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1.
  • Wang, D., et al. (author)
  • Targeting the metabolic profile of amino acids to identify the key metabolic characteristics in cerebral palsy
  • 2023
  • In: Frontiers in Molecular Neuroscience. - 1662-5099. ; 16
  • Journal article (peer-reviewed)abstract
    • Background: Cerebral palsy (CP) is a neurodevelopmental disorder characterized by motor impairment. In this study, we aimed to describe the characteristics of amino acids (AA) in the plasma of children with CP and identify AA that could play a potential role in the auxiliary diagnosis and treatment of CP. Methods: Using high performance liquid chromatography, we performed metabolomics analysis of AA in plasma from 62 CP children and 60 healthy controls. Univariate and multivariate analyses were then applied to characterize different AA. AA markers associated with CP were then identified by machine learning based on the Lasso regression model for the validation of intra-sample interactions. Next, we calculated a discriminant formula and generated a receiver operating characteristic (ROC) curve based on the marker combination in the discriminant diagnostic model. Results: A total of 33 AA were detected in the plasma of CP children and controls. Compared with controls, 5, 7, and 10 different AA were identified in total participants, premature infants, and full-term infants, respectively. Of these, beta-amino-isobutyric acid [p = 2.9*10(-4), Fold change (FC) = 0.76, Variable importance of protection ( VIP) = 1.75], tryptophan [p = 5.4*10(-4), FC = 0.87, VIP = 2.22], and asparagine [p = 3.6*10(-3), FC = 0.82, VIP = 1.64], were significantly lower in the three groups of CP patients than that in controls. The combination of beta-amino-isobutyric acid, tryptophan, and taurine, provided high levels of diagnostic classification and risk prediction efficacy for preterm children with an area under the curve (AUC) value of 0.8741 [95% confidence interval (CI): 0.7322-1.000]. The discriminant diagnostic formula for preterm infant with CP based on the potential marker combination was defined by p = 1/(1 + e-(8.295-0.3848* BAIBA-0.1120*Trp + 0.0108*Tau)). Conclusion: Full-spectrum analysis of amino acid metabolomics revealed a distinct profile in CP, including reductions in the levels of beta-amino-isobutyric acid, tryptophan, and taurine. Our findings shed new light on the pathogenesis and diagnosis of premature infants with CP.
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2.
  • Cheng, Ye, et al. (author)
  • Genetic variants in the HLA region contribute to the risk of cerebral palsy
  • 2024
  • In: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE. - 0925-4439 .- 1879-260X. ; 1870:3
  • Journal article (peer-reviewed)abstract
    • Cerebral palsy (CP) is the most common physical disability in childhood, and genetic factors play an important role in its pathogenesis. However, the genetic contributions remain incompletely elucidated. Here, we conducted a two-stage association study between 1090 CP cases and 1100 healthy controls after whole exome sequencing. The human leukocyte antigen (HLA) allelic predispositions were further analyzed in overall CP and subgroups using multivariate logistic regression. We found a strong signal in the HLA region on chromosome 6, where rs3131787 harbored the most significant association with CP (P = 2.05 x 10-14, OR = 2.22). In comparison to controls, the carrier frequencies of HLA-B*13:02 were significantly higher in children with CP (9.82 % in control vs 19.27 % in CP, P = 1.03 x 10-4, OR = 2.17). Furthermore, the effect of HLA-B*13:02 on increasing the risk of CP mainly existed in cryptogenic CP without exposure to premature birth, low birth weight, birth asphyxia, or periventricular leukomalacia. This study indicated a strong association of HLA variants with CP, which implied that immune dysregulation resulting from immunogenetic variants might underlie the pathogenesis of CP. Our findings provide genetic evidence that an immunomodulator may serve as a promising therapeutic intervention for patients with CP by reinstating the neuroinflammation hemostasis.
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3.
  • Huo, Kaiming, et al. (author)
  • Risk factors for neurodevelopmental deficits in congenital hypothyroidism after early substitution treatment.
  • 2011
  • In: Endocrine Journal. - 1348-4540 .- 0918-8959. ; 58:5, s. 355-61
  • Journal article (peer-reviewed)abstract
    • Neurodevelopment in children with congenital hypothyroidism who receive early treatment is generally good. However, subtle neurological deficits still exist in some patients. The aim of this investigation was to evaluate factors that may influence neurodevelopmental outcome in congenital hypothyroidism patients. The developmental quotient (DQ) of 155 children with congenital hypothyroidism was evaluated at 24 months of age, using Gesell Developmental Schedules (GDS), and compared with that of 310 healthy controls. Mean DQ scores in congenital hypothyroidism patients were 7.5 points lower for adaptive behavior than in control patients (p
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4.
  • Li, Tao, et al. (author)
  • AIF Overexpression Aggravates Oxidative Stress in Neonatal Male Mice After Hypoxia-Ischemia Injury
  • 2022
  • In: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 59:11, s. 6613-6631
  • Journal article (peer-reviewed)abstract
    • There are sex differences in the severity, mechanisms, and outcomes of neonatal hypoxia-ischemia (HI) brain injury, and apoptosis-inducing factor (AIF) may play a critical role in this discrepancy. Based on previous findings that AIF over-expression aggravates neonatal HI brain injury, we further investigated potential sex differences in the severity and molecular mechanisms underlying the injury using mice that overexpress AIF from homozygous transgenes. We found that the male sex significantly aggravated AIF-driven brain damage, as indicated by the injury volume in the gray matter (2.25 times greater in males) and by the lost volume of subcortical white matter (1.71 greater in males) after HI. As compared to females, male mice exhibited more severe brain injury, correlating with reduced antioxidant capacities, more pronounced protein carbonylation and nitration, and increased neuronal cell death. Under physiological conditions (without HI), the doublecortin-positive area in the dentate gyrus of females was 1.15 times larger than in males, indicating that AIF upregulation effectively promoted neurogenesis in females in the long term. We also found that AIF stimulated carbohydrate metabolism in young males. Altogether, these findings corroborate earlier studies and further demonstrate that AIF is involved in oxidative stress, which contributes to the sex-specific differences observed in neonatal HI brain injury.
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5.
  • Qiao, Y. M., et al. (author)
  • An association study of IL2RA polymorphisms with cerebral palsy in a Chinese population
  • 2022
  • In: Bmc Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 15:1
  • Journal article (peer-reviewed)abstract
    • Background Cerebral palsy (CP), the most common physical disability of childhood, is a nonprogressive movement disorder syndrome. Eighty percent of cases are considered idiopathic without a clear cause. Evidence has shown that cytokine abnormalities are widely thought to contribute to CP. Methods An association between 6 SNPs (rs12244380, rs2025345, rs12722561, rs4749926, rs2104286 and rs706778) in IL2RA (interleukin 2 receptor subunit alpha) and CP was investigated using a case-control method based on 782 CP cases and 778 controls. The allele, genotype and haplotype frequencies of SNPs were assessed using the SHEsis program. Subgroup analyses based on complications and clinical subtypes were also conducted. Results Globally, no differences in genotype or allele frequencies for any SNPs remained significant after Bonferroni correction between patients and controls, except rs706778, which deviated from Hardy-Weinberg equilibrium and was excluded from further analyses. However, subgroup analysis revealed a significant association of rs2025345 with spastic tetraplegia (P genotype = 0.048 after correction) and rs12722561 with CP accompanied by global developmental delay (P allele = 0.045 after correction), even after Bonferroni correction. Conclusions These findings indicated that genetic variations in IL2RA are significantly associated with CP susceptibility in the Chinese Han population, suggesting that IL2RA is likely involved in the pathogenesis of CP. Further investigation with a larger sample size in a multiethnic population is needed to confirm the association.
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6.
  • Rodriguez, Juan, 1983, et al. (author)
  • Inhibiting the interaction between apoptosis-inducing factor and cyclophilin A prevents brain injury in neonatal mice after hypoxia-ischemia
  • 2020
  • In: Neuropharmacology. - : Elsevier BV. - 0028-3908 .- 1873-7064. ; 171
  • Journal article (peer-reviewed)abstract
    • © 2020 The Authors The interaction between apoptosis-inducing factor (AIF) and cyclophilin A (CypA) has been shown to contribute to caspase-independent apoptosis. Blocking the AIF/CypA interaction protects against glutamate-induced neuronal cell death in vitro, and the purpose of this study was to determine the in vivo effect of an AIF/CypA interaction blocking peptide (AIF(370-394)-TAT) on neonatal mouse brain injury after hypoxia-ischemia (HI). The pups were treated with AIF (370-394)-TAT peptide intranasally prior to HI. Brain injury was significantly reduced at 72 h after HI in the AIF(370-394)-TAT peptide treatment group compared to vehicle-only treatment for both the gray matter and the subcortical white matter, and the neuroprotection was more pronounced in males than in females. Neuronal cell death was evaluated in males at 8 h and 24 h post-HI, and it was decreased significantly in the CA1 region of the hippocampus and the nucleus habenularis region after AIF(370-394)-TAT treatment. Caspase-independent apoptosis was decreased in the cortex, striatum, and nucleus habenularis after AIF(370-394)-TAT treatment, but no significant change was found on caspase-dependent apoptosis as indicated by the number of active caspase-3-labeled cells. Further analysis showed that both AIF and CypA nuclear accumulation were decreased after treatment with the AIF(370-394)-TAT peptide. These results suggest that AIF(370-394)-TAT inhibited AIF/CypA translocation to the nucleus and reduced HI-induced caspase-independent apoptosis and brain injury in young male mice, suggesting that blocking AIF/CypA might be a potential therapeutic target for neonatal brain injury.
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7.
