychobiology Research Laboratory, Mazor Mental Health Center, Akko, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
| | - Idit Golani
- Department of Biotechnology Engineering, Braude College of Engineering, Karmiel, Israel
| | - Saher Abu-Ata
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel; Research Institute of Galilee Medical Center, Nahariya, Israel
| | - Yaseen Awad-Igbaria
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel; Research Institute of Galilee Medical Center, Nahariya, Israel
| | - Nizar Khatib
- Department of Obstetrics and Gynecology, Rambam Medical Center, Haifa, Israel
| | - Yuval Ginsberg
- Department of Obstetrics and Gynecology, Rambam Medical Center, Haifa, Israel
| | - Eilam Palzur
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel; Research Institute of Galilee Medical Center, Nahariya, Israel
| | - Ron Beloosesky
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel; Department of Obstetrics and Gynecology, Rambam Medical Center, Haifa, Israel.
| | - Alon Shamir
- Psychobiology Research Laboratory, Mazor Mental Health Center, Akko, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
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Ahmed A, Hawken S, Gunz A, Talarico R, Yu C, Messerlian C, Zhang Y, Chen H, Weichenthal S, van Donkelaar A, Martin RV, Lavigne É. Prenatal exposure to fine particulate matter composition and risk of cerebral palsy: A population-based retrospective cohort study in Ontario, Canada. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2025; 375:126302. [PMID: 40280264 DOI: 10.1016/j.envpol.2025.126302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 04/16/2025] [Accepted: 04/22/2025] [Indexed: 04/29/2025]
Abstract
BACKGROUND Existing literature suggests an association between prenatal exposure to fine particulate air pollution (PM2.5) and cerebral palsy (CP). However, the impact of individual PM2.5 components (SO42-, NH4+, NO3-, SS, BC, dust, OM) on CP risk remains unknown. OBJECTIVE To examine the associations between prenatal exposure to PM2.5 components, and risk of CP among term births in Ontario, Canada. METHODS This was a retrospective cohort study that examined term births (gestational age ≥37 completed weeks) from April 2002 to December 2020. PM2.5 total mass and composition measures were assigned to maternal residence at birth using satellite-based estimates and ground-level monitoring data. Cohort data were compiled using health administrative databases. Single-pollutant distributed lag cox proportional hazard models, with and without additional adjustment for PM2.5 residuals, were used to investigate the associations between gestational exposures to PM2.5 total mass and its components. RESULTS 2,193,427 mother-infant pairs were identified, of which 3907 were diagnosed with CP during the follow-up period. Increased risk of CP was found for SO42- exposure during early pregnancy in both residual-adjusted (HR: 1.052, 95 % CI: 1.009-1.097, per IQR = 0.94 μg/m3), and non-adjusted models (HR: 1.050, 95 % CI: 1.007-1.095, per IQR = 0.94 μg/m3). The concentration-response relationship between the sensitive window found for SO42- and CP risk (weeks 4-9 of gestation) showcased a supralinear pattern. CONCLUSIONS Prenatal exposure to SO42- may be associated with increased CP risk during the early pregnancy period. Associations between prenatal PM2.5 total mass and composition exposure and CP risk should be further investigated.
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Affiliation(s)
- Amrin Ahmed
- Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada; School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
| | - Steven Hawken
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada; The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; ICES UOttawa, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Anna Gunz
- Children's Health Research Institute, London, Ontario, Canada; Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Robert Talarico
- ICES UOttawa, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Chengchun Yu
- ICES UOttawa, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Carmen Messerlian
- Department of Environmental Health, Harvard T.H. Chan School of Public Heath, Boston, MA, United States of America; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, United States of America; Massachusetts General Hospital Fertility Center, Department of Obstetrics and Gynecology, Boston, MA, United States of America
| | - Yu Zhang
- Department of Environmental Health, Harvard T.H. Chan School of Public Heath, Boston, MA, United States of America
| | - Hong Chen
- Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada; ICES UOttawa, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
| | - Scott Weichenthal
- Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada
| | - Aaron van Donkelaar
- Department of Energy, Environmental, and Chemical Engineering McKelvey School of Engineering, St. Louis, Missouri, United States of America
| | - Randall V Martin
- Department of Energy, Environmental, and Chemical Engineering McKelvey School of Engineering, St. Louis, Missouri, United States of America
| | - Éric Lavigne
- Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada; School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada; ICES UOttawa, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
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Srivastava V, O'Reilly C. Characteristics of cerebrospinal fluid in autism spectrum disorder - A systematic review. Neurosci Biobehav Rev 2025; 174:106202. [PMID: 40354953 DOI: 10.1016/j.neubiorev.2025.106202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 04/05/2025] [Accepted: 05/05/2025] [Indexed: 05/14/2025]
Abstract
Autism Spectrum Disorder (ASD) is a range of neurodevelopmental conditions characterized by impaired social interaction, learning, and restricted or repetitive behaviors. The underlying causes of ASD are still debated, but researchers have found many physiological traits like gut problems and impaired immune system to help understand the etiology of ASD. Cerebrospinal fluid (CSF) plays a critical role in maintaining the homeostasis of the neuronal environment and has, therefore, been analyzed in multiple conditions impacting the central nervous system. The study of CSF is crucial to understanding neurological disorders as its composition changes with the disorders, and these changes may indicate various disorder-related physiological mechanisms. For this systematic review, we searched PubMed, Scopus, and Web of Science for studies published between 1977 and 2025 and selected 49 studies after manual screening. We took stock of the evidence supporting the hypothesis that ASD alters the properties and composition of CSF. We systematically report on the different attributes of CSF in the ASD population that could be potential biomarkers and assist in understanding the origins and progression of ASD. We found that in CSF, immune markers, proteins, extra-axial CSF, folate, oxytocin, and vasopressin showed changes in ASD compared to the neurotypicals. We observed gaps in the literature due to variations in age and sample size and noted biases related to sex (i.e., samples are predominantly including male participants) and age (i.e., a handful of studies were conducted on adults). Our review highlights the need for more research on CSF in ASD to improve our understanding of this disorder and identify CSF biomarkers.
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Affiliation(s)
- Vandana Srivastava
- AI Institute, University of South Carolina, 5th floor, 1112 Greene St., Columbia, SC 29201, USA; Department of Computer Science and Engineering, University of South Carolina, 550 Assembly Street, Columbia, SC 29201, USA; Carolina Autism and Neurodevelopment Research Center, University of South Carolina, 1800 Gervais Street, Columbia, SC 29201, USA.
| | - Christian O'Reilly
- AI Institute, University of South Carolina, 5th floor, 1112 Greene St., Columbia, SC 29201, USA; Department of Computer Science and Engineering, University of South Carolina, 550 Assembly Street, Columbia, SC 29201, USA; Carolina Autism and Neurodevelopment Research Center, University of South Carolina, 1800 Gervais Street, Columbia, SC 29201, USA; Institute for Mind and Brain, University of South Carolina, 1800 Gervais Street, Columbia, SC 29201, USA.
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Huang PW, Chia-Min C, Sun CK, Cheng YS, Tang YH, Liu C, Hung KC. Therapeutic effects of probiotics on symptoms of irritability/emotional lability associated with neurodevelopmental conditions: A systematic review and meta-analysis of placebo-controlled trials. Complement Ther Med 2025; 89:103132. [PMID: 39864755 DOI: 10.1016/j.ctim.2025.103132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 12/24/2024] [Accepted: 01/17/2025] [Indexed: 01/28/2025] Open
Abstract
OBJECTIVES The current study aimed at investigating the efficacies of probiotics in alleviating the symptoms of irritability/emotional lability in individuals with a neurodevelopmental condition. METHODS Randomized placebo-controlled trials were identified through searching major electronic databases from inception to December, 2023. The outcome of interests included improvements in the symptoms of irritability/emotional lability. Outcomes were quantitatively expressed as effect size (ES) based on standardized mean difference (SMD) with 95 % confidence interval (CI). RESULTS Seven studies with 1479 participants were included in this meta-analysis. The primary results revealed a significant improvement in the symptoms of irritability/emotional lability in individuals with neurodevelopmental conditions receiving probiotics compared with the placebos (SMD= -0.17, p = 0.03). Subgroup analyses demonstrated an association between a significant improvement in the symptoms of irritability/emotional lability and the use probiotics relative to placebos only in studies using multiple-strain probiotics (SMD=-0.19, p = 0.04, three studies with 452 participant) but not in those adopting single-strain regimens. CONCLUSIONS Our study supported the use of probiotics for alleviating the symptoms of irritability/emotional lability in individuals with neurodevelopmental conditions, mainly in those receiving multiple-strain probiotics as supplements. Nevertheless, the limited number of studies targeting irritability as their primary outcomes, and most did not investigate other confounding factors such as dietary habits or consumption of other nutritional supplements may impair the robustness of evidence. Our results, which were derived from a limited number of available trials, warrant further large-scale clinical investigations for verification.
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Affiliation(s)
- Ping-Wen Huang
- Department of Emergency Medicine, Show Chwan Memorial Hospital, Changhua City, Taiwan
| | - Chen Chia-Min
- Department of Natural Biotechnology, Nanhua University, Chiayi, Taiwan
| | - Cheuk-Kwan Sun
- Department of Emergency Medicine, E-Da Dachang Hospital, I-Shou University, Kaohsiung City, Taiwan; School of Medicine, College of Medicine, I-Shou University, Kaohsiung City, Taiwan
| | - Yu-Shian Cheng
- Department of Psychiatry, Tsyr-Huey Mental Hospital, Kaohsiung Jen-Ai's Home, Taiwan
| | - Yen-Hsiang Tang
- Department of Critical Care Medicine, MacKay Memorial Hospital, Taipei, Taiwan; Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
| | - Cheng Liu
- Department of Physical Education, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Kuo-Chuan Hung
- Department of Anesthesiology, Chi Mei Medical Center, Tainan City, Taiwan.
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Villamor E, Beer RJ, Seeley AL, López‐Arana S, Marín C, Mora‐Plazas M. Infectious morbidity and white blood cell count associated with grade repetition and school absenteeism. Acta Paediatr 2025; 114:954-963. [PMID: 39569796 PMCID: PMC11976128 DOI: 10.1111/apa.17513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 10/17/2024] [Accepted: 11/14/2024] [Indexed: 11/22/2024]
Abstract
AIM Infections can impair cognitive development, but their role on adverse childhood educational outcomes is unknown. We examined the associations of infectious morbidity and inflammatory biomarkers with grade repetition and school absenteeism. METHODS We followed 2762 Colombian children aged 5-12 years for a school year. We quantified inflammatory biomarkers at enrolment and prospectively recorded incidence of gastrointestinal and respiratory infections, doctor visits and absent days from school using pictorial diaries. We estimated adjusted relative risks (ARR) with 95% confidence intervals (CI) for grade repetition and absenteeism by infectious morbidity burden and inflammatory biomarker categories, and percentages of the associations mediated through absenteeism. RESULTS Morbidity was associated with increased risk of grade repetition. ARR (95% CI) of grade repetition comparing high versus no incidence of gastrointestinal, respiratory and ear infections were, respectively, 2.17 (1.00, 4.72), 2.31 (1.28, 4.16) and 2.57 (1.13, 5.86). Infections also predicted school absenteeism, which mediated 35%, 31% and 38% of the corresponding morbidity-grade repetition associations. Elevated white blood cells (WBC), especially granulocytes, were related to increased grade repetition and school absenteeism risks. CONCLUSION Childhood infections and elevated WBC are associated with grade repetition and school absenteeism. Absenteeism does not fully explain the morbidity-grade repetition associations.
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Affiliation(s)
- Eduardo Villamor
- Department of EpidemiologyUniversity of Michigan School of Public HealthAnn ArborMichiganUSA
| | - Rachael J. Beer
- Department of EpidemiologyUniversity of Michigan School of Public HealthAnn ArborMichiganUSA
| | - Allison L. Seeley
- Department of EpidemiologyUniversity of Michigan School of Public HealthAnn ArborMichiganUSA
| | - Sandra López‐Arana
- Escuela de Nutrición y Dietética, Facultad de MedicinaUniversidad Finis TerraeSantiagoChile
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Lu W, Xu J, Zhang S, Zhang M, Huang J, Lu H. Immunotoxicity and neurotoxicity induced by natural borneol and synthetic borneol in zebrafish (Danio rerio). ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 296:118055. [PMID: 40220362 DOI: 10.1016/j.ecoenv.2025.118055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 03/05/2025] [Accepted: 03/12/2025] [Indexed: 04/14/2025]
Abstract
Borneol is widely used in the world, but in China, as a component of traditional Chinese medicine (TCM), it has a long history. According to the difference of composition and structure, borneol can be divided into natural borneol (NB) and synthetic borneol (SB). To explore the effect of borneol toxicity on environmental health, especially on aquatic animals, 6-hour post fertilization (hpf) zebrafish embryos were exposed to 10, 30, 50, or 70 mg/L NB or SB for 96 h. Various concentrations of borneol were applied to zebrafish embryos for 96 h, and the lethal curve was obtained. The exposure of borneol caused the heart rate to slow down and yolk sac edema. After exposure to borneol, the number of macrophages and neutrophils and the development of thymus were inhibited in zebrafish larvae. The gene expression level of cxcl-c1c, il-8 and il-1β were up-regulated after borneol exposure. While the expression level of chemokines ccl1 were decreased. After exposure to NB, the gene expression level of IFN-γ showed a trend of increasing first, then decreasing and then increasing, but it always showed an upward trend in the SB exposure group. After exposure to NB, the gene expression level of rag1 decreased, but in the SB exposure group, it increased first and then decreased. Through H&E staining, we also evaluated the pathologic changes of the spleen in adult zebrafish treated with borneol and found that the spleen was injured in borneol treated group. Finally, the locomotor behavior of zebrafish larvae was decreased after NB and SB exposure. NB and SB exposure affected the expression level of neurodevelopmental-related genes (epfa4, gap43, gfap, synapsinlla) and the specific expression of related genes (krox-20, pax2) in the brain region. Therefore, our research results show that borneol has immune and neurotoxic effects on zebrafish larvae, and the toxicity of SB was higher than that of NB, which is helpful to evaluate the safety of this drug more comprehensively.
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Affiliation(s)
- Wuting Lu
- Center for Clinical Medicine Research, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, China; Research Institute of Microbiology, Jiangxi Academy of Sciences, Nanchang 330012, China
| | - Jinkun Xu
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Developmental Biology of Organs, Jinggangshan University Medical Science Center, Ji'an 343009, China
| | - Shengping Zhang
- Faculty of Civil and Architectural Engineering, Nanchang Institute of Technology, Nanchang 330099, China
| | - Minhong Zhang
- Center for Clinical Medicine Research, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, China
| | - Junyun Huang
- Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, China.
| | - Huiqiang Lu
- Center for Clinical Medicine Research, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, China.
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García-Soto XR, Villanueva-Alameda MI, Fernández-Solana J, González-Bernal JJ, Bernal-Jiménez A, Santos-Martín L, García-Mellado J, Calvo-Simal S, Vélez-Santamaría R. Quality of Life and Psychological Functioning in Children with PFAPA Syndrome. Pediatr Rep 2025; 17:51. [PMID: 40407576 PMCID: PMC12101420 DOI: 10.3390/pediatric17030051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 04/05/2025] [Accepted: 04/17/2025] [Indexed: 05/26/2025] Open
Abstract
BACKGROUND/OBJECTIVES This study analyzes the impact of PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis, and adenitis) on health-related quality of life (HRQoL) and the psychological functioning of children and adolescents aged 2 to 1 years. METHODS A cross-sectional descriptive study was conducted with 62 participants (31 males and 31 females) diagnosed with PFAPA. The Strengths and Difficulties Questionnaire (SDQ) and the Family Impact Module scale of Pediatric Quality of Life Inventory (PedsQL) were used to assess psychological functioning and HRQoL, respectively. RESULTS Participants exhibited predominantly low HRQoL, particularly in physical health and emotional functioning. School functioning was also affected. However, social functioning and family relationships showed more favorable scores. A positive correlation was observed between age and emotional symptoms. Family concern was the most significantly impacted aspect. CONCLUSIONS PFAPA syndrome has a significant impact on the HRQoL of affected children and adolescents, particularly in physical and emotional aspects. A holistic approach is necessary for disease management, considering not only physical symptoms but also psychosocial and academic factors, as well as the impact on the family.
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Affiliation(s)
- Xosé Ramón García-Soto
- Clinical Psychology, University Hospital of Burgos, 09006 Burgos, Spain; (X.R.G.-S.); (M.I.V.-A.); (A.B.-J.); (L.S.-M.)
| | | | - Jessica Fernández-Solana
- Department of Health Sciences, University of Burgos, 09001 Burgos, Spain; (J.J.G.-B.); (R.V.-S.)
| | | | - Arancha Bernal-Jiménez
- Clinical Psychology, University Hospital of Burgos, 09006 Burgos, Spain; (X.R.G.-S.); (M.I.V.-A.); (A.B.-J.); (L.S.-M.)
| | - Lara Santos-Martín
- Clinical Psychology, University Hospital of Burgos, 09006 Burgos, Spain; (X.R.G.-S.); (M.I.V.-A.); (A.B.-J.); (L.S.-M.)
| | | | - Sara Calvo-Simal
- Research Unit, University Hospital of Burgos, 09006 Burgos, Spain;
| | - Rodrigo Vélez-Santamaría
- Department of Health Sciences, University of Burgos, 09001 Burgos, Spain; (J.J.G.-B.); (R.V.-S.)
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Ernst LM, Freedman AA, Odom‐Konja RM, Keenan‐Devlin L, Miller GE, Cole S, Crockett A, Borders A. Associations of Serum Inflammatory Biomarkers During Pregnancy With Placental Pathology and Placental Gene Expression at Delivery. Am J Reprod Immunol 2025; 93:e70062. [PMID: 40173254 PMCID: PMC11964289 DOI: 10.1111/aji.70062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 02/05/2025] [Accepted: 02/19/2025] [Indexed: 04/04/2025] Open
Abstract
PROBLEM We sought to investigate whether maternal inflammatory cytokines during pregnancy are associated with histologic inflammatory or vascular lesions in the placenta and/or correlated with gene expression patterns in the placenta. METHOD OF STUDY We leveraged data from a large randomized controlled trial (RCT) at a single site. Maternal serum was collected in the second and third trimesters, and a composite inflammatory score was created using five measured biomarkers (CRP, IL-6, IL-1ra, IL-10, and TNF-α). Placentas were collected at delivery for histological analysis and four major patterns of placental injury were characterized. Fresh small chorionic villous biopsies were collected for placental genome-wide mRNA profiling. Transcripts showing >2-fold differential expression over the 4-SD range of circulating inflammatory biomarkers were reported, adjusting for potential confounders. RESULTS The primary analysis included 601 participants. A one standard deviation increase in the third-trimester inflammatory composite was associated with increased odds of chronic inflammation in the placenta (OR: 1.23, 95% CI 1.01, 1.51;). This was driven primarily by elevations in IL-10 (OR: 1.37; 99% CI: 1.06, 1.77). Higher maternal IL-10 in circulation was associated with bioinformatic indications of reduced pro-inflammatory gene regulation pathways in the placenta (AP1 decreased 25%, p = 0.003; NF-kB decreased 53%, p = 0.003) and indications of increased STAT family signaling pathways which mediate signaling through the IL-10 receptor (increased 73%, p = 0.002). CONCLUSIONS Our results indicate that elevated maternal circulating IL-10 during pregnancy is associated with chronic inflammatory lesions in the placenta at delivery. Additionally, higher levels of circulating IL-10 are associated with upregulated STAT signaling pathways in placental tissues.
