Publications by authors named "Changlian Zhu"

147 Publications

Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia.

Brain 2021 May 10. Epub 2021 May 10.

Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.

Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.
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http://dx.doi.org/10.1093/brain/awab041DOI Listing
May 2021

Erythropoietin Improves Poor Outcomes in Preterm Infants with Intraventricular Hemorrhage.

CNS Drugs 2021 May 6. Epub 2021 May 6.

Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.

Background: Intraventricular hemorrhage (IVH) is a common complication in preterm infants that has poor outcomes, especially in severe cases, and there are currently no widely accepted effective treatments. Erythropoietin has been shown to be neuroprotective in neonatal brain injury.

Objective: The objective of this study was to evaluate the protective effect of repeated low-dose recombinant human erythropoietin (rhEPO) in preterm infants with IVH.

Methods: This was a single-blinded prospective randomized controlled trial. Preterm infants ≤ 32 weeks gestational age who were diagnosed with IVH within 72 h after birth were randomized to receive rhEPO 500 IU/kg or placebo (equivalent volume of saline) every other day for 2 weeks. The primary outcome was death or neurological disability assessed at 18 months of corrected age.

Results: A total of 316 eligible infants were included in the study, with 157 in the rhEPO group and 159 in the placebo group. Although no significant differences in mortality (p = 0.176) or incidence of neurological disability (p = 0.055) separately at 18 months of corrected age were seen between the rhEPO and placebo groups, significantly fewer infants had poor outcomes (death and neurological disability) in the rhEPO group: 14.9 vs. 26.4%; odds ratio (OR) 0.398; 95% confidence interval (CI) 0.199-0.796; p = 0.009. In addition, the incidence of Mental Development Index scores of < 70 was lower in the rhEPO group than in the placebo group: 7.2 vs. 15.3%; OR 0.326; 95% CI 0.122-0.875; p = 0.026.

Conclusions: Treatment with repeated low-dose rhEPO improved outcomes in preterm infants with IVH.

Trial Registration: The study was retrospectively registered on ClinicalTrials.gov on 16 April 2019 (NCT03914690).
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http://dx.doi.org/10.1007/s40263-021-00817-wDOI Listing
May 2021

Population Pharmacokinetics of Lithium in Young Pediatric Patients With Intellectual Disability.

Front Pharmacol 2021 15;12:650298. Epub 2021 Apr 15.

Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Institute of Neuroscience and Third Affiliated Hospital and of Zhengzhou University, Zhengzhou, China.

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. 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. 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. 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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http://dx.doi.org/10.3389/fphar.2021.650298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082156PMC
April 2021

Iatrogenic vs. Spontaneous Preterm Birth: A Retrospective Study of Neonatal Outcome Among Very Preterm Infants.

Front Neurol 2021 23;12:649749. Epub 2021 Mar 23.

Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

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. 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. 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. 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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http://dx.doi.org/10.3389/fneur.2021.649749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021792PMC
March 2021

The different mechanisms of peripheral and central TLR4 on chronic postsurgical pain in rats.

J Anat 2021 Jul 17;239(1):111-124. Epub 2021 Mar 17.

The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

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-κB) signaling pathway plays an important role in chronic pain. However, the precise role of the TLR4/NF-κB 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-κB 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-κB signaling pathway is involved in the SMIR-induced CPSP by different mechanisms. In the peripheral nervous system, we revealed that the TLR4/NF-κB 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-κB 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-κB signaling pathway involved in the development of SMIR-induced CPSP.
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http://dx.doi.org/10.1111/joa.13406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197940PMC
July 2021

Inhibition of Colony Stimulating Factor 1 Receptor Suppresses Neuroinflammation and Neonatal Hypoxic-Ischemic Brain Injury.

Front Neurol 2021 18;12:607370. Epub 2021 Feb 18.

Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Hypoxic-ischemic (HI) brain injury is a major cause of neonatal death or lifetime disability without widely accepted effective pharmacological treatments. It has been shown that the survival of microglia requires colony-stimulating factor 1 receptor (CSF1R) signaling and microglia participate in neonatal HI brain injury. We therefore hypothesize that microglia depletion during a HI insult period could reduce immature brain injury. In this study, CD1 mouse pups were treated with a CSF1R inhibitor (PLX3397, 25 mg/kg/daily) or a vehicle from postnatal day 4 to day 11 (P4-11), and over 90% of total brain microglia were deleted at P9. Unilateral hemisphere HI injury was induced at P9 by permanently ligating the left common carotid arteries and exposing the pups to 10% oxygen for 30 min to produce moderate left hemisphere injury. We found that the PLX3397 treatment reduced HI brain injury by 46.4%, as evaluated by the percentage of brain infarction at 48 h after HI. Furthermore, CSF1R inhibition suppressed the infiltration of neutrophils (69.7% reduction, = 0.038), macrophages (77.4% reduction, = 0.009), and T cells (72.9% reduction, = 0.008) to the brain, the production of cytokines and chemokines (such as CCL12, CCL6, CCL21, CCL22, CCL19, IL7, CD14, and WISP-1), and reduced neuronal apoptosis as indicated by active caspase-3 labeled cells at 48 h after HI (615.20 ± 156.84/mm vs. 1,205.00 ± 99.15/mm, = 0.013). Our results suggest that CSF1R inhibition suppresses neuroinflammation and neonatal brain injury after acute cerebral hypoxia-ischemia in neonatal mice.
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http://dx.doi.org/10.3389/fneur.2021.607370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930561PMC
February 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

The Association Study of Polymorphisms With Cerebral Palsy in Chinese Population.

Front Neurosci 2020 25;14:590098. Epub 2020 Nov 25.

Institutes of Biomedical Science and Children's Hospital, Fudan University, Shanghai, China.

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. We recruited 782 children with CP as the case group and 770 healthy children as the control group. The association between 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. There were differences in the allele and genotype frequencies between CP cases and controls at the rs11805303 and rs10889677 SNPs (allele = 0.014 and 0.048, respectively; genotype = 0.023 and 0.008, respectively), and the difference in genotype frequency of rs10889677 remained significant after Bonferroni correction (genotype = 0.048). Subgroup analysis revealed a more significant association of rs10889677 with CP accompanied by global developmental delay (genotype = 0.024 after correction) and neonatal encephalopathy (genotype = 0.024 after correction). The present results showed a significant association between and CP, suggesting that may play a potential role in CP pathogenesis.
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http://dx.doi.org/10.3389/fnins.2020.590098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724030PMC
November 2020

Luminal polyethylene glycol solution delays the onset of preservation injury in the human intestine.

Am J Transplant 2021 Jun 18;21(6):2220-2230. Epub 2021 Jan 18.

The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden.

The organ damage incurred during the cold storage (CS) of intestinal grafts has short and long-term consequences. Animal studies suggest that additional luminal preservation (LP) with polyethylene glycol (PEG) may alleviate this damage. This study aims to validate these findings using human intestines. Ileal segments, perfused intravascularly with IGL-1 solution, were procured from 32 multiorgan donors and divided into two parts: one containing a PEG 3350-based solution introduced luminally (LP group) and another one without luminal treatment (control). Sampling was performed after 4 h, 8 h, 14 h, and 24 h of CS. Histology was assessed using the Chiu/Park score. Tight junctions (TJ), several inflammatory markers, and transcription factors were examined by immunofluorescence, ddPCR, and western blot. Tissue water content (edema) was also measured. Apoptotic activity was assessed with caspase -2, -3, and -9 assays. LP significantly lowered mucosal injury at all time points. Redistribution of TJ proteins occurred earlier and more severely in the control group. After 24 h of CS, LP intestines showed an emerging unfolding protein response. Increased caspase-3 and -9 activity was found in the control group. The current results indicate that luminal PEG is safe and effective in reducing damage to the intestinal epithelium during CS.
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http://dx.doi.org/10.1111/ajt.16418DOI Listing
June 2021

Epidemiological and Clinical Characteristics of COVID-19 in Children: A Systematic Review and Meta-Analysis.

Front Pediatr 2020 2;8:591132. Epub 2020 Nov 2.

Henan Key Laboratory of Child Brain Injury, Department of Pediatrics, The Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou, China.