  • Wang, Yafeng, 1985, et al. (author)
  • Autophagy Inhibition Reduces Irradiation-Induced Subcortical White Matter Injury Not by Reducing Inflammation, but by Increasing Mitochondrial Fusion and Inhibiting Mitochondrial Fission
  • 2022
  • In: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 59:2, s. 1199-1213
  • Journal article (peer-reviewed)abstract
    • Radiotherapy is an effective tool in the treatment of malignant brain tumors, but irradiation-induced late-onset toxicity remains a major problem. The purpose of this study was to investigate if genetic inhibition of autophagy has an impact on subcortical white matter development in the juvenile mouse brain after irradiation. Ten-day-old selective neural Atg7 knockout (KO) mice and wild-type (WT) littermates were subjected to a single 6-Gy dose of whole-brain irradiation and evaluated at 5 days after irradiation. Neural Atg7 deficiency partially prevented myelin disruption compared to the WT mice after irradiation, as indicated by myelin basic protein staining. Irradiation induced oligodendrocyte progenitor cell loss in the subcortical white matter, and Atg7 deficiency partly prevented this. There was no significant change between the KO and WT mice in the number of microglia and astrocytes in the subcortical white matter after irradiation. Transcriptome analysis showed that the GO mitochondrial gene expression pathway was significantly enriched in the differentially expressed genes between the KO and WT group after irradiation. Compared with WT mice, expression of the mitochondrial fusion protein OPA1 and phosphorylation of the mitochondrial fission protein DRP1 (P-DRP1) were dramatically decreased in KO mice under physiological conditions. The protein levels of OPA1and P-DRP1 showed no differences in WT mice between the non-irradiated group and the irradiated group but had remarkably increased levels in the KO mice after irradiation. These results indicate that inhibition of autophagy reduces irradiation-induced subcortical white matter injury not by reducing inflammation, but by increasing mitochondrial fusion and inhibiting mitochondrial fission.
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8.
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9.
  • Yu, T., et al. (author)
  • Association of NOS1 gene polymorphisms with cerebral palsy in a Han Chinese population: a case-control study
  • 2018
  • In: Bmc Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 11:1
  • Journal article (peer-reviewed)abstract
    • Background: Cerebral palsy (CP) is the leading cause of motor disability in children; however, its pathogenesis is unknown in most cases. Growing evidence suggests that Nitric oxide synthase 1 (NOS1) is involved in neural development and neurologic diseases. The purpose of this study was to determine whether genetic variants of NOS1 contribute to CP susceptibility in a Han Chinese population. Methods: A case-control study involving 652 CP patients and 636 healthy controls was conducted. Six SNPs in the NOS1 gene (rs3782219, rs6490121, rs2293054, rs10774909, rs3741475, and rs2682826) were selected, and the MassARRAY typing technique was applied for genotyping. Data analysis was conducted using SHEsis online software, and multiple test corrections were performed using SNPSpD online software. Results: There were no significant differences in genotype and allele frequencies between patients and controls for the SNPs except rs6490121, which deviated from Hardy-Weinberg equilibrium and was excluded from further analyses. Subgroup analysis revealed differences in genotype frequencies between the CP with neonatal encephalopathy group (CP + NE) and control group for rs10774909, rs3741475, and rs2682826 (after SNPSpD correction, p = 0.004, 0.012, and 0. 002, respectively). The T allele of NOS1 SNP rs3782219 was negatively associated with spastic quadriplegia (OR = 0.742, 95% CI = 0.600-0.918, after SNPSpD correction, p = 0.023). There were no differences in allele or genotype frequencies between CP subgroups and controls for the other genetic polymorphisms. Conclusions: NOS1 is associated with CP + NE and spastic quadriplegia, suggesting that NOS1 is likely involved in the pathogenesis of CP and that it is a potential therapeutic target for treatment of cerebral injury.
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10.
  • Bi, D., et al. (author)
  • The association between sex-related interleukin-6 gene polymorphisms and the risk for cerebral palsy
  • 2014
  • In: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 11
  • Journal article (peer-reviewed)abstract
    • Background: The relationship between genetic factors and the development of cerebral palsy (CP) has recently attracted much attention. Polymorphisms in the genes encoding proinflammatory cytokines have been shown to be associated with susceptibility to perinatal brain injury and development of CP. Interleukin-6 (IL-6) is a proinflammatory cytokine that plays a pivotal role in neonatal brain injury, but conflicting results have been reported regarding the association between IL-6 single nucleotide polymorphisms (SNPs) and CP. The purpose of this study was to analyze IL-6 gene polymorphisms and protein expression and to explore the role of IL-6 in the Chinese CP population. Methods: A total of 753 healthy controls and 713 CP patients were studied to detect the presence of five SNPs (rs1800796, rs2069837, rs2066992, rs2069840, and rs10242595) in the IL-6 locus. Of these, 77 healthy controls and 87 CP patients were selected for measurement of plasma IL-6 by Luminex assay. The SHEsis program was used to analyze the genotyping data. For all comparisons; multiple testing on each individual SNP was corrected by the SNPSpD program. Results: There were no differences in allele or genotype frequencies between the overall CP patients and controls among the five genetic polymorphisms. However, subgroup analysis found significant sex-related differences in allele and genotype frequencies. Differences were found between spastic CP and controls in males for rs2069837; between CP with periventricular leukomalacia and controls in males for rs1800796 and rs2066992; and between term CP and controls in males for rs2069837. Plasma IL-6 levels were higher in CP patients than in the controls, and this difference was more robust in full-term male spastic CP patients. Furthermore, the genotype has an effect on IL-6 synthesis. Conclusions: The influence of IL-6 gene polymorphisms on IL-6 synthesis and the susceptibility to CP is related to sex and gestational age.
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11.
  • Ding, X., et al. (author)
  • Gut microbiota changes in patients with autism spectrum disorders
  • 2020
  • In: Journal of Psychiatric Research. - : Elsevier BV. - 0022-3956 .- 1879-1379. ; 129, s. 149-159
  • Journal article (peer-reviewed)abstract
    • Autism spectrum disorder (ASD) has a high incidence of intestinal comorbidity, indicating a strong association with gut microbiota. The purpose of this study was to characterize gut microbiota profiles in children with ASD. Seventy-seven children with ASD [33 with mild ASD and 44 with severe ASD according to the Childhood Autism Rating Scale score] and 50 age-matched healthy children were enrolled. Compared with children in the healthy control (HC) group, those in the ASD group showed higher biomass, richness, and biodiversity of gut microbiota, and an altered microbial community structure. At the genus level, there was a significant increase in the relative abundance of unidentified Lachnospiraceae, Clostridiales, Erysipelotrichaceae, Dorea, Collinsella, and Lachnoclostridium, whereas Bacteroides, Faecalibacterium, Parasutterella, and Paraprevotella were significantly lower in the ASD group than in the control group. The presence of unidentified Erysipelotrichaceae, Faecalibacterium, and Lachnospiraceae was positively correlated with ASD severity. Notably, three microbial markers (Faecalitalea, Caproiciproducens and Collinsella) were identified in a random forest model with an area under the curve (AUC) of 0.94 for differentiation between HCs and ASD patients. Furthermore, the validation model was consistent with the discovery set (AUC = 0.98, 95% CI: 97.9%-100%). The training and testing sets were more effective when the number of bacteria was increased. In addition, the functional properties (such as galactose metabolism, glycosyltransferase activity, and glutathione metabolism) displayed significant differences between the ASD and HC groups. The current study provides evidence for the relationship between gut microbiota and ASD, with the findings suggesting that gut microbiota could contribute to symptomology. Thus, modulation of gut microbiota may be a new therapeutic strategy for ASD.
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12.
  • Duan, Jiajia, et al. (author)
  • Histological chorioamnionitis and pathological stages on very preterm infant outcomes
  • 2024
  • In: HISTOPATHOLOGY. - 0309-0167 .- 1365-2559.
  • Journal article (peer-reviewed)abstract
    • Aims: Histological chorioamnionitis (HCA) is a condition linked to preterm birth and neonatal infection and its relationship with various pathological stages in extremely preterm neonates, and with their associated short- and long-term consequences, remains a subject of research. This study investigated the connection between different pathological stages of HCA and both short-term complications and long-term outcomes in preterm infants born at or before 32 weeks of gestational age. Methods: Preterm infants born at <= 32 weeks of gestation who underwent placental pathology evaluation and were followed-up at 18-24 months of corrected age were included. Neonates were classified based on their exposure to HCA and were further subdivided into different groups according to maternal inflammatory responses (MIR) and fetal inflammatory responses (FIR) stages. We compared short-term complications during their hospital stay between the HCA-exposed and -unexposed groups and examined the influence of HCA stages on long-term outcomes. Results: The HCA group exhibited distinct characteristics such as higher rates of premature rupture of membranes > 18 h, reduced amniotic fluid, early-onset sepsis, bronchopulmonary dysplasia and intraventricular haemorrhage (IVH) grades III-IV (P < 0.05). The moderate-severe HCA group displayed lower gestational age, lower birth weight and higher incidence of IVH (grades III-IV) and preterm sepsis compared with the mild HCA group (P < 0.05). After adjusting for confounders, the MIR stages 2-3 group showed associations with cognitive impairment and cerebral palsy (P < 0.05), and the FIR stages 2-3 group also showed poor long-term outcomes and cognitive impairment (P < 0.05). Conclusions: Moderate-severe HCA was associated with increased early-onset sepsis, severe IVH and poor long-term outcomes, including cognitive impairment and cerebral palsy. Vigilant prevention strategies are warranted for severe HCA cases in order to mitigate poorer clinical outcomes.
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13.
  • Gustafsson Brywe, Katarina, 1965, et al. (author)
  • IGF-I neuroprotection in the immature brain after hypoxia-ischemia, involvement of Akt and GSK3beta?
  • 2005
  • In: Eur J Neurosci. - : Wiley. - 0953-816X. ; 21:6, s. 1489-502
  • Journal article (peer-reviewed)abstract
    • Insulin-like growth factor I (IGF-I) is a neurotrophic factor that promotes neuronal growth, differentiation and survival. Neuroprotective effects of IGF-I have previously been shown in adult and juvenile rat models of brain injury. We wanted to investigate the neuroprotective effect of IGF-I after hypoxia-ischemia (HI) in 7-day-old neonatal rats and the mechanisms of IGF-I actions in vivo. We also wanted to study effects of HI and/or IGF-I on the serine/threonine kinases Akt and glycogen synthase kinase 3beta (GSK3beta) in the phophatidylinositol-3 kinase (PI3K) pathway. Immediately after HI, phosphorylated Akt (pAkt) and phosphorylated GSK3beta (pGSK3beta) immunoreactivity was lost in the ipsilateral and reduced in the contralateral hemisphere. After 45 min, pAkt levels were restored to control values, whereas pGSK3beta remained low 4 h after HI. Administration of IGF-I (50 microg i.c.v.) after HI resulted in a 40% reduction in brain damage (loss of microtubule-associated protein) compared with vehicle-treated animals. IGF-I treatment without HI was shown to increase pAkt whereas pGSK3beta decreased in the cytosol, but increased in the nuclear fraction. IGF-I treatment after HI increased pAkt in the cytosol and pGSK3beta in both the cytosol and the nuclear fraction in the ipsilateral hemisphere compared with vehicle-treated rats, concomitant with a reduced caspase-3- and caspase-9-like activity. In conclusion, IGF-I induces activation of Akt during recovery after HI which, in combination with inactivation of GSK3beta, may explain the attenuated activation of caspases and reduction of injury in the immature brain.