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Affiliation(s)
- Linda M. Ernst
- Department of Pathology and Laboratory MedicineEndeavor HealthEvanstonIllinoisUSA
- Department of PathologyUniversity of Chicago Pritzker School of MedicineChicagoIllinoisUSA
| | - Alexa A. Freedman
- Department of Preventive MedicineNorthwestern University Feinberg School of MedicineChicagoIllinoisUSA
| | | | - Lauren Keenan‐Devlin
- Department of Obstetrics and GynecologyEndeavor HealthEvanstonIllinoisUSA
- Department of Obstetrics and GynecologyUniversity of Chicago Pritzker School of MedicineChicagoIllinoisUSA
| | - Gregory E. Miller
- Department of Psychology and Institute for Policy ResearchNorthwestern UniversityEvanstonIllinoisUSA
| | - Steve Cole
- Department of Medicine, Division of Hematology‐Oncology, and Department of Psychiatry and Biobehavioral SciencesUniversity of CaliforniaLos AngelesCaliforniaUSA
| | - Amy Crockett
- Department of Obstetrics and GynecologyPrisma HealthGreenvilleSouth CarolinaUSA
| | - Ann Borders
- Department of Obstetrics and GynecologyEndeavor HealthEvanstonIllinoisUSA
- Department of Obstetrics and GynecologyUniversity of Chicago Pritzker School of MedicineChicagoIllinoisUSA
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Wang H, Cheng Z, Xu Z, Wang M, Sun X, Liu W, Wang J, Yang Q, Zhang T, Song J, Du Y, Zhang X. Systemic Inflammatory Factors and Neuropsychiatric Disorders: A Bidirectional Mendelian Randomization Study. Brain Behav 2025; 15:e70478. [PMID: 40200869 PMCID: PMC11979492 DOI: 10.1002/brb3.70478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 03/04/2025] [Accepted: 03/06/2025] [Indexed: 04/10/2025] Open
Abstract
BACKGROUND The present study employed Mendelian randomization to scrutinize the causal connections that may exist between 91 distinct inflammatory markers and six neuropsychiatric disorders, namely Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), anxiety disorders (ANX), depressive disorders (DEP), and unexplained encephalopathy (UE). DISCUSSION The methodology utilized involved the standard inverse variance weighting method within a two-sample, two-way Mendelian randomization framework and integrated statistics from genome-wide association studies. To ascertain the robustness of the identified causal associations, sensitivity analyses were performed with the aid of the MR-Egger method and the weighted median test. CONCLUSION The results revealed that 14 distinct systemic inflammatory modulators are potentially causally linked to the risk of developing various neuropsychiatric disorders. Specifically, five were associated with AD, eight with ANX, six with DEP, and one with UE. However, the causal associations involving systemic inflammatory markers with PD and MS require further investigation, particularly with the identification of additional significant genetic variants. Furthermore, the concentration levels of 33 systemic inflammatory factors could be modulated by the occurrence of neuropsychiatric conditions, indicated by this study. These include five affected by AD, eight by PD, six by MS, 12 by ANX, five by DEP, and five by UE.
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Affiliation(s)
- Hao Wang
- College of Acupuncture‐Moxibustion and OrthopedicsHubei University of Chinese MedicineWuhanChina
| | - Ziji Cheng
- Department of Anatomy, College of Chinese Integrative MedicineShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Zixuan Xu
- School of Basic MedicineHubei University of Chinese MedicineWuhanChina
| | - Min Wang
- College of Acupuncture‐Moxibustion and OrthopedicsHubei University of Chinese MedicineWuhanChina
| | - Xingyang Sun
- School of Basic MedicineHubei University of Chinese MedicineWuhanChina
| | - Wen Liu
- College of Acupuncture‐Moxibustion and OrthopedicsHubei University of Chinese MedicineWuhanChina
| | - Jingtian Wang
- College of Acupuncture‐Moxibustion and OrthopedicsHubei University of Chinese MedicineWuhanChina
| | - Qian Yang
- College of Acupuncture‐Moxibustion and OrthopedicsHubei University of Chinese MedicineWuhanChina
| | - Tuo Zhang
- College of Acupuncture‐Moxibustion and OrthopedicsHubei University of Chinese MedicineWuhanChina
| | - Jie Song
- College of Acupuncture‐Moxibustion and OrthopedicsHubei University of Chinese MedicineWuhanChina
| | - Yanjun Du
- College of Acupuncture‐Moxibustion and OrthopedicsHubei University of Chinese MedicineWuhanChina
| | - Xiaoming Zhang
- College of Acupuncture‐Moxibustion and OrthopedicsHubei University of Chinese MedicineWuhanChina
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Ju XD, Zhang PH, Li Q, Bai QY, Hu B, Xu J, Lu C. Peripheral Blood Monocytes as Biomarkers of Neurodevelopmental Disorders: A Systematic Review and Meta-Analysis. Res Child Adolesc Psychopathol 2025; 53:583-595. [PMID: 40053221 DOI: 10.1007/s10802-025-01303-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/20/2025] [Indexed: 04/26/2025]
Abstract
Accumulating evidence implicates immune dysregulation and chronic inflammation in neurodevelopmental disorders (NDDs), often manifesting as abnormal alterations in peripheral blood immune cell levels. The mononuclear phagocyte system, including monocytes and microglia, has been increasingly recognized for its involvement in the pathogenesis of NDDs. However, due to inconsistent findings in the literature, whether monocytes can serve as a reliable biomarker for NDDs remains controversial. To address this issue, we conducted a systematic review and meta-analysis of studies examining monocyte counts in NDD individuals. A comprehensive search was conducted across PubMed, Web of Science, and Scopus databases. Variables extracted for analysis encompassed the author's name, year of study, sample size, patient's age, type of disease, mean, standard deviation of monocytes and sex ratio. A total of 2503 articles were found by searching the three databases. After removed duplicates and screening titles, abstracts, and full texts, 17 articles met the inclusion criteria, and 20 independent studies were included in the meta-analysis. The results indicated significantly increased monocyte counts in 5 type NDDs compared to Typical Development (TD) groups (g = 0.36, 95%CI [0.23, 0.49]). Subgroup analyses revealed no significant differences in monocyte counts across different NDD types, gender, or age. These findings suggest that aberrant alterations in monocyte counts are common in NDD cases, indicating their potential as biomarkers for these conditions. Future research should further investigate the role of monocyte in understanding the mechanisms, early detection, and clinical diagnosis of NDDs.
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Affiliation(s)
- Xing-Da Ju
- School of Psychology, Northeast Normal University, Changchun, China
- Jilin Provincial Key Laboratory of Cognitive Neuroscience and Brain Development, Changchun, China
- Autism Centre of Excellence, Northeast Normal University, Changchun, China
| | - Pai-Hao Zhang
- School of Psychology, Northeast Normal University, Changchun, China
| | - Qiang Li
- School of Psychology, Northeast Normal University, Changchun, China
| | - Qiu-Yu Bai
- Yancheng College of Mechatronic Technology, Yancheng, China
| | - Bo Hu
- School of Psychology, Northeast Normal University, Changchun, China
- School of Social and Behavioral Science, Nanjing University, Nanjing, China
| | - Jing Xu
- School of Life Sciences, Northeast Normal University, Changchun, China
| | - Chang Lu
- School of Psychology, Northeast Normal University, Changchun, China.
- Jilin Provincial Key Laboratory of Cognitive Neuroscience and Brain Development, Changchun, China.
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Zeming KK, Llanora G, Quek K, Goh CR, Ng NZH, Han J, Yeo KT. Whole blood biophysical immune profiling of newborn infants correlates with immune responses. Pediatr Res 2025:10.1038/s41390-025-03952-y. [PMID: 40164874 DOI: 10.1038/s41390-025-03952-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Accepted: 02/10/2025] [Indexed: 04/02/2025]
Abstract
BACKGROUND There is a current, absence of reliable, blood-sparing, diagnostic tools to measure and trend real-time changes in the levels of inflammation and its effects on the immune cells in the infant. METHODS We deployed the BiophysicaL Immune Profiling for Infants (BLIPI) system in the neonatal intensive care unit to describe immune cell biophysical profiles using 50 microliters of blood per sample from term and preterm infants. RESULTS A total of 19 infants (8 term, 11 preterm) were recruited and 24 blood samples were collected in their first month. Based on the profiles of immune cells' size and deformation, there was a clear distinction between term and preterm infants, with 48/50 markers significantly different. A preterm infant with late-onset bacterial sepsis had notable size and deformability differences compared to the rest of the preterm cohort. There was a significant correlation between immune cell biophysical profiles and clinical markers such as C-reactive protein, white blood cell counts, and immature-to-total neutrophil (I:T) ratios, with Pearson correlation coefficients for linear regression models of 0.98, 0.97 and 0.94 respectively. CONCLUSION This study highlights the potential for the biophysical immune cell profiling system to provide an overview of the infant's current immune activation and response. IMPACT We present a novel, minimally invasive diagnostic system that leverages the physical properties of immune cells to provide a rapid and direct assessment of the immune status, requiring 20 times less blood volume than standard tests. This study demonstrates the potential of a compact, deployable system that is capable of performing biophysical profiling to assess immune cell activation in term and preterm infants, by revealing distinct differences in cell size and deformation between groups. The system's sensitive, quantitative measures were correlated with routine clinical biomarkers, highlighting its ability to provide a rapid, minimally invasive, real-time monitoring of neonatal immune status.
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Affiliation(s)
- Kerwin Kwek Zeming
- Critical Analytics for Manufacturing of Personalized Medicine, Singapore-MIT Alliance for Research and Technology, Singapore, Singapore
| | - Genevieve Llanora
- Department of Neonatology, KK Women's & Children's Hospital, Singapore, Singapore
| | - Kaiyun Quek
- Critical Analytics for Manufacturing of Personalized Medicine, Singapore-MIT Alliance for Research and Technology, Singapore, Singapore
| | - Chin Ren Goh
- Critical Analytics for Manufacturing of Personalized Medicine, Singapore-MIT Alliance for Research and Technology, Singapore, Singapore
| | - Nicholas Zhi Heng Ng
- Critical Analytics for Manufacturing of Personalized Medicine, Singapore-MIT Alliance for Research and Technology, Singapore, Singapore
| | - Jongyoon Han
- Critical Analytics for Manufacturing of Personalized Medicine, Singapore-MIT Alliance for Research and Technology, Singapore, Singapore.
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
- Department of Electrical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
- Antimicrobial Resistance, Singapore-MIT Alliance for Research and Technology, Singapore, Singapore.
| | - Kee Thai Yeo
- Department of Neonatology, KK Women's & Children's Hospital, Singapore, Singapore.
- Duke-NUS Medical School, Singapore, Singapore.
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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Lee JH, Shin T, Park JM, Seol JH. Linking Kawasaki Disease to Mental Health: A Nationwide Study on Long-Term Neurological Risks. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:604. [PMID: 40282895 PMCID: PMC12028643 DOI: 10.3390/medicina61040604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Revised: 03/21/2025] [Accepted: 03/25/2025] [Indexed: 04/29/2025]
Abstract
Background and Objectives: Kawasaki disease (KD) is a childhood systematic vasculitis. Emerging evidence suggests a link between KD and long-term neurological implications. This study examines the association between KD and subsequent neuropsychiatric and neurodevelopmental disorders using national health data from South Korea. Materials and Methods: Using the National Health Information Database, we identified KD patients diagnosed between 2002 and 2021 and selected those born between 2008 and 2015. Propensity score matching with a 1:4 ratio was applied to create a control group. The incidence of neuropsychiatric and neurodevelopmental disorders from 2017 to 2021 was analyzed using Cox proportional hazard models, adjusting for age, sex, and urbanicity. Results: This study included 41,806 KD subjects and 163,829 matched controls. KD was associated with an increased risk of certain neuropsychiatric disorders: anxiety disorder (HR: 1.124, 1.047-1.207), sleep-related disorder (HR: 1.257, 1.094-1.444), movement disorder (HR: 1.227, 1.030-1.461), and any neuropsychiatric disorder (HR: 1.102, 1.053-1.153). For neurodevelopmental disorders, KD patients showed a lower incidence of intellectual disability (HR: 0.747, 0.641-0.871) but an increased risk of tic disorder (HR: 1.148, 1.020-1.292). Male gender and urban residency were associated with higher incidence rates for certain conditions. Conclusions: This study demonstrates that KD patients show increased risks for anxiety, sleep-related disorder, movement disorder, and tic disorder, a reduced incidence of intellectual disability, and a higher risk of tic disorder. These findings highlight the need for long-term neurological monitoring in KD patients and provide insights into its potential neurodevelopmental impact.
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Affiliation(s)
- Ji-Ho Lee
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea;
| | - Taewoo Shin
- Department of Pediatrics, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea;
| | - Jung-Min Park
- Department of Pediatrics, National Health Insurance Service Ilsan Hospital, Goyang 10444, Republic of Korea
| | - Jae-Hee Seol
- Department of Pediatrics, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea;
- Department of Pediatrics, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
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Díaz-Pons A, Castaño-Castaño S, Ortiz-García de la Foz V, Yorca-Ruiz Á, Martínez-Asensi C, Munarriz-Cuezva E, Ayesa-Arriola R. Understanding the potential impact of trimester-specific maternal immune activation due to SARS-CoV-2 on early human neurodevelopment and the role of cytokine balance. Brain Behav Immun Health 2025; 44:100956. [PMID: 39990281 PMCID: PMC11846590 DOI: 10.1016/j.bbih.2025.100956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 12/23/2024] [Accepted: 01/22/2025] [Indexed: 02/25/2025] Open
Abstract
Purpose The COVID-19 pandemic presents significant future health challenges. Its impact on pregnant women and their newborn is a particular area of concern. This study aims to examine the potential role of maternal immune activation (MIA), due to SARS-CoV-2 infection, on early neurodevelopment. Methods We analysed 107 mother-infant dyads from the COGESTCOV-19 study in Cantabria, Spain, which included 59 SARS-CoV-2 exposed (cases) and 48 unexposed (controls) mothers, recruited between December 2020 and February 2022. Cytokine levels (IL-6 and IL-10) were obtained from maternal blood and cord blood. Neurodevelopment was assessed using the Neonatal Behavioral Assessment Scale (NBAS) at six weeks of age. Trimester of infection was considered in the main analyses. Results Results showed no significant overall delays in early neurodevelopment due to maternal SARS-CoV-2 infection. Control infants performed better in some NBAS items. However, cases infants showed trimester-specific differences. First-trimester exposure was related to motor and reflex delays, second-trimester to poorer performances in motor tasks and autonomic stability, and third-trimester to weaker state organization, regulation, and reflexes. Some correlations between cytokine levels and NBAS performance showed moderate associations. Conclusions These findings highlight the need for ongoing neurodevelopmental monitoring of infants born during the COVID-19 pandemic. The study enhances our understanding of MIA's impact on early development, emphasizing the importance of addressing homeostatic mechanisms in mothers and newborns.
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Affiliation(s)
- Alexandre Díaz-Pons
- Departamento de Investigación en Enfermedades Mentales, Instituto de Investigación Marqués de Valdecilla (IDIVAL), 39011, Santander, Spain
- Escuela de Doctorado de la Universidad de Cantabria (EDUC), Universidad de Cantabria (UC), 39005, Santander, Spain
- Departamento de Medicina y Ciencias de la Salud, Facultad de Medicina, Universidad de Cantabria (UC), 39011, Santander, Spain
- Facultad de Psicología, Universidad Nacional de Educación a Distancia (UNED), 28015, Madrid, Spain
| | - Sergio Castaño-Castaño
- Departamento de Psicobiología, Facultad de Psicología, Universidad de Oviedo (UO), 33003, Oviedo, Spain
- Instituto de Neurociencias del Principado de Asturias (INEUROPA), 33003, Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011, Oviedo, Spain
| | - Víctor Ortiz-García de la Foz
- Departamento de Investigación en Enfermedades Mentales, Instituto de Investigación Marqués de Valdecilla (IDIVAL), 39011, Santander, Spain
| | - Ángel Yorca-Ruiz
- Departamento de Investigación en Enfermedades Mentales, Instituto de Investigación Marqués de Valdecilla (IDIVAL), 39011, Santander, Spain
- Escuela de Doctorado de la Universidad de Cantabria (EDUC), Universidad de Cantabria (UC), 39005, Santander, Spain
- Departamento de Biología Molecular, Facultad de Medicina, Universidad de Cantabria (UC), 39011, Santander, Spain
| | - Carlos Martínez-Asensi
- Departamento de Investigación en Enfermedades Mentales, Instituto de Investigación Marqués de Valdecilla (IDIVAL), 39011, Santander, Spain
- Facultad de Psicología, Universidad Nacional de Educación a Distancia (UNED), 28015, Madrid, Spain
| | - Eva Munarriz-Cuezva
- Departamento de Farmacología, Facultad de Medicina y Enfermería, Universidad del País Vasco/ Euskal Herriko Unibertsitatea (UPV/EHU), 48940, Leioa, Spain
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Rosa Ayesa-Arriola
- Departamento de Investigación en Enfermedades Mentales, Instituto de Investigación Marqués de Valdecilla (IDIVAL), 39011, Santander, Spain
- Departamento de Medicina y Ciencias de la Salud, Facultad de Medicina, Universidad de Cantabria (UC), 39011, Santander, Spain
- Facultad de Psicología, Universidad Nacional de Educación a Distancia (UNED), 28015, Madrid, Spain
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, 28029, Madrid, Spain
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Tusa BS, Alati R, Betts K, Ayano G, Dachew B. Associations of maternal perinatal depressive disorders with autism spectrum disorder in offspring: Findings from a data-linkage cohort study. Aust N Z J Psychiatry 2025; 59:282-292. [PMID: 39895367 PMCID: PMC11837418 DOI: 10.1177/00048674251315641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
BACKGROUND There is limited research on the association between maternal depression and autism spectrum disorder, and existing studies face significant limitations, including inadequate control for confounders, reliance on self-reported data, small sample sizes and lack of investigation into mediating factors. This study addresses these gaps by examining the direct relationship and the potential mediating effects of preterm birth, low birth weight and low Apgar scores. METHODS We analysed linked administrative health data involving 223,068 mother-offspring pairs in New South Wales, Australia. Maternal perinatal depressive disorders and offspring autism spectrum disorder were assessed using the International Classification of Diseases, Tenth Revision, Australian Modification (ICD-10 AM). A generalised linear model was employed to examine the association. The mediation effects of preterm birth, low birth weight and low Apgar scores were assessed through mediation analysis. RESULTS After adjusting for a range of potential confounders, offspring of mothers with antenatal, postnatal and overall perinatal depressive disorders had a 61% (risk ratio = 1.61, 95% confidence interval = [1.12, 2.32]), 85% (risk ratio = 1.85, 95% confidence interval = [1.20, 2.86]) and 80% (risk ratio = 1.80, 95% confidence interval = [1.33, 2.43]) higher risk of autism spectrum disorder, respectively. Only about 1.29% and 1.31% of the effect of maternal antenatal depressive disorders on offspring autism spectrum disorder was mediated by preterm birth and low Apgar scores, respectively. Low birth weight had no significant mediating effect on the association. CONCLUSION Maternal perinatal depressive disorders are associated with an increased risk of autism spectrum disorder in offspring. Preterm birth and low Apgar scores were weak mediators of this association. Early intervention strategies that aim to enhance maternal mental health and mitigate the risk of exposed offspring are needed.
