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Sökning: WFRF:(Zhu Changlian 1964)

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1.
  • Klionsky, Daniel J., et al. (författare)
  • Guidelines for the use and interpretation of assays for monitoring autophagy
  • 2012
  • Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
  • Forskningsöversikt (refereegranskat)abstract
    • In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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2.
  • Duan, Jiajia, et al. (författare)
  • Histological chorioamnionitis and pathological stages on very preterm infant outcomes
  • 2024
  • Ingår i: HISTOPATHOLOGY. - 0309-0167 .- 1365-2559.
  • Tidskriftsartikel (refereegranskat)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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3.
  • Shao, Linus Ruijin, 1964, et al. (författare)
  • Nuclear progesterone receptor A and B isoforms in mouse fallopian tube and uterus: implications for expression, regulation, and cellular function
  • 2006
  • Ingår i: American journal of physiology. - : American Physiological Society. - 0193-1849. ; 291:1
  • Tidskriftsartikel (refereegranskat)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.
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4.
  • Xu, Jianhua, et al. (författare)
  • A Variant of the Autophagy-Related 5 Gene is Associated with Child Cerebral Palsy
  • 2017
  • Ingår i: Frontiers in Cellular Neuroscience. - : Frontiers Media SA. - 1662-5102. ; 18
  • Tidskriftsartikel (refereegranskat)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.
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5.
  • Bi, D., et al. (författare)
  • The association between sex-related interleukin-6 gene polymorphisms and the risk for cerebral palsy
  • 2014
  • Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 11
  • Tidskriftsartikel (refereegranskat)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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6.
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7.
  • Chen, M. J., et al. (författare)
  • Association of Interleukin 6 gene polymorphisms with genetic susceptibilities to spastic tetraplegia in males: A case-control study
  • 2013
  • Ingår i: Cytokine. - : Elsevier BV. - 1043-4666. ; 61:3, s. 826-830
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Cerebral palsy (CP) is a group of non-progressive motor impairment and permanent disorders causing limitation of activity and abnormal posture. It may be caused by infection (such as chorioamnionitis), asphyxia or multiple genetic factors. The Interleukin 6 gene (IL6) was suggested to be involved in the susceptibilities to CP risk as a kind of proinflammatory cytokine. Objective To explore the genetic association between the polymorphisms of the IL6 gene and CP in the Chinese population. Methods A total of 542 CP patients and 483 healthy control children were recruited in this study to detect five single nucleotide polymorphisms (rs1800796, rs2069837, rs2066992, rs2069840, and rs10242595) in the IL6 locus. Genotyping of SNPs was performed by the MassArray platform-based genotyping approach. The SHEsis program was applied to analyze the genotyping data. Results Of the five selected SNPs, no significant allelic and genotypic association was found between CP patients and controls. However, subgroup analysis found significant differences in allele frequencies between spastic tetraplegia in males compared with controls at rs1800796 (OR = 1.39, P = 0.033, P = 0.099 after SNPSpD correction) and rs2069837 (OR = 1.58, P = 0.012, P = 0.035 after SNPSpD correction). The frequencies of the C allele of rs1800796 and the A allele of rs2069837 were greater in males with spastic tetraplegia than in the controls. The two SNPs haplotype rs1800796 (G) – rs2069837 (G) were also associated with a decreased risk of spastic tetraplegia in males (OR = 0.619, P = 0.009, P = 0.027 after Bonferroni correction). Conclusion Genetic variation of the IL6 gene may influence susceptibility to spastic tetraplegia in males and its role in cerebral palsy deserves further evaluation in a large-scale and well-designed study.
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8.
  • Shao, Linus Ruijin, 1964, et al. (författare)
  • Ciliated epithelial-specific and regional-specific expression and regulation of the estrogen receptor-beta2 in the fallopian tubes of immature rats: a possible mechanism for estrogen-mediated transport process in vivo
  • 2007
  • Ingår i: American journal of physiology. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 293:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Several ERbeta isoforms have been identified in human and rodent tissues, but it is unclear whether each isoform has distinctly different cellular targeting characteristics and physiological functions. We have investigated the intracellular localization and regulatory patterns for ERbeta isoforms in rat fallopian tubes. Western blot analysis reveals that two ERbeta isoforms corresponding to ERbeta1 and ERbeta2 are expressed in rat fallopian tubes. However, ERbeta2 is the predominant form of ERbeta in this tissue. High-resolution confocal imaging and immunohistochemical analysis provide ample evidence that ERbeta expression is limited almost exclusively to the ciliated epithelial cells, in contrast to ERalpha, which is widely distributed. Furthermore, within the ciliated epithelial cells, ERbeta is colocalized with beta-tubulin IV at stem portion of the cilia. We show that ERbeta2 protein expression is tightly regulated by E(2) or DPN in a time-dependent manner without changes in ERbeta1 expression. These estrogenic effects are inhibited by an ER antagonist, ICI 182,780. In addition, significant alteration of ERbeta immunoreactivity is detected only histologically in the ampullary region. Since the cilia are considered an essential determinant of tubal transport, we further demonstrate that E(2)- or DPN-induced ERbeta2 activation is associated with alterations in tubal protein expression crucial for the regulation of calcium-dependent ciliary beating. Given the coordinated regulation and interaction of ER and progesterone receptor in the cilia, we hypothesize that tubal ERbeta2 may facilitate the estrogen-mediated transport process by processing protein-protein interaction under physiological and/or pathological conditions. We show for the first time that a previously unrecognized localization of ERbeta isoform in rat fallopian tubes can combine with estrogen to individually control the expression of ER beta-isoforms in normal target tissues.
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9.
  • Sun, H. Q., et al. (författare)
  • The Use of the WINROP Screening Algorithm for the Prediction of Retinopathy of Prematurity in a Chinese Population
  • 2013
  • Ingår i: Neonatology. - : S. Karger AG. - 1661-7800 .- 1661-7819. ; 104:2, s. 127-132
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Retinopathy of prematurity (ROP) is a gestational age (GA)-related illness that can lead to blindness in premature infants. Timely screening of premature infants could improve visual prognosis. Objective: To evaluate the WINROP algorithm as a method of predicting severe ROP in a Chinese population. Methods: 590 infants with a GA <32 weeks were entered into an online surveillance system (www.winrop.com) that included ROP evaluations and weekly weight measurements from birth to a corrected GA of 40 weeks. If the rate of weight gain decreased to a certain degree, the algorithm signaled an alarm that the infant was at risk for developing sight-threatening ROP. Each infant was categorized as having no, mild, or severe ROP. Results: Among the 590 infants with a GA <32 weeks, an alarm was triggered in 85 infants (14.4%), 50 of which developed severe ROP and were identified in this alarm group. Twenty-seven infants triggered the alarm signal in the first week after birth and 7 infants triggered the alarm at birth. Seven of the infants developed proliferative ROP and the median GA at birth for these infants was 31 weeks. Conclusions: The WINROP system had a sensitivity of 87.5% in a Chinese population for the early identification of infants that developed severe ROP. Postnatal weight gain may help predict ROP in lower birth weight infants. Copyright (C) 2013 S. Karger AG, Basel
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10.