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14.
  • Jin, S. C., et al. (author)
  • Mutations disrupting neuritogenesis genes confer risk for cerebral palsy
  • 2020
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 52:10
  • Journal article (peer-reviewed)abstract
    • Whole-exome sequencing of 250 parent-offspring trios identifies an enrichment of rare damaging de novo mutations in individuals with cerebral palsy and implicates genetically mediated dysregulation of early neuronal connectivity in the etiology of this disorder. In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1AandCTNNB1) met genome-wide significance. We identified two novel monogenic etiologies,FBXO31andRHOB, and showed that theRHOBmutation enhances active-state Rho effector binding while theFBXO31mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in aDrosophilareverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.
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15.
  • Li, Kenan, et al. (author)
  • Sex differences in neonatal mouse brain injury after hypoxia-ischemia and adaptaquin treatment
  • 2019
  • In: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 150:6, s. 759-775
  • Journal article (peer-reviewed)abstract
    • Hypoxia-inducible factor prolyl 4-hydroxylases (HIF-PHDs) are important targets against oxidative stress. We hypothesized that inhibition HIF-PHD by adaptaquin reduces hypoxic-ischemic brain injury in a neonatal mouse model. The pups were treated intraperitoneally immediately with adaptaquin after hypoxia-ischemia (HI) and then every 24 h for 3 days. Adaptaquin treatment reduced infarction volume by an average of 26.3% at 72 h after HI compared to vehicle alone, and this reduction was more pronounced in males (34.8%) than in females (11.7%). The protection was also more pronounced in the cortex. The subcortical white matter injury as measured by tissue loss volume was reduced by 24.4% in the adaptaquin treatment group, and this reduction was also more pronounced in males (28.4%) than in females (18.9%). Cell death was decreased in the cortex as indicated by Fluoro-Jade labeling, but not in other brain regions with adaptaquin treatment. Furthermore, in the brain injury area, adaptaquin did not alter the number of cells positive for caspase-3 activation or translocation of apoptosis-inducing factor to the nuclei. Adaptaquin treatment increased glutathione peroxidase 4 mRNA expression in the cortex but had no impact on 3-nitrotyrosine, 8-hydroxy-2 deoxyguanosine, or malondialdehyde production. Hif1 alpha mRNA expression increased after HI, and adaptaquin treatment also stimulated Hif1 alpha mRNA expression, which was also more pronounced in males than in females. However, nuclear translocation of HIF1 alpha protein was decreased after HI, and adaptaquin treatment had no influence on HIF1 alpha expression in the nucleus. These findings demonstrate that adaptaquin treatment is neuroprotective, but the potential mechanisms need further investigation. Open Science Badges This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at .
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16.
  • Li, Tao, et al. (author)
  • Overexpression of apoptosis inducing factor aggravates hypoxic-ischemic brain injury in neonatal mice
  • 2020
  • In: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 11:1
  • Journal article (peer-reviewed)abstract
    • Apoptosis inducing factor (AIF) has been shown to be a major contributor to neuron loss in the immature brain after hypoxia-ischemia (HI). Indeed, mice bearing a hypomorphic mutation causing reduced AIF expression are protected against neonatal HI. To further investigate the possible molecular mechanisms of this neuroprotection, we generated an AIF knock-in mouse by introduction of a latent transgene coding for flagged AIF protein into the Rosa26 locus, followed by its conditional activation by a ubiquitously expressed Cre recombinase. Such AIF transgenic mice overexpress the pro-apoptotic splice variant of AIF (AIF1) at both the mRNA (5.9 times higher) and protein level (2.4 times higher), but not the brain-specific AIF splice-isoform (AIF2). Excessive AIF did not have any apparent effects on the phenotype or physiological functions of the mice. However, brain injury (both gray and white matter) after neonatal HI was exacerbated in mice overexpressing AIF, coupled to enhanced translocation of mitochondrial AIF to the nucleus as well as enhanced caspase-3 activation in some brain regions, as indicated by immunohistochemistry. Altogether, these findings corroborate earlier studies demonstrating that AIF plays a causal role in neonatal HI brain injury.
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17.
  • Li, W. L., et al. (author)
  • Association between bronchopulmonary dysplasia and death or neurodevelopmental impairment at 3 years in preterm infants without severe brain injury
  • 2023
  • In: Frontiers in Neurology. - 1664-2295. ; 14
  • Journal article (peer-reviewed)abstract
    • ObjectiveWe investigated the association between bronchopulmonary dysplasia (BPD) and 3 years death or neurodevelopmental impairment (NDI) in very preterm infants without severe brain injury.MethodOur prospective cohort study recruited preterm infants who were born prior to 32 weeks of gestational age and survived in the neonatal intensive care unit until 36 weeks of corrected age. Upon reaching 3 years of age, each infant was assessed for death or NDI such as cerebral palsy, cognitive deficit, hearing loss, and blindness. Correlations between BPD and death or NDI were determined using multiple logistic regression analyses adjusted for confounding factors.ResultA total of 1,417 infants without severe brain injury who survived until 36 weeks of corrected age were initially enrolled in the study. Over the study period, 201 infants were lost to follow-up and 5 infants were excluded. Our final dataset, therefore, included 1,211 infants, of which 17 died after 36 weeks of corrected age and 1,194 were followed up to 3 years of age. Among these infants, 337 (27.8%) developed BPD. Interestingly, by 3 years of age, BPD was demonstrated to be independently associated with death or NDI, with an adjusted odds ratio of 1.935 (95% confidence interval: 1.292-2.899, p = 0.001), in preterm infants without severe neonatal brain injury.ConclusionOur findings indicate that BPD is strongly associated with death or NDI in preterm infants without severe neonatal brain injury at 3 years of age. Further research is needed to understand the mechanisms linking the development of BPD with death or NDI and whether appropriate treatment of BPD may ameliorate or prevent the development of neurological complications.
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18.
  • Qiu, H., et al. (author)
  • Umbilical cord blood cells for the treatment of preterm white matter injury: Potential effects and treatment options
  • 2021
  • In: Journal of Neuroscience Research. - : Wiley. - 0360-4012 .- 1097-4547. ; 99:3, s. 778-792
  • Research review (peer-reviewed)abstract
    • Preterm birth is a global public health problem. A large number of preterm infants survive with preterm white matter injury (PWMI), which leads to neurological deficits, and has multifaceted etiology, clinical course, monitoring, and outcomes. The principal upstream insults leading to PWMI initiation are hypoxia-ischemia and infection and/or inflammation and the key target cells are late oligodendrocyte precursor cells. Current PWMI treatments are mainly supportive, and thus have little effect in terms of protecting the immature brain or repairing injury to improve long-term outcomes. Umbilical cord blood (UCB) cells comprise abundant immunomodulatory and stem cells, which have the potential to reduce brain injury, mainly due to anti-inflammatory and immunomodulatory mechanisms, and also through their release of neurotrophic or growth factors to promote endogenous neurogenesis. In this review, we briefly summarize PWMI pathogenesis and pathophysiology, and the specific properties of different cell types in UCB. We further explore the potential mechanism by which UCB can be used to treat PWMI, and discuss the advantages of and potential issues related to UCB cell therapy. Finally, we suggest potential future studies of UCB cell therapy in preterm infants.
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19.
  • Rodriguez, Juan, 1983, et al. (author)
  • Lack of the brain-specific isoform of apoptosis-inducing factor aggravates cerebral damage in a model of neonatal hypoxia-ischemia.
  • 2018
  • In: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 10:1
  • Journal article (peer-reviewed)abstract
    • Apoptosis-inducing factor (AIF) may contribute to neuronal cell death, and its influence is particularly prominent in the immature brain after hypoxia-ischemia (HI). A brain-specific AIF splice-isoform (AIF2) has recently been discovered, but has not yet been characterized at the genetic level. The aim of this study was to determine the functional and regulatory profile of AIF2 under physiological conditions and after HI in mice. We generated AIF2 knockout (KO) mice by removing the AIF2-specific exon and found that the relative expression of Aif1 mRNA increased in Aif2 KO mice and that this increase became even more pronounced as Aif2 KO mice aged compared to their wild-type (WT) littermates. Mitochondrial morphology and function, reproductive function, and behavior showed no differences between WT and Aif2 KO mice. However, lack of AIF2 enhanced brain injury in neonatal mice after HI compared to WT controls, and this effect was linked to increased oxidative stress but not to caspase-dependent or -independent apoptosis pathways. These results indicate that AIF2 deficiency exacerbates free radical production and HI-induced neonatal brain injury.
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20.