Given the relatively low rate and limited publicly available data regarding children with SARS-CoV-2 infection, this knowledge gap should be addressed with urgency. This systematic review with meta-analysis aimed to evaluate the epidemiological spectrum and clinical characteristics of children infected with SARS-CoV-2. Relevant international and Chinese public databases were systematically searched to identify all case studies from January 1, 2020 to May 7, 2020. This study consisted of 96 studies involving 7004 cases. The mean age of pediatric cases was 6.48 years (95% CI 52.0-77.5), 90% had household contact, and 66% presented with mild to moderate clinical syndromes. The main symptoms were fever (47%, 95% CI 41-53%) and cough (42%, 95% CI 36-48%). About 23% of children were asymptomatic, 27% had comorbidity, and 29% had a co-infection. The pooled mean incubation period was 9.57 days (95% CI 7.70-11.44). The shedding of SARS-CoV-2 in the upper respiratory tract lasted 11.43 days, and 75% of patients had virus particles in their stool. A total of 34% of the children had neutropenia and 26% had lymphocytosis. Interferon-alpha (81%) was the most commonly used antiviral drug in the children. The discharge and death rates were 79 and 1%. In conclusion, the transmissibility of pediatric COVID-19 should be not ignored because of the relatively long incubation period, shedding duration, and mild clinical syndromes.
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http://dx.doi.org/10.3389/fped.2020.591132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667131PMC
November 2020

Umbilical cord blood cells for the treatment of preterm white matter injury: Potential effects and treatment options.

J Neurosci Res 2021 03 18;99(3):778-792. Epub 2020 Nov 18.

Key Laboratory of Neonatal Diseases of Health Commission of the People's Republic of China, Shanghai, China.

Preterm birth is a global public health problem. A large number of preterm infants survive with preterm white matter injury (PWMI), which leads to neurological deficits, and has multifaceted etiology, clinical course, monitoring, and outcomes. The principal upstream insults leading to PWMI initiation are hypoxia-ischemia and infection and/or inflammation and the key target cells are late oligodendrocyte precursor cells. Current PWMI treatments are mainly supportive, and thus have little effect in terms of protecting the immature brain or repairing injury to improve long-term outcomes. Umbilical cord blood (UCB) cells comprise abundant immunomodulatory and stem cells, which have the potential to reduce brain injury, mainly due to anti-inflammatory and immunomodulatory mechanisms, and also through their release of neurotrophic or growth factors to promote endogenous neurogenesis. In this review, we briefly summarize PWMI pathogenesis and pathophysiology, and the specific properties of different cell types in UCB. We further explore the potential mechanism by which UCB can be used to treat PWMI, and discuss the advantages of and potential issues related to UCB cell therapy. Finally, we suggest potential future studies of UCB cell therapy in preterm infants.
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http://dx.doi.org/10.1002/jnr.24751DOI Listing
March 2021

Constitutive PGC-1α Overexpression in Skeletal Muscle Does Not Contribute to Exercise-Induced Neurogenesis.

Mol Neurobiol 2021 Apr 16;58(4):1465-1481. Epub 2020 Nov 16.

Center for Brain Repair and Rehabilitation, Institute for Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.

Physical exercise can improve age-dependent decline in cognition, which in rodent is partly mediated by restoration of an age-dependent decline in neurogenesis. Exercise-inducible myokines in the circulation present a link in muscle-brain crosstalk. The transcription factor PGC-1α regulates the release of such myokines with neurotrophic properties into the circulation. We study how chronic muscular overexpression of PGC-1α could contribute to exercise-induced effects on hippocampal neurogenesis and if this effect could be enhanced in a running wheel paradigm. We used 3- and 11-month-old transgenic mice with overexpression of PGC-1α under the control of muscle creatinine kinase promoter (MCK-PGC-1α), which have a constitutively developed endurance muscle phenotype. Wild-type and MCK-PGC-1α mice were single housed with free access to running wheels. Four weeks of running in female animals increased the levels of newborn cells, immature neurons, and, for young animals, new mature neurons, compared to sedentary controls. However, no difference in these parameters was observed between wild-type and transgenic mice under sedentary or running conditions. Multiplex analysis of serum cytokines, chemokines, and myokines suggested several differences in serum protein concentrations between genotypes with musclin found to be significantly upregulated 4-fold in male MCK-PGC-1α animals. We conclude that constitutive muscular overexpression of PGC-1α, despite systemic changes and difference in serum composition, does not translate into exercise-induced effects on hippocampal neurogenesis, independent of the age of the animal. This suggests that chronic activation of PGC-1α in skeletal muscle is by itself not sufficient to mimic exercise-induced effects or to prevent decline of neurogenesis in aging.
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http://dx.doi.org/10.1007/s12035-020-02189-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932943PMC
April 2021

Cranial irradiation alters neuroinflammation and neural proliferation in the pituitary gland and induces late-onset hormone deficiency.