  • Sun, L. Y., et al. (författare)
  • Variants of the OLIG2 Gene are Associated with Cerebral Palsy in Chinese Han Infants with Hypoxic-Ischemic Encephalopathy
  • 2019
  • Ingår i: Neuromolecular Medicine. - : Springer Science and Business Media LLC. - 1535-1084 .- 1559-1174. ; 21:1, s. 75-84
  • Tidskriftsartikel (refereegranskat)abstract
    • Cerebral palsy (CP) is a leading cause of neurological disability among young children. Congenial and adverse perinatal clinical conditions, such as genetic factors, perinatal infection, and asphyxia, are risk factors for CP. Oligodendrocyte transcription factor (OLIG2) is a protein that is expressed in brain oligodendrocyte cells and is involved in neuron repair after brain injury. In this study, we employed a Chinese Han cohort of 763 CP infants and 738 healthy controls to study the association of OLIG2 gene polymorphisms with CP. We found marginal association of the SNP rs6517135 with CP (p=0.044) at the genotype level, and the association was greatly strengthened when we focused on the subgroup of CP infants who suffered from hypoxic-ischemic encephalopathy (HIE) after birth, with p=0.003 (OR=0.558) at the allele level and p=0.007 at the genotype level, indicating a risk-associated role of the T allele of the SNP rs6517135 under HIE conditions. The haplotype CTTG for rs6517135-rs1005573-rs6517137-rs9653711 in OLIG2 was also significantly associated with the occurrence of CP in infants with HIE (p=0.01, OR=0.521). Our results indicate that in the Han Chinese population, the polymorphisms of OLIG2 were associated with CP, especially in patients who had suffered HIE injury. This finding could be used to develop personalized care for infants with high susceptibility to CP.
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11.
  • Wang, H. L., et al. (författare)
  • Genetic association study of adaptor protein complex 4 with cerebral palsy in a Han Chinese population
  • 2013
  • Ingår i: Molecular Biology Reports. - : Springer Science and Business Media LLC. - 0301-4851 .- 1573-4978. ; 40:11, s. 6459-6467
  • Tidskriftsartikel (refereegranskat)abstract
    • Adaptor protein complex 4 (AP-4) plays a key role in vesicle formation, trafficking, and sorting processes that are critical for brain development and function. AP-4 consists of four subunits encoded by the AP4E1, AP4B1, AP4M1, and AP4S1 genes. A number of studies have pointed to the involvement of AP-4-mediated vesicular trafficking pathways in the etiology of cerebral palsy (CP), the most notable of which are the causative mutations that have recently been identified in each of the AP-4 genes in different CP families. We postulated, therefore, that variations in AP-4 genes might influence an indivual's susceptibility to CP. In the present study, 16 SNPs were genotyped among 517 CP patients and 502 healthy controls from the Han Chinese population. We systematically analyzed the association of the AP4E1, AP4B1, AP4M1, and AP4S1 genes with CP on the basis of clinical characteristics. No significant associations were found between these variants and the overall risk of CP. Subgroup analysis showed that rs1217401 of AP4B1 was significantly associated with CP as a sequela of hypoxic-ischemic encephalopathy (HIE) (CP + HIE) (allele: p = 0.042151; genotype: p = 4.46 x 10(-6)). Our results indicate that the 16 variants studied in the genes of the four subunits of AP-4 have no detectable effects on the overall susceptibility to CP, but AP4B1 appears to be a susceptibility gene for CP + HIE in the Han Chinese population.
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12.
  • Wang, Y. G., et al. (författare)
  • The Association Study of IL-23R Polymorphisms With Cerebral Palsy in Chinese Population
  • 2020
  • Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 14
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Cerebral palsy (CP) is a syndrome of non-progressive motor dysfunction caused by early brain development injury. Recent evidence has shown that immunological abnormalities are associated with an increased risk of CP. Methods: We recruited 782 children with CP as the case group and 770 healthy children as the control group. The association between IL-23R single nucleotide polymorphisms (SNPs; namely, rs10889657, rs6682925, rs1884444, rs17375018, rs1004819, rs11805303, and rs10889677) and CP was studied by using a case-control method and SHEsis online software. Subgroup analysis based on complications and clinical subtypes was also carried out. Results: There were differences in the allele and genotype frequencies between CP cases and controls at the rs11805303 and rs10889677 SNPs (Pallele = 0.014 and 0.048, respectively; Pgenotype = 0.023 and 0.008, respectively), and the difference in genotype frequency of rs10889677 remained significant after Bonferroni correction (Pgenotype = 0.048). Subgroup analysis revealed a more significant association of rs10889677 with CP accompanied by global developmental delay (Pgenotype = 0.024 after correction) and neonatal encephalopathy (Pgenotype = 0.024 after correction). Conclusion: The present results showed a significant association between IL-23R and CP, suggesting that IL-23R may play a potential role in CP pathogenesis.
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13.
  • Wang, Yangong, et al. (författare)
  • TEP1 is a risk gene for sporadic cerebral palsy
  • 2021
  • Ingår i: Journal of genetics and genomics. - : Elsevier BV. - 1673-8527. ; 48:12, s. 1134-1138
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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14.
  • Xia, L., et al. (författare)
  • Autophagy-Related Gene 7 Polymorphisms and Cerebral Palsy in Chinese Infants
  • 2019
  • Ingår i: Frontiers in Cellular Neuroscience. - : Frontiers Media SA. - 1662-5102. ; 13
  • Tidskriftsartikel (refereegranskat)abstract
    • Cerebral palsy (CP) is a group of non-progressive motor impairment syndromes that are secondary to brain injury in the early stages of brain development. Numerous etiologies and risk factors of CP have been reported, and genetic contributions have recently been identified. Autophagy has an important role in brain development and pathological process, and autophagy-related gene 7 (ATG7) is essential for autophagosome biogenesis. The purpose of this study was to investigate the genetic association between ATG7 gene single nucleotide polymorphisms (SNPs) and CP in Han Chinese children. Six SNPs (rs346078, rs1470612, rs11706903, rs2606750, rs2594972, and rs4684787) were genotyped in 715 CP patients and 658 healthy controls using the MassArray platform. Plasma ATG7 protein was determined in 73 CP patients and 79 healthy controls. The differences in the allele and genotype frequencies of the rs1470612 and rs2594972 SNPs were determined between the CP patients and controls (p(allele) = 0.02 and 0.0004, p(genotype) = 0.044 and 0.0012, respectively). Subgroup analysis revealed a more significant association of rs1470612 (p(allele) = 0.004, p(genotype) = 0.0036) and rs2594972 (p(allele) = 0.0004, p(genotype) < 0.0001) with male CP, and more significant differences in allele and genotype frequencies were also noticed between CP patients with spastic diplegia and controls for rs1470612 (p(allele) = 0.0024, p(genotype) = 0.008) and rs2594972 (p(allele) < 0.0001, p(genotype) = 0.006). The plasma ATG7 level was higher in CP patients compared to the controls (10.58 +/- 0.85 vs. 8.18 +/- 0.64 pg/mL, p = 0.024). The luciferase reporter gene assay showed that the T allele of rs2594972 SNP could significantly increase transcriptional activity of the ATG7 promoter compared to the C allele (p = 0.009). These findings suggest that an association exists between genetic variants of ATG7 and susceptibility to CP, which provides novel evidence for the role of ATG7 in CP and contributes to our understanding of the molecular mechanisms of this neurodevelopmental disorder.
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15.
  • Xia, L., et al. (författare)
  • Combined analysis of interleukin-10 gene polymorphisms and protein expression in children with cerebral palsy
  • 2018
  • Ingår i: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 9:MAR
  • Tidskriftsartikel (refereegranskat)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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16.
  • Xu, Yiran, 1988, et al. (författare)
  • Cranial irradiation alters neuroinflammation and neural proliferation in the pituitary gland and induces late-onset hormone deficiency.
  • 2020
  • Ingår i: Journal of cellular and molecular medicine. - : Wiley. - 1582-4934 .- 1582-1838. ; 24:24, s. 14571-14582
  • Tidskriftsartikel (refereegranskat)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.
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17.
  • Xu, Yiran, 1988, et al. (författare)
  • Cranial Irradiation Induces Hypothalamic Injury and Late-Onset Metabolic Disturbances in Juvenile Female Rats.