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Affiliation(s)
- Biruk Shalmeno Tusa
- School of Population Health, Curtin University, Perth, WA, Australia
- Department of Epidemiology and Biostatistics, College of Health and Medical Sciences, Haramaya University, Haramaya, Ethiopia
| | - Rosa Alati
- School of Population Health, Curtin University, Perth, WA, Australia
- Institute for Social Science Research, The University of Queensland, Brisbane, QLD, Australia
| | - Kim Betts
- School of Population Health, Curtin University, Perth, WA, Australia
| | - Getinet Ayano
- School of Population Health, Curtin University, Perth, WA, Australia
| | - Berihun Dachew
- School of Population Health, Curtin University, Perth, WA, Australia
- enAble Institute, Curtin University, 1 Kyle Avenue, Bentley, WA, 6102 Australia
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15
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Padilla-Valdez MM, Santana-Bejarano MB, Godínez-Rubí M, Ortuño-Sahagún D, Rojas-Mayorquín AE. Prenatal Alcohol Exposure Disrupts CXCL16 Expression in Rat Hippocampus: Temporal and Sex Differences. Int J Mol Sci 2025; 26:1920. [PMID: 40076549 PMCID: PMC11900973 DOI: 10.3390/ijms26051920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 02/17/2025] [Accepted: 02/20/2025] [Indexed: 03/14/2025] Open
Abstract
Prenatal alcohol exposure (PAE) affects around 40,000 newborns every year and poses a significant health risk. Although much is already known about the neurotoxic mechanisms of PAE, new findings continue to emerge. Studies with mouse models show that PAE leads to overexpression of proinflammatory cytokines and chemokines in the brain, which disrupts important neurodevelopmental processes such as cell migration, survival and proliferation of neurons. The chemokine CXCL16 is overexpressed in the brain following various impairments, including PAE. This study shows that CXCL16 expression varies by developmental stage and sex, consistent with known sexual dimorphism in immune responses. In females, CXCL16 expression may be influenced by estrogen-related mechanisms, possibly related to the alcohol-mediated rebound effect described here. In contrast, the male hippocampus shows greater resilience to PAE-induced CXCL16 changes. Furthermore, the presence of CXCL16 in neuronal nuclei suggests a role in gene regulation, similar to other chemokines such as CCL5 and CXCL4. These findings shed light on the role of chemokines in hippocampal neuroplasticity and may pave the way for better treatment of fetal alcohol spectrum disorder (FASD).
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Affiliation(s)
- Mayra Madeleine Padilla-Valdez
- Laboratorio de Neuroinmunobiología Molecular, Instituto de Investigación en Ciencias Biomédicas (IICB), Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara C.P. 44340, Mexico;
| | - Margarita Belem Santana-Bejarano
- Laboratorio de Patología Diagnóstica e Inmunohistoquímica, Centro de Investigación y Diagnóstico en Patología, Departamento de Microbiología y Patología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara C.P. 44340, Mexico; (M.B.S.-B.); (M.G.-R.)
| | - Marisol Godínez-Rubí
- Laboratorio de Patología Diagnóstica e Inmunohistoquímica, Centro de Investigación y Diagnóstico en Patología, Departamento de Microbiología y Patología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara C.P. 44340, Mexico; (M.B.S.-B.); (M.G.-R.)
| | - Daniel Ortuño-Sahagún
- Laboratorio de Neuroinmunobiología Molecular, Instituto de Investigación en Ciencias Biomédicas (IICB), Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara C.P. 44340, Mexico;
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Rojo-Romero MA, Gutiérrez-Nájera NA, Cruz-Fuentes CS, Romero-Pimentel AL, Mendoza-Morales R, García-Dolores F, Morales-Marín ME, Castro-Martínez X, González-Sáenz E, Torres-Campuzano J, Medina-Sánchez T, Hernández-Fonseca K, Nicolini-Sánchez H, Jiménez-García LF. Proteome analysis of the prefrontal cortex and the application of machine learning models for the identification of potential biomarkers related to suicide. Front Psychiatry 2025; 15:1429953. [PMID: 40051599 PMCID: PMC11882514 DOI: 10.3389/fpsyt.2024.1429953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 12/24/2024] [Indexed: 03/09/2025] Open
Abstract
Introduction Suicide is a significant public health problem, with increased rates in low- and middle-income countries such as Mexico; therefore, suicide prevention is important. Suicide is a complex and multifactorial phenomenon in which biological and social factors are involved. Several studies on the biological mechanisms of suicide have analyzed the proteome of the dorsolateral prefrontal cortex (DLPFC) in people who have died by suicide. The aim of this work was to analyze the protein expression profile in the DLPFC of individuals who died by suicide in comparison to age-matched controls in order to gain information on the molecular basis in the brain of these individuals and the selection of potential biomarkers for the identification of individuals at risk of suicide. In addition, this information was analyzed using machine learning (ML) algorithms to propose a model for predicting suicide. Methods Brain tissue (Brodmann area 9) was sampled from male cases (n=9) and age-matched controls (n=7). We analyzed the proteomic differences between the groups using two-dimensional polyacrylamide gel electrophoresis and mass spectrometry. Bioinformatics tools were used to clarify the biological relevance of the differentially expressed proteins. In addition, this information was analyzed using machine learning (ML) algorithms to propose a model for predicting suicide. Results Twelve differentially expressed proteins were also identified (t 14 ≤ 0.5). Using Western blotting, we validated the decrease in expression of peroxiredoxin 2 and alpha-internexin in the suicide cases. ML models were trained using densitometry data from the 2D gel images of each selected protein and the models could differentiate between both groups (control and suicide cases). Discussion Our exploratory pathway analysis highlighted oxidative stress responses and neurodevelopmental pathways as key processes perturbed in the DLPFC of suicides. Regarding ML models, KNeighborsClassifier was the best predicting conditions. Here we show that these proteins of the DLPFC may help to identify brain processes associated with suicide and they could be validated as potential biomarkers of this outcome.
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Affiliation(s)
- Manuel Alejandro Rojo-Romero
- Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
- Psychiatric and Neurodegenerative Diseases Laboratory, National Institute of Genomic Medicine, Mexico City, Mexico
- National Institute of Psychiatry “Ramón de la Fuente Muñíz”, Mexico City, Mexico
| | - Nora Andrea Gutiérrez-Nájera
- Psychiatric and Neurodegenerative Diseases Laboratory, National Institute of Genomic Medicine, Mexico City, Mexico
| | | | - Ana Luisa Romero-Pimentel
- Psychiatric and Neurodegenerative Diseases Laboratory, National Institute of Genomic Medicine, Mexico City, Mexico
| | - Roberto Mendoza-Morales
- Institute of Expert Services and Forensic Sciences of Mexico City (INCIFO), Mexico City, Mexico
| | - Fernando García-Dolores
- Institute of Expert Services and Forensic Sciences of Mexico City (INCIFO), Mexico City, Mexico
| | - Mirna Edith Morales-Marín
- Psychiatric and Neurodegenerative Diseases Laboratory, National Institute of Genomic Medicine, Mexico City, Mexico
| | - Xóchitl Castro-Martínez
- Psychiatric and Neurodegenerative Diseases Laboratory, National Institute of Genomic Medicine, Mexico City, Mexico
| | | | - Jonatan Torres-Campuzano
- Psychiatric and Neurodegenerative Diseases Laboratory, National Institute of Genomic Medicine, Mexico City, Mexico
| | - Tania Medina-Sánchez
- National Institute of Psychiatry “Ramón de la Fuente Muñíz”, Mexico City, Mexico
| | | | - Humberto Nicolini-Sánchez
- Psychiatric and Neurodegenerative Diseases Laboratory, National Institute of Genomic Medicine, Mexico City, Mexico
| | - Luis Felipe Jiménez-García
- Cell Nanobiology Laboratory, Faculty of Sciences, National Autonomous University of Mexico, Mexico City, Mexico
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Leathers TA, Ramarapu R, Rogers CD. Spatiotemporal characterization of cyclooxygenase pathway enzymes during vertebrate embryonic development. Dev Biol 2025; 518:61-70. [PMID: 39581452 PMCID: PMC11890202 DOI: 10.1016/j.ydbio.2024.11.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 11/04/2024] [Accepted: 11/21/2024] [Indexed: 11/26/2024]
Abstract
Vertebrate development is regulated by several complex well-characterized morphogen signaling pathways, transcription factors, and structural proteins, but less is known about the enzymatic pathways that regulate early development. We have identified that factors from the inflammation-mediating cyclooxygenase (COX) signaling pathway are expressed at early stages of development in avian embryos. Using Gallus gallus (chicken) as a research model, we characterized the spatiotemporal expression of a subset of genes and proteins in the COX pathway during early neural development stages. Specifically, here we show expression patterns of COX-1, COX-2, and microsomal prostaglandin E synthase-2 (mPGES-2) as well as the genes encoding these enzymes (PTGS1, PTGS2, and PTGES-2). Unique expression patterns of individual players within the COX pathway suggest that they may play non-canonical/non-traditional roles in the embryo compared to their roles in the adult. Future work should examine the function of the COX pathway in tissue specification and morphogenesis and determine if these expression patterns are conserved across species.
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Affiliation(s)
- Tess A Leathers
- Department of Anatomy, Physiology, and Cell Biology, University of California, Davis, School of Veterinary Medicine, Davis, CA, USA
| | - Raneesh Ramarapu
- Department of Anatomy, Physiology, and Cell Biology, University of California, Davis, School of Veterinary Medicine, Davis, CA, USA
| | - Crystal D Rogers
- Department of Anatomy, Physiology, and Cell Biology, University of California, Davis, School of Veterinary Medicine, Davis, CA, USA.
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Mohamed ZA, Li J, Wen J, Jia F, Banerjee S. The KCNB2 gene and its role in neurodevelopmental disorders: Implications for genetics and therapeutic advances. Clin Chim Acta 2025; 566:120056. [PMID: 39577484 DOI: 10.1016/j.cca.2024.120056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 11/15/2024] [Accepted: 11/16/2024] [Indexed: 11/24/2024]
Abstract
Neurodevelopmental disorders (NDDs) are increasingly linked to genetic mutations that disrupt key neuronal processes. The KCNB2 gene encodes a crucial component of voltage-gated potassium channels, essential for regulating neuronal excitability and synaptic transmission. Mutations in KCNB2 typically alter potassium channel inactivation, leading to various NDDs, including autism spectrum disorders (ASD), intellectual disabilities (ID), and epilepsy. This narrative review synthesizes findings from genetic, molecular, and clinical studies on the KCNB2 gene and its role in NDDs. Relevant literature was identified through database searches in PubMed, Embase, PsycINFO, Scopus, and Web of Science, focusing on studies that examine KCNB2's molecular mechanisms, pathogenic mutations, and clinical implications in NDDs. In addition to its role in excitability, KCNB2's impact on cognitive processes, such as memory and attention, is considered, highlighting the need for further research. Potential interventions, including pharmacological modulation and gene therapy, are also discussed. Future research should focus on characterizing KCNB2 variants, expanding genetic screening, and advancing targeted therapies to improve outcomes for individuals affected by KCNB2-related disorders.
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Affiliation(s)
- Zakaria Ahmed Mohamed
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; Department of Developmental and Behavioral Pediatrics, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Jinghua Li
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China
| | - Jianping Wen
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun 130021, China
| | - Feiyong Jia
- Department of Developmental and Behavioral Pediatrics, The First Hospital of Jilin University, Jilin University, Changchun, China.
| | - Santasree Banerjee
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
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Gargus M, Ben-Azu B, Landwehr A, Dunn J, Errico JP, Tremblay MÈ. Mechanisms of vagus nerve stimulation for the treatment of neurodevelopmental disorders: a focus on microglia and neuroinflammation. Front Neurosci 2025; 18:1527842. [PMID: 39881804 PMCID: PMC11774973 DOI: 10.3389/fnins.2024.1527842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 12/27/2024] [Indexed: 01/31/2025] Open
Abstract
The vagus nerve (VN) is the primary parasympathetic nerve, providing two-way communication between the body and brain through a network of afferent and efferent fibers. Evidence suggests that altered VN signaling is linked to changes in the neuroimmune system, including microglia. Dysfunction of microglia, the resident innate immune cells of the brain, is associated with various neurodevelopmental disorders, including schizophrenia, attention deficit hyperactive disorder (ADHD), autism spectrum disorder (ASD), and epilepsy. While the mechanistic understanding linking the VN, microglia, and neurodevelopmental disorders remains incomplete, vagus nerve stimulation (VNS) may provide a better understanding of the VN's mechanisms and act as a possible treatment modality. In this review we examine the VN's important role in modulating the immune system through the inflammatory reflex, which involves the cholinergic anti-inflammatory pathway, which releases acetylcholine. Within the central nervous system (CNS), the direct release of acetylcholine can also be triggered by VNS. Homeostatic balance in the CNS is notably maintained by microglia. Microglia facilitate neurogenesis, oligodendrogenesis, and astrogenesis, and promote neuronal survival via trophic factor release. These cells also monitor the CNS microenvironment through a complex sensome, including groups of receptors and proteins enabling microglia to modify neuroimmune health and CNS neurochemistry. Given the limitations of pharmacological interventions for the treatment of neurodevelopmental disorders, this review seeks to explore the application of VNS as an intervention for neurodevelopmental conditions. Accordingly, we review the established mechanisms of VNS action, e.g., modulation of microglia and various neurotransmitter pathways, as well as emerging preclinical and clinical evidence supporting VNS's impact on symptoms associated with neurodevelopmental disorders, such as those related to CNS inflammation induced by infections. We also discuss the potential of adapting non-invasive VNS for the prevention and treatment of these conditions. Overall, this review is intended to increase the understanding of VN's potential for alleviating microglial dysfunction involved in schizophrenia, ADHD, ASD, and epilepsy. Additionally, we aim to reveal new concepts in the field of CNS inflammation and microglia, which could serve to understand the mechanisms of VNS in the development of new therapies for neurodevelopmental disorders.
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Affiliation(s)
- Makenna Gargus
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | - Benneth Ben-Azu
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Department of Pharmacology, Faculty of Basic Medical Sciences, Delta State University, Abraka, Nigeria
| | - Antonia Landwehr
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | - Jaclyn Dunn
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | | | - Marie-Ève Tremblay
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, BC, Canada
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20
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Yuan Z, Su T, Yang L, Xi L, Wang HJ, Ji Y. Maternal Glycemia and Its Pattern Associated with Offspring Neurobehavioral Development: A Chinese Birth Cohort Study. Nutrients 2025; 17:257. [PMID: 39861387 PMCID: PMC11767945 DOI: 10.3390/nu17020257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 01/02/2025] [Accepted: 01/09/2025] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND/OBJECTIVES This study investigates the impact of maternal glycemic levels during early and late pregnancy on offspring neurodevelopment in China. METHODS Fasting plasma glucose (FPG) and triglyceride (TG) levels were measured in maternal blood during pregnancy, and the TyG index was calculated to assess insulin resistance. Hyperglycemia was defined as FPG > 5.1 mmol/L. Neurodevelopmental outcomes in offspring aged 6-36 months were evaluated using the China Developmental Scale for Children, focusing on developmental delay (DD) and developmental quotient (DQ). Mothers were categorized into four glycemic groups: healthy glycemia group (HGG), early pregnancy hyperglycemia group (EHG), late pregnancy hyperglycemia group (LHG), and full-term hyperglycemia group (FHG). Linear and logistic regression models were applied. RESULTS Among 1888 mother-child pairs, hyperglycemia and FPG were associated with an increased risk of overall DD (aOR = 1.68; 95% CI 1.07-2.64) and lower DQ (aBeta = -1.53; 95% CI -2.70 to -0.36). Elevated FPG was linked to DD in fine motor and social behaviors. Compared to HGG, LHG and FHG significantly increased the risk of overall DD (aOR = 2.18; 95% CI 1.26-3.77; aOR = 2.64; 95% CI 1.38-5.05), whereas EHG did not. Male offspring were particularly vulnerable to early pregnancy hyperglycemia (aBeta = -2.80; 95% CI -4.36 to -1.34; aOR = 2.05; 95% CI 1.10-3.80). CONCLUSIONS Maternal glycemic levels during pregnancy influence offspring neurodevelopment, with persistent hyperglycemia significantly increasing DD risk. Early pregnancy hyperglycemia particularly affects male offspring, underscoring the need for glycemic management during pregnancy.
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Affiliation(s)
- Zhichao Yuan
- Department of Maternal and Child Health, School of Public Health, Peking University, Beijing 100191, China
| | - Tao Su
- Tongzhou Maternal and Child Health Care Hospital of Beijing, Beijing 101101, China
| | - Li Yang
- Tongzhou Maternal and Child Health Care Hospital of Beijing, Beijing 101101, China
| | - Lei Xi
- Tongzhou Maternal and Child Health Care Hospital of Beijing, Beijing 101101, China
| | - Hai-Jun Wang
- Department of Maternal and Child Health, School of Public Health, Peking University, Beijing 100191, China
| | - Yuelong Ji
- Department of Maternal and Child Health, School of Public Health, Peking University, Beijing 100191, China
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21
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Yadav V, Nayak S, Guin S, Mishra A. Impact of Oxidative Stress and Neuroinflammation on Sarco/Endoplasmic Reticulum Ca 2+-ATPase 2b Downregulation and Endoplasmic Reticulum Stress in Temporal Lobe Epilepsy. ACS Pharmacol Transl Sci 2025; 8:173-188. [PMID: 39816806 PMCID: PMC11730250 DOI: 10.1021/acsptsci.4c00556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 11/24/2024] [Accepted: 11/29/2024] [Indexed: 01/18/2025]
Abstract
Epilepsy is one of the most common neurological disorders. Calcium dysregulation and neuroinflammation are essential and common mechanisms in epileptogenesis. Sarco/endoplasmic reticulum (ER) Ca2+-ATPase 2b (SERCA2b), a crucial calcium regulatory pump, plays pathological roles in various calcium dysregulation-related diseases. However, the link between SERCA2b and neuroinflammation in epilepsy remains undetermined. This study aimed to establish the relationship between SERCA2b, oxidative stress, and neuroinflammation in epilepsy to elucidate the underlying molecular mechanism in epileptogenesis. Neuroinflammation and oxidative stress were induced in N2a cells using lipopolysaccharide (LPS) and hydrogen peroxide (H2O2). However, experimental temporal lobe epilepsy (TLE) was induced in mice using pilocarpine. Further, effects of oxidative stress and neuroinflammation on SERCA2b and ER stress markers were assessed at protein and mRNA levels. Calcium imaging was employed to determine intracellular calcium levels. SERCA2b expression significantly decreased after LPS, H2O2, and pilocarpine exposure at both mRNA and protein levels, mediated by upregulating neuroinflammation. This downregulation of SERCA2b was associated with increased production of reactive oxygen species and elevated intracellular calcium levels, leading to elevated ER stress markers. Our findings highlight a link between oxidative stress, neuroinflammation and SERCA2b in TLE. The results suggest that targeting SERCA2b could restore calcium homeostasis and ER stress processes, potentially providing a therapeutic option for TLE. This study underscores the importance of SERCA2b in the pathophysiology of epilepsy and its potential as a therapeutic target.