  • Shao, Linus Ruijin, 1964, et al. (author)
  • Nuclear progesterone receptor A and B isoforms in mouse fallopian tube and uterus: implications for expression, regulation, and cellular function
  • 2006
  • In: American journal of physiology. - : American Physiological Society. - 0193-1849. ; 291:1
  • Journal article (peer-reviewed)abstract
    • Progesterone and its interaction with nuclear progesterone receptors (PR) PR-A and PR-B play a critical role in the regulation of female reproductive function in all mammals. However, our knowledge of the regulation and possible cellular function of PR protein isoforms in the fallopian tube and uterus in vivo is still very limited. In the present study, we revealed that equine chorionic gonadotropin (eCG) treatment resulted in a time-dependent increase in expression of both isoforms, reaching a maximal level at 48 h in the fallopian tube. Regulation of PR-A protein expression paralleled that of PR-B protein expression. However, in the uterus PR-B protein levels increased and peaked earlier than PR-A protein levels after eCG treatment. With prolonged exposure to eCG, PR-B protein levels decreased, whereas PR-A protein levels continued to increase. Furthermore, subsequent treatment with human (h)CG decreased the levels of PR protein isoforms in both tissues in parallel with increased endogenous serum progesterone levels. To further elucidate whether progesterone regulates PR protein isoforms, we demonstrated that a time-dependent treatment with progesterone (P(4)) decreased the expression of PR protein isoforms in both tissues, whereas decreases in p27, cyclin D(2), and proliferating cell nuclear antigen protein levels were observed only in the uterus. To define the potential PR-mediated effects on apoptosis, we demonstrated that the PR antagonist treatment increased the levels of PR protein isoforms, induced mitochondrial-associated apoptosis, and decreased in epidermal growth factor (EGF) and EGF receptor protein expression in both tissues. Interestingly, immunohistochemistry indicated that the induction of apoptosis by PR antagonists was predominant in the epithelium, whereas increase in PR protein expression was observed in stromal cells of both tissues. Taken together, these observations suggest that 1) the tissue-specific and hormonal regulation of PR isoform expression in mouse fallopian tube and uterus, where they are potentially involved in regulation of mitochondrial-mediated apoptosis depending on the cellular compartment; and 2) a possible interaction between functional PR protein and growth factor signaling may have a coordinated role for regulating apoptotic process in both tissues in vivo.
  •  
21.
  • Song, J., et al. (author)
  • Early amplitude-integrated electroencephalography predicts brain injury and neurological outcome in very preterm infants
  • 2015
  • In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
  • Journal article (peer-reviewed)abstract
    • Early amplitude-integrated electroencephalography (aEEG) has been widely used in term infants with brain injury to predict neurodevelopmental outcomes; however, the prognostic value of early aEEG in preterm infants is unclear. We evaluated how well early aEEG could predict brain damage and long-term neurodevelopmental outcomes in very preterm infants compared with brain imaging assessments. We found that severe aEEG abnormalities (p = 0.000) and aEEG total score < 5 (p = 0.006) within 72 h after birth were positively correlated with white-matter damage, but aEEG abnormalities were not associated with intracranial hemorrhage (p = 0.186). Severe abnormalities in aEEG recordings, head ultrasound, and cranial magnetic resonance imaging (MRI) were all positively correlated with poor outcome at 18 months corrected age. The predictive power of poor outcomes of the aEEG and MRI combination was the same as the aEEG, MRI, and head ultrasound combination with a sensitivity of 52.4%, specificity of 96.2%, positive predictive value of 78.6%, and negative predictive value of 88.4%. These results indicate that severely abnormal aEEG recordings within 72 h after birth can predict white-matter damage and long-term poor outcomes in very preterm infants. Thus aEEG can be used as an early marker to monitor very preterm infants.
  •  
22.
  • Song, J., et al. (author)
  • Erythropoietin Improves Poor Outcomes in Preterm Infants with Intraventricular Hemorrhage
  • 2021
  • In: CNS Drugs. - : Springer Science and Business Media LLC. - 1172-7047 .- 1179-1934. ; 35, s. 681-690
  • Journal article (peer-reviewed)abstract
    • Background: Intraventricular hemorrhage (IVH) is a common complication in preterm infants that has poor outcomes, especially in severe cases, and there are currently no widely accepted effective treatments. Erythropoietin has been shown to be neuroprotective in neonatal brain injury. Objective: The objective of this study was to evaluate the protective effect of repeated low-dose recombinant human erythropoietin (rhEPO) in preterm infants with IVH. Methods: This was a single-blinded prospective randomized controlled trial. Preterm infants ≤32 weeks gestational age who were diagnosed with IVH within 72 h after birth were randomized to receive rhEPO 500 IU/kg or placebo (equivalent volume of saline) every other day for 2 weeks. The primary outcome was death or neurological disability assessed at 18 months of corrected age. Results: A total of 316 eligible infants were included in the study, with 157 in the rhEPO group and 159 in the placebo group. Although no significant differences in mortality (p=0.176) or incidence of neurological disability (p=0.055) separately at 18 months of corrected age were seen between the rhEPO and placebo groups, significantly fewer infants had poor outcomes (death and neurological disability) in the rhEPO group: 14.9 vs. 26.4%; odds ratio (OR) 0.398; 95% confidence interval (CI) 0.199–0.796; p=0.009. In addition, the incidence of Mental Development Index scores of <70 was lower in the rhEPO group than in the placebo group: 7.2 vs. 15.3%; OR 0.326; 95% CI 0.122–0.875; p=0.026. Conclusions: Treatment with repeated low-dose rhEPO improved outcomes in preterm infants with IVH. Trial Registration: The study was retrospectively registered on ClinicalTrials.gov on 16 April 2019 (NCT03914690). © 2021, The Author(s).
  •  
23.
  • Song, Juan, et al. (author)
  • Temporal brain transcriptome analysis reveals key pathological events after germinal matrix hemorrhage in neonatal rats
  • 2022
  • In: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 42:9, s. 1632-1649
  • Journal article (peer-reviewed)abstract
    • Germinal matrix hemorrhage (GMH) is a common complication in preterm infants and is associated with high risk of adverse neurodevelopmental outcomes. We used a rat GMH model and performed RNA sequencing to investigate the signaling pathways and biological processes following hemorrhage. GMH induced brain injury characterized by early hematoma and subsequent tissue loss. At 6 hours after GMH, gene expression indicated an increase in mitochondrial activity such as ATP metabolism and oxidative phosphorylation along with upregulation of cytoprotective pathways and heme metabolism. At 24 hours after GMH, the expression pattern suggested an increase in cell cycle progression and downregulation of neurodevelopmental-related pathways. At 72 hours after GMH, there was an increase in genes related to inflammation and an upregulation of ferroptosis. Hemoglobin components and genes related to heme metabolism and ferroptosis such as Hmox1, Alox15, and Alas2 were among the most upregulated genes. We observed dysregulation of processes involved in development, mitochondrial function, cholesterol biosynthesis, and inflammation, all of which contribute to neurodevelopmental deterioration following GMH. This study is the first temporal transcriptome profile providing a comprehensive overview of the molecular mechanisms underlying brain injury following GMH, and it provides useful guidance in the search for therapeutic interventions.
  •  
24.
  • Sun, H., et al. (author)
  • Effect of early prophylactic low-dose recombinant human erythropoietin on retinopathy of prematurity in very preterm infants
  • 2020
  • In: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 18:1
  • Journal article (peer-reviewed)abstract
    • Background: Very preterm infants are at risk of developing retinopathy of prematurity (ROP). Recombinant human erythropoietin (rhEPO) is routinely used to prevent anemia in preterm infants; however, the effect of rhEPO on ROP development is still controversial. The purpose of this study was to evaluate the effect of early prophylactic low-dose rhEPO administration on ROP development in very preterm infants. Methods: A total of 1898 preterm infants born before 32weeks of gestation were included. Preterm infants received rhEPO (n = 950; 500 U/kg, rhEPO group) or saline (n = 948, control group) intravenously within 72h of birth and then once every other day for 2weeks. Results: The total incidence of ROP was not significantly different between the two groups (10.2% vs. 13.2%, p = 0.055). Further analysis showed that rhEPO group had lower rates of type 2 ROP than the control group (2.2% vs. 4.1%, RR 0.98; 95% CI 0.96–1.00; p = 0.021). Subgroup analysis found that rhEPO treatment significantly decreased the incidence of type 2 ROP in infant boys (1.8% vs. 4.3%, p = 0.021) and in those with a gestational age of 28–296/7weeks (1.1% vs. 4.9%, p = 0.002) and birth weight of 1000–1499g (1.2% vs. 4.2%, p = 0.002). There was a small increasing tendency for the incidence of ROP in infants with a gestational age of < 28weeks after rhEPO treatment. Conclusions: Repeated low-dose rhEPO administration has no significant influence on the development of ROP; however, it may be effective for type 2 ROP in infant boys or in infants with gestational age > 28weeks and birth weight > 1500g. Trial registration The data of this study were retrieved from two clinical studies registered ClinicalTrials.gov (NCT 02036073) on January 14, 2014, https://clinicaltrials.gov/ct2/show/NCT02036073; and (NCT03919500) on April 18, 2019. https://clinicaltrials.gov/ct2/show/NCT03919500. © 2020, The Author(s).
  •  
25.
  • Wang, Xiaoyang, 1965, et al. (author)
  • The nonerythropoietic asialoerythropoietin protects against neonatal hypoxia-ischemia as potently as erythropoietin.
  • 2004
  • In: Journal of neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 91:4, s. 900-10
  • Journal article (peer-reviewed)abstract
    • Recently, erythropoietin (EPO) and the nonerythropoietic derivative asialoEPO have been linked to tissue protection in the nervous system. In this study, we tested their effects in a model of neonatal hypoxia-ischemia (HI) in 7-day-old rats (unilateral carotid ligation and exposure to 7.7% O(2) for 50 min). EPO (10 U/g body weight = 80 ng/g; n = 24), asialoEPO (80 ng/g; n = 23) or vehicle (phosphate-buffered saline with 0.1% human serum albumin; n = 24) was injected intraperitoneally 4 h before HI. Both drugs were protective, as judged by measuring the infarct volumes, neuropathological score and gross morphological score. The infarct volumes were significantly reduced by both EPO (52%) and asialoEPO (55%) treatment, even though the plasma levels of asialoEPO had dropped below the detection limit (1 pm) at the onset of HI, while those of EPO were in the nanomolar range. Thus, a brief trigger by asialoEPO before the insult appears to be sufficient for protection. Proteomics analysis after asialoEPO treatment alone (no HI) revealed at least one differentially up-regulated protein, synaptosome-associated protein of 25 kDa (SNAP-25). Activation (phosphorylation) of ERK was significantly reduced in asialoEPO-treated animals after HI. EPO and the nonerythropoietic asialoEPO both provided significant and equal neuroprotection when administered 4 h prior to HI in 7-day-old rats. The protection might be related to reduced ERK activation and up-regulation of SNAP-25.
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26.