  • 2018
  • Ingår i: Developmental Neuroscience. - : S. Karger AG. - 0378-5866 .- 1421-9859. ; 40:2, s. 120-33
  • Tidskriftsartikel (refereegranskat)abstract
    • Cranial radiotherapy is one of the most effective tools for treating children with brain tumors. However, radiotherapy-induced late-onset side effects have a significant impact on patients' quality of life. The purpose of this study was to investigate the effects of irradiation on metabolism and the possible molecular and cellular mechanisms behind such effects. Female Wistar rats were subjected to a single dose of 6-Gy whole-brain irradiation on postnatal day 11. The animals were sacrificed 6 h or 20 weeks after irradiation. Cell death and proliferation, microglial activation, and inflammation were analyzed and RNA sequencing was performed. We found that irradiation led to a significantly increased body weight from 15 weeks (p < 0.05) along with white adipose tissue accumulation and adipocyte hypertrophy at 20 weeks, and these changes were accompanied by glucose and lipid metabolic disturbances as indicated by reduced glucose tolerance, increased insulin resistance, increased serum triglycerides, and an increased leptin/adiponectin ratio. Furthermore, irradiation induced cell death, microglial activation, inflammation, and persistent astrocyte reactivity in the hypothalamus. Hypothalamic transcriptome analysis showed that 865 genes were downregulated and 290 genes were upregulated in the irradiated group 20 weeks after irradiation, and further pathway analysis showed that the insulin resistance-related PI3K-Akt signaling pathway and the energy expenditure-related adipocytokine signaling pathway were downregulated. Gene Ontology enrichment analysis showed that the expression of fatty acid metabolism-related proteins and effector proteins was significantly different in the irradiation group. This study demonstrates that ionizing radiation to the juvenile female brain induces hypothalamic damage that is likely to be associated with delayed metabolic abnormalities, and this critical vulnerability of the hypothalamus to irradiation should be taken into consideration in the development of future protective strategies for radiotherapy.
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18.
  • Xu, Y. R., et al. (författare)
  • The association of apolipoprotein E gene polymorphisms with cerebral palsy in Chinese infants
  • 2014
  • Ingår i: Molecular Genetics and Genomics. - : Springer Science and Business Media LLC. - 1617-4615 .- 1617-4623. ; 289:3, s. 411-416
  • Tidskriftsartikel (refereegranskat)abstract
    • Apolipoprotein E (APOE, protein; ApoE, gene) is a lipid transport protein abundantly present in brain cells. Previous studies have suggested that there is an association between genetic variants of ApoE and susceptibility to cerebral palsy (CP). The purpose of this study was to explore whether the ApoE gene is involved in the etiology of CP in the Chinese population. In this study, 350 CP patients and 242 healthy control children were recruited. Genomic DNA was prepared from venous blood and all five single nucleotide polymorphisms (SNPs) in ApoE (rs769446, rs405509, rs121918399, rs429358, and rs190853081) were detected by the MassARRAY platform-based genotyping approach. The SHEsis program was used to analyze the genotyping data, and we systemically analyzed the association of the ApoE SNPs with different subtypes of CP. No significant association was detected between the e4 identified by the C allele of rs429358 and CP, but there were significant differences in allelic frequencies between the CP patients and controls at rs769446 (P = 0.005, P = 0.025 after Bonferroni correction), as well as between the CP patients with preterm birth (< 34 gestational weeks) and controls at rs769446 (P = 0.001, P = 0.005 after Bonferroni correction). A haplotype consisting of the five SNPs rs769446(C), rs405509(C), rs121918399(C), rs429358(T), and rs190853081(G) was associated with a decreased risk of CP (P = 0.002 after Bonferroni correction). However, we found no significant association between any of the other three SNPs and CP based on different subgroup analyses. This study provides the first evidence that ApoE gene polymorphisms are a potential risk factor for CP in the Chinese population.
  •  
19.
  • Yu, T., et al. (författare)
  • Association of NOS1 gene polymorphisms with cerebral palsy in a Han Chinese population: a case-control study
  • 2018
  • Ingår i: Bmc Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 11:1
  • Tidskriftsartikel (refereegranskat)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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20.
  • Yuan, Junying, et al. (författare)
  • Cerebral Palsy Heterogeneity: Clinical Characteristics and Diagnostic Significance from a Large-Sample Analysis
  • 2024
  • Ingår i: NEUROEPIDEMIOLOGY. - 0251-5350 .- 1423-0208.
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Cerebral palsy (CP) is a nonprogressive movement disorder resulting from a prenatal or perinatal brain injury that benefits from early diagnosis and intervention. The timing of early CP diagnosis remains controversial, necessitating analysis of clinical features in a substantial cohort. Methods: We retrospectively reviewed medical records from a university hospital, focusing on children aged >= 24 months or followed up for >= 24 months and adhering to the International Classification of Diseases-10 for diagnosis and subtyping. Results: Among the 2012 confirmed CP cases, 68.84% were male and 51.44% had spastic diplegia. Based on the Gross Motor Function Classification System (GMFCS), 62.38% were in levels I and II and 19.88% were in levels IV and V. Hemiplegic and diplegic subtypes predominantly fell into levels I and II, while quadriplegic and mixed types were mainly levels IV and V. White matter injuries appeared in 46.58% of cranial MRI findings, while maldevelopment was rare (7.05%). Intellectual disability co-occurred in 43.44% of the CP cases, with hemiplegia having the lowest co-occurrence (20.28%, 58/286) and mixed types having the highest co-occurrence (73.85%, 48/65). Additionally, 51.67% (697/1,349) of the children with CP aged >= 48 months had comorbidities. Conclusions: This study underscores white matter injury as the primary CP pathology and identifies intellectual disability as a common comorbidity. Although CP can be identified in infants under 1 year old, precision in diagnosis improves with development. These insights inform early detection and tailored interventions, emphasizing their crucial role in CP management.
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21.
  • Yuan, J., et al. (författare)
  • Lithium treatment is safe in children with intellectual disability
  • 2018
  • Ingår i: Frontiers in Molecular Neuroscience. - : Frontiers Media SA. - 1662-5099. ; 11
  • Tidskriftsartikel (refereegranskat)abstract
    • Lithium is a widely used and effective treatment for individuals with psycho-neurological disorders, and it exhibits protective and regenerative properties in multiple brain injury animal models, but the clinical experience in young children is limited due to potential toxicity. As an interim analysis, this paper reports the safety/tolerability profiles of low-dose lithium treatment in children with intellectual disability (ID) and its possible beneficial effects. In a randomized, single-center clinical trial, 124 children with ID were given either oral lithium carbonate 6 mg/kg twice per day or the same dose of calcium carbonate as a placebo (n = 62/group) for 3 months. The safety of low-dose lithium treatment in children, and all the adverse events were monitored. The effects of low-dose lithium on cognition was evaluated by intelligence quotient (IQ), adaptive capacity was assessed by the Infant-Junior Middle School Students Social-Life Abilities Scale (IJMSSSLAS), and overall performance was evaluated according to the Clinical Global Impression-Improvement (CGI-I) scale. After 3 months of lithium treatment, 13/61 children (21.3%) presented with mild side effects, including 4 (6.6%) with gastrointestinal symptoms, 4 (6.6%) with neurological symptoms, 2 (3.3%) with polyuria, and 3 (4.9%) with other symptoms—one with hyperhidrosis, one with alopecia, and one with drooling. Four children in the lithium group had elevated blood thyroid stimulating hormone, which normalized spontaneously after lithium discontinuation. Both IQ and IJMSSSAS scores increased following 3 months of lithium treatment (F = 11.03, p = 0.002 and F = 7.80, p = 0.007, respectively), but such increases were not seen in the placebo group. CGI-I scores in the lithium group were 1.25 points lower (better) than in the placebo group (F = 82.66, p < 0.001) after 3 months of treatment. In summary, lithium treatment for 3 months had only mild and reversible side effects and had positive effects on cognition and overall performance in children with ID. © 2018 Yuan, Song, Zhu, Sun, Xia, Zhang, Gao, Agam, Wang, Blomgren and Zhu.