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Affiliation(s)
| | | | - Sandeep Guin
- Department of Pharmacology and Toxicology, National Institute of
Pharmaceutical Education and Research (NIPER)—Guwahati, Changsari,
Kamrup, Assam 781101, India
| | - Awanish Mishra
- Department of Pharmacology and Toxicology, National Institute of
Pharmaceutical Education and Research (NIPER)—Guwahati, Changsari,
Kamrup, Assam 781101, India
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22
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Shahabi B, Hernández-Martínez C, Jardí C, Aparicio E, Arija V. Maternal Omega-6/Omega-3 Concentration Ratio During Pregnancy and Infant Neurodevelopment: The ECLIPSES Study. Nutrients 2025; 17:170. [PMID: 39796604 PMCID: PMC11723212 DOI: 10.3390/nu17010170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 12/28/2024] [Accepted: 01/01/2025] [Indexed: 01/13/2025] Open
Abstract
BACKGROUND The balance of omega-6/omega-3 (n-6/n-3) is crucial for proper brain function as they have opposite physiological roles. OBJECTIVES To analyze the association between maternal serum ratios of n-6/n-3 in the first and third trimesters of pregnancy and the neurodevelopment of their children in the early days after birth in the population of Northern Spain's Mediterranean region. METHODS Longitudinal study in which 336 mother-child pairs participated. Mother serum concentrations of long-chain polyunsaturated fatty acids (LCPUFAs), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (ARA) were determined. Sociodemographic, clinical, lifestyle habits, and obstetrical variables were collected. The Bayley Scales of Infant and Toddler Development (BSID-III) was used to assess infant neurodevelopment. Multiple linear regression models adjusting for confounding factors were performed. RESULTS In the third trimester, a higher maternal n-6/n-3 ratio was negatively associated with infant motor development (β = -0.124, p = 0.023). Similarly, higher ARA/DHA ratios were negatively associated with total motor (β = -2.005, p = 0.002) and fine motor development (β = -0.389, p = 0.001). No significant associations were observed in the first trimester nor for the ARA/EPA ratio in the third trimester. CONCLUSIONS Our findings indicate that an elevated n-6/n-3 ratio and ARA/DHA ratio in the third trimester of pregnancy are associated with poorer motor development outcomes in infants. These results highlight the importance of optimizing maternal fatty acid balance during pregnancy to support fetal neurodevelopment, suggesting a need for further research to verify these associations and elucidate underlying mechanisms.
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Affiliation(s)
- Behnaz Shahabi
- Nutrition and Mental Health (NUTRISAM) Research Group, Universitat Rovira i Virgili, 43201 Reus, Spain; (B.S.); (C.H.-M.); (C.J.); (E.A.)
| | - Carmen Hernández-Martínez
- Nutrition and Mental Health (NUTRISAM) Research Group, Universitat Rovira i Virgili, 43201 Reus, Spain; (B.S.); (C.H.-M.); (C.J.); (E.A.)
- Institut d’Investigació Sanitària Pere Virgili (IISPV), 43003 Tarragona, Spain
- Research Center for Behavioural Assessment (CRAMC), Department of Psychology, Universitat Rovira i Virgili, 43007 Tarragona, Spain
| | - Cristina Jardí
- Nutrition and Mental Health (NUTRISAM) Research Group, Universitat Rovira i Virgili, 43201 Reus, Spain; (B.S.); (C.H.-M.); (C.J.); (E.A.)
- Institut d’Investigació Sanitària Pere Virgili (IISPV), 43003 Tarragona, Spain
| | - Estefanía Aparicio
- Nutrition and Mental Health (NUTRISAM) Research Group, Universitat Rovira i Virgili, 43201 Reus, Spain; (B.S.); (C.H.-M.); (C.J.); (E.A.)
- Institut d’Investigació Sanitària Pere Virgili (IISPV), 43003 Tarragona, Spain
| | - Victoria Arija
- Nutrition and Mental Health (NUTRISAM) Research Group, Universitat Rovira i Virgili, 43201 Reus, Spain; (B.S.); (C.H.-M.); (C.J.); (E.A.)
- Institut d’Investigació Sanitària Pere Virgili (IISPV), 43003 Tarragona, Spain
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23
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Kim DH, Croen LA, Iosif AM, Ames JL, Alexeeff S, Qian Y, Yolken RH, Ashwood P, Van de Water J. The association of maternal COVID-19-infection during pregnancy on the neonatal immune profile and associations with later diagnosis of neurodevelopmental disorders. Brain Behav Immun 2025; 123:1071-1080. [PMID: 39532198 DOI: 10.1016/j.bbi.2024.11.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 10/15/2024] [Accepted: 11/08/2024] [Indexed: 11/16/2024] Open
Abstract
Despite the prevalence and significant concern of COVID-19 in maternal and offspring health, little is known about the impact of COVID-19 during pregnancy on newborn immunity and neurodevelopment. This study aimed to examine 1) the relationship between maternal COVID-19 during pregnancy and newborn immune profiles and investigate the 2) associations between specific newborn immune profiles and the risk of subsequent diagnosis of a neurodevelopmental disorder (NDD) among children with prenatal exposure to COVID-19. Newborn dried bloodspots (NBS) from 545 children born at Kaiser Permanente Northern California between January 2020 and September 2021 (460 [223 males, 237 females] to COVID-19-infected [COVID+] mothers; 85 [45 males, 40 females] to COVID-19-uninfected [COVID-] mothers) were used to profile newborn immune molecules via a 42-plex cytokine/chemokine assay. Among the 460 children born to COVID+ mothers, 73 (47 males, 27 females) were later diagnosed with an NDD. In the first set of analyses examining the association between maternal COVID-19 infection during pregnancy and newborn immune profile, the results adjusted for covariates but uncorrected for multiple comparisons showed that newborns of COVID+ mothers had significantly higher levels of IL-22 (estimate [est.] = 0.16, 95 % Cl 0.01, 0.3, p = 0.04) and GM-CSF (est. = 0.27, 95 % Cl 0.09, 0.46, p = 0.004) compared to newborns of COVID- mothers. These differences were no longer statistically significant after multiple comparison adjustments. In the second analysis exploring the association between newborn profile and later diagnosis of NDD among newborns born to COVID+ mothers, the results adjusted for covariates revealed an association between higher neonatal levels of IL-22 (hazard ratio [HR] = 0.49, 95 % Cl 0.33, 0.75, p = 0.001) and lower risk of a later diagnosis of an NDD, which remained significant after multiple comparison adjustments (p = 0.04). Other neonatal cytokines/chemokines/growth factors such as sCD40L (HR = 0.7, 95 % Cl 0.57, 0.9, p = 0.009), IP-10 (HR = 0.46, 95 % Cl 0.25, 0.83, p = 0.009), MIG (HR = 0.52, 95 % Cl 0.3, 0.9, p = 0.02), FLT-3L (HR = 0.45, 95 % Cl 0.24, 0.83, p = 0.01), PDGF AB/BB (HR = 0.56, 95 % Cl 0.36, 0.99, p = 0.046), VEGF (HR = 0.57, 95 % Cl 0.34, 0.98, p = 0.04), and IL-4 (HR = 0.48, 95 % Cl 0.26, 0.93, p = 0.03) were no longer statistically significant after multiple comparison adjustments. Despite the imbalance between the number of COVID-19 exposed and unexposed newborns in this study cohort, our novel findings enhance our understanding of the potential impact of maternal COVID-19 infection during pregnancy on the developing neonatal immune system. Our findings highlight the role of immune molecules, beyond those considered to be pro-inflammatory, that may be crucial in maternal and newborn immunity against COVID-19 infection during pregnancy. Furthermore, our results suggest that reduced levels of neonatal immune molecules in newborns of COVID + mothers may be linked to an increased risk of a subsequent diagnosis of an NDD.
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Affiliation(s)
- Danielle Hj Kim
- Department of Internal Medicine, Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA, USA; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Lisa A Croen
- Division of Research, Kaiser Permanente Northern California, Pleasanton, CA, USA
| | - Ana-Maria Iosif
- Department of Public Health Sciences, Division of Biostatistics, University of California, Davis, CA, USA
| | - Jennifer L Ames
- Division of Research, Kaiser Permanente Northern California, Pleasanton, CA, USA
| | - Stacey Alexeeff
- Division of Research, Kaiser Permanente Northern California, Pleasanton, CA, USA
| | - Yinge Qian
- Division of Research, Kaiser Permanente Northern California, Pleasanton, CA, USA
| | - Robert H Yolken
- Stanley Division of Developmental Neurovirology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Paul Ashwood
- Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA; MIND Institute, University of California, Davis, CA, USA
| | - Judy Van de Water
- Department of Internal Medicine, Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA, USA; Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA; MIND Institute, University of California, Davis, CA, USA.
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24
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Martinez VO, Dos Santos NR, Bah HAF, Gomes EA, Costa DO, Souza MISS, de Carvalho CF, Andrade NC, Menezes-Filho JA. Impact of chronic toxoplasmosis in pregnancy: Association between maternal IgG antibodies against T. gondii and neurocognitive development effects. Neurotoxicology 2025; 106:10-16. [PMID: 39638154 DOI: 10.1016/j.neuro.2024.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 11/24/2024] [Accepted: 12/01/2024] [Indexed: 12/07/2024]
Abstract
Toxoplasmosis presents notable hazards in the context of pregnancy, impacting the health of the mother and the neurodevelopment of the fetus via immune reactions and possible vertical transmission. The maternal immune response from chronic Toxoplasma gondii (T. gondii) infection may negatively influence fetal neurodevelopment. This research evaluated the association between the seroprevalence of chronic T. gondii and cytomegalovirus infection in pregnant women and the neuropsychological development of their children at 12 months of age. A follow-up study evaluated women during the gestational period and their respective infants. The pregnant women were tested for the presence of antibodies to infectious agents: T. gondii, cytomegalovirus (CMV), syphilis, human immunodeficiency virus (HIV), hepatitis B and C. Detailed information about the newborns was extracted from medical records. At 12 ± 3 months of age, the infant's neurodevelopment was assessed using the Bayley-III Scales of Infant and Toddler Development by a trained specialist under the supervision of a neuropsychologist. A statistically significant association was found between maternal IgG anti-T. gondii levels and lower scores on the Bayley-III cognition scale, with a non-standardized β-coefficient of -0.078 (95 %-CI: -0.144 to -0.013), accounting for 35.1 % of the variation in this outcome. These results suggest that chronic maternal T. gondii infection, even without vertical transmission, may be associated with subtle changes in the child's cognitive development. Therefore, monitoring and early intervention are essential to identify and address possible delays in childhood neurodevelopment related to chronic maternal toxoplasmosis.
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Affiliation(s)
- Victor Otero Martinez
- Graduate Program in Pharmacy, College of Pharmacy, Federal University of Bahia, Salvador, Bahia, Brazil.
| | - Nathália Ribeiro Dos Santos
- Graduate Program in Pharmacy, College of Pharmacy, Federal University of Bahia, Salvador, Bahia, Brazil; Laboratory of Toxicology, College of Pharmacy, Federal University of Bahia, Salvador, Bahia, Brazil
| | - Homègnon Antonin Ferréol Bah
- Laboratory of Toxicology, College of Pharmacy, Federal University of Bahia, Salvador, Bahia, Brazil; Graduate Program in Public Health, Federal University of Bahia, Salvador, Bahia, Brazil
| | - Erival Amorim Gomes
- Laboratory of Toxicology, College of Pharmacy, Federal University of Bahia, Salvador, Bahia, Brazil
| | - Daisy Oliveira Costa
- Graduate Program in Pharmacy, College of Pharmacy, Federal University of Bahia, Salvador, Bahia, Brazil; Laboratory of Toxicology, College of Pharmacy, Federal University of Bahia, Salvador, Bahia, Brazil
| | | | | | | | - José Antônio Menezes-Filho
- Graduate Program in Pharmacy, College of Pharmacy, Federal University of Bahia, Salvador, Bahia, Brazil; Laboratory of Toxicology, College of Pharmacy, Federal University of Bahia, Salvador, Bahia, Brazil; Graduate Program in Public Health, Federal University of Bahia, Salvador, Bahia, Brazil
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25
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Chen L, Liu M, Dai X, He C, Wang K, Tang J, Yang Y. Untargeted Metabolomics Reveals Metabolic Link Between Histone H3K27 Demethylase UTX and Neurodevelopment. J Cell Mol Med 2025; 29:e70334. [PMID: 39779477 PMCID: PMC11710934 DOI: 10.1111/jcmm.70334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 11/19/2024] [Accepted: 12/23/2024] [Indexed: 01/11/2025] Open
Abstract
Ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) is a chromatin modifier responsible for regulating the demethylation of histone H3 lysine 27 trimethylation (H3K27me3), which is crucial for human neurodevelopment. To date, the impact of UTX on neurodevelopment remains elusive. Therefore, this study aimed to investigate the potential molecular mechanisms underlying the effects of UTX on neurodevelopment through untargeted metabolomics based on ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). We found that UTX knockout in neurones leads to cell death and apoptosis in the hippocampus and cortex, as well as induces impaired learning and memory functions in mice. Moreover, UTX deletion contributed to significant metabolic perturbations in brain tissues. A total of 223 differential metabolites were identified between wild-type (WT) and UTX cKO mice. Pathway analysis indicated that the metabolic pathways mainly affected by UTX deletion were alanine, aspartate, and glutamate metabolism, resulting in significant alterations in L-alanine, L-aspartate, D-aspartate, N-acetylaspartylglutamate, L-glutamate, and argininosuccinic acid. These data emphasised that UTX may exert a key effect in neurodevelopment and that the underlying mechanism may be related to the regulation of the alanine, aspartate, and glutamate metabolism pathways, especially the characteristic metabolites involved in this pathway.
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Affiliation(s)
- Lin Chen
- Department of PharmacyChongqing Health Center for Women and Children, Women and Children's Hospital of Chongqing Medical UniversityChongqingChina
| | - Maozhu Liu
- Center of Infectious Diseases, West China HospitalSichuan UniversityChengduChina
| | - Xinhua Dai
- Department of Laboratory Medicine, West China HospitalSichuan UniversityChengduChina
| | - Cuilin He
- Department of PharmacyThe First People's Hospital of Shuangliu DistrictChengduChina
| | - Kejing Wang
- Department of PharmacyChongqing Health Center for Women and Children, Women and Children's Hospital of Chongqing Medical UniversityChongqingChina
| | - Jinhua Tang
- Department of PharmacyChongqing Health Center for Women and Children, Women and Children's Hospital of Chongqing Medical UniversityChongqingChina
| | - Yang Yang
- Department of PharmacyChongqing Health Center for Women and Children, Women and Children's Hospital of Chongqing Medical UniversityChongqingChina
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Lee JC, Chen CM, Sun CK, Tsai IT, Cheng YS, Chiu HJ, Wang MY, Tang YH, Hung KC. The therapeutic effects of probiotics on core and associated behavioral symptoms of autism spectrum disorders: a systematic review and meta-analysis. Child Adolesc Psychiatry Ment Health 2024; 18:161. [PMID: 39702309 DOI: 10.1186/s13034-024-00848-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 12/03/2024] [Indexed: 12/21/2024] Open
Abstract
BACKGROUND We aimed at investigating the efficacies of probiotics in alleviating the core and associated symptoms of autism spectrum disorder (ASD). METHODS Randomized placebo-controlled trials were identified from major electronic databases from inception to Nov 2023. The outcomes of interests including improvements in the total and associated symptoms of ASD were quantitatively expressed as effect size (ES) based on standardized mean difference (SMD) with 95% confidence interval (CI). RESULTS Ten studies with 522 participants (mean age = 8.11) were included in this meta-analysis. The primary results revealed significant improvement in total symptoms in the probiotics group compared with the controls (SMD = - 0.19, p = 0.03, ten studies, n = 522) but not the core symptoms (i.e., repetitive restricted behaviors, As affiliations 3 and 5 are same, we have deleted the duplicate affiliations and renumbered accordingly. Please check and confirm.problems with social behaviors/communication). Subgroup analyses demonstrated improvement in total symptoms in probiotics users relative to their controls only in studies using multiple-strain probiotics (SMD = - 0.26, p = 0.03, five studies, n = 288) but not studies using single-strain regimens. Secondary results showed improvement in adaptation (SMD = 0.37, p = 0.03, three studies, n = 139) and an improvement trend in anxiety symptoms in the probiotics group compared with controls (SMD = - 0.29, 95% CI - 0.60 to 0.02, p = 0.07, three studies, n = 163) but failed to demonstrate greater improvement in the former regarding symptoms of irritability/aggression, hyperactivity/impulsivity, inattention, and parental stress. CONCLUSIONS Our study supported probiotics use against the overall behavioral symptoms of ASD, mainly in individuals receiving multiple-strain probiotics as supplements. However, our results showed that probiotics use was only associated with improvement in adaptation and perhaps anxiety, but not core symptoms, highlighting the impact of adaptation on quality of life rather than just the core symptoms. Nevertheless, the limited number of included trials warrants further large-scale clinical investigations.
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Affiliation(s)
- Jen-Chin Lee
- Department of General Psychiatry, Taoyuan Psychiatric Center, Ministry of Health and Welfare, Taoyuan City, Taiwan
| | - Chia-Min Chen
- Department of Natural Biotechnology, Nanhua University, Chiayi, Taiwan
| | - Cheuk-Kwan Sun
- Department of Emergency Medicine, E-Da Dachang Hospital, I-Shou University, Kaohsiung City, Taiwan
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung City, Taiwan
| | - I-Ting Tsai
- Department of Emergency Medicine, E-Da Dachang Hospital, I-Shou University, Kaohsiung City, Taiwan
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung City, Taiwan
| | - Yu-Shian Cheng
- Department of Psychiatry, Tsyr-Huey Mental Hospital, Kaohsiung Jen-Ai's Home, Kaohsiung City, Taiwan
| | - Hsien-Jane Chiu
- Department of General Psychiatry, Taoyuan Psychiatric Center, Ministry of Health and Welfare, Taoyuan City, Taiwan
- Institute of Hospital and Health Care Administration, National Yang-Ming Chiao Tung University, Taipei City, Taiwan
| | - Ming Yu Wang
- Department of Psychiatry, China Medical University Hsinchu Hospital, China Medical University, Hsinchu, Taiwan
- Department of Health Services Administration, China Medical University, Taichung, Taiwan
| | - Yen-Hsiang Tang
- Department of Critical Care Medicine, MacKay Memorial Hospital, Taipei, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
| | - Kuo-Chuan Hung
- Department of Anesthesiology, Chi Mei Medical Center, No.901, ChungHwa Road, YungKung Dist, Tainan, 71004, Taiwan.
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27
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He WQ, Moore HC, Miller JE, Burgner DP, Swann O, Lain SJ, Nassar N. Impact of early childhood infection on child development and school performance: a population-based study. J Epidemiol Community Health 2024; 79:27-35. [PMID: 39216990 PMCID: PMC11671983 DOI: 10.1136/jech-2024-222040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 08/25/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND Childhood infection might be associated with adverse child development and neurocognitive outcomes, but the results have been inconsistent. METHODS Two population-based record-linkage cohorts of all singleton children born at term in New South Wales, Australia, from 2001 to 2014, were set up and followed up to 2019 for developmental outcome (N=276 454) and school performance (N=644 291). The primary outcome was developmentally high risk (DHR) at age 4-6 years and numeracy and reading below the national minimum standard at age 7-9 years. Cox regression was used to assess the association of childhood infection ascertained from hospital records with each outcome adjusting for maternal, birth and child characteristics, and sensitivity analyses were conducted assessing E-values and sibling analysis for discordant exposure. RESULTS A higher proportion of children with an infection-related hospitalisation were DHR (10.9% vs 8.7%) and had numeracy (3.7% vs 2.7%) and reading results (4.3% vs 3.1%) below the national minimum standard, compared with those without infection-related hospitalisation. In the multivariable analysis, children with infection-related hospitalisation were more likely to be DHR (adjusted HR 1.12, 95% CI 1.08 to 1.15) and have numeracy (adjusted HR 1.22, 95% CI 1.18 to 1.26) and reading results (adjusted HR 1.16, 95% CI 1.12 to 1.20) below the national minimum standard. However, these results may be impacted by unmeasured confounding, based on E-values of 1.48-1.74, and minimal association with education outcome was found in the sibling analysis. CONCLUSIONS Infection-related hospitalisation was modestly associated with adverse child development and school performance, but the association may be explained by shared familial factors, particularly in those with most socioeconomic disadvantages.