  • Wang, Xiaoyang, 1965, et al. (author)
  • X-linked inhibitor of apoptosis (XIAP) protein protects against caspase activation and tissue loss after neonatal hypoxia-ischemia
  • 2004
  • In: Neurobiol Dis. - Univ Gothenburg, Dept Physiol, Perinatal Ctr, SE-40530 Gothenburg, Sweden. Zhengzhou Univ, Affiliated Hosp 3, Dept Pediat, Zhengzhou 450052, Peoples R China. Univ Gothenburg, Sahlgrens Univ Hosp, Dept Obstet & Gynecol, SE-41685 Gothenburg, Sweden. Uppsala Univ, Dept Neurosci, SE-75123 Uppsala, Sweden. Univ Gothenburg, Dept Med Biophys, SE-40530 Gothenburg, Sweden. Univ Gothenburg, Queen Silvia Childrens Hosp, Dept Pediat, SE-41685 Gothenburg, Sweden. : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0969-9961 .- 1095-953X. ; 16:1, s. 179-89
  • Journal article (peer-reviewed)abstract
    • Nine-day-old transgenic XIAP overexpressing (TG-XIAP) and wild-type mice were subjected to left carotid artery ligation and 10% O(2) for 60 min, leading to widespread infarctions in the ipsilateral hemisphere during reperfusion. The activation of caspase-3 and -9 seen in wild-type animals was virtually abolished in TG-XIAP mice. Tissue loss was significantly reduced from 54.4 +/- 4.1 mm(3) (mean +/- SEM) in wild-type mice to 33.1 +/- 2.1 mm(3) in the TG-XIAP mice. Injured neurons displayed stronger XIAP staining during reperfusion, particularly in the nuclei. XIAP was colocalized with XAF-1, Smac, and HtrA2 in injured neurons after hypoxia-ischemia (HI). XIAP was cleaved after HI, and Smac immunoprecipitation co-precipitated a 25-kDa C-terminal fragment of XIAP, indicating that Smac preferentially bound to cleaved XIAP. These findings provide the first evidence that increased XIAP levels protect the neonatal brain against HI.
  •  
27.
  • Wang, Y., et al. (author)
  • Erythropoietin prevents necrotizing enterocolitis in very preterm infants: a randomized controlled trial
  • 2020
  • In: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 18:1
  • Journal article (peer-reviewed)abstract
    • Background: Necrotizing enterocolitis (NEC) is one of the most severe complications in very preterm infants, but there are currently no accepted methods to prevent NEC. Studies have shown that erythropoietin (EPO) has the potential to prevent NEC or improve outcomes of preterm NEC. This study aimed to determine whether recombinant human EPO (rhEPO) could protect against NEC in very preterm infants. Methods: The study was a prospective randomized clinical trial performed among four NICU centers. A total of 1327 preterm infants with gestational age <= 32 weeks were admitted to the centers, and 42 infants were excluded leaving 1285 eligible infants to be randomized to the rhEPO or control group. Infants in the rhEPO group were given 500 IU/kg rhEPO intravenously every other day for 2 weeks, while the control group was given the same volume of saline. The primary outcome was the incidence of NEC in very preterm infants at 36 weeks of corrected gestational age. Results: A total of 1285 infants were analyzed at 36 weeks of corrected age for the incidence of NEC. rhEPO treatment significantly decreased the incidence of NEC (stage I, II and III) (12.0% vs. 17.1%, p = 0.010), especially confirmed NEC (stage II and III) (3.0% vs. 5.4%, p = 0.027). Meanwhile, rhEPO treatment significantly reduced the number of red blood cells transfusion in the confirmed NEC cases (1.2 +/- 0.4 vs. 2.7 +/- 1.0, p = 0.004). Subgroup analyses showed that rhEPO treatment significantly decreased the incidence of confirmed NEC at gestational age < 28 weeks (p = 0.019), and the incidence of all stages NEC in preterm infants with hemoglobin < 90 g/l (p = 0.000) and 5 min Apgar score > 5 (p = 0.028). Conclusion: Repeated low-dose rhEPO treatment is beneficial against NEC in very preterm infants.
  •  
28.
  • Wang, Yangong, et al. (author)
  • Exome sequencing reveals genetic heterogeneity and clinically actionable findings in children with cerebral palsy
  • 2024
  • In: NATURE MEDICINE. - 1078-8956 .- 1546-170X. ; 30, s. 1395-1405
  • Journal article (peer-reviewed)abstract
    • Cerebral palsy (CP) is the most common motor disability in children. To ascertain the role of major genetic variants in the etiology of CP, we conducted exome sequencing on a large-scale cohort with clinical manifestations of CP. The study cohort comprised 505 girls and 1,073 boys. Utilizing the current gold standard in genetic diagnostics, 387 of these 1,578 children (24.5%) received genetic diagnoses. We identified 412 pathogenic and likely pathogenic (P/LP) variants across 219 genes associated with neurodevelopmental disorders, and 59 P/LP copy number variants. The genetic diagnostic rate of children with CP labeled at birth with perinatal asphyxia was higher than the rate in children without asphyxia (P = 0.0033). Also, 33 children with CP manifestations (8.5%, 33 of 387) had findings that were clinically actionable. These results highlight the need for early genetic testing in children with CP, especially those with risk factors like perinatal asphyxia, to enable evidence-based medical decision-making. Using exome sequencing data from one of the largest cohorts of children with cerebral palsy, the genetic diagnostic rates of single-nucleotide and copy number variants were assessed and a sizeable fraction found to be clinically actionable.
  •  
29.
  • Wang, Yafeng, 1985, et al. (author)
  • Iron Metabolism and Brain Development in Premature Infants
  • 2019
  • In: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 10
  • Journal article (peer-reviewed)abstract
    • Iron is important for a remarkable array of essential functions during brain development, and it needs to be provided in adequate amounts, especially to preterm infants. In this review article, we provide an overview of iron metabolism and homeostasis at the cellular level, as well as its regulation at the mRNA translation level, and we emphasize the importance of iron for brain development in fetal and early life in preterm infants. We also review the risk factors for disrupted iron metabolism that lead to high risk of developing iron deficiency and subsequent adverse effects on neurodevelopment in preterm infants. At the other extreme, iron overload, which is usually caused by excess iron supplementation in iron-replete preterm infants, might negatively impact brain development or even induce brain injury. Maintaining the balance of iron during the fetal and neonatal periods is important, and thus iron status should be monitored routinely and evaluated thoroughly during the neonatal period or before discharge of preterm infants so that iron supplementation can be individualized.
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30.
  • Wang, Yafeng, 1985, et al. (author)
  • Selective Neural Deletion of the Atg7 Gene Reduces Irradiation-Induced Cerebellar White Matter Injury in the Juvenile Mouse Brain by Ameliorating Oligodendrocyte Progenitor Cell Loss
  • 2019
  • In: Frontiers in Cellular Neuroscience. - : Frontiers Media SA. - 1662-5102. ; 13
  • Journal article (peer-reviewed)abstract
    • Radiotherapy is an effective tool for treating brain tumors, but irradiation-induced toxicity to the normal brain tissue remains a major problem. Here, we investigated if selective neural autophagy related gene 7 (Atg7) deletion has a persistent effect on irradiation-induced juvenile mouse brain injury. Ten-day-old Atg7 knockout under a nestin promoter (KO) mice and wild-type (WT) littermates were subjected to a single dose of 6 Gy whole-brain irradiation. Cerebellar volume, cell proliferation, microglia activation, inflammation, and myelination were evaluated in the cerebellum at 5 days after irradiation. We found that neural Atg7 deficiency partially prevented myelin disruption compared to the WT mice after irradiation, as indicated by myelin basic protein staining. Irradiation induced oligodendrocyte progenitor cell (OPC) loss in the white matter of the cerebellum, and Atg7 deficiency partly prevented this. The mRNA expression of oligodendrocyte and myelination-related genes (Olig2, Cldn11, CNP, and MBP) was higher in the cerebellum in Atg7 KO mice compared with WT littermates. The total cerebellar volume was significantly reduced after irradiation in both Atg7 KO and WT mice. Atg7-deficient cerebellums were in a regenerative state before irradiation, as judged by the increased OPC-related and neurogenesis-related transcripts and the increased numbers of microglia; however, except for the OPC parameters these were the same in both genotypes after irradiation. Finally, there was no significant change in the number of astrocytes in the cerebellum after irradiation. These results suggest that selective neural Atg7 deficiency reduces irradiation-induced cerebellar white matter injury in the juvenile mouse brain, secondary to prevention of OPC loss.
  •  
31.
  • Xia, L., et al. (author)
  • Changes in the Incidence of Congenital Anomalies in Henan Province, China, from 1997 to 2011
  • 2015
  • In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 10:7
  • Journal article (peer-reviewed)abstract
    • Aim To investigate changes in incidence and characteristics of congenital anomalies in infants in Henan Province of China over a period of 15 years. Population-based surveillance in Henan Province was conducted from 1997 to 2011 in 75 hospitals (40 urban districts and 35 rural counties, comprising about 20% of the total births). Basic population information was obtained from the healthcare network. All live births, intrauterine deaths after 28 weeks, and stillbirths were included. Congenital anomalies were diagnosed and reported to Henan Provincial Maternal and Pediatric Healthcare Hospital. Of 1,815,920 births from 1997 to 2011, 15,660 cases of congenital anomalies were identified, resulting in an average incidence of 86.2 cases per 10,000 births. The incidence of congenital anomalies showed a significant downward trend (p < 0.0001) in rural areas and the whole province (p < 0.0001), but an increase in urban areas (p = 0.003). The incidence was much higher in rural than in urban areas in 1997, but this discrepancy decreased rapidly and no difference was seen between rural and urban areas in 2003. The incidence in females was higher than in males in 1997-1999 but decreased to a similar level as that in males in 2000. Maternal age exceeding 35 years was associated with a higher incidence of congenital anomalies. Among the 23 types of congenital anomalies recorded, neural tube defects were the most common; the incidence declined from 39.3 cases per 10,000 births in 1997 to 6.1 cases per 10,000 births in 2011. The incidence of congenital anomalies has decreased in Henan Province over the past 15 years due to significant reductions in rural areas and among girls. This decrease was partly related to a reduction in neural tube defects that was likely the result of a folic acid intervention in the province.
  •  
32.