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22.
  • Yuan, J. Y., et al. (författare)
  • Population Pharmacokinetics of Lithium in Young Pediatric Patients With Intellectual Disability
  • 2021
  • Ingår i: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 12
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Lithium is a well-established treatment for bipolar disorders and has been shown to be neuroprotective, and thus low doses might be useful for the treatment of childhood brain injury and neurological sequelae. However, pharmacokinetic (PK) data in children are limited. This study was to investigate the PKs after oral administration of low-dose lithium carbonate in young children with intellectual disability. Methods: Fifty-two children with intellectual disability aged 4-10 years old were enrolled. A series of blood samples were collected after a single-dose administration of lithium carbonate. The serum lithium concentration was measured using a validated ion chromatography assay, and the PK concentration data were modeled using a nonlinear mixed effect model in the NONMEM program. Results: The lithium concentration over time was adequately described by a two-compartment disposition, with a transient absorption and first-order elimination process. The inclusion of body weight as an allometric factor significantly improved the model fit, but age and gender were not associated with the PKs of lithium. The clearance, central volume, inter-compartmental clearance, and peripheral volume estimates from the final population PK model were 0.98 L/h, 13.1 L, 0.84 L/h, and 8.2 L for children with a body weight of 20 kg. The model evaluation suggested that there is no obvious discrepancy between the observations and predictions in the proposed model. A visual predictive check demonstrated the good predictive performance of the final model. Conclusions: The lithium PK properties in young children were similar to those in older children and adults. The proposed model can be used for further PK/PD analysis to optimize the dosage regimen of lithium in children.
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23.
  • Zhang, X. L., et al. (författare)
  • Germinal matrix hemorrhage induces immune responses, brain injury, and motor impairment in neonatal rats
  • 2023
  • Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 43:2_suppl, s. 49-65
  • Tidskriftsartikel (refereegranskat)abstract
    • Germinal matrix hemorrhage (GMH) is a major complication of prematurity that causes secondary brain injury and is associated with long-term neurological disabilities. This study used a postnatal day 5 rat model of GMH to explore immune response, brain injury, and neurobehavioral changes after hemorrhagic injury. The results showed that CD45(high)/CD11b(+) immune cells increased in the brain after GMH and were accompanied by increased macrophage-related chemokine/cytokines and inflammatory mediators. Hematoma formed as early as 2 h after injection of collagenase VII and white matter injury appeared not only in the external capsule and hippocampus, but also in the thalamus. In addition, GMH caused abnormal motor function as revealed by gait analysis, and locomotor hyperactivity in the elevated plus maze, though no other obvious anxiety or recognition/memory function changes were noted when examined by the open field test and novel object recognition test. The animal model used here partially reproduces the GMH-induced brain injury and motor dysfunction seen in human neonates and therefore can be used as a valid tool in experimental studies for the development of effective therapeutic strategies for GMH-induced brain injury.
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24.
  • Zhou, K., et al. (författare)
  • An overlooked subset of Cx3cr1(wt/wt) microglia in the Cx3cr1(CreER-Eyfp/wt) mouse has a repopulation advantage over Cx3cr1(CreER-Eyfp/wt) microglia following microglial depletion
  • 2022
  • Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 19:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Fluorescent reporter labeling and promoter-driven Cre-recombinant technologies have facilitated cellular investigations of physiological and pathological processes, including the widespread use of the Cx3cr1(CreER-Eyfp/wt) mouse strain for studies of microglia. Methods Immunohistochemistry, Flow Cytometry, RNA sequencing and whole-genome sequencing were used to identify the subpopulation of microglia in Cx3cr1(CreER-Eyfp/wt) mouse brains. Genetically mediated microglia depletion using Cx3cr1(CreER-Eyfp/wt)Rosa26(DTA/wt) mice and CSF1 receptor inhibitor PLX3397 were used to deplete microglia. Primary microglia proliferation and migration assay were used for in vitro studies. Results We unexpectedly identified a subpopulation of microglia devoid of genetic modification, exhibiting higher Cx3cr1 and CX3CR1 expression than Cx3cr1(CreER-Eyfp/wt)Cre(+)Eyfp(+) microglia in Cx3cr1(CreER-Eyfp/wt) mouse brains, thus termed Cx3cr1(high)Cre(-)Eyfp(-) microglia. This subpopulation constituted less than 1% of all microglia under homeostatic conditions, but after Cre-driven DTA-mediated microglial depletion, Cx3cr1(high)Cre(-)Eyfp(-) microglia escaped depletion and proliferated extensively, eventually occupying one-third of the total microglial pool. We further demonstrated that the Cx3cr1(high)Cre(-)Eyfp(-) microglia had lost their genetic heterozygosity and become homozygous for wild-type Cx3cr1. Therefore, Cx3cr1(high)Cre(-)Eyfp(-) microglia are Cx3cr1(wt/wt)Cre(-)Eyfp(-). Finally, we demonstrated that CX3CL1-CX3CR1 signaling regulates microglial repopulation both in vivo and in vitro. Conclusions Our results raise a cautionary note regarding the use of Cx3cr1(CreER-Eyfp/wt) mouse strains, particularly when interpreting the results of fate mapping, and microglial depletion and repopulation studies.
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25.
  • Albertsson, Anna-Maj, et al. (författare)
  • The immune response after hypoxia-ischemia in a mouse model of preterm brain injury.
  • 2014
  • Ingår i: Journal of neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 11:1
  • Tidskriftsartikel (refereegranskat)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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26.
  • Albertsson, Anna-Maj, et al. (författare)
  • γδ T cells contribute to injury in the developing brain.
  • 2018
  • Ingår i: The American journal of pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 188:3, s. 757-767
  • Tidskriftsartikel (refereegranskat)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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27.
  • Badiola, N, et al. (författare)
  • Induction of ER stress in response to oxygen-glucose deprivation of cortical cultures involves the activation of the PERK and IRE-1 pathways and of caspase-12.
  • 2011
  • Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 2
  • Tidskriftsartikel (refereegranskat)abstract
    • Disturbance of calcium homeostasis and accumulation of misfolded proteins in the endoplasmic reticulum (ER) are considered contributory components of cell death after ischemia. However, the signal-transducing events that are activated by ER stress after cerebral ischemia are incompletely understood. In this study, we show that caspase-12 and the PERK and IRE pathways are activated following oxygen-glucose deprivation (OGD) of mixed cortical cultures or neonatal hypoxia-ischemia (HI). Activation of PERK led to a transient phosphorylation of eIF2α, an increase in ATF4 levels and the induction of gadd34 (a subunit of an eIF2α-directed phosphatase). Interestingly, the upregulation of ATF4 did not lead to an increase in the levels of CHOP. Additionally, IRE1 activation was mediated by the increase in the processed form of xbp1, which would be responsible for the observed expression of edem2 and the increased levels of the chaperones GRP78 and GRP94. We were also able to detect caspase-12 proteolysis after HI or OGD. Processing of procaspase-12 was mediated by NMDA receptor and calpain activation. Moreover, our data suggest that caspase-12 activation is independent of the unfolded protein response activated by ER stress.
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28.