J Cell Mol Med 2020 12 10;24(24):14571-14582. Epub 2020 Nov 10.

Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

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 6 Gy whole-head irradiation, and hormone levels and organ structure in the reproductive system were examined at 20 weeks 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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http://dx.doi.org/10.1111/jcmm.16086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754041PMC
December 2020

Effect of early prophylactic low-dose recombinant human erythropoietin on retinopathy of prematurity in very preterm infants.

J Transl Med 2020 10 19;18(1):397. Epub 2020 Oct 19.

Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.

Background: Very preterm infants are at risk of developing retinopathy of prematurity (ROP). Recombinant human erythropoietin (rhEPO) is routinely used to prevent anemia in preterm infants; however, the effect of rhEPO on ROP development is still controversial. The purpose of this study was to evaluate the effect of early prophylactic low-dose rhEPO administration on ROP development in very preterm infants.

Methods: A total of 1898 preterm infants born before 32 weeks of gestation were included. Preterm infants received rhEPO (n = 950; 500 U/kg, rhEPO group) or saline (n = 948, control group) intravenously within 72 h of birth and then once every other day for 2 weeks.

Results: The total incidence of ROP was not significantly different between the two groups (10.2% vs. 13.2%, p = 0.055). Further analysis showed that rhEPO group had lower rates of type 2 ROP than the control group (2.2% vs. 4.1%, RR 0.98; 95% CI 0.96-1.00; p = 0.021). Subgroup analysis found that rhEPO treatment significantly decreased the incidence of type 2 ROP in infant boys (1.8% vs. 4.3%, p = 0.021) and in those with a gestational age of 28-29 weeks (1.1% vs. 4.9%, p = 0.002) and birth weight of 1000-1499 g (1.2% vs. 4.2%, p = 0.002). There was a small increasing tendency for the incidence of ROP in infants with a gestational age of < 28 weeks after rhEPO treatment.

Conclusions: Repeated low-dose rhEPO administration has no significant influence on the development of ROP; however, it may be effective for type 2 ROP in infant boys or in infants with gestational age > 28 weeks and birth weight > 1500 g. Trial registration The data of this study were retrieved from two clinical studies registered ClinicalTrials.gov (NCT02036073) on January 14, 2014, https://clinicaltrials.gov/ct2/show/NCT02036073 ; and (NCT03919500) on April 18, 2019. https://clinicaltrials.gov/ct2/show/NCT03919500 .
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http://dx.doi.org/10.1186/s12967-020-02562-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574422PMC
October 2020

Mutations disrupting neuritogenesis genes confer risk for cerebral palsy.

Nat Genet 2020 10 28;52(10):1046-1056. Epub 2020 Sep 28.

Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.
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http://dx.doi.org/10.1038/s41588-020-0695-1DOI Listing
October 2020

Gut microbiota changes in patients with autism spectrum disorders.

J Psychiatr Res 2020 10 18;129:149-159. Epub 2020 Jul 18.

Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou, 450052, China; Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden; Department of Women's and Children's Health, Karolinska Institutet, Stockholm, 17176, Sweden. Electronic address:

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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http://dx.doi.org/10.1016/j.jpsychires.2020.06.032DOI Listing
October 2020

The effect of vitamin D supplementation in treatment of children with autism spectrum disorder: a systematic review and meta-analysis of randomized controlled trials.

Nutr Neurosci 2020 Sep 7:1-11. Epub 2020 Sep 7.

Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou, People's Republic of China.

The effect of vitamin D supplementation on the risk of Autism Spectrum Disorder (ASD) is conflicting. The aim of this study was to estimate the efficacy of vitamin D supplementation on ASD in children. We conducted a meta-analysis of randomized controlled trials (RCTs) in which vitamin D supplementation was used as a therapy in children with ASD. The PubMed, PsychINFO, Cochrane CENTRAL library, Web of Science, and Cinahl databases were searched from inception to March 20, 2019, for all publications on vitamin D and ASD with no restrictions. Studies involving individuals aged <18 years diagnosed with ASD and with all functional outcomes assessed by measurement scales for ASD were included. Mean differences were pooled, and a meta-analysis was performed using a random-effects model due to differences between the individual RCTs. There were five RCTs with 349 children with ASD in the review, of which three RCTs were included in the meta-analysis. Vitamin D supplementation indicated a small but significant improvement in hyperactivity scores (pooled MD: -3.20; 95% CI: [-6.06, -0.34]) with low heterogeneity (  = 10%,  = 0.33), but there were no other statistically significant differences in ASD symptoms between groups as measured by validated scales. Vitamin D supplementation appears to be beneficial for hyperactivity but not for core symptoms or other co-existing behaviors and conditions of ASD. Future RCTs with large sample sizes examining the effect of vitamin D supplementation on ASD among individuals with low serum vitamin D levels at baseline are needed.
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http://dx.doi.org/10.1080/1028415X.2020.1815332DOI Listing
September 2020