  • Xia, L., et al. (author)
  • Combined analysis of interleukin-10 gene polymorphisms and protein expression in children with cerebral palsy
  • 2018
  • In: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 9:MAR
  • Journal article (peer-reviewed)abstract
    • Background: Interleukin-10 (IL-10) is an important anti-inflammatory and immunosuppressive cytokine, and it has indispensable functions in both the onset and development of inflammatory disorders. The association between persistent inflammation and the development of cerebral palsy (CP) has attracted much attention. Objective: The purpose of this study was to investigate whether IL-10 gene polymorphisms and plasma protein expression are associated with CP and to analyze the role of IL-10 in CP. Methods: A total of 282 CP patients and 197 healthy controls were genotyped for IL-10 polymorphisms (rs1554286, rs1518111, rs3024490, rs1800871, and rs1800896). Among them, 95 CP patients and 93 healthy controls were selected for plasma IL-10 measurement. Results: The differences in the rs3024490 (p = 0.033) and rs1800871 (p = 0.033) allele frequencies of IL-10 were determined between CP patients and controls. The frequencies of allele and genotype between CP patients with spastic tetraplegia and normal controls of IL-10 polymorphisms showed significant differences for rs1554286, rs151811, rs3024490, rs1800871, and rs1800896 (pallele = 0.015, 0.009, 0.006, 0.003, and 0.006, pgenotype = 0.039, 0.018, 0.027, 0.012, and 0.03, respectively). The plasma IL-10 protein level in CP patients was higher than normal controls (9.13 ± 0.77 vs. 6.73 ± 0.63 pg/ml, p = 0.017). IL-10 polymorphisms and protein association analysis showed that the TT genotype had higher plasma IL-10 protein levels compared to the GG + GT genotype at rs3024490 (11.14 ± 7.27 vs. 7.44 ± 6.95 pg/ml, p = 0.045, respectively) in CP cases. Conclusion: These findings provide an important contribution toward explaining the pleiotropic role of IL-10 in the complex etiology of CP. © 2018 Xia, Chen, Bi, Song, Zhang, Wang, Zhu, Shang, Xu, Wang, Xing and Zhu.
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33.
  • Xu, Jianhua, et al. (author)
  • A Variant of the Autophagy-Related 5 Gene is Associated with Child Cerebral Palsy
  • 2017
  • In: Frontiers in Cellular Neuroscience. - : Frontiers Media SA. - 1662-5102. ; 18
  • Journal article (peer-reviewed)abstract
    • Cerebral palsy (CP) is a major cause of childhood disability in developed and developing countries, but the pathogenic mechanisms of CP development remain largely unknown. Autophagy is a highly conserved cellular self-digestion of damaged organelles and dysfunctional macromolecules. Growing evidence suggests that autophagy-related gene 5 (ATG5)-dependent autophagy is involved in neural development, neuronal differentiation, and neurological degenerative diseases. The aim of this study was to analyze ATG5 protein expression and gene polymorphisms in Chinese patients with CP and to evaluate the importance of ATG5 in the development of CP. Five polymorphisms from different regions of the ATG5 gene (rs510432, rs3804338, rs573775, rs2299863, and rs6568431) were analyzed in 715 CP patients and 658 controls using MassARRAY. Of these, 58 patients and 56 controls were selected for measurement of plasma ATG5 level using ELISA. The relevance of disease-associated SNPs was evaluated using the SHEsis program. We identified a significant association between rs6568431 and CP (OR = 1.388, 95% CI = 1.173∼1.643, Pallele = 0.0005, Pgenotype = 0.0015). Subgroup analysis showed a highly significant association of rs6568431 with spastic CP (n = 468, OR = 1.511, 95% CI = 1.251∼1.824, Pallele = 8.50e−005, Pgenotype = 1.57e−004) and spastic quadriplegia (OR = 1.927, 95% CI = 1.533∼2.421, Pallele = 7.35e−008, Pgenotype = 3.24e−009). Furthermore, mean plasma ATG5 levels were lower in CP patients than in controls, and individuals carrying the AA genotype of rs6568431 that was positively associated with CP had lower plasma ATG5 levels (P < 0.05). This study demonstrated an association of an ATG5 gene variant and low level of ATG5 protein with CP, and stronger associations with severe clinical manifestations were identified. Our results provide novel evidence for a role of ATG5 in CP and shed light on the molecular mechanisms underlying this neurodevelopmental disorder.
  •  
34.
  • Xu, Yiran, 1988, et al. (author)
  • Cranial irradiation alters neuroinflammation and neural proliferation in the pituitary gland and induces late-onset hormone deficiency.
  • 2020
  • In: Journal of cellular and molecular medicine. - : Wiley. - 1582-4934 .- 1582-1838. ; 24:24, s. 14571-14582
  • Journal article (peer-reviewed)abstract
    • Cranial radiotherapy induces endocrine disorders and reproductive abnormalities, particularly in long-term female cancer survivors, and this might in part be caused by injury to the pituitary gland, but the underlying mechanisms are unknown. The aim of this study was to investigate the influence of cranial irradiation on the pituitary gland and related endocrine function. Female Wistar rat pups on postnatal day 11 were subjected to a single dose of 6Gy whole-head irradiation, and hormone levels and organ structure in the reproductive system were examined at 20weeks after irradiation. We found that brain irradiation reduced cell proliferation and induced persistent inflammation in the pituitary gland. The whole transcriptome analysis of the pituitary gland revealed that apoptosis and inflammation-related pathways were up-regulated after irradiation. In addition, irradiation led to significantly decreased levels of the pituitary hormones, growth hormone, adrenocorticotropic hormone, thyroid-stimulating hormone and the reproductive hormones testosterone and progesterone. To conclude, brain radiation induces reduction of pituitary and reproduction-related hormone secretion, this may due to reduced cell proliferation and increased pituitary inflammation after irradiation. Our results thus provide additional insight into the molecular mechanisms underlying complications after head irradiation and contribute to the discovery of preventive and therapeutic strategies related to brain injury following irradiation.
  •  
35.
  • You, Fengzhi, et al. (author)
  • Maternal mortality in Henan Province, China: changes between 1996 and 2009.
  • 2012
  • In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 7:10
  • Journal article (peer-reviewed)abstract
    • Background: Maternal deaths occur mostly in developing countries and the majority of them are preventable. This study analyzes changes in maternal mortality and related causes in Henan Province, China, between 1996 and 2009, in an attempt to provide a reliable basis for introducing effective interventions to reduce the maternal mortality ratio (MMR), part of the fifth Millennium Development Goal. Methods and Findings: This population-based maternal mortality survey in Henan Province was carried out from 1996 to 2009. Basic information was obtained from the health care network for women and children and the vital statistics system, from specially trained monitoring personnel in 25 selected monitoring sites and by household survey in each case of maternal death. This data was subsequently reported to the Henan Provincial Maternal and Child Healthcare Hospital. The total MMR in Henan Province declined by 78.4%, from 80.1 per 100 000 live births in 1996 to 17.3 per 100 000 live births in 2009. The decline was more pronounced in rural than in urban areas. The most common causes of maternal death during this period were obstetric hemorrhage (43.8%), pregnancy-induced hypertension (15.8%), amniotic fluid embolism (13.9%) and heart disease (8.0%). The MMR was higher in rural areas with lower income, less education and poorer health care. Conclusion: There was a remarkable decrease in the MMR in Henan Province between 1996 and 2009 mainly in the rural areas and MMR due to direct obstetric causes such as obstetric hemorrhage. This study indicates that improving the health care network for women, training of obstetric staff at basic-level units, promoting maternal education, and increasing household income are important interventional strategies to reduce the MMR further.
  •  
36.
  • Zhang, Lingling, et al. (author)
  • Integrative analysis of γδT cells and dietary factors reveals predictive values for autism spectrum disorder in children
  • 2023
  • In: Brain, behavior, and immunity. - 0889-1591 .- 1090-2139. ; 111, s. 76-89
  • Journal article (peer-reviewed)abstract
    • Background: Autism spectrum disorder (ASD) includes a range of multifactorial neurodevelopmental disabilities characterized by a variable set of neuropsychiatric symptoms. Immunological abnormalities have been considered to play important roles in the pathogenesis of ASD, but it is still unknown which abnormalities are more prominent. Methods: A total of 105 children with ASD and 105 age and gender-matched typically developing (TD) children were recruited. An eating and mealtime behavior questionnaire, dietary habits, and the Bristol Stool Scale were investigated. The immune cell profiles in peripheral blood were analyzed by flow cytometry, and cytokines (IFN-γ, IL-8, IL-10, IL-17A, and TNF-α) in plasma were examined by Luminex assay. The obtained results were further validated using an external validation cohort including 82 children with ASD and 51 TD children. Results: Compared to TD children, children with ASD had significant eating and mealtime behavioral changes and gastrointestinal symptoms characterized by increased food fussiness and emotional eating, decreased fruit and vegetable consumption, and increased stool astriction. The proportion of γδT cells was significantly higher in children with ASD than TD children (β: 0.156; 95% CI: 0.888 ∼ 2.135, p < 0.001) even after adjusting for gender, eating and mealtime behaviors, and dietary habits. In addition, the increased γδT cells were evident in all age groups (age < 48 months: β: 0.288; 95% CI: 0.420 ∼ 4.899, p = 0.020; age ≥ 48 months: β: 0.458; 95% CI: 0.694 ∼ 9.352, p = 0.024), as well as in boys (β: 0.174; 95% CI: 0.834 ∼ 2.625, p < 0.001) but not in girls. These findings were also confirmed by an external validation cohort. Furthermore, IL-17, but not IFN-γ, secretion by the circulating γδT cells was increased in ASD children. Machine learning revealed that the area under the curve in nomogram plots for increased γδT cells combined with eating behavior/dietary factors was 0.905, which held true in both boys and girls and in all the age groups of ASD children. The decision curves showed that children can receive significantly higher diagnostic benefit within the threshold probability range from 0 to 1.0 in the nomogram model. Conclusions: Children with ASD present with divergent eating and mealtime behaviors and dietary habits as well as gastrointestinal symptoms. In peripheral blood, γδT cells but not αβT cells are associated with ASD. The increased γδT cells combined with eating and mealtime behavior/dietary factors have a high value for assisting in the diagnosis of ASD.
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37.