  • Bi, D., et al. (författare)
  • Association of COL4A1 gene polymorphisms with cerebral palsy in a Chinese Han population
  • 2016
  • Ingår i: Clinical Genetics. - : Wiley. - 0009-9163. ; 90:2, s. 149-155
  • Tidskriftsartikel (refereegranskat)abstract
    • The basement membrane (BM) is an extracellular matrix associated with overlying cells and is important for proper tissue development, stability, and physiology. COL4A1 is the most abundant component of type IV collagen in the BM, and COL4A1 variants can present with variable phenotypes that might be related to cerebral palsy (CP). We postulated, therefore, that variations in the COL4A1 gene might play an important role in the etiology of CP. In this study, six single nucleotide polymorphisms (SNPs) in the COL4A1 gene were genotyped among 351 CP patients and 220 healthy controls from the Chinese Han population. Significant association was found for an association between CP and rs1961495 (allele: p = 0.008, odds ratio (OR) = 1.387, 95% confidence interval (CI) = 1.088–1.767) and rs1411040 (allele: p = 0.009, OR = 1.746, 95% CI = 1.148–2.656) SNPs of the COL4A1 gene. Multifactor dimensionality reduction analysis suggested that these SNPs had interactive effects on the risk of CP. This study is the first attempt to investigate the contribution of polymorphisms in the COL4A1 gene to the susceptibility of CP in a Chinese Han population. This study shows an association of the COL4A1 gene with CP and suggests a potential role of COL4A1 in the pathogenesis of CP. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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29.
  • Chen, X., et al. (författare)
  • Iatrogenic vs. Spontaneous Preterm Birth: A Retrospective Study of Neonatal Outcome Among Very Preterm Infants
  • 2021
  • Ingår i: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 12
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Preterm birth is a leading contributor to childhood morbidity and mortality, and the incidence tends to increase and is higher in developing countries. The aim of this study was to analyze the potential impact of preterm birth in different etiology groups on neonatal complications and outcomes and to gain insight into preventive strategies. Methods: We performed a retrospective cohort study of preterm infants less than 32 weeks' gestation in the Third Affiliated Hospital of Zhengzhou University from 2014 to 2019. Preterm births were categorized as spontaneous or iatrogenic, and these groups were compared for maternal and neonatal characteristics, neonatal complications, and outcomes. All infants surviving at discharge were followed up at 12 months of corrected age to compare the neurodevelopmental outcomes. Results: A total of 1,415 mothers and 1,689 neonates were included, and the preterm population consisted of 1,038 spontaneous preterm infants and 651 iatrogenic preterm infants. There was a significant difference in the incidence of small for gestational age between the two groups. Infants born following spontaneous labor presented with a higher risk of intraventricular hemorrhage, whereas iatrogenic preterm birth was associated with higher risk of necrotizing enterocolitis and coagulopathy and higher risk of pathoglycemia. There was no difference in mortality between the two groups. Follow-up data were available for 1,114 infants, and no differences in neurologic outcomes were observed between the two preterm birth subtypes. Conclusions: Preterm births with different etiologies were associated with some neonatal complications, but not with neurodevelopmental outcomes at 12 months of corrected age.
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30.
  • Cheng, Ye, et al. (författare)
  • Genetic variants in the HLA region contribute to the risk of cerebral palsy
  • 2024
  • Ingår i: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE. - 0925-4439 .- 1879-260X. ; 1870:3
  • Tidskriftsartikel (refereegranskat)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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31.
  • Culmsee, C., et al. (författare)
  • Apoptosis-inducing factor triggered by poly(ADP-ribose) polymerase and Bid mediates neuronal cell death after oxygen-glucose deprivation and focal cerebral ischemia
  • 2005
  • Ingår i: J Neurosci. ; 25:44, s. 10262-72
  • Tidskriftsartikel (refereegranskat)abstract
    • Delayed neuronal cell death occurring hours after reperfusion is a hallmark of ischemic stroke and a primary target for neuroprotective strategies. In the present study, we investigated whether apoptosis-inducing factor (AIF), a caspase-independent proapoptotic protein, is responsible for neuronal cell death after glutamate toxicity and oxygen-glucose deprivation (OGD) in vitro and after experimental stroke in vivo. AIF translocated to the nucleus in which it colocalized with DNA fragmentation and nuclear apoptotic morphology after exposure to glutamate or OGD in cultured neurons or after transient middle cerebral artery occlusion (MCAo) in mice. Small inhibitory RNA-mediated downregulation of AIF reduced glutamate- and OGD-induced neuronal apoptosis by 37 and 60%, respectively (p < 0.01). Moreover, Harlequin mutant mice, which express AIF at low levels (approximately 20% of wild-type mice), displayed smaller infarct volumes (-43%; p < 0.03) and showed dramatically reduced cell death in the ischemic penumbra after 45 min of MCAo compared with wild-type littermates. Inhibition of poly(ADP-ribose) polymerase and Bid reduced nuclear AIF translocation. These results provide the first evidence for a causal role of AIF in ischemic neuronal cell death. Therefore, caspase-independent cell death signaling may provide a promising novel target for therapeutic interventions in cerebrovascular diseases.
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32.
  • D'angelo, Barbara, et al. (författare)
  • GSK3β inhibition protects the immature brain from hypoxic-ischaemic insult via reduced STAT3 signalling
  • 2016
  • Ingår i: Neuropharmacology. - : Elsevier BV. - 0028-3908. ; 101, s. 13-23
  • Tidskriftsartikel (refereegranskat)abstract
    • Hypoxic-ischaemic (HI) injury is an important cause of neurological morbidity in neonates. HI leads to pathophysiological responses, including inflammation and oxidative stress that culminate in cell death. Activation of glycogen synthase kinase 3β (GSK3β) and the signal transducer and activator of transcription (STAT3) promotes brain inflammation. The purpose of this study was to test whether inhibition of GSK3β signalling protects against neonatal HI brain injury. Mice were subjected to HI at postnatal day (PND) 9 and treated with a selective GSK3β inhibitor, SB216763. Brain injury and caspase-3 activation, anti-oxidant and inflammatory mRNA responses and activation of STAT3 were analysed. Our results show that HI reduced phosphorylation of GSK3β, thus promoting its kinase activity. The GSK3β inhibitor reduced caspase-3 activation and neuronal cell death elicited by HI and reverted the effects of HI on gene expression of the anti-oxidant enzyme sod2 and mitochondrial factor pgc1α. The HI insult activated STAT3 in glial cells and GSK3β inhibition attenuated STAT3 phosphorylation and its nuclear translocation following HI. Further, GSK3β inhibition reduced HI-induced gene expression of pro-inflammatory cytokines tnfα and Il-6, while promoted the anti-inflammatory factor Il-10. In summary, data show that GSK3β inhibition is neuroprotective in neonatal HI brain injury likely via reduced pro-inflammatory responses by blocking STAT3 signalling. Our study suggests that pharmacological interventions built upon GSK3β silencing strategies could represent a novel therapy in neonatal brain injury. © 2015 Elsevier Ltd. All rights reserved.
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33.
  • Ding, X., et al. (författare)
  • Gut microbiota changes in patients with autism spectrum disorders
  • 2020
  • Ingår i: Journal of Psychiatric Research. - : Elsevier BV. - 0022-3956 .- 1879-1379. ; 129, s. 149-159
  • Tidskriftsartikel (refereegranskat)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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34.