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Affiliation(s)
- Wen-Qiang He
- Child Population and Translational Health Research, Children's Hospital Westmead Clinical School, The University of Sydney, Sydney, New South Wales, Australia
- Menzies Centre for Health Policy and Economics, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia
| | - Hannah Catherine Moore
- Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kids Institute, The University of Western Australia, Perth, Perth, Australia
- School of Population Health, Curtin University, Bentley, Western Australia, Australia
| | - Jessica E Miller
- Murdoch Children’s Research Institute, The Royal Children's Hospital Melbourne, Melbourne, Victoria, Australia
- Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia
| | - David P Burgner
- Murdoch Children’s Research Institute, The Royal Children's Hospital Melbourne, Melbourne, Victoria, Australia
- Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia
- Department of Paediatrics, Monash University, Clayton, Victoria, Australia
| | - Olivia Swann
- Department of Child Life and Health, The University of Edinburgh, Edinburgh, UK
- Centre for Medical Informatics, Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, UK
| | - Samantha J Lain
- Child Population and Translational Health Research, Children's Hospital Westmead Clinical School, The University of Sydney, Sydney, New South Wales, Australia
- Menzies Centre for Health Policy and Economics, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia
| | - Natasha Nassar
- Child Population and Translational Health Research, Children's Hospital Westmead Clinical School, The University of Sydney, Sydney, New South Wales, Australia
- Menzies Centre for Health Policy and Economics, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia
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Nomakuchi TT, Teferedegn EY, Li D, Muirhead KJ, Dubbs H, Leonard J, Muraresku C, Sergio E, Arnold K, Pizzino A, Skraban CM, Zackai EH, Wang K, Ganetzky RD, Vanderver AL, Ahrens-Nicklas RC, Bhoj EJK. Utility of genome sequencing in exome-negative pediatric patients with neurodevelopmental phenotypes. Am J Med Genet A 2024; 194:e63817. [PMID: 39031459 PMCID: PMC11540733 DOI: 10.1002/ajmg.a.63817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 07/03/2024] [Accepted: 07/07/2024] [Indexed: 07/22/2024]
Abstract
Exome sequencing (ES) has emerged as an essential tool in the evaluation of neurodevelopmental disorders (NDD) of unknown etiology. Genome sequencing (GS) offers advantages over ES due to improved detection of structural, copy number, repeat number and non-coding variants. However, GS is less commonly utilized due to higher cost and more intense analysis. Here, we present nine cases of pediatric NDD that were molecularly diagnosed with GS between 2017 and 2022, following non-diagnostic ES. All individuals presented with global developmental delay or regression. Other features present in our cohort included epilepsy, white matter abnormalities, brain malformation and dysmorphic features. Two cases were diagnosed on GS due to newly described gene-disease relationship or variant reclassification (MAPK8IP3, CHD3). Additional features missed on ES that were later detected on GS were: intermediate-size deletions in three cases who underwent ES that were not validated for CNV detection, pathogenic variants within the non-protein coding genes SNORD118 and RNU7-1, pathogenic variant within the promoter region of GJB1, and a coding pathogenic variant within BCAP31 which was not sufficiently covered on ES. GS following non-diagnostic ES led to the identification of pathogenic variants in this cohort of nine cases, four of which would not have been identified by reanalysis alone.
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Affiliation(s)
- Tomoki T. Nomakuchi
- Division of Human Genetics, Children’s Hospital of
Philadelphia, Philadelphia, Pennsylvania, USA
| | - Eden Y. Teferedegn
- Division of Human Genetics, Children’s Hospital of
Philadelphia, Philadelphia, Pennsylvania, USA
| | - Dong Li
- Division of Human Genetics, Children’s Hospital of
Philadelphia, Philadelphia, Pennsylvania, USA
| | - Kayla J. Muirhead
- Division of Neurology, Children’s Hospital of
Philadelphia, Philadelphia, Pennsylvania, USA
| | - Holly Dubbs
- Division of Neurology, Children’s Hospital of
Philadelphia, Philadelphia, Pennsylvania, USA
| | - Jacqueline Leonard
- Division of Human Genetics, Children’s Hospital of
Philadelphia, Philadelphia, Pennsylvania, USA
| | - Colleen Muraresku
- Division of Human Genetics, Children’s Hospital of
Philadelphia, Philadelphia, Pennsylvania, USA
| | - Emily Sergio
- Division of Neurology, Children’s Hospital of
Philadelphia, Philadelphia, Pennsylvania, USA
| | - Kaley Arnold
- Division of Neurology, Children’s Hospital of
Philadelphia, Philadelphia, Pennsylvania, USA
| | - Amy Pizzino
- Division of Neurology, Children’s Hospital of
Philadelphia, Philadelphia, Pennsylvania, USA
| | - Cara M. Skraban
- Division of Human Genetics, Children’s Hospital of
Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Pediatrics, Perelman School of Medicine,
University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Elaine H. Zackai
- Division of Human Genetics, Children’s Hospital of
Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Pediatrics, Perelman School of Medicine,
University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Kai Wang
- Division of Human Genetics, Children’s Hospital of
Philadelphia, Philadelphia, Pennsylvania, USA
| | - Rebecca D. Ganetzky
- Division of Human Genetics, Children’s Hospital of
Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Pediatrics, Perelman School of Medicine,
University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Adeline L. Vanderver
- Department of Neurology, Perelman School of Medicine,
University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Rebecca C. Ahrens-Nicklas
- Division of Human Genetics, Children’s Hospital of
Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Pediatrics, Perelman School of Medicine,
University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Elizabeth J. K. Bhoj
- Division of Human Genetics, Children’s Hospital of
Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Pediatrics, Perelman School of Medicine,
University of Pennsylvania, Philadelphia, Pennsylvania, USA
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29
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Anderson KG, Lazarus MF, Bruckert L, Poblaciones RV, Scala M, Marchman VA, Feldman HM, Travis KE. Neonatal inflammation and near-term white matter microstructure in infants born very preterm. NEUROIMAGE. REPORTS 2024; 4:100226. [PMID: 39822573 PMCID: PMC11737600 DOI: 10.1016/j.ynirp.2024.100226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/19/2025]
Abstract
Background Severe neonatal inflammatory conditions in very preterm infants (VPT: <32 weeks gestational age, GA) are linked to adverse neurodevelopmental outcomes. Differences in white matter (WM) microstructure of the corpus callosum (CC) have been observed at age 6 in VPT children with a history of severe neonatal inflammation. The goal of this study was to determine whether these CC differences can be detected at term-equivalent age using diffusion MRI (dMRI), and whether neonatal inflammation is associated with altered WM in additional tracts implicated in the encephalopathy of prematurity. Methods We conducted a retrospective study of VPT infants (n = 152) born at 22-32 weeks GA, classified based on the presence (I+, n = 80) or absence (I-, n = 72) of severe neonatal inflammatory conditions (bronchopulmonary dysplasia, necrotizing enterocolitis, or culture-positive sepsis). Analysis of covariance (ANCOVA) assessed group differences in near-term dMRI mean fractional anisotropy (FA) and mean diffusivity (MD) across seven segments of the CC and the anterior thalamic radiation, arcuate fasciculus, cingulum, corticospinal tract, inferior longitudinal fasciculus, superior cerebellar peduncle, and uncinate fasciculus. Due to imbalance of GA in the full sample, secondary ANCOVA analyses were performed in a GA-matched subset (n = 42) to further isolate the effect of inflammation. Results FA was significantly lower in the I+ group compared to the I- group in the anterior frontal, posterior parietal, temporal, and occipital segments of the CC, and in the cingulum, inferior longitudinal fasciculus, and superior cerebellar peduncle. This general pattern persisted in the GA-matched subset, with significant differences in the anterior frontal and temporal CC segments. Conclusions VPT infants with severe neonatal inflammation had lower FA in multiple white matter tracts, suggesting that inflammation-related alterations in WM development begin in the neonatal period. The observed differences detected using dMRI at term-equivalent age corroborate prior findings and may provide a window of opportunity for early identification of VPT infants at increased risk of poor neurodevelopmental outcomes.
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Affiliation(s)
| | - Molly F. Lazarus
- Department of Pediatrics, Division of Developmental-Behavioral Pediatrics, Stanford University, Stanford, CA, USA
- Burke-Cornell Medical Research Institute at Weill Cornell Medicine and Department of Pediatrics, Weill Medical College, Cornell University, New York, NY, USA
| | - Lisa Bruckert
- Department of Pediatrics, Division of Developmental-Behavioral Pediatrics, Stanford University, Stanford, CA, USA
| | - Rocio V. Poblaciones
- Department of Pediatrics, Division of Developmental-Behavioral Pediatrics, Stanford University, Stanford, CA, USA
| | - Melissa Scala
- Department of Pediatrics, Division of Neonatology, Stanford University, Stanford, CA, USA
| | - Virginia A. Marchman
- Department of Pediatrics, Division of Developmental-Behavioral Pediatrics, Stanford University, Stanford, CA, USA
- Department of Psychology, Stanford University, Stanford, CA, USA
| | - Heidi M. Feldman
- Department of Pediatrics, Division of Developmental-Behavioral Pediatrics, Stanford University, Stanford, CA, USA
| | - Katherine E. Travis
- Department of Pediatrics, Division of Developmental-Behavioral Pediatrics, Stanford University, Stanford, CA, USA
- Burke-Cornell Medical Research Institute at Weill Cornell Medicine and Department of Pediatrics, Weill Medical College, Cornell University, New York, NY, USA
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Sun X, Shukla M, Wang W, Li S. Unlocking gut-liver-brain axis communication metabolites: energy metabolism, immunity and barriers. NPJ Biofilms Microbiomes 2024; 10:136. [PMID: 39587086 PMCID: PMC11589602 DOI: 10.1038/s41522-024-00610-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 11/14/2024] [Indexed: 11/27/2024] Open
Abstract
The interaction between the gut-microbiota-derived metabolites and brain has long been recognized in both health and disease. The liver, as the primary metabolic organ for nutrients in animals or humans, plays an indispensable role in signal transduction. Therefore, in recent years, Researcher have proposed the Gut-Liver-Brain Axis (GLBA) as a supplement to the Gut-Brain Axis. The GLBA plays a crucial role in numerous physiological and pathological mechanisms through a complex interplay of signaling pathways. However, gaps remain in our knowledge regarding the developmental and functional influences of the GLBA communication pathway. The gut microbial metabolites serve as communication agents between these three distant organs, functioning prominently within the GLBA. In this review, we provide a comprehensive overview of the current understanding of the GLBA, focusing on signaling molecules role in animal and human health and disease. In this review paper elucidate its mechanisms of communication, explore its implications for immune, and energy metabolism in animal and human, and highlight future research directions. Understanding the intricate communication pathways of the GLBA holds promise for creating innovative treatment approaches for a wide range of immune and metabolic conditions.
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Affiliation(s)
- Xiaoge Sun
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, P. R. China
- Department of Neurosurgery, College of Medicine, The Pennsylvania State University, Hershey, PA, 17033, USA
| | - Manish Shukla
- Department of Neurosurgery, College of Medicine, The Pennsylvania State University, Hershey, PA, 17033, USA
| | - Wei Wang
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, P. R. China.
| | - Shengli Li
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, P. R. China.
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Vallese A, Cordone V, Ferrara F, Guiotto A, Gemmo L, Cervellati F, Hayek J, Pecorelli A, Valacchi G. NLRP3 inflammasome-mitochondrion loop in autism spectrum disorder. Free Radic Biol Med 2024; 225:581-594. [PMID: 39433111 DOI: 10.1016/j.freeradbiomed.2024.10.297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 10/17/2024] [Accepted: 10/18/2024] [Indexed: 10/23/2024]
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and the presence of restricted interests and repetitive behavior. To date, no single cause has been demonstrated but both genetic and environmental factors are believed to be involved in abnormal brain development. In recent years, immunological and mitochondrial dysfunctions acquired particular interest in the study of the molecular mechanisms underlying the pathophysiology of ASD. For this reason, our study focused on evaluating the mitochondrial component and activation of the NLRP3 inflammasome, a critical player of the innate immune system. The assembly of NLRP3 with ASC mediates activation of Caspase-1, which in turn, by proteolytic cleavage, activates Gasdermin D and the proinflammatory cytokines IL-1β/IL-18 with their subsequent secretion. Using primary fibroblasts of autistic and control patients we studied basal and stimulated conditions. Specifically, LPS and ATP were used to activate the NLRP3 inflammasome and MCC950 for its inhibition. In addition, FCCP was used as a mitochondrial stressor and MitoTEMPO as a scavenger of mitochondrial ROS. Our results showed a hyperactivation of NLRP3 inflammasome in ASDs, as evidenced by the co-localization of the two main components, NLRP3 and ASC, by the higher levels of ASC specks, oligomers and dimers and by the increased amounts of active Caspase-1 and IL-1β. In addition, increased mitochondrial superoxide anion and reduced mitochondrial membrane potential were detected in ASD cells. These data are in accordance with the abnormal mitochondrial morphology evidenced by transmission electron microscopy analysis. Interestingly, NLRP3 inflammasome inhibition with MCC950 improved mitochondrial parameters, while the use of MitoTEMPO, in addition to decrease mitochondrial ROS production, was able to prevent NLRP3 inflammasome activation suggesting for the first time an abnormal bidirectional crosstalk between mitochondria and NLRP3 inflammasome in ASD.
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Affiliation(s)
- Andrea Vallese
- Dept. of Environmental and Prevention Sciences, University of Ferrara, Ferrara, Italy; Animal Science Dept., Plants for Human Health Institute, North Carolina State University, Kannapolis, NC, USA
| | - Valeria Cordone
- Dept. of Environmental and Prevention Sciences, University of Ferrara, Ferrara, Italy
| | - Francesca Ferrara
- Dept. of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy
| | - Anna Guiotto
- Dept. of Environmental and Prevention Sciences, University of Ferrara, Ferrara, Italy; Animal Science Dept., Plants for Human Health Institute, North Carolina State University, Kannapolis, NC, USA
| | - Laura Gemmo
- Dept. of Environmental and Prevention Sciences, University of Ferrara, Ferrara, Italy
| | - Franco Cervellati
- Dept. of Neuroscience and Rehabilitation, University of Ferrara, Ferrara, Italy
| | | | - Alessandra Pecorelli
- Dept. of Environmental and Prevention Sciences, University of Ferrara, Ferrara, Italy; Dept. of Food, Bioprocessing and Nutrition Sciences, Plants for Human Health Institute, North Carolina State University, Kannapolis, NC, USA.
| | - Giuseppe Valacchi
- Dept. of Environmental and Prevention Sciences, University of Ferrara, Ferrara, Italy; Animal Science Dept., Plants for Human Health Institute, North Carolina State University, Kannapolis, NC, USA; Dept. of Food and Nutrition, Kyung Hee University, Seoul, South Korea.
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32
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Geng C, Chen C. Association between elevated systemic inflammatory markers and the risk of cognitive decline progression: a longitudinal study. Neurol Sci 2024; 45:5253-5259. [PMID: 38890170 DOI: 10.1007/s10072-024-07654-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 06/11/2024] [Indexed: 06/20/2024]
Abstract
BACKGROUND Chronic systemic inflammation is linked to cognitive decline pathogenesis. This study investigates the association between systemic inflammation markers and cognitive decline progression in a clinical cohort. METHODS This prospective observational cohort study enrolled 295 participants. Cognitive decline progression was defined by an increase in clinical dementia rating (CDR) scores. The study examines the correlation between systemic inflammation markers, including systemic Inflammation Response Index (SIRI), systemic Immune-Inflammation Index (SII), prognostic Inflammatory and Nutritional Index (PIV), and cognitive impairment progression. RESULTS The presence of the APOE 4 allele and diabetes mellitus was associated with elevated PIV levels (P < 0.05). Additionally, AD patients had the highest SII levels, indicating increased inflammation compared to individuals with MCI and SCD (P < 0.05). After a mean follow-up of 17 months, 117 patients (51.31%) experienced cognitive decline progression. AD diagnosis, CDR, and SII were significant predictors of cognitive decline progression (All P < 0.05). CONCLUSION This study highlights the clinical significance of elevated systemic inflammation markers in identifying individuals at risk of cognitive decline. Addressing inflammation may offer a promising approach to improving cognitive health and mitigating age-related cognitive decline.
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Affiliation(s)
- Chaofan Geng
- Department of Neurology & Innovation Center for Neurological Disorders, Xuanwu Hospital, National Center for Neurological Disorders, Capital Medical University, Beijing, China
| | - Chen Chen
- Department of Neurology, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, 7 Weiwu Street, Zhengzhou, 450000, China.
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Suleri A, Creasey N, Walton E, Muetzel R, Felix JF, Duijts L, Bergink V, Cecil CAM. Mapping prenatal predictors and neurobehavioral outcomes of an epigenetic marker of neonatal inflammation - A longitudinal population-based study. Brain Behav Immun 2024; 122:483-496. [PMID: 39209009 PMCID: PMC11784988 DOI: 10.1016/j.bbi.2024.08.053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 08/19/2024] [Accepted: 08/26/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND DNA methylation levels at specific sites can be used to proxy C-reactive protein (CRP) levels, providing a potentially more stable and accurate indicator of sustained inflammation and associated health risk. However, its use has been primarily limited to adults or preterm infants, and little is known about determinants for - or offspring outcomes of - elevated levels of this epigenetic proxy in cord blood. The aim of this study was to comprehensively map prenatal predictors and long-term neurobehavioral outcomes of neonatal inflammation, as assessed with an epigenetic proxy of inflammation in cord blood, in the general pediatric population. METHODS Our study was embedded in the prospective population-based Generation R Study (n = 2,394). We created a methylation profile score of CRP (MPS-CRP) in cord blood as a marker of neonatal inflammation and validated it against serum CRP levels in mothers during pregnancy, as well as offspring at birth and in childhood. We then examined (i) which factors (previously associated with sustained inflammation) explain variability in MPS-CRP at birth, including a wide range of prenatal lifestyle and clinical conditions, pro-inflammatory exposures, as well as child genetic liability to elevated CRP levels; and (ii) whether MPS-CRP at birth associates with child neurobehavioral outcomes, including global structural MRI and DTI measures (child mean age 10 and 14 years) as well as psychiatric symptoms over time (Child Behavioral Checklist, at mean age 1.5, 3, 6, 10 and 14 years). RESULTS MPS-CRP at birth was validated with serum CRP in cord blood (cut-off > 1 mg/L) (AUC = 0.72). Prenatal lifestyle pro-inflammatory factors explained a small part (i.e., < 5%) of the variance in the MPS-CRP at birth. No other prenatal predictor or the polygenic score of CRP in the child explained significant variance in the MPS-CRP at birth. The MPS-CRP at birth prospectively associated with a reduction in global fractional anisotropy over time on mainly a nominal threshold (β = -0.014, SE = 0.007, p = 0.032), as well as showing nominal associations with structural differences (amygdala [(β = 0.016, SE = 0.006, p = 0.010], cerebellum [(β = -0.007, SE = 0.003, p = 0.036]). However, no associations with child psychiatric symptoms were observed. CONCLUSION Prenatal exposure to lifestyle-related pro-inflammatory factors was the only prenatal predictor that accounted for some of the individual variability in MPS-CRP levels at birth. Further, while the MPS-CRP prospectively associated with white matter alterations over time, no associations were observed at the behavioral level. Thus, the relevance and potential utility of using epigenetic data as a marker of neonatal inflammation in the general population remain unclear. In the future, the use of epigenetic proxies for a wider range of immune markers may lend further insights into the relationship between neonatal inflammation and adverse neurodevelopment within the general pediatric population.