  • Zhang, Shan, et al. (author)
  • Alpha1-antitrypsin protects the immature mouse brain following hypoxic-ischemic injury
  • 2023
  • In: Frontiers in Cellular Neuroscience. - : Frontiers Media SA. - 1662-5102. ; 17
  • Journal article (peer-reviewed)abstract
    • Introduction: Preterm brain injury often leads to lifelong disabilities affecting both cognitive and motor functions, and effective therapies are limited. Alpha1-antitrypsin (AAT), an endogenous inhibitor of serine proteinases with anti-inflammatory, anti-apoptotic, and cytoprotective properties, might be beneficial in treating preterm brain injury. The aim of this study was to investigate whether AAT has neuroprotective effects in a mouse preterm brain injury model.Methods: Preterm brain injury was induced on postnatal day 5, and mouse pups' right common carotid arteries were cut between two ligations followed by hypoxia induction. Brain injury was evaluated through immunohistochemistry staining and magnetic resonance imaging. Fluoro-Jade B and immunohistochemistry staining were performed to investigate the neuronal cell death and blood-brain barrier (BBB) permeability. The motor function and anxiety-like behaviors were revealed by CatWalk gait analysis and the open field test.Results: After hypoxia-ischemia (HI) insult, brain injury was alleviated by AAT treatment, and this was accompanied by reduced BBB permeability, reduced neuronal cell death and caspase-3 activation, and inhibition of microglia activation. In addition, AAT administration significantly improved HI-induced motor function deficiencies in mice. The neuroprotective effect of AAT was more pronounced in male mice.Conclusion: AAT treatment is neuroprotective against preterm brain injury in neonatal mice, and the effect is more pronounced in males.
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38.
  • Albertsson, Anna-Maj, et al. (author)
  • The effect of osteopontin and osteopontin-derived peptides on preterm brain injury.
  • 2014
  • In: Journal of neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 11:1
  • Journal article (peer-reviewed)abstract
    • BackgroundOsteopontin (OPN) is a highly phosphorylated sialoprotein and a soluble cytokine that is widely expressed in a variety of tissues, including the brain. OPN and OPN-derived peptides have been suggested to have potential neuroprotective effects against ischemic brain injury, but their role in preterm brain injury is unknown.MethodsWe used a hypoxia-ischemia (HI)-induced preterm brain injury model in postnatal day 5 mice. OPN and OPN-derived peptides were given intracerebroventricularly and intranasally before HI. Brain injury was evaluated at 7days after the insults.ResultsThere was a significant increase in endogenous OPN mRNA and OPN protein in the mouse brain after the induction of HI at postnatal day 5. Administration of full-length OPN protein and thrombin-cleaved OPN did not affect preterm brain injury. This was demonstrated with both intracerebroventricular and intranasal administration of OPN as well as in OPN-deficient mice. Interestingly, both N134¿153 and C154¿198 OPN-derived peptides increased the severity of brain injury in this HI-induced preterm brain injury model.ConclusionsThe neuroprotective effects of OPN are age-dependent, and, in contrast to the more mature brain, OPN-derived peptides potentiate injury in postnatal day 5 mice. Intranasal administration is an efficient way of delivering drugs to the central nervous system (CNS) in neonatal mice and is likely to be an easy and noninvasive method of drug delivery to the CNS in preterm infants.
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39.
  • Albertsson, Anna-Maj, et al. (author)
  • The immune response after hypoxia-ischemia in a mouse model of preterm brain injury.
  • 2014
  • In: Journal of neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 11:1
  • Journal article (peer-reviewed)abstract
    • BackgroundPreterm brain injury consists primarily of periventricular leukomalacia accompanied by elements of gray-matter injury, and these injuries are associated with cerebral palsy and cognitive impairments. Inflammation is believed to be an important contributing factor to these injuries. The aim of this study was to examine the immune response in a postnatal day (PND) 5 mouse model of preterm brain injury induced by hypoxia-ischemia (HI) that is characterized by focal white and gray-matter injury.MethodsC57Bl/6 mice at PND 5 were subjected to unilateral HI induced by left carotid artery ligation and subsequent exposure to 10% O2 for 50 minutes, 70 minutes, or 80 minutes. At seven days post-HI, the white/gray-matter injury was examined. The immune responses in the brain after HI were examined at different time points after HI using RT-PCR and immunohistochemical staining.ResultsHI for 70 minutes in PND 5 mice induced local white-matter injury with focal cortical injury and hippocampal atrophy, features that are similar to those seen in preterm brain injury in human infants. HI for 50 minutes resulted in a small percentage of animals being injured, and HI for 80 minutes produced extensive infarction in multiple brain areas. Various immune responses, including changes in transcription factors and cytokines that are associated with a T-helper (Th)1/Th17-type response, an increased number of CD4+ T-cells, and elevated levels of triggering receptor expressed on myeloid cells 2 (TREM-2) and its adaptor protein DNAX activation protein of 12 kDa (DAP12) were observed using the HI 70 minute preterm brain injury model.ConclusionsWe have established a reproducible model of HI in PND 5 mice that produces consistent local white/gray-matter brain damage that is relevant to preterm brain injury in human infants. This model provides a useful tool for studying preterm brain injury. Both innate and adaptive immune responses are observed after HI, and these show a strong pro-inflammatory Th1/Th17-type bias. Such findings provide a critical foundation for future studies on the mechanism of preterm brain injury and suggest that blocking the Th1/Th17-type immune response might provide neuroprotection after preterm brain injury.
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40.
  • Albertsson, Anna-Maj, et al. (author)
  • γδ T cells contribute to injury in the developing brain.
  • 2018
  • In: The American journal of pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 188:3, s. 757-767
  • Journal article (peer-reviewed)abstract
    • Brain injury in premature infants, especially periventricular leukomalacia, is an important cause of neurological disabilities. Inflammation contributes to the development of perinatal brain injury, but the essential mediators leading to brain injury in early life remain largely unknown. Neonates have reduced capacity for mounting conventional αβT-cell responses. However γδT-cells are already functionally competent during early development and are important in early life immunity. We investigated the potential contribution of γδT-cells to preterm brain injury by using postmortem brains from human preterm infants with periventricular leukomalacia and two animal models of preterm brain injury-the hypoxic-ischemic mouse model and a fetal sheep asphyxia model. Large numbers of γδT-cells were observed in the brains of mice, sheep, and postmortem preterm infants after injury, and depletion of γδT-cells provided protection in the mouse model. The common γδT-cell associated cytokines interferon-γ and interleukin (IL)-17A were not detectable in the brain. Although there were increased mRNA levels of Il17f and Il22 in the mouse brains after injury, neither IL-17F nor IL-22 cytokines contributed to preterm brain injury. These findings highlight unique features of injury in the developing brain where, unlike injury in the mature brain, γδT-cells function as important initiators of injury independently of common γδT-cell associated cytokines. This new finding will help to identify therapeutic targets for preventing or treating preterm infants with brain injury.
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41.
  • Ali, Abukar, 1988, et al. (author)
  • Antibiotic-killed Staphylococcus aureus induces destructive arthritis in mice.
  • 2015
  • In: Arthritis & rheumatology (Hoboken, N.J.). - : Wiley. - 2326-5205 .- 2326-5191. ; 67:1, s. 107-116
  • Journal article (peer-reviewed)abstract
    • Objective: Permanent reduction in joint function is a severe post-infectious complication in patients with Staphylococcus aureus septic arthritis. This reduction in joint function might be caused by persistent joint inflammation after the adequate eradication of bacteria by antibiotics. Methods: We studied whether antibiotic-killed S. aureus induced joint inflammation in mice and elucidated the molecular and cellular mechanism of this type of arthritis. Results: The intraarticular injection of antibiotic-killed S. aureus induced mild to moderate synovitis and bone erosions that lasted for a minimum of 14 days. The frequency and severity of synovitis were significantly reduced in tumor necrosis factor receptor 1 (TNFR1), receptor for Advanced Glycation End Products (RAGE), and toll like receptor 2 (TLR2) knockout mice compared with wild-type animals. The combined depletion of monocytes and neutrophils resulted in a significantly lower frequency of synovitis. Among bacterial factors, insoluble cell debris played a more important role than bacterial DNA or soluble components in inducing joint inflammation. Importantly, anti-TNF therapy abrogated the joint inflammation induced by antibiotic-killed S. aureus. Conclusion: Antibiotic-killed S. aureus induced and maintained the joint inflammation that is mediated through TLR2, TNFR1, and RAGE receptor. The cross-talk between neutrophils and monocytes is responsible for this type of arthritis. Anti-TNF therapy might be used as a novel therapeutic strategy, in combination with antibiotics, to treat staphylococcal septic arthritis. © 2014 American College of Rheumatology.
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42.
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43.
  • Carlsson, Ylva, 1975, et al. (author)
  • Combined effect of hypothermia and caspase-2 gene deficiency on neonatal hypoxic-ischemic brain injury.
  • 2012
  • In: Pediatric research. - : Springer Science and Business Media LLC. - 1530-0447 .- 0031-3998. ; 71:5, s. 566-72
  • Journal article (peer-reviewed)abstract
    • Intoduction:Hypoxia-ischemia (HI) injury in term infants develops with a delay during the recovery phase, opening up a therapeutic window after the insult. Hypothermia is currently an established neuroprotective treatment in newborns with neonatal encephalopathy (NE), saving one in nine infants from developing neurological deficits. Caspase-2 is an initiator caspase, a key enzyme in the route to destruction and, therefore, theoretically a potential target for a pharmaceutical strategy to prevent HI brain damage.Methods:The aim of this study was to explore the neuroprotective efficacy of hypothermia in combination with caspase-2 gene deficiency using the neonatal Rice-Vannucci model of HI injury in mice.Results:HI brain injury was moderately reduced in caspase-2(-/-) mice as compared with wild-type (WT) mice. Five hours of hypothermia (33°C ) vs. normothermia (36°C) directly after HI provided additive protection overall (temperature P = 0.0004, caspase-2 genotype P = 0.0029), in the hippocampus and thalamus, but not in other gray matter regions or white matter. Delayed hypothermia initiated 2h after HI in combination with caspase-2 gene deficiency reduced injury in the hippocampus, but not in other brain areas.Discussion:In conclusion, caspase-2 gene deficiency combined with hypothermia provided enhanced neuroprotection as compared with hypothermia alone.
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44.
  • Carlsson, Ylva, 1975, et al. (author)
  • Genetic inhibition of caspase-2 reduces hypoxic-ischemic and excitotoxic neonatal brain injury.