  • Dong, H. F., et al. (författare)
  • Screening inflammatory protein biomarkers on premature infants with necrotizing enterocolitis
  • 2023
  • Ingår i: Inflammation Research. - : Springer Science and Business Media LLC. - 1023-3830 .- 1420-908X. ; 72:4, s. 757-768
  • Tidskriftsartikel (refereegranskat)abstract
    • ObjectiveThis study aimed to explore potential inflammatory biomarkers for early prediction of necrotizing enterocolitis (NEC) in premature infants.MethodsPlasma samples were collected from premature infants with NEC (n = 30), sepsis (n = 29), and controls without infection (n = 29). The 92 inflammatory-related proteins were assessed via high-throughput OLINK proteomics platform.ResultsThere were 11 inflammatory proteins that significate differences (p < 0.05) among NEC, sepsis and control preterm infants, which include IL-8, TRAIL, IL-24, MMP-10, CCL20, CXCL1, OPG, TSLP, MCP-4, TNFSF14 and LIF. A combination of these 11 proteins could serve as differential diagnosis between NEC and control infants (AUC = 0.972), or between NEC and sepsis infants (AUC = 0.881). Furthermore, the combination of IL-8, OPG, MCP-4, IL-24, LIF and CCL20 could distinguish Stage II and III of NEC (AUC = 0.977). Further analysis showed the combination of IL-8, IL-24 and CCL20 have the best prediction value for NEC and control (AUC = 0.947), NEC and sepsis (AUC = 0.838) and different severity of NEC (AUC = 0.842).ConclusionInflammatory proteins were different expressed in premature infants with NEC compared with controls or sepsis. Combining these proteins provide a higher diagnostic potential for preterm NEC infants.
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35.
  • Du, M. M., et al. (författare)
  • Serum vitamin B12 is a promising auxiliary index for the diagnosis of methylmalonic acidemia in children: A single center study in China
  • 2023
  • Ingår i: Clinica Chimica Acta. - 0009-8981. ; 546
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and aims: Vitamin B12 (cobalamin, VitB12) is an essential coenzyme of methylmalonyl-CoA mutase and methionine synthase. Variations in VitB12 metabolism, absorption, transport, or intake may cause changes in methylmalonic acidemia (MMA) biomarkers. We aimed to investigate whether serum Vitamin B12 levels could be used in the early detection of MMA.Materials and methods: We included 241 children with MMA and 241 healthy matched controls. We measured serum VitB12 levels by an enzyme immunoassay and investigated the relationship between abnormal VitB12 levels and hematologic parameters as potential risk factors for MMA symptoms.Results: Compared with controls, the serum levels of VitB12 were increased in the MMA group (p < 0.001). Serum VitB12 distinguished patients with MMA from healthy children (p < 0.001). Serum VitB12 combined with homocysteine and ammonia identified cblC and mut type MMA, respectively (p < 0.001). Homocysteine, folate, ammonia, NLR, and red blood cells contributed to serum VitB12 in cblC type MMA (p < 0.001); homocysteine, ammonia, and red blood cells, contributed in mut type MMA (p < 0.001); and elevated VitB12 was an inde-pendent predictor of MMA clinical onset (p < 0.001).Conclusion: Serum VitB12 can be used as an early diagnostic biomarker for MMA in children.
  •  
36.
  • Du, Xiaonan, et al. (författare)
  • Systemic stimulation of TLR2 impairs neonatal mouse brain development.
  • 2011
  • Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 6:5
  • Tidskriftsartikel (refereegranskat)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.
  •  
37.
  • Dung, Y., et al. (författare)
  • MicroRNA-135a participates in the development of astrocytes derived from bacterial meningitis by downregulating HIF-1 alpha
  • 2019
  • Ingår i: American Journal of Physiology-Cell Physiology. - : American Physiological Society. - 0363-6143 .- 1522-1563. ; 316:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Accumulating evidence has highlighted the potential of microRNAs (miRs) as biomarkers in various human diseases. However, the roles of miRs in bacterial meningitis (BM), a severe infectious condition, still remain unclear. Thus, the present study aimed to investigate the effects of miR-135a on proliferation and apoptosis of astrocytes in BM. Neonatal rats were injected with Streptococcus pneumoniae to establish the BM model. The expression of miR-135a and hypoxia-inducible factor 1 alpha (HIF-1 alpha) in the BM rat models were characterized, followed by determination of their interaction. Using gain- and loss-of-function approaches, the effects of miR-135a on proliferation, apoptosis. and expression of glial fibrillary acidic protein (GFAP), in addition to apoptosis-related factors in astrocytes were examined accordingly. The regulatory effect of HIF-1 alpha was also determined along with the overexpression or knockdown of HIF-1 alpha. The results obtained indicated that miR-135a was poorly expressed, whereas HIF-1 alpha was highly expressed in the BM rat models. In addition, restored expression levels of miR-135a were determined to promote proliferation while inhibiting the apoptosis of astrocytes, along with downregulated Bax and Bad, as well as upregulated Bcl-2, Bcl-XL. and GFAP. As a target gene of miR-135a, HIF-1 alpha expression was determined to be diminished by miR-135a. The upregulation of HIF-1 alpha reversed the miR-135a-induced proliferation of astrocytes. Taken together, the key findings of the current study present evidence suggesting that miR-135a can downregulate HIF-1 alpha and play a contributory role in the development of astrocytes derived from BM. providing a novel theoretical perspective for BM treatment approaches.
  •  
38.
  • Fukuda, Hirotsugu, et al. (författare)
  • Irradiation-induced progenitor cell death in the developing brain is resistant to erythropoietin treatment and caspase inhibition
  • 2004
  • Ingår i: Cell Death Differ. - Univ Gothenburg, Dept Physiol, Perinatal Ctr, SE-40530 Gothenburg, Sweden. Osaka Univ, Sch Med, Dept Obstet & Gynecol, Suita, Osaka 5650871, Japan. Zhengzhou Univ, Affiliated Hosp 3, Dept Pediat, Zhengzhou 450052, Peoples R China. Uppsala Univ, Dept Neurosci, SE-75123 Uppsala, Sweden. Sahlgrens Univ Hosp, Dept Radiat Phys, SE-41345 Gothenburg, Sweden. H Lundbeck & Co AS, Mol Dis Biol, DK-2500 Copenhagen, Denmark. Sahlgrens Univ Hosp, Dept Oncol, SE-41345 Gothenburg, Sweden. Queen Silvia Childrens Hosp, Dept Pediat, SE-41685 Gothenburg, Sweden. : NATURE PUBLISHING GROUP. - 1350-9047 .- 1476-5403. ; 11:11, s. 1166-78
  • Tidskriftsartikel (refereegranskat)abstract
    • One hemisphere of postnatal day 8 (P8) rats or P10 mice was irradiated with a single dose of 4-12 Gy, and animals were killed from 2 h to 8 weeks after irradiation (IR). In the subventricular zone (SVZ) and the granular cell layer (GCL) of the dentate gyrus, harboring neural and other progenitor cells, nitrosylation and p53 peaked 2-12 h after IR, followed by markers for active caspase-3, apoptosis-inducing factor and TUNEL (6-24 h). Ki67-positive (proliferating) cells had disappeared by 12 h and partly reappeared by 7 days post-IR. The SVZ and GCL areas decreased approximately 50% 7 days after IR. The development of white matter was hampered, resulting in 50-70% less myelin basic protein staining. Pretreatment with erythropoietin did not confer protection against IR. Caspase inhibition by overexpression of XIAP prevented caspase-9 and caspase-3 activation but not cell death, presumably because of increased caspase-independent cell death.
  •  
39.
  • Gao, Qi, et al. (författare)
  • The Association Between Branched-Chain Amino Acid Concentrations and the Risk of Autism Spectrum Disorder in Preschool-Aged Children
  • 2024
  • Ingår i: MOLECULAR NEUROBIOLOGY. - 0893-7648 .- 1559-1182.