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Affiliation(s)
- Anna Suleri
- Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Nicole Creasey
- Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Clinical, Educational & Health Psychology, Division of Psychology & Language Sciences, Faculty of Brain Sciences, University College London, London, UK
| | - Esther Walton
- Department of Psychology, University of Bath, Bath, UK
| | - Ryan Muetzel
- Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Radiology and Nuclear Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Janine F Felix
- The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Liesbeth Duijts
- Department of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Veerle Bergink
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Charlotte A M Cecil
- Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Biomedical Data Sciences, Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
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Wang L, Chen B, Xie D, Wang Y. Bioinformatics and network pharmacology discover the molecular mechanism of Liuwei Dihuang pills in treating cerebral palsy. Medicine (Baltimore) 2024; 103:e40166. [PMID: 39470545 PMCID: PMC11521014 DOI: 10.1097/md.0000000000040166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 10/01/2024] [Accepted: 10/02/2024] [Indexed: 10/30/2024] Open
Abstract
A collection of chronic central motor, postural, and activity restriction symptoms are referred to as cerebral palsy (CP). Previous research suggests that a number of perinatal variables, including hypoxia, may be linked to CP. And the pathophysiological process that causes brain injury in growing fetuses is mostly caused by amniotic fluid infection and intra-amniotic inflammation. Still, there is still much to learn about the molecular mechanism of CP. The goal of this study was to identify the molecular mechanism of Liuwei Dihuang pill (LWDHP) in the treatment of CP using network pharmacology and bioinformatics. The Chinese medicine database provided the LWDHP components and targets, the CP illness gene data set was gathered from a disease, and the expression profile of children with CP was chosen from anther database. Using the Kyoto Encyclopedia of Genes and Genomes and gene ontology databases, a network of interactions between proteins was created, and functional enrichment analysis was carried out. Analysis of traditional Chinese medicine found that the key active ingredients of LWDHP are quercetin, Stigmasterol and kaempferol. Through enrichment analysis, it was found that the hub genes for LWDHP treatment of CP are CXCL8, MMP9, EGF, PTGS2, SPP1, BCL2L1, MMP1, and AR. K EGG analysis found that LWDHP treatment of CP mainly regulates PI3K-Akt signaling pathway, IL-17 signaling pathway, Jak-STAT signaling pathway, NF-kappa B signaling pathway, etc. To summarize, LWDHP regulates immunological and inflammatory variables through a variety of components, targets, and signaling pathways, which plays a significant role in the development and management of CP.
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Affiliation(s)
- Ling Wang
- Department of Operating Room, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, China
| | - Bo Chen
- Department of Rehabilitation, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, China
- Department of Rehabilitation Science, Hong Kong Polytechnic University, Hong Kong, China
| | - Dongke Xie
- Pediatric Surgery, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, China
- Sichuan Clinical Research Center for Birth Defects, the Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, China
| | - Yuanhui Wang
- Pediatric Surgery, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, China
- Sichuan Clinical Research Center for Birth Defects, the Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, China
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Ortiz-Valladares M, Gonzalez-Perez O, Pedraza-Medina R. Bridging the gap: Prenatal nutrition, myelination, and schizophrenia etiopathogenesis. Neuroscience 2024; 558:58-69. [PMID: 39159841 DOI: 10.1016/j.neuroscience.2024.08.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 08/02/2024] [Accepted: 08/13/2024] [Indexed: 08/21/2024]
Abstract
Schizophrenia (SZ) is a complex mental illness characterized by disturbances in thinking, emotionality, and behavior, significantly impacting the quality of life for individuals affected and those around them. The etiology of SZ involves intricate interactions between genetic and environmental factors, although the precise mechanisms remain incompletely understood. Genetic predisposition, neurotransmitter dysregulation (particularly involving dopamine and serotonin), and structural brain abnormalities, including impaired prefrontal cortex function, have been implicated in SZ development. However, increasing evidence reveals the role of environmental factors, such as nutrition, during critical periods like pregnancy and lactation. Epidemiological studies suggest that early malnutrition significantly increases the risk of SZ symptoms manifesting in late adolescence, a crucial period coinciding with peak myelination and brain maturation. Prenatal undernutrition may disrupt myelin formation, rendering individuals more susceptible to SZ pathology. This review explores the potential relationship between prenatal undernutrition, myelin alterations, and susceptibility to SZ. By delineating the etiopathogenesis, examining genetic and environmental factors associated with SZ, and reviewing the relationship between SZ and myelination disorders, alongside the impact of malnutrition on myelination, we aim to examine how malnutrition might be linked to SZ by altering myelination processes, which contribute to increasing the understanding of SZ etiology and help identify targets for intervention and management.
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Affiliation(s)
| | - Oscar Gonzalez-Perez
- Laboratory of Neuroscience, School of Psychology, University of Colima, Colima 28040. México
| | - Ricardo Pedraza-Medina
- Medical Science Postgraduate Program, School of Medicine, University of Colima, Colima 28040. México
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Prentice RE, Hunt RW, Spittle AJ, Ditchfield M, Chen J, Burns M, Flanagan EK, Wright E, Ross AL, Goldberg R, Bell SJ. Well controlled maternal inflammatory bowel disease does not increase the risk of abnormal neurocognitive outcome screening in offspring. Brain Behav Immun Health 2024; 40:100827. [PMID: 39149622 PMCID: PMC11326492 DOI: 10.1016/j.bbih.2024.100827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 06/26/2024] [Accepted: 07/20/2024] [Indexed: 08/17/2024] Open
Abstract
Background Exposure to maternal inflammation is associated with an increased risk of neurocognitive and developmental disorders in offspring. Early diagnosis and intervention improves childhood motor and cognitive functioning. Neonatal cerebral MRI and remote app-based generalised movement assessments (GMAs) are both predictive of adverse neurocognitive outcomes but have only been used in infants at significantly increased risk for these outcomes, rather than following in utero exposure to maternal inflammatory disorders. Methods Pregnant women with inflammatory bowel disease were assessed clinically and biochemically in each trimester of pregnancy in this single centre prospective study. Neonatal cerebral MRIs were performed at 6-12 weeks post-corrected term. Two GMA videos were filmed using the 'BabyMoves' app from 12 to 16 weeks of age. MRIs and GMAs were assessed by a blinded highly qualified practitioner using validated scoring systems. Results 40/53 of invited maternal-infant dyads were recruited. C-reactive protein was elevated antenatally in less than 13%. 5/37 neonatal MRIs had incidental or obstetric trauma related gross anatomical abnormalities, with none abnormal on validated gross abnormality scoring. 3/35 GMAs were abnormal, with one GMA abnormality being clinically significant. Of those with abnormal GMAs, 2/3 were in exposed to severely active IBD in-utero. Conclusion Neonatal cerebral MRI and GMA for neurocognitive screening is feasible in the setting of maternal inflammatory bowel disease, where the risk of cerebral palsy is poorly defined and thus burdensome screening interventions are less appealing to parents. Larger studies are required to stratify adverse neurocognitive outcome risk in infants born to women with maternal inflammatory disorders, but these data are reassuring for women with IBD in remission antenatally.
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Affiliation(s)
- Ralley E Prentice
- Department of Gastroenterology, Monash Health, Melbourne, VIC, Australia
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, VIC, Australia
- Department of Medicine, Monash University, Melbourne, VIC, Australia
| | - Rod W Hunt
- Department of Neonatal Medicine, Monash Health, Melbourne, VIC, Australia
- Department of Paediatrics, Monash University, Melbourne, VIC, Australia
- Cerebral Palsy Alliance, Australia
| | - Alicia J Spittle
- Department of Physiotherapy, University of Melbourne, Melbourne, VIC, Australia
- Victorian Infant Brain Studies, Murdoch Children's Research Institute, Melbourne, VIC, Australia
| | - Michael Ditchfield
- Department of Paediatrics, Monash University, Melbourne, VIC, Australia
- Department of Medical Imaging, Monash Children's Hospital, Melbourne, VIC, Australia
| | - Jeff Chen
- Department of Medical Imaging, Monash Children's Hospital, Melbourne, VIC, Australia
| | - Megan Burns
- Department of Gastroenterology, Monash Health, Melbourne, VIC, Australia
| | - Emma K Flanagan
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, VIC, Australia
- Department of Medicine, University of Melbourne, Melbourne, VIC, Australia
| | - Emily Wright
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, VIC, Australia
- Department of Medicine, University of Melbourne, Melbourne, VIC, Australia
| | - Alyson L Ross
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, VIC, Australia
| | - Rimma Goldberg
- Department of Gastroenterology, Monash Health, Melbourne, VIC, Australia
- Department of Medicine, Monash University, Melbourne, VIC, Australia
| | - Sally J Bell
- Department of Gastroenterology, Monash Health, Melbourne, VIC, Australia
- Department of Medicine, Monash University, Melbourne, VIC, Australia
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Nilsson IAK, Ozsvar J, Gissler M, Lavebratt C. Maternal Eating Disorders, Body Mass Index, and Offspring Psychiatric Diagnoses. JAMA Netw Open 2024; 7:e2440517. [PMID: 39436646 PMCID: PMC11581519 DOI: 10.1001/jamanetworkopen.2024.40517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 08/28/2024] [Indexed: 10/23/2024] Open
Abstract
Importance Maternal nutrition is essential in fetal development; thus, disordered eating may influence this process and contribute to the development of offspring psychiatric disorders. Objective To investigate the association of maternal eating disorders and prepregnancy body mass index (BMI) with offspring psychiatric diagnoses. Design, Setting, and Participants This population-based cohort study used Finnish national registers to assess all live births from January 1, 2004, through December 31, 2014, with follow-up until December 31, 2021. The data analyses were conducted from September 1, 2023, to September 30, 2024. Exposures Maternal eating disorder and prepregnancy BMI. Main Outcomes and Measures Primary outcomes were 9 neurodevelopmental and psychiatric offspring diagnoses. Cox proportional hazards modeling adjusted for potential risk factors in the development of the outcome disorders was applied in 2 models. Secondary analyses were stratified for adverse birth outcomes (prematurity, small size for gestational age, and low Apgar score) or comorbid offspring eating disorders. Categories of BMI (calculated as weight in kilograms divided by height in meters squared) included underweight (BMI <18.5), normal weight (18.5-24.9), overweight (25.0-29.9), obesity (30.0-34.9), and severe obesity (≥35.0). Results The mean (SD) age of 392 098 included mothers was 30.15 (5.38) years, 42 590 mothers (10.86%) were born outside of Finland, 6273 mothers (1.60%) had a history of an eating disorder, 23 114 mothers (5.89%) had prepregnancy underweight, and 208 335 (53.13%) mothers had overweight or obesity. Among 649 956 included offspring, 332 359 (51.14%) were male, and 106 777 (16.43%) had received a neurodevelopmental or psychiatric diagnosis. Maternal eating disorders, prepregnancy underweight, and overweight or obesity were associated with most of the studied mental diagnoses in offspring, even after adjusting for potential covariates. The largest effect sizes were observed for maternal eating disorders not otherwise specified in association with offspring sleep disorders (hazard ratio [HR], 3.34 [95% CI, 2.39-4.67]) and social functioning and tic disorders (HR, 2.79 [95% CI, 2.21-3.52]), while for maternal severe prepregnancy obesity, offspring intellectual disabilities (HR, 2.04 [95% CI, 1.83-2.28]) had the largest effect size. Adverse birth outcomes further increased the risk of offspring having other feeding disturbances of childhood and infancy (eg, HR, 4.53 [95% CI, 2.97-6.89] for maternal eating disorders) and attention-deficit/hyperactivity disorder and conduct disorder (eg, HR, 2.27 [95% CI, 1.74-2.96] for maternal anorexia nervosa). Conclusions and Relevance In this population-based cohort study including 392 098 mothers and 649 956 offspring, offspring from mothers with an eating disorder history or prepregnancy BMI outside normal weight were at higher risk of psychiatric disorders. The results differed somewhat between the 2 exposures with regard to which offspring diagnoses had associations, and effect sizes were typically larger for maternal eating disorders vs BMI. These findings suggest a need to consider these 2 exposures clinically to help prevent offspring mental illness.
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Affiliation(s)
- Ida A. K. Nilsson
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden
- Centre for Eating Disorders Innovation, Karolinska Institutet, Stockholm, Sweden
| | - Judit Ozsvar
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Mika Gissler
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden
- Department of Knowledge Brokers, Finnish Institute for Health and Welfare, Helsinki, Finland
- Research Centre for Child Psychiatry, University of Turku, Turku, Finland
| | - Catharina Lavebratt
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden
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Anastasescu CM, Gheorman V, Stoicanescu EC, Popescu F, Gheorman V, Udriștoiu I. Immunological Biomarkers in Autism Spectrum Disorder: The Role of TNF-Alpha and Dependent Trends in Serum IL-6 and CXCL8. Life (Basel) 2024; 14:1201. [PMID: 39337983 PMCID: PMC11432970 DOI: 10.3390/life14091201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 09/12/2024] [Accepted: 09/20/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND Autism spectrum disorder (ASD) has seen a rise in prevalence, and the immune system's role in brain development is increasingly recognized. This study investigates the relationship between immune dysregulation and ASD by examining serum concentrations of interleukin 6 (IL-6), interleukin 8 (CXCL8), and tumor necrosis factor alpha (TNF-alpha) in children. METHODS Serum samples from 45 children with ASD and 30 controls, aged 2 to 12 years, were analyzed using electrochemiluminescence, chemiluminescent microparticle immunoassay, and chemiluminescent immunoassay. ASD symptoms were assessed using the Autism Spectrum Rating Scale (ASRS) and Social Communication Questionnaire (SCQ). RESULTS No significant correlation was observed between CXCL8 levels and ASD. IL-6 levels showed a trend toward elevation in boys with ASD. TNF-alpha levels were significantly higher in children with ASD under 5 years compared to older children and controls, though no correlation with symptom severity was found. CONCLUSIONS TNF-alpha may be a potential biomarker for early ASD detection, especially in younger children. Further research on larger cohorts is needed to understand the role of immune dysregulation in ASD.
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Affiliation(s)
| | - Veronica Gheorman
- Department of Medical Semiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Eugen-Cristi Stoicanescu
- Pediatry Department, Emergency Clinical Hospital Râmnicu-Vâlcea, 200300 Râmnicu-Vâlcea, Romania;
| | - Florica Popescu
- Pharmacology Department, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Victor Gheorman
- Department of Psychiatry, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (V.G.); (I.U.)
| | - Ion Udriștoiu
- Department of Psychiatry, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (V.G.); (I.U.)
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Diez-Ahijado L, Cilleros-Portet A, Fernández-Jimenez N, Fernández MF, Guxens M, Julvez J, Llop S, Lopez-Espinosa MJ, Subiza-Pérez M, Lozano M, Ibarluzea J, Sunyer J, Bustamante M, Cosin-Tomas M. Evaluating the association between placenta DNA methylation and cognitive functions in the offspring. Transl Psychiatry 2024; 14:383. [PMID: 39304652 DOI: 10.1038/s41398-024-03094-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 08/31/2024] [Accepted: 09/04/2024] [Indexed: 09/22/2024] Open
Abstract
The placenta plays a crucial role in protecting the fetus from environmental harm and supports the development of its brain. In fact, compromised placental function could predispose an individual to neurodevelopmental disorders. Placental epigenetic modifications, including DNA methylation, could be considered a proxy of placental function and thus plausible mediators of the association between intrauterine environmental exposures and genetics, and childhood and adult mental health. Although neurodevelopmental disorders such as autism spectrum disorder have been investigated in relation to placenta DNA methylation, no studies have addressed the association between placenta DNA methylation and child's cognitive functions. Thus, our goal here was to investigate whether the placental DNA methylation profile measured using the Illumina EPIC array is associated with three different cognitive domains (namely verbal score, perceptive performance score, and general cognitive score) assessed by the McCarthy Scales of Children's functions in childhood at age 4. To this end, we conducted epigenome-wide association analyses, including data from 255 mother-child pairs within the INMA project, and performed a follow-up functional analysis to help the interpretation of the findings. After multiple-testing correction, we found that methylation at 4 CpGs (cg1548200, cg02986379, cg00866476, and cg14113931) was significantly associated with the general cognitive score, and 2 distinct differentially methylated regions (DMRs) (including 27 CpGs) were significantly associated with each cognitive dimension. Interestingly, the genes annotated to these CpGs, such as DAB2, CEP76, PSMG2, or MECOM, are involved in placenta, fetal, and brain development. Moreover, functional enrichment analyses of suggestive CpGs (p < 1 × 10-4) revealed gene sets involved in placenta development, fetus formation, and brain growth. These findings suggest that placental DNA methylation could be a mechanism contributing to the alteration of important pathways in the placenta that have a consequence on the offspring's brain development and cognitive function.
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Affiliation(s)
- Laia Diez-Ahijado
- ISGlobal, Institute for Global Health, Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- CIBER Epidemiología y Salud Pública, Madrid, Spain
| | - Ariadna Cilleros-Portet
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU) and Biocruces-Bizkaia Health Research Institute, Basque Country, Spain
| | - Nora Fernández-Jimenez
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU) and Biocruces-Bizkaia Health Research Institute, Basque Country, Spain
| | - Mariana F Fernández
- CIBER Epidemiología y Salud Pública, Madrid, Spain
- University of Granada, Biomedical Research Centre, Instituto de Investigación Biosanitaria (ibs.GRANADA), Granada, Spain
| | - Monica Guxens
- ISGlobal, Institute for Global Health, Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- CIBER Epidemiología y Salud Pública, Madrid, Spain
- Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Jordi Julvez
- ISGlobal, Institute for Global Health, Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- CIBER Epidemiología y Salud Pública, Madrid, Spain
- Clinical and Epidemiological Neuroscience, Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain
| | - Sabrina Llop
- CIBER Epidemiología y Salud Pública, Madrid, Spain
- Epidemiology and Environmental Health Joint Research Unit, FISABIO-Public Health, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain
| | - Maria-Jose Lopez-Espinosa
- CIBER Epidemiología y Salud Pública, Madrid, Spain
- Epidemiology and Environmental Health Joint Research Unit, FISABIO-Public Health, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain
- Faculty of Nursing and Chiropody, University of Valencia, Valencia, Spain
| | - Mikel Subiza-Pérez
- CIBER Epidemiología y Salud Pública, Madrid, Spain
- Department of Clinical and Health Psychology and Research Methods, University of the Basque Country UPV/EHU, Avenida Tolosa 70, 20018, Donostia-San Sebastián, Spain
- Bradford Institute for Health Research, Temple Bank House, Bradford Royal Infirmary, Duckworth Lane, BD9 6RJ, Bradford, UK
- Biodonostia Health Research Institute, Group of Environmental Epidemiology and Child Development, Paseo Doctor Begiristain s/n, 20014, Donostia- San Sebastián, Spain
| | - Manuel Lozano
- Epidemiology and Environmental Health Joint Research Unit, FISABIO-Public Health, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain
- Preventive Medicine and Public Health, Food Sciences, Toxicology and Forensic Medicine Department, Universitat de València, Valencia, Spain
| | - Jesus Ibarluzea
- CIBER Epidemiología y Salud Pública, Madrid, Spain
- Biodonostia Health Research Institute, Group of Environmental Epidemiology and Child Development, Paseo Doctor Begiristain s/n, 20014, Donostia- San Sebastián, Spain
- Ministry of Health of the Basque Government, Sub-Directorate for Public Health and Addictions of Gipuzkoa, San Sebastian, Spain
| | - Jordi Sunyer
- ISGlobal, Institute for Global Health, Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- CIBER Epidemiología y Salud Pública, Madrid, Spain
| | - Mariona Bustamante
- ISGlobal, Institute for Global Health, Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- CIBER Epidemiología y Salud Pública, Madrid, Spain
| | - Marta Cosin-Tomas
- ISGlobal, Institute for Global Health, Barcelona, Spain.