  • 2011
  • In: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 70:5, s. 781-9
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: Perinatal brain injury is a major cause of neurodevelopmental handicaps. Multiple pathways of oxidant stress, inflammation, and excitotoxicity lead to cell damage and death, including caspase-dependent apoptosis. Caspase-2 (Casp2; Nedd-2, Ich-1) is a developmentally regulated initiator caspase, which poorly cleaves other caspases but can initiate mitochondrial outer membrane permeabilization. We have investigated if Casp2 could mediate perinatal ischemic brain damage. METHODS: Casp2 expression in human neonatal brains and developmental patterns in rats and mice were evaluated. Casp2-deficient (Casp2(-/-) ), wild-type (WT), and heterozygous (Casp2(+/-) ) newborn C57BL/6 mice were subjected to hypoxia-ischemia (unilateral carotid occlusion + exposure to 10% oxygen for 50 minutes) or intracerebral injection of the excitotoxic N-methyl-D-aspartate-receptor agonist ibotenate. In addition, Casp2 specific siRNAs were preinjected into the brain of WT newborn mice 24 hours before ibotenate treatment. Brain tissues were examined by immunohistochemical staining (cresyl violet, MAP2, NF68, Casp2, Casp3) and Western blotting. Lesion volumes and injury in the cortical plates and white matter were quantified together with activated Casp3. RESULTS: Casp2 is highly expressed in the neonatal brain. Casp2-deficient mice subjected to hypoxia-ischemia at postnatal day 9 present significantly lower cerebral infarction, reduced white matter injury, and reduced Casp3 activation in the thalamus and hippocampus. Both Casp2(-/-) mice and siRNA-administered WT mice conferred reduction of gray and white matter injury after excitotoxic insult at postnatal day 5. Casp3 activation was also found reduced in Casp2-deficient mice subjected to excitotoxicity. INTERPRETATION: These data suggest for the first time a role of Casp2 in neonatal brain damage. ANN NEUROL 2011;
  •  
45.
  • Carlsson, Ylva, 1975, et al. (author)
  • Role of mixed lineage kinase inhibition in neonatal hypoxia-ischemia.
  • 2009
  • In: Developmental neuroscience. - : S. Karger AG. - 1421-9859 .- 0378-5866. ; 31:5, s. 420-6
  • Journal article (peer-reviewed)abstract
    • Hypoxic-ischemic brain injury is often delayed and involves both apoptotic and immunoregulatory mechanisms. In this study, we used a neonatal model of hypoxia-ischemia to examine the effect of the mixed lineage kinase (MLK) inhibitor CEP-1347 on brain damage, apoptosis and inflammation. The tissue volume loss was reduced by 28% (p = 0.019) in CEP-1347-treated versus vehicle-treated rats and CEP-1347 significantly attenuated microgliosis at 7 days (p = 0.038). CEP-1347 decreased TUNEL-positive staining as well as cleaved caspase 3 immunoreactivity. CEP-1347 did not affect the expression of pro-inflammatory cytokines IL-1 beta, IL-6 and MCP-1, nor did it affect the expression of OX-42 (CR3) and OX-18 (MHC I) 24 h after the insult. In conclusion, the MLK inhibitor CEP-1347 has protective effects in a neonatal rat model of hypoxia-ischemia, which is mainly related to reduced apoptosis.
  •  
46.
  • Chauvier, D, et al. (author)
  • Targeting neonatal ischemic brain injury with a pentapeptide-based irreversible caspase inhibitor.
  • 2011
  • In: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 2
  • Journal article (peer-reviewed)abstract
    • Brain protection of the newborn remains a challenging priority and represents a totally unmet medical need. Pharmacological inhibition of caspases appears as a promising strategy for neuroprotection. In a translational perspective, we have developed a pentapeptide-based group II caspase inhibitor, TRP601/ORPHA133563, which reaches the brain, and inhibits caspases activation, mitochondrial release of cytochrome c, and apoptosis in vivo. Single administration of TRP601 protects newborn rodent brain against excitotoxicity, hypoxia-ischemia, and perinatal arterial stroke with a 6-h therapeutic time window, and has no adverse effects on physiological parameters. Safety pharmacology investigations, and toxicology studies in rodent and canine neonates, suggest that TRP601 is a lead compound for further drug development to treat ischemic brain damage in human newborns.
  •  
47.
  • Correa, Fernando, et al. (author)
  • Time-Dependent Effects of Systemic Lipopolysaccharide Injection on Regulators of Antioxidant Defence Nrf2 and PGC-1α in the Neonatal Rat Brain.
  • 2013
  • In: Neuroimmunomodulation. - : S. Karger AG. - 1423-0216 .- 1021-7401. ; 20:4, s. 185-193
  • Journal article (peer-reviewed)abstract
    • Background/Aims: Both excitotoxicity and neuroinflammation are associated with oxidative stress. One transcription factor, nuclear factor E2-related factor 2 (Nrf2), and one transcription cofactor, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), increase the endogenous antioxidant defence and can thus modulate neuronal cell death. Here, we investigated the temporal effects (after 24 and 72 h) of systemic (i.p.) administration of lipopolysaccharide (LPS) on the cerebral Nrf2 and PGC-1α systems. Methods and Results: Seven-day-old rat pups were injected with LPS (0.3 mg/kg). After 24 h, the protein levels of γ-glutamylcysteine ligase modulatory subunit, γ-glutamylcysteine ligase catalytic subunit, Nrf2, PGC-1α and manganese superoxide dismutase (MnSOD) were increased in parallel with decreased levels of Keap1. These effects were correlated with an increased level of phosphorylated Akt and elevated acetylation of histone 4. In contrast, 72 h following LPS, a decrease in the components of the Nrf2 system in parallel with an increase in Keap1 was observed. The down-regulation after 72 h correlated with phosphorylation of p38 mitogen-activated protein kinase, while there were no changes in PGC-1α and MnSOD protein levels or the acetylation/methylation pattern of histones. Conclusion: Systemic LPS in neonatal rats induced time-dependent changes in brain Nrf2 and PGC-1α that correlated well with the protective effect observed after 24 h (pre-conditioning) and the deleterious effects observed after 72 h (sensitizing) of systemic LPS reported earlier. Collectively, the results point towards Nrf2 and PGC-1α as a possible mechanism behind these effects.
  •  
48.
  • Dean, J., et al. (author)
  • Microglial MyD88 signaling regulates acute neuronal toxicity of LPS-stimulated microglia in vitro
  • 2010
  • In: Brain, Behavior, and Immunity. - : Elsevier BV. - 0889-1591. ; 24:5, s. 776-83
  • Journal article (peer-reviewed)abstract
    • Although the role of microglial activation in neural injury remains controversial, there is increasing evidence for a detrimental effect in the immature brain, which may occur in response to release of neurotoxic substances including pro-inflammatory cytokines. However, the signaling mechanisms involved in microglial-induced neuronal cell death are unclear. Microglia isolated from the brains of wild-type (WT) or MyD88 knockout (KO) mice were exposed to PBS or the TLR4-ligand LPS (100 ng/mL) for 2, 6, 14, or 24 h, and the microglia-conditioned medium (MCM) collected. Detection of multiple inflammatory molecules in MCM was performed using a mouse 22-plex cytokine microbead array kit. Primary neuronal cultures were supplemented with the 14 h or 24 h MCM, and the degree of neuronal apoptosis examined after exposure for 24 h. Results showed a rapid and sustained elevation in multiple inflammatory mediators in the MCM of WT microglia exposed to LPS, which was largely inhibited in MyD88 KO microglia. There was a significant increase in apoptotic death measured at 24 h in cultured neurons exposed to CM from either 14 h or 24 h LPS-stimulated WT microglia (p < .05 vs. WT control). By contrast, there was no increase in apoptotic death in cultured neurons exposed to CM from 14 h or 24 h LPS-stimulated MyD88 KO microglia (p = .15 vs. MyD88 KO control). These data suggest that MyD88-dependent activation of microglia by LPS causes release of factors directly toxic to neurons.
  •  
49.
  • Du, Xiaonan, et al. (author)
  • Systemic stimulation of TLR2 impairs neonatal mouse brain development.
  • 2011
  • In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 6:5
  • Journal article (peer-reviewed)abstract
    • Inflammation is associated with perinatal brain injury but the underlying mechanisms are not completely characterized. Stimulation of Toll-like receptors (TLRs) through specific agonists induces inflammatory responses that trigger both innate and adaptive immune responses. The impact of engagement of TLR2 signaling pathways on the neonatal brain is still unclear. The aim of this study was to investigate the potential effect of a TLR2 agonist on neonatal brain development.
  •  
50.
  • Eklind, Saskia, et al. (author)
  • Effect of lipopolysaccharide on global gene expression in the immature rat brain
  • 2006
  • In: Pediatr Res. ; 60:2, s. 161-8
  • Journal article (peer-reviewed)abstract
    • To improve the understanding of the molecular mechanisms whereby lipopolysaccharide (LPS) affects the immature brain, global gene expression following LPS exposure was investigated in neonatal rats. Brains (n = 5/time point) were sampled 2, 6, and 72 h after LPS and compared with age-matched controls. The mRNA from each brain was analyzed separately on Affymextrix GeneChip Rat Expression Set 230. The number of genes regulated after LPS were 847 at 2 h, 1564 at 6 h, and 1546 genes at 72 h. Gene ontology analysis demonstrated that, at both 2 and 6 h after LPS, genes associated with protein metabolism, response to external stimuli and stress (immune and inflammatory response, chemotaxis) and cell death were overrepresented. At 72 h, the most strongly regulated genes belonged to secretion of neurotransmitters, transport, synaptic transmission, cell migration, and neurogenesis. Several pathways associated with cell death/survival were identified (caspase-tumor necrosis factor alpha [TNF-alpha]-, p53-, and Akt/phosphatidylinositol-3-kinase (PI3 K)-dependent mechanisms). Caspase-3 activity increased and phosphorylation of Akt decreased 8 h after peripheral LPS exposure. These results show a complex cerebral response to peripheral LPS exposure. In addition to the inflammatory response, a significant number of cell death-associated genes were identified, which may contribute to increased vulnerability of the immature brain to hypoxia-ischemia (HI) following LPS exposure.
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