  • Tidskriftsartikel (refereegranskat)abstract
    • Several studies have linked branched-chain amino acid (BCAA) metabolism disorders with autism spectrum disorder (ASD), but the results have been inconsistent. The purpose of this study was to explore the association between BCAA concentrations and the risk of ASD. A total of 313 participants were recruited from two tertiary referral hospitals from May 2018 to July 2021. Concentrations of BCAAs in dried blood spots were analyzed using liquid chromatography-tandem mass spectrometry-based analysis. Multivariate analyses and restricted cubic spline models were used to identify the association between BCAAs and the risk of ASD, and a nomogram was developed by using multivariate logistic regression and the risk was determined by receiver operating characteristic curve analysis and calibration curve analysis. Concentrations of total BCAA, valine, and leucine/isoleucine were higher in the ASD group, and all of them were positively and non-linearly associated with the risk of ASD even after adjusting for potential confounding factors such as age, gender, body mass index, and concentrations of BCAAs (P < 0.05). The nomogram integrating total BCAA and valine showed a good discriminant AUC value of 0.756 (95% CI 0.676-0.835). The model could yield net benefits across a reasonable range of risk thresholds. In the stratified analysis, the diagnostic ability of the model was more pronounced in children older than 3 years. We provide evidence that increased levels of BCAAs are associated with the risk of ASD, and the nomogram model of BCAAs presented here can serve as a marker for the early diagnosis of ASD.
  •  
40.
  • Hagberg, Henrik, 1955, et al. (författare)
  • PARP-1 gene disruption in mice preferentially protects males from perinatal brain injury
  • 2004
  • Ingår i: J Neurochem. ; 90:5, s. 1068-75
  • Tidskriftsartikel (refereegranskat)abstract
    • Poly(ADP-ribose) polymerase-1 is over-activated in the adult brain in response to ischemia and contributes to neuronal death, but its role in perinatal brain injury remains uncertain. To address this issue, 7-day-old wild-type (wt) and PARP-1 gene deficient (parp+/- and parp-/-) Sv129/CD-1 hybrid mice were subjected to unilateral hypoxia-ischemia and histologic damage was assessed 10 days later by two evaluators. Poly(ADP-ribose) polymerase-1 knockout produced moderate but significant (p < 0.05) protection in the total group of animals, but analysis by sex revealed that males were strongly protected (p < 0.05) in contrast to females in which there was no significant effect. Separate experiments demonstrated that PARP-1 was activated over 1-24 h in both females and males after the insult in neonatal wt mice and rats using immnocytochemistry and western blotting for poly(ADP-ribose). Brain levels of NAD+ were also significantly reduced, but the decrease of NAD+ during the early post-hypoxia-ischemia (HI) phase was only seen in males. The results indicate that hypoxia-ischemia activates Poly(ADP-ribose) polymerase-1 in the neonatal brain and that the sex of the animal strongly influences its role in the pathogenesis of brain injury.
  •  
41.
  • Han, W., et al. (författare)
  • Cranial irradiation induces transient microglia accumulation, followed by long-lasting inflammation and loss of microglia
  • 2016
  • Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:50, s. 82305-82323
  • Tidskriftsartikel (refereegranskat)abstract
    • The relative contribution of resident microglia and peripheral monocyte-derived macrophages in neuroinflammation after cranial irradiation is not known. A single dose of 8 Gy was administered to postnatal day 10 (juvenile) or 90 (adult) CX3CR1(GFP/+) CCR2(RFP/+) mouse brains. Microglia accumulated in the subgranular zone of the hippocampal granule cell layer, where progenitor cell death was prominent. The peak was earlier (6 h vs. 24 h) but less pronounced in adult brains. The increase in juvenile, but not adult, brains was partly attributed to proliferation. Microglia numbers then decreased over time to 39% (juvenile) and 58% (adult) of controls 30 days after irradiation, largely as a result of cell death. CD68 was expressed in 90% of amoeboid microglia in juvenile hippocampi but only in 9% of adult ones. Isolated hippocampal microglia revealed reduced CD206 and increased IL1-beta expression after irradiation, more pronounced in juvenile brains. CCL2 and IL-1 beta increased after irradiation, more in juvenile hippocampi, and remained elevated at all time points. In summary, microglia activation after irradiation was more pronounced, protracted and pro-inflammatory by nature in juvenile than in adult hippocampi. Common to both ages was long-lasting inflammation and the absence of monocyte-derived macrophages.
  •  
42.
  • Han, Wei, et al. (författare)
  • Delayed, Long-Term Administration of the Caspase Inhibitor Q-VD-OPh Reduced Brain Injury Induced by Neonatal Hypoxia-Ischemia.
  • 2014
  • Ingår i: Developmental neuroscience. - : S. Karger AG. - 1421-9859 .- 0378-5866. ; 36:1, s. 64-72
  • Tidskriftsartikel (refereegranskat)abstract
    • Apoptosis contributes greatly to the morphological and biochemical features of cell death after neonatal cerebral hypoxia-ischemia (HI), making this mode of cell death a promising therapeutic target. We previously showed that 10 mg/kg of the caspase inhibitor Q-VD-OPh at the onset of and immediately after HI on postnatal day 9 reduced brain infarct volume. In this study, delayed administration of Q-VD-OPh, 12 and 36 h after HI, decreased HI-induced caspase-3 activity (DEVD cleavage) by 23% and diminished the levels of the proinflammatory chemokines CCL2 (MCP-1) and CCL3 (MIP-1α) by 29.3 and 29.1%, respectively, but not the levels of the anti-inflammatory cytokines IL-4 and IL-10. Long-term administration of Q-VD-OPh initiated at 12 h after HI, and continued at 24-hour intervals for 2 weeks, reduced total brain tissue loss by 31.3% from 41.5 ± 3.1 mm(3) in the vehicle group to 28.5 ± 3.0 mm(3) in the Q-VD-OPh group when evaluated 16 weeks after HI (p = 0.004). Q-VD-OPh treatment also ameliorated the loss of sensorimotor function, as evaluated by a cylinder rearing test (Q-VD-OPh: 30.8 ± 4.3% vs. vehicle: 59.7 ± 6.3% in nonimpaired forepaw preference) 3 weeks after HI, and reduced HI-induced hyperactivity, as measured in an open field test (Q-VD-OPh: 4,062 ± 198 cm vs. vehicle: 4,792 ± 205 cm in distance moved) 7 weeks after the insult. However, the functional protection was no longer observed when analyzed again at later time points. The mechanisms underlying the discrepancy between sustained morphological protection and transient functional protection remain to be elucidated. © 2014 S. Karger AG, Basel.
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43.
  • Han, W., et al. (författare)
  • Dying transplanted neural stem cells mediate survival bystander effects in the injured brain
  • 2023
  • Ingår i: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 14:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Neural stem and progenitor cell (NSPC) transplants provide neuroprotection in models of acute brain injury, but the underlying mechanisms are not fully understood. Here, we provide evidence that caspase-dependent apoptotic cell death of NSPCs is required for sending survival signals to the injured brain. The secretome of dying NSPCs contains heat-stable proteins, which protect neurons against glutamate-induced toxicity and trophic factor withdrawal in vitro, and from ischemic brain damage in vivo. Our findings support a new concept suggesting a bystander effect of apoptotic NSPCs, which actively promote neuronal survival through the release of a protective "farewell" secretome. Similar protective effects by the secretome of apoptotic NSPC were also confirmed in human neural progenitor cells and neural stem cells but not in mouse embryonic fibroblasts (MEF) or human dopaminergic neurons, suggesting that the observed effects are cell type specific and exist for neural progenitor/stem cells across species.
  •  
44.