- Universitat Pompeu Fabra (UPF), Barcelona, Spain.
- CIBER Epidemiología y Salud Pública, Madrid, Spain.
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Yu YM, Jin GH, Zhong C, Qian H, Wang L, Zhan F. Exploring the role of interleukin-6 receptor blockade in epilepsy and associated neuropsychiatric conditions through a mendelian randomization study. World J Psychiatry 2024; 14:1244-1253. [PMID: 39165549 PMCID: PMC11331385 DOI: 10.5498/wjp.v14.i8.1244] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 07/05/2024] [Accepted: 07/11/2024] [Indexed: 08/12/2024] Open
Abstract
BACKGROUND The interplay between inflammation, immune dysregulation, and the onset of neurological disorders, including epilepsy, has become increasingly recognized. Interleukin (IL)-6, a pro-inflammatory cytokine, is suspected to not only mediate traditional inflammatory pathways but also contribute to neuroinflammatory responses that could underpin neuropsychiatric symptoms and broader psychiatric disorders in epilepsy patients. The role of IL-6 receptor (IL6R) blockade presents an intriguing target for therapeutic intervention due to its potential to attenuate these processes. AIM To explore the potential of IL6R blockade in reducing the risk of epilepsy and investigate whether this pathway might also influence associated psychiatric and neuropsychiatric conditions due to neuroinflammation. METHODS Mendelian randomization (MR) analysis employing single nucleotide polymorphisms (SNPs) in the vicinity of the IL6R gene (total individuals = 408225) was used to evaluate the putative causal relationship between IL6R blockade and epilepsy (total cases/controls = 12891/312803), focal epilepsy (cases/controls = 7526/399290), and generalized epilepsy (cases/controls = 1413/399287). SNP weights were determined by their effect on C-reactive protein (CRP) levels and integrated using inverse variance-weighted meta-analysis as surrogates for IL6R effects. To address potential outlier and pleiotropic influences, sensitivity analyses were conducted employing a variety of MR methods under different modeling assumptions. RESULTS The genetic simulation targeting IL6R blockade revealed a modest but significant reduction in overall epilepsy risk [inverse variance weighting: Odds ratio (OR): 0.827; 95% confidence interval (CI): 0.685-1.000; P = 0.05]. Subtype analysis showed variability, with no significant effect observed in generalized, focal, or specific childhood and juvenile epilepsy forms. Beyond the primary inflammatory marker CRP, the findings also suggested potential non-inflammatory pathways mediated by IL-6 signaling contributing to the neurobiological landscape of epilepsy, hinting at possible links to neuroinflammation, psychiatric symptoms, and associated mental disorders. CONCLUSION The investigation underscored a tentative causal relationship between IL6R blockade and decreased epilepsy incidence, likely mediated via complex neuroinflammatory pathways. These results encouraged further in-depth studies involving larger cohorts and multifaceted psychiatric assessments to corroborate these findings and more thoroughly delineate the neuro-psychiatric implications of IL-6 signaling in epilepsy. The exploration of IL6R blockade could herald a novel therapeutic avenue not just for seizure management but also for addressing the broader psychiatric and cognitive disturbances often associated with epilepsy.
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Affiliation(s)
- Yan-Mei Yu
- Department of Pediatrics, The First People's Hospital of Chuzhou, Chuzhou 239001, Anhui Province, China
| | - Gui-Hong Jin
- Department of Pediatrics, The First People's Hospital of Chuzhou, Chuzhou 239001, Anhui Province, China
| | - Chong Zhong
- Department of Pediatrics, The First People's Hospital of Chuzhou, Chuzhou 239001, Anhui Province, China
| | - Hao Qian
- Department of Pediatrics, The First People's Hospital of Chuzhou, Chuzhou 239001, Anhui Province, China
| | - Lei Wang
- Department of Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325000, Zhejiang Province, China
| | - Feng Zhan
- Department of Pediatrics, The First People's Hospital of Chuzhou, Chuzhou 239001, Anhui Province, China
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Skvortsova L, Perfilyeva A, Bespalova K, Kuzovleva Y, Kabysheva N, Khamdiyeva O. 7p22.3 microdeletion: a case study of a patient with congenital heart defect, neurodevelopmental delay and epilepsy. Orphanet J Rare Dis 2024; 19:301. [PMID: 39152504 PMCID: PMC11330011 DOI: 10.1186/s13023-024-03321-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 08/08/2024] [Indexed: 08/19/2024] Open
Abstract
BACKGROUND Chromosome 7 has regions enriched with low copy repeats (LCRs), which increase the likelihood of chromosomal microdeletion disorders. Documented microdeletion disorders on chromosome 7 include both well-known Williams syndrome and more rare cases. It is noteworthy that most cases of various microdeletions are characterized by phenotypic signs of neuropsychological developmental disorders, which, however, have a different genetic origin. The localization of the microdeletions, the genes included in the region, as well as the structural features of the sequences of these genes have a cumulative influence on the phenotypic characteristics of the individuals for each specific case and the severity of the manifestations of disorders. The consideration of these features and their detailed analysis is important for a correct and comprehensive assessment of the disease. RESULTS The article describes a clinical case of 7p22.3 microdeletion in a patient with congenital heart defect and neurological abnormalities - epilepsy, combined with moderate mental and motor developmental delay. CONCLUSIONS Through detailed genetic analyses, we are improving the clinical description of the rare 7p22.3 microdeletion and thus creating a basis for future genetic counseling and research into targeted therapies.
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Affiliation(s)
- Liliya Skvortsova
- Laboratory of Molecular Genetics, Institute of Genetics and Physiology, Almaty, 050060, Kazakhstan
| | - Anastassiya Perfilyeva
- Laboratory of Molecular Genetics, Institute of Genetics and Physiology, Almaty, 050060, Kazakhstan
| | - Kira Bespalova
- Laboratory of Molecular Genetics, Institute of Genetics and Physiology, Almaty, 050060, Kazakhstan.
- Department of Molecular Biology and Genetics, Al-Farabi Kazakh National University, Almaty, 050040, Kazakhstan.
| | - Yelena Kuzovleva
- Laboratory of Molecular Genetics, Institute of Genetics and Physiology, Almaty, 050060, Kazakhstan
| | - Nailya Kabysheva
- Laboratory of Molecular Genetics, Institute of Genetics and Physiology, Almaty, 050060, Kazakhstan
| | - Ozada Khamdiyeva
- Laboratory of Molecular Genetics, Institute of Genetics and Physiology, Almaty, 050060, Kazakhstan
- Department of Molecular Biology and Genetics, Al-Farabi Kazakh National University, Almaty, 050040, Kazakhstan
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Ahmed Mohamed Z, Yang J, Wen J, Jia F, Banerjee S. SEPHS1 Gene: A new master key for neurodevelopmental disorders. Clin Chim Acta 2024; 562:119844. [PMID: 38960024 DOI: 10.1016/j.cca.2024.119844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 06/30/2024] [Accepted: 06/30/2024] [Indexed: 07/05/2024]
Abstract
The SEPHS1 (Selenophosphate Synthetase 1) gene encodes a critical enzyme for synthesizing selenophosphate, the active donor of selenium (Se) necessary for selenoprotein biosynthesis. Selenoproteins are vital for antioxidant defense, thyroid hormone metabolism, and cellular homeostasis. Mutations in SEPHS1 gene, are associated with neurodevelopmental disorders with developmental delay, poor growth, hypotonia, and dysmorphic features. Due to Se's critical role in brain development and function, SEPHS1 gene has taken center stage in neurodevelopmental research. This review explores the structure and function of the SEPHS1 gene, its role in neurodevelopment, and the implications of its dysregulation for neurodevelopmental disorders. Therapeutic strategies, including Se supplementation, gene therapy, and targeted therapies, are discussed as potential interventions to address SEPHS1 associated neurodevelopmental dysfunction. The study's findings reveal how SEPHS1 mutations disrupt neurodevelopment, emphasizing the gene's intolerance to loss of function. Future research should focus on functional characterization of SEPHS1 variants, broader genetic screenings, and therapeutic developments.
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Affiliation(s)
- Zakaria Ahmed Mohamed
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; Department of Developmental and Behavioral Pediatrics, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Jianli Yang
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun 130021, China
| | - Jianping Wen
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun 130021, China
| | - Feiyong Jia
- Department of Developmental and Behavioral Pediatrics, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Santasree Banerjee
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
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Christoff RR, Liesner IL, Gavino-Leopoldino D, Andrade B, Oliveira de Campos B, Salgado I, Simões-Lemos F, Da Poian AT, Assunção-Miranda I, Figueiredo CP, Clarke JR. TNF-α blockage prevents late neurological consequences of Zika virus infection in mice. Behav Brain Res 2024; 471:115114. [PMID: 38878972 DOI: 10.1016/j.bbr.2024.115114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 06/12/2024] [Accepted: 06/13/2024] [Indexed: 06/29/2024]
Abstract
Zika virus (ZIKV) is a neurotropic Orthoflavivirus that causes a myriad of neurological manifestations in newborns exposed in uterus. Despite the devastating consequences of ZIKV on the developing brain, strategies to prevent or treat the consequences of viral infection are not yet available. We previously showed that short-term treatment with the TNF-α neutralizing monoclonal antibody. Infliximab could prevent seizures at acute and chronic stages of ZIKV infection, but had no impact on long-term cognitive and motor dysfunction. Due to the central role of inflammation in ZIKV-neuropathology, we hypothesized that prolonged treatment with the anti-TNF-α monoclonal antibody Infliximab could provide complete rescue of long-term behavioral deficits associated with neonatal ZIKV infection in mice. Here, neonatal (post-natal day 3) Swiss mice were submitted to subcutaneous (s.c.) injection of 106 PFU of ZIKV or mock medium and were then treated with Infliximab (20 μg/day) or sterile saline intraperitoneally (i.p.), for 40 days starting on the day of infection, and behavioral assessment started at 60 days post-infection (dpi). Infliximab prevented ZIKV-induced cognitive and motor impairments in mice. In addition, microgliosis and cell death found in mice following ZIKV infection were partially reversed by TNF-α blockage. Altogether, these results suggest that TNF-α-mediated inflammation is central for late ZIKV-induced behavioral deficits and cell death and strategies targeting this cytokine may be promising approaches to treat subjects exposed to the virus during development.
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Affiliation(s)
- Raissa R Christoff
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, RJ, Brazil
| | - Isabelle L Liesner
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, RJ, Brazil
| | | | - Bruna Andrade
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, RJ, Brazil
| | | | - Isabella Salgado
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, RJ, Brazil
| | - Felipe Simões-Lemos
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, RJ, Brazil; Instituto Oswaldo Cruz, RJ, Brazil
| | - Andrea T Da Poian
- Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, RJ, Brazil
| | | | | | - Julia R Clarke
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, RJ, Brazil.
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Benazzato C, Lojudice F, Pöehlchen F, Leite PEC, Manucci AC, Van der Linden V, Jungmann P, Sogayar MC, Bruni-Cardoso A, Russo FB, Beltrão-Braga P. Zika virus vertical transmission induces neuroinflammation and synapse impairment in brain cells derived from children born with Congenital Zika Syndrome. Sci Rep 2024; 14:18002. [PMID: 39097642 PMCID: PMC11297915 DOI: 10.1038/s41598-024-65392-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 06/18/2024] [Indexed: 08/05/2024] Open
Abstract
Zika virus (ZIKV) infection was first reported in 2015 in Brazil as causing microcephaly and other developmental abnormalities in newborns, leading to the identification of Congenital Zika Syndrome (CZS). Viral infections have been considered an environmental risk factor for neurodevelopmental disorders outcome, such as Autism Spectrum Disorder (ASD). Moreover, not only the infection per se, but maternal immune system activation during pregnancy, has been linked to fetal neurodevelopmental disorders. To understand the impact of ZIKV vertical infection on brain development, we derived induced pluripotent stem cells (iPSC) from Brazilian children born with CZS, some of the patients also being diagnosed with ASD. Comparing iPSC-derived neurons from CZS with a control group, we found lower levels of pre- and postsynaptic proteins and reduced functional synapses by puncta co-localization. Furthermore, neurons and astrocytes derived from the CZS group showed decreased glutamate levels. Additionally, the CZS group exhibited elevated levels of cytokine production, one of which being IL-6, already associated with the ASD phenotype. These preliminary findings suggest that ZIKV vertical infection may cause long-lasting disruptions in brain development during fetal stages, even in the absence of the virus after birth. These disruptions could contribute to neurodevelopmental disorders manifestations such as ASD. Our study contributes with novel knowledge of the CZS outcomes and paves the way for clinical validation and the development of potential interventions to mitigate the impact of ZIKV vertical infection on neurodevelopment.
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Affiliation(s)
- Cecilia Benazzato
- Microbiology Department, Institute of Biomedical Sciences (ICB-II), University of São Paulo, Av. Prof Lineu Prestes, 1374, 2Nd Floor, Room 235, São Paulo, SP, 05508-000, Brazil
| | - Fernando Lojudice
- Cell and Molecular Therapy Center (NUCEL), School of Medicine, University of São Paulo, São Paulo-SP, 01246-903, Brazil
| | - Felizia Pöehlchen
- Microbiology Department, Institute of Biomedical Sciences (ICB-II), University of São Paulo, Av. Prof Lineu Prestes, 1374, 2Nd Floor, Room 235, São Paulo, SP, 05508-000, Brazil
- Westfälische Wilhelms-Universität Münster, Münster, Germany
| | - Paulo Emílio Corrêa Leite
- Clinical Research Unit of the Antonio Pedro Hospital, Federal Fluminense University, Rio de Janeiro, 24220-900, Brazil
| | - Antonio Carlos Manucci
- Biochemistry Department, Chemistry Institute, University of São Paulo, São Paulo, SP, 05508-900, Brazil
| | | | - Patricia Jungmann
- Pathology Department, University of Pernambuco, Recife, 50670-901, Brazil
| | - Mari C Sogayar
- Cell and Molecular Therapy Center (NUCEL), School of Medicine, University of São Paulo, São Paulo-SP, 01246-903, Brazil
- Biochemistry Department, Chemistry Institute, University of São Paulo, São Paulo, SP, 05508-900, Brazil
| | - Alexandre Bruni-Cardoso
- Biochemistry Department, Chemistry Institute, University of São Paulo, São Paulo, SP, 05508-900, Brazil
| | - Fabiele B Russo
- Microbiology Department, Institute of Biomedical Sciences (ICB-II), University of São Paulo, Av. Prof Lineu Prestes, 1374, 2Nd Floor, Room 235, São Paulo, SP, 05508-000, Brazil.
| | - Patricia Beltrão-Braga
- Microbiology Department, Institute of Biomedical Sciences (ICB-II), University of São Paulo, Av. Prof Lineu Prestes, 1374, 2Nd Floor, Room 235, São Paulo, SP, 05508-000, Brazil.
- Institute Pasteur of São Paulo, Av. Prof. Lucio Martins Rodrigues 370, A-Building, 4Th Floor, São Paulo-SP, 05508-020, Brazil.
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Mercado L, Rose S, Escalona-Vargas D, Dajani N, Siegel ER, Preissl H, Eswaran H. Correlating maternal and cord-blood inflammatory markers and BDNF with human fetal brain activity recorded by magnetoencephalography: An exploratory study. Brain Behav Immun Health 2024; 39:100804. [PMID: 38979093 PMCID: PMC11228641 DOI: 10.1016/j.bbih.2024.100804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 06/10/2024] [Indexed: 07/10/2024] Open
Abstract
Background During gestation, the brain development of the fetus is affected by many biological markers, where inflammatory processes and neurotrophic factors have been of particular interest in the past decade. Aim This exploratory study is the first attempt to explore the relationships between biomarker levels in maternal and cord-blood samples and human fetal brain activity measured with non-invasive fetal magnetoencephalography (fMEG). Method Twenty-three women were enrolled in this study for collection of maternal serum and fMEG tracings immediately prior to their scheduled cesarean delivery. Twelve of these women had a preexisting diabetic condition. At the time of delivery, umbilical cord blood was also collected. Biomarker levels from both maternal and cord blood were measured and subsequently analyzed for correlations with fetal brain activity in four frequency bands extracted from fMEG power spectral densities. Results Relative power in the delta, alpha, and beta frequency bands exhibited moderate-sized correlations with maternal BDNF and cord-blood CRP levels before and after adjusting for confounding diabetic status. These correlations were negative for the delta band, and positive for the alpha and beta bands. Maternal CRP and cord-blood BDNF and IL-6 exhibited negligible correlations with relative power in all four bands. Diabetes did not appear to be a strong confounding factor affecting the studied biomarkers. Conclusions Maternal BDNF levels and cord-blood CRP levels appear to have a direct correlation to fetal brain activity. Our findings indicate the potential use of these biomarkers in conjunction with fetal brain electrophysiology to track fetal neurodevelopment.
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Affiliation(s)
- Luis Mercado
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Shannon Rose
- Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children’s Research Institute, Little Rock, AR, USA
| | - Diana Escalona-Vargas
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
- Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children’s Research Institute, Little Rock, AR, USA
| | - Nafisa Dajani
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Eric R. Siegel
- Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Hubert Preissl
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, German Center for Diabetes Research (DZD), Tübingen, Germany
| | - Hari Eswaran
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
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Tuomivaara ST, Fisher SJ, Hall SC, Goin DE, Mattis AN, Den Besten PK. Fluoride-related changes in the fetal cord blood proteome; a pilot study. Environ Health 2024; 23:66. [PMID: 39044276 PMCID: PMC11267808 DOI: 10.1186/s12940-024-01102-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 07/02/2024] [Indexed: 07/25/2024]
Abstract
BACKGROUND Fluoride exposure during pregnancy has been associated with various effects on offspring, including changes in behavior and IQ. To provide clues to possible mechanisms by which fluoride may affect human fetal development, we completed proteomic analyses of cord blood serum collected from second-trimester pregnant women residing in northern California, USA. OBJECTIVE To identify changes in cord blood proteins associated with maternal serum fluoride concentration in pregnant women. METHODS The proteomes of 19 archived second-trimester cord blood samples from women living in northern California, USA, and having varied serum fluoride concentrations, were analyzed by quantitative mass spectrometry. The 327 proteins that were quantified were characterized by their abundance relative to maternal serum fluoride concentration, and subjected to pathway analyses using PANTHER and Ingenuity Pathway Analysis processes. RESULTS Pathway analyses showed significant increases in process related to reactive oxygen species and cellular oxidant detoxification, associated with increasing maternal serum fluoride concentrations. Pathways showing significant decreases included complement cascade, suggesting alterations in alterations in process associated with inflammation. CONCLUSION Maternal fluoride exposure, as measured by serum fluoride concentrations in a small, but representative sample of women from northern California, USA, showed significant changes in the second trimester cord blood proteome relative to maternal serum fluoride concentration.
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Affiliation(s)
- Sami T Tuomivaara
- Department of Obstetrics, Gynecology, and Reproductive Sciences Sandler-Moore Mass Spectrometry Core Facility, University of California, San Francisco, CA, USA
| | - Susan J Fisher
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Translational Research in Perinatal Biology and Medicine, University of California, San Francisco, CA, USA
| | - Steven C Hall
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, CA, USA
| | - Dana E Goin
- Program on Reproductive Health and the Environment, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, CA, USA
| | - Aras N Mattis
- Department of Pathology, University of Californa, San Francisco, CA, USA
| | - Pamela K Den Besten
- Department of Orofacial Sciences, School of Dentistry, University of California, San Francisco, CA, USA.
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Cosemans C, Madhloum N, Sleurs H, Alfano R, Verheyen L, Wang C, Vanbrabant K, Vanpoucke C, Lefebvre W, Nawrot TS, Plusquin M. Prenatal particulate matter exposure is linked with neurobehavioural development in early life. ENVIRONMENTAL RESEARCH 2024; 252:118879. [PMID: 38579996 DOI: 10.1016/j.envres.2024.118879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 02/22/2024] [Accepted: 04/03/2024] [Indexed: 04/07/2024]
Abstract
BACKGROUND Early life exposure to ambient particulate matter (PM) may negatively affect neurobehavioral development in children, influencing their cognitive, emotional, and social functioning. Here, we report a study on prenatal PM2.5 exposure and neurobehavioral development focusing on different time points in the first years of life. METHODS This study was part of the ENVIRONAGE birth cohort that follows mother-child pairs longitudinally. First, the Neonatal Behavioral Assessment Scale (NBAS) was employed on 88 newborns aged one to two months to assess their autonomic/physiological regulation, motor organisation, state organisation/regulation, and attention/social interaction. Second, our study included 393 children between the ages of four and six years, for which the Strengths and Difficulties Questionnaire (SDQ) was used to assess the children's emotional problems, hyperactivity, conduct problems, peer relationship, and prosocial behaviour. Prenatal PM2.5 exposure was determined using a high-resolution spatial-temporal method based on the maternal address. Multiple linear and multinomial logistic regression models were used to analyse the relationship between prenatal PM2.5 exposure and neurobehavioral development in newborns and children, respectively. RESULTS A 5 μg/m³ increase in first-trimester PM2.5 concentration was associated with lower NBAS range of state cluster scores (-6.11%; 95%CI: -12.00 to -0.23%; p = 0.04) in one-to-two-month-old newborns. No other behavioural clusters nor the reflexes cluster were found to be associated with prenatal PM2.5 exposure. Furthermore, a 5 μg/m³ increment in first-trimester PM2.5 levels was linked with higher odds of a child experiencing peer problems (Odds Ratio (OR) = 3.89; 95%CI: 1.39 to 10.87; p = 0.01) at ages four to six. Additionally, a 5 μg/m³ increase in second-trimester PM2.5 concentration was linked to abnormal prosocial behaviour (OR = 0.49; 95%CI: 0.25 to 0.98; p = 0.04) at four to six years old. No associations were found between in utero PM2.5 exposure and hyperactivity or conduct problems. CONCLUSIONS Our findings suggest that prenatal exposure to PM may impact neurobehavioural development in newborns and preschool children. We identified sensitive time windows during early-to-mid pregnancy, possibly impacting stage changes in newborns and peer problems and prosocial behaviour in children.
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Affiliation(s)
- Charlotte Cosemans
- Centre for Environmental Sciences, Hasselt University, Agoralaan Building D, 3590, Diepenbeek, Belgium
| | - Narjes Madhloum
- Centre for Environmental Sciences, Hasselt University, Agoralaan Building D, 3590, Diepenbeek, Belgium; Faculty of Medicine and Life Sciences, Hasselt University, Agoralaan Building D, 3590, Diepenbeek, Belgium
| | - Hanne Sleurs
- Centre for Environmental Sciences, Hasselt University, Agoralaan Building D, 3590, Diepenbeek, Belgium
| | - Rossella Alfano
- Centre for Environmental Sciences, Hasselt University, Agoralaan Building D, 3590, Diepenbeek, Belgium
| | - Lore Verheyen
- Centre for Environmental Sciences, Hasselt University, Agoralaan Building D, 3590, Diepenbeek, Belgium
| | - Congrong Wang
- Centre for Environmental Sciences, Hasselt University, Agoralaan Building D, 3590, Diepenbeek, Belgium
| | - Kenneth Vanbrabant
- Centre for Environmental Sciences, Hasselt University, Agoralaan Building D, 3590, Diepenbeek, Belgium
| | - Charlotte Vanpoucke
- Belgian Interregional Environment Agency, IRCEL-CELINE, Gaucheretstraat 92-94, 1030, Brussels, Belgium
| | - Wouter Lefebvre
- Flemish Institute for Technological Research, VITO, Boeretang 200, 2400, Mol, Belgium
| | - Tim S Nawrot
- Centre for Environmental Sciences, Hasselt University, Agoralaan Building D, 3590, Diepenbeek, Belgium; School of Public Health, Occupational & Environmental Medicine, Leuven University, Oude Markt 13, 3000, Leuven, Belgium
| | - Michelle Plusquin
- Centre for Environmental Sciences, Hasselt University, Agoralaan Building D, 3590, Diepenbeek, Belgium.
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Silvente Troncoso C, Hern'ández-Mart'ínez C, Voltas Moreso N, Canals Sans J, Jard'í Piñana C, Basora Gallisà J, Arija Val V. Impact of physical activity during pregnancy on infant neurodevelopment. J Reprod Infant Psychol 2024; 42:620-635. [PMID: 36539407 DOI: 10.1080/02646838.2022.2155626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 12/01/2022] [Indexed: 12/24/2022]
Abstract
OBJECTIVES To investigate prospectively the impact of physical activity during pregnancy on infant neurodevelopment, considering relevant confounding factors, physical activity intensity and the trimester of pregnancy in which it is performed. METHODS Prospective follow-up study of 791 pregnant women from the first trimester of pregnancy to 40 days postpartum. Three intensity levels of physical activity were assessed in each trimester of pregnancy by the International Physical Activity Questionnaire (IPAQ). Infant neuro development was assessed at 40 days postpartum by the third edition of the Bayley Scales for Infant Development-Third Edition (BSID-III). Analysis adjusted by sociodemographics, anxiety symptoms, lifestyle habits, quality of diet, body mass index, postpartum depressive symptoms and mother-infant attachment. RESULTS ANCOVA analysis have shown that 40 days old infants of mothers in the moderate and high PA groups in the third trimester obtained 3.2 and 3.8 points higher scores respectively in the language total scale; and 4.1 and 5.1 points higher scores respectively in the motor total scale than infants of mothers in the low PAgroup. CONCLUSION Moderate to high intensity physical activity during pregnancy has a positive impact on infant neurodevelopment. More specific recommendations must be incorporated in international guidelines and into maternal education sessions to improve infants' neurodevelopment.
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Affiliation(s)
- Cristina Silvente Troncoso
- Research Group in Nutrition and Mental Health (NUTRISAM), Universitat Rovira i Virgili, Tarragona, Spain
| | - Carmen Hern'ández-Mart'ínez
- Research Group in Nutrition and Mental Health (NUTRISAM), Universitat Rovira i Virgili, Tarragona, Spain
- Research Center for Behavioral Assessment (CRAMC), Department of Psychology, Universitat Rovira i Virgili, Tarragona, Spain
- Department of Psychology, Educational Sciences and Psychology Faculty, Universitat Rovira i Virgili, Tarragona, Spain
| | - N'úria Voltas Moreso
- Research Group in Nutrition and Mental Health (NUTRISAM), Universitat Rovira i Virgili, Tarragona, Spain
- Research Center for Behavioral Assessment (CRAMC), Department of Psychology, Universitat Rovira i Virgili, Tarragona, Spain
- Department of Psychology, Educational Sciences and Psychology Faculty, Universitat Rovira i Virgili, Tarragona, Spain
- Serra Húnter Fellow, Department of Psychology, Faculty of Education Sciences and Psychology, Universitat Rovira i Virgili, Tarragona, Spain
| | - Josefa Canals Sans
- Research Group in Nutrition and Mental Health (NUTRISAM), Universitat Rovira i Virgili, Tarragona, Spain
- Research Center for Behavioral Assessment (CRAMC), Department of Psychology, Universitat Rovira i Virgili, Tarragona, Spain
- Department of Psychology, Educational Sciences and Psychology Faculty, Universitat Rovira i Virgili, Tarragona, Spain
| | - Cristina Jard'í Piñana
- Research Group in Nutrition and Mental Health (NUTRISAM), Universitat Rovira i Virgili, Tarragona, Spain
- Nutrition and Public Health Unit, Department of Basic Medical Sciences, Faculty of Medicine and Health Science, Universitat Rovira i Virgili, Reus, Spain
| | - Josep Basora Gallisà
- Collaborative Research Group on Lifestyles, Nutrition and Smoking (CENIT). Jordi Gol Primary Care Research Institute (IDIAPJGol), Reus, Spain
- Pere Virgili Institute for Health Research (IISPV), Universitat Rovira i Virgili, Avinguda de la Universitat, Reus, Spain
- Research Support Unit Tarragona, Institut Universitari d'Investigació en Atenció Primària Jordi Gol (IDIAPJGol), Reus, Spain
| | - Victoria Arija Val
- Research Group in Nutrition and Mental Health (NUTRISAM), Universitat Rovira i Virgili, Tarragona, Spain
- Nutrition and Public Health Unit, Department of Basic Medical Sciences, Faculty of Medicine and Health Science, Universitat Rovira i Virgili, Reus, Spain
- Pere Virgili Institute for Health Research (IISPV), Universitat Rovira i Virgili, Avinguda de la Universitat, Reus, Spain
- Research Support Unit Tarragona, Institut Universitari d'Investigació en Atenció Primària Jordi Gol (IDIAPJGol), Reus, Spain
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Ceprián N, Martínez de Toda I, Maté I, Garrido A, Gimenez-Llort L, De la Fuente M. Prodromic Inflammatory-Oxidative Stress in Peritoneal Leukocytes of Triple-Transgenic Mice for Alzheimer's Disease. Int J Mol Sci 2024; 25:6976. [PMID: 39000092 PMCID: PMC11241217 DOI: 10.3390/ijms25136976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 06/24/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
Inflammatory-oxidative stress is known to be pivotal in the pathobiology of Alzheimer's disease (AD), but the involvement of this stress at the peripheral level in the disease's onset has been scarcely studied. This study investigated the pro-inflammatory profile and oxidative stress parameters in peritoneal leukocytes from female triple-transgenic mice for AD (3xTgAD) and non-transgenic mice (NTg). Peritoneal leukocytes were obtained at 2, 4, 6, 12, and 15 months of age. The concentrations of TNFα, INFγ, IL-1β, IL-2, IL-6, IL-17, and IL-10 released in cultures without stimuli and mitogen concanavalin A and lipopolysaccharide presence were measured. The concentrations of reduced glutathione (GSH), oxidized glutathione (GSSG), lipid peroxidation, and Hsp70 were also analyzed in the peritoneal cells. Our results showed that although there was a lower release of pro-inflammatory cytokines by 3xTgAD mice, this response was uncontrolled and overstimulated, especially at a prodromal stage at 2 months of age. In addition, there were lower concentrations of GSH in leukocytes from 3xTgAD and higher amounts of lipid peroxides at 2 and 4 months, as well as, at 6 months, a lower concentration of Hsp70. In conclusion, 3xTgAD mice show a worse pro-inflammatory response and higher oxidative stress than NTg mice during the prodromal stages, potentially supporting the idea that Alzheimer's disease could be a consequence of peripheral alteration in the leukocyte inflammation-oxidation state.
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Affiliation(s)
- Noemí Ceprián
- Animal Physiology Unit, Department of Genetics, Physiology and Microbiology, Faculty of Biological Sciences, Complutense University of Madrid, 28040 Madrid, Spain
- Institute of Investigation Hospital 12 Octubre (imas12), 28041 Madrid, Spain
| | - Irene Martínez de Toda
- Animal Physiology Unit, Department of Genetics, Physiology and Microbiology, Faculty of Biological Sciences, Complutense University of Madrid, 28040 Madrid, Spain
- Institute of Investigation Hospital 12 Octubre (imas12), 28041 Madrid, Spain
| | - Ianire Maté
- Department of Immunology, Microbiology and Parasitology, Faculty of Pharmacy, University of the Basque Country, 01006 Vitoria-Gasteiz, Spain
| | - Antonio Garrido
- Department of Biosciences, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, 28670 Madrid, Spain
| | - Lydia Gimenez-Llort
- Department of Psychiatry and Forensic Medicine, Institute of Neuroscience, School of Medicine, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, 08193 Barcelona, Spain
| | - Mónica De la Fuente
- Animal Physiology Unit, Department of Genetics, Physiology and Microbiology, Faculty of Biological Sciences, Complutense University of Madrid, 28040 Madrid, Spain
- Institute of Investigation Hospital 12 Octubre (imas12), 28041 Madrid, Spain
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50
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Calado CMSDS, Manhães-de-Castro R, da Conceição Pereira S, da Silva Souza V, Barbosa LNF, Dos Santos Junior OH, Lagranha CJ, Juárez PAR, Torner L, Guzmán-Quevedo O, Toscano AE. Resveratrol Reduces Neuroinflammation and Hippocampal Microglia Activation and Protects Against Impairment of Memory and Anxiety-Like Behavior in Experimental Cerebral Palsy. Mol Neurobiol 2024; 61:3619-3640. [PMID: 38001357 DOI: 10.1007/s12035-023-03772-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 10/20/2023] [Indexed: 11/26/2023]
Abstract
Cerebral palsy (CP) is a neurodevelopmental disorder characterized by motor and postural impairments. However, early brain injury can promote deleterious effects on the hippocampus, impairing memory. This study aims to investigate the effects of resveratrol treatment on memory, anxiety-like behavior, and neuroinflammation markers in rats with CP. Male Wistar rats were subjected to perinatal anoxia (P0-P1) and sensory-motor restriction (P2-P28). They were treated with resveratrol (10 mg/kg, 0.1 ml/100 g) or saline from P3-P21, being divided into four experimental groups: CS (n = 15), CR (n = 15), CPS (n = 15), and CPR (n = 15). They were evaluated in the tests of novel object recognition (NORT), T-Maze, Light-Dark Box (LDB), and Elevated Plus Maze (EPM). Compared to the CS group, the CPS group has demonstrated a reduced discrimination index on the NORT (p < 0.0001) and alternation on the T-Maze (p < 0.01). In addition, the CPS group showed an increase in permanence time on the dark side in LDB (p < 0.0001) and on the close arms of the EPM (p < 0.001). The CPR group demonstrated an increase in the object discrimination index (p < 0.001), on the alternation (p < 0.001), on the permanence time on the light side (p < 0.0001), and on the open arms (p < 0.001). The CPR group showed a reduction in gene expression of IL-6 (p = 0.0175) and TNF-α (p = 0.0007) and an increase in Creb-1 levels (p = 0.0020). The CPS group showed an increase in the activated microglia and a reduction in cell proliferation in the hippocampus, while CPR animals showed a reduction of activated microglia and an increase in cell proliferation. These results demonstrate promising effects of resveratrol in cerebral palsy behavior impairment through reduced neuroinflammation in the hippocampus.
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Affiliation(s)
- Caio Matheus Santos da Silva Calado
- Studies in Nutrition and Phenotypic Plasticity Unit, Center for Health Sciences, Federal University of Pernambuco, Recife, Pernambuco, 50670-420, Brazil
- Graduate Program in Neuropsychiatry and Behavioral Sciences, Center for Medical Sciences, Federal University of Pernambuco, Recife, Pernambuco, 50670-901, Brazil
| | - Raul Manhães-de-Castro
- Studies in Nutrition and Phenotypic Plasticity Unit, Center for Health Sciences, Federal University of Pernambuco, Recife, Pernambuco, 50670-420, Brazil
- Graduate Program in Neuropsychiatry and Behavioral Sciences, Center for Medical Sciences, Federal University of Pernambuco, Recife, Pernambuco, 50670-901, Brazil
- Graduate Program in Nutrition, Center for Health Sciences, Federal University of Pernambuco, Recife, Pernambuco, 50670-420, Brazil
| | - Sabrina da Conceição Pereira
- Studies in Nutrition and Phenotypic Plasticity Unit, Center for Health Sciences, Federal University of Pernambuco, Recife, Pernambuco, 50670-420, Brazil
- Graduate Program in Neuropsychiatry and Behavioral Sciences, Center for Medical Sciences, Federal University of Pernambuco, Recife, Pernambuco, 50670-901, Brazil
| | - Vanessa da Silva Souza
- Studies in Nutrition and Phenotypic Plasticity Unit, Center for Health Sciences, Federal University of Pernambuco, Recife, Pernambuco, 50670-420, Brazil
- Graduate Program in Neuropsychiatry and Behavioral Sciences, Center for Medical Sciences, Federal University of Pernambuco, Recife, Pernambuco, 50670-901, Brazil
| | - Leticia Nicoly Ferreira Barbosa
- Studies in Nutrition and Phenotypic Plasticity Unit, Center for Health Sciences, Federal University of Pernambuco, Recife, Pernambuco, 50670-420, Brazil
| | - Osmar Henrique Dos Santos Junior
- Graduate Program in Neuropsychiatry and Behavioral Sciences, Center for Medical Sciences, Federal University of Pernambuco, Recife, Pernambuco, 50670-901, Brazil
| | - Claudia Jacques Lagranha
- Graduate Program in Neuropsychiatry and Behavioral Sciences, Center for Medical Sciences, Federal University of Pernambuco, Recife, Pernambuco, 50670-901, Brazil
- Graduate Program in Biochemistry and Physiology, Federal University of Pernambuco, Recife, Pernambuco, Brazil
| | - Pedro Alberto Romero Juárez
- Laboratory of Experimental Neuronutrition and Food Engineering, Tecnológico Nacional de México (TECNM), Instituto Tecnológico Superior de Tacámbaro, 61651, Tacámbaro, Michoacán, Mexico
- Centro de Investigación Biomédica de Michoacán, Instituto Mexicano del Seguro Social, 58330, Morelia, Michoacán, Mexico
| | - Luz Torner
- Centro de Investigación Biomédica de Michoacán, Instituto Mexicano del Seguro Social, 58330, Morelia, Michoacán, Mexico
| | - Omar Guzmán-Quevedo
- Graduate Program in Neuropsychiatry and Behavioral Sciences, Center for Medical Sciences, Federal University of Pernambuco, Recife, Pernambuco, 50670-901, Brazil
- Laboratory of Experimental Neuronutrition and Food Engineering, Tecnológico Nacional de México (TECNM), Instituto Tecnológico Superior de Tacámbaro, 61651, Tacámbaro, Michoacán, Mexico
- Centro de Investigación Biomédica de Michoacán, Instituto Mexicano del Seguro Social, 58330, Morelia, Michoacán, Mexico
| | - Ana Elisa Toscano
- Studies in Nutrition and Phenotypic Plasticity Unit, Center for Health Sciences, Federal University of Pernambuco, Recife, Pernambuco, 50670-420, Brazil.
- Graduate Program in Neuropsychiatry and Behavioral Sciences, Center for Medical Sciences, Federal University of Pernambuco, Recife, Pernambuco, 50670-901, Brazil.
- Graduate Program in Nutrition, Center for Health Sciences, Federal University of Pernambuco, Recife, Pernambuco, 50670-420, Brazil.
- Nursing Unit, Vitória Academic Center, Federal University of Pernambuco, Rua Do Alto Do Reservatório S/N, Bela Vista, Vitória de Santo Antão, Pernambuco, 55608-680, Brazil.
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