  • Han, X. M., et al. (författare)
  • The different mechanisms of peripheral and central TLR4 on chronic postsurgical pain in rats
  • 2021
  • Ingår i: Journal of Anatomy. - : Wiley. - 0021-8782 .- 1469-7580. ; 239:1, s. 111-124
  • Tidskriftsartikel (refereegranskat)abstract
    • Chronic postsurgical pain (CPSP) is a common complication after surgery; however, the underlying mechanisms of CPSP are poorly understood. As one of the most important inflammatory pathways, the Toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-kappa B) signaling pathway plays an important role in chronic pain. However, the precise role of the TLR4/NF-kappa B signaling pathway in CPSP remains unclear. In the present study, we established a rat model of CPSP induced by skin/muscle incision and retraction (SMIR) and verified the effects and mechanisms of central and peripheral TLR4 and NF-kappa B on hyperalgesia in SMIR rats. The results showed that TLR4 expression was increased in both the spinal dorsal horn and dorsal root ganglia (DRGs) of SMIR rats. However, the TLR4 expression pattern in the spinal cord was different from that in DRGs. In the spinal cord, TLR4 was expressed in both neurons and microglia, whereas it was expressed in neurons but not in satellite glial cells in DRGs. Further results demonstrate that the central and peripheral TLR4/NF-kappa B signaling pathway is involved in the SMIR-induced CPSP by different mechanisms. In the peripheral nervous system, we revealed that the TLR4/NF-kappa B signaling pathway induced upregulation of voltage-gated sodium channel 1.7 (Nav1.7) in DRGs, triggering peripheral hyperalgesia in SMIR-induced CPSP. In the central nervous system, the TLR4/NF-kappa B signaling pathway participated in SMIR-induced CPSP by activating microglia in the spinal cord. Ultimately, our findings demonstrated that activation of the peripheral and central TLR4/NF-kappa B signaling pathway involved in the development of SMIR-induced CPSP.
  •  
45.
  • Hangen, E, et al. (författare)
  • A brain-specific isoform of mitochondrial apoptosis-inducing factor: AIF2.
  • 2010
  • Ingår i: Cell death and differentiation. - : Springer Science and Business Media LLC. - 1476-5403 .- 1350-9047. ; 17:7, s. 1155-66
  • Tidskriftsartikel (refereegranskat)abstract
    • Apoptosis-inducing factor (AIF) has important supportive as well as potentially lethal roles in neurons. Under normal physiological conditions, AIF is a vital redox-active mitochondrial enzyme, whereas in pathological situations, it translocates from mitochondria to the nuclei of injured neurons and mediates apoptotic chromatin condensation and cell death. In this study, we reveal the existence of a brain-specific isoform of AIF, AIF2, whose expression increases as neuronal precursor cells differentiate. AIF2 arises from the utilization of the alternative exon 2b, yet uses the same remaining 15 exons as the ubiquitous AIF1 isoform. AIF1 and AIF2 are similarly imported to mitochondria in which they anchor to the inner membrane facing the intermembrane space. However, the mitochondrial inner membrane sorting signal encoded in the exon 2b of AIF2 is more hydrophobic than that of AIF1, indicating a stronger membrane anchorage of AIF2 than AIF1. AIF2 is more difficult to be desorbed from mitochondria than AIF1 on exposure to non-ionic detergents or basic pH. Furthermore, AIF2 dimerizes with AIF1, thereby preventing its release from mitochondria. Conversely, it is conceivable that a neuron-specific AIF isoform, AIF2, may have been 'designed' to be retained in mitochondria and to minimize its potential neurotoxic activity.Cell Death and Differentiation advance online publication, 29 January 2010; doi:10.1038/cdd.2009.211.
  •  
46.
  • Hangen, Emilie, et al. (författare)
  • Interaction between AIF and CHCHD4 Regulates Respiratory Chain Biogenesis
  • 2015
  • Ingår i: Molecular cell. - : Elsevier BV. - 1097-4164 .- 1097-2765. ; 58:6, s. 1001-1014
  • Tidskriftsartikel (refereegranskat)abstract
    • Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein that, beyond its apoptotic function, is required for the normal expression of major respiratory chain complexes. Here we identified an AIF-interacting protein, CHCHD4, which is the central component of a redox-sensitive mitochondrial intermembrane space import machinery. Depletion or hypomorphic mutation of AIF caused a downregulation of CHCHD4 protein by diminishing its mitochondrial import. CHCHD4 depletion sufficed to induce a respiratory defect that mimicked that observed in AIF-deficient cells. CHCHD4 levels could be restored in AIF-deficient cells by enforcing its AIF-independent mitochondrial localization. This modified CHCHD4 protein reestablished respiratory function in AIF-deficient cells and enabled AIF-deficient embryoid bodies to undergo cavitation, a process of programmed cell death required for embryonic morphogenesis. These findings explain how AIF contributes to the biogenesis of respiratory chain complexes, and they establish an unexpected link between the vital function of AIF and the propensity of cells to undergo apoptosis.
  •  
47.
  • Helbig, K. L., et al. (författare)
  • De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias
  • 2018
  • Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 103:5, s. 666-678
  • Tidskriftsartikel (refereegranskat)abstract
    • Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the alpha(1)-subunit of the voltage-gated Ca(V)2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed Ca(V)2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.
  •  
48.
  • Huo, Kaiming, et al. (författare)
  • Lithium reduced neural progenitor apoptosis in the hippocampus and ameliorated functional deficits after irradiation to the immature mouse brain.
  • 2012
  • Ingår i: Molecular and cellular neurosciences. - : Elsevier BV. - 1095-9327 .- 1044-7431. ; 51:1-2, s. 32-42
  • Tidskriftsartikel (refereegranskat)abstract
    • Lithium was recently shown to inhibit apoptosis and promote survival of neural progenitor cells after hypoxia-ischemia in the immature rat brain. Our aim was to evaluate the effects of lithium on cell death and proliferation in the hippocampus after irradiation (IR) to the immature brain. Male mice were injected with 2 mmol/kg lithium chloride i.p. on postnatal day 9 (P9) and additional lithium injections, 1 mmol/kg, were administered at 24 h intervals for up to 7 days. BrdU was injected 4 h after lithium injections on P9 and P10. The left hemisphere received a single dose of 8 Gy (MV photons) on P11. The animals were euthanized 6 h or 7 weeks after IR. The number of BrdU-labeled cells in the subgranular zone (SGZ) of the granule cell layer (GCL) 6h after IR was 24% higher in the lithium-treated mice. The number of proliferating, phospho-histone H3-positive cells in the SGZ 7 weeks after IR was 59% higher in the lithium group, so the effect was long-lasting. The number of apoptotic cells in the SGZ 6 h after IR was lower in the lithium group, as judged by 3 different parameters, pyknosis, staining for active caspase-3 and TUNEL. Newly formed cells (BrdU-labeled 1 or 2 days before IR) showed the greatest degree of protection, as judged by 50% fewer TUNEL-positive cells, whereas non-BrdU-labeled cells showed 38% fewer TUNEL-positive cells 6 h after IR. Consequently, the growth retardation of the GCL was less pronounced in the lithium group. The number and size of microglia in the DG were also lower in the lithium group, indicating reduced inflammation. Learning was facilitated after lithium treatment, as judged by improved context-dependent fear conditioning, and improved place learning, as judged by assessment in the IntelliCage platform. In summary, lithium administration could decrease IR-induced neural progenitor cell apoptosis in the GCL of the hippocampus and ameliorate learning impairments. It remains to be shown if lithium can be used to prevent the debilitating cognitive late effects seen in children treated with cranial radiotherapy.
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49.
  •  
50.
  • Huo, Kaiming, et al. (författare)
  • Risk factors for neurodevelopmental deficits in congenital hypothyroidism after early substitution treatment.
  • 2011
  • Ingår i: Endocrine Journal. - 1348-4540 .- 0918-8959. ; 58:5, s. 355-61
  • Tidskriftsartikel (refereegranskat)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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