Role of apoptosis-inducing factor in perinatal hypoxic-ischemic brain injury.

Neural Regen Res 2021 Feb;16(2):205-213

Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.

Perinatal complications, such as asphyxia, can cause brain injuries that are often associated with subsequent neurological deficits, such as cerebral palsy or mental retardation. The mechanisms of perinatal brain injury are not fully understood, but mitochondria play a prominent role not only due to their central function in metabolism but also because many proteins with apoptosis-related functions are located in the mitochondrion. Among these proteins, apoptosis-inducing factor has already been shown to be an important factor involved in neuronal cell death upon hypoxia-ischemia, but a better understanding of the mechanisms behind these processes is required for the development of more effective treatments during the early stages of perinatal brain injury. In this review, we focus on the molecular mechanisms of hypoxic-ischemic encephalopathy, specifically on the importance of apoptosis-inducing factor. The relevance of apoptosis-inducing factor is based not only because it participates in the caspase-independent apoptotic pathway but also because it plays a crucial role in mitochondrial energetic functionality, especially with regard to the maintenance of electron transport during oxidative phosphorylation and in oxidative stress, acting as a free radical scavenger. We also discuss all the different apoptosis-inducing factor isoforms discovered, focusing especially on apoptosis-inducing factor 2, which is only expressed in the brain and the functions of which are starting now to be clarified. Finally, we summarized the interaction of apoptosis-inducing factor with several proteins that are crucial for both apoptosis-inducing factor functions (pro-survival and pro-apoptotic) and that are highly important in order to develop promising therapeutic targets for improving outcomes after perinatal brain injury.
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http://dx.doi.org/10.4103/1673-5374.290875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896227PMC
February 2021

Erythropoietin prevents necrotizing enterocolitis in very preterm infants: a randomized controlled trial.

J Transl Med 2020 08 8;18(1):308. Epub 2020 Aug 8.

Henan Key Laboratory of Child Brain Injury, Department of Neonatology, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.

Background: Necrotizing enterocolitis (NEC) is one of the most severe complications in very preterm infants, but there are currently no accepted methods to prevent NEC. Studies have shown that erythropoietin (EPO) has the potential to prevent NEC or improve outcomes of preterm NEC. This study aimed to determine whether recombinant human EPO (rhEPO) could protect against NEC in very preterm infants.

Methods: The study was a prospective randomized clinical trial performed among four NICU centers. A total of 1327 preterm infants with gestational age ≤ 32 weeks were admitted to the centers, and 42 infants were excluded leaving 1285 eligible infants to be randomized to the rhEPO or control group. Infants in the rhEPO group were given 500 IU/kg rhEPO intravenously every other day for 2 weeks, while the control group was given the same volume of saline. The primary outcome was the incidence of NEC in very preterm infants at 36 weeks of corrected gestational age.

Results: A total of 1285 infants were analyzed at 36 weeks of corrected age for the incidence of NEC. rhEPO treatment significantly decreased the incidence of NEC (stage I, II and III) (12.0% vs. 17.1%, p = 0.010), especially confirmed NEC (stage II and III) (3.0% vs. 5.4%, p = 0.027). Meanwhile, rhEPO treatment significantly reduced the number of red blood cells transfusion in the confirmed NEC cases (1.2 ± 0.4 vs. 2.7 ± 1.0, p = 0.004). Subgroup analyses showed that rhEPO treatment significantly decreased the incidence of confirmed NEC at gestational age < 28 weeks (p = 0.019), and the incidence of all stages NEC in preterm infants with hemoglobin < 90 g/l (p = 0.000) and 5 min Apgar score > 5 (p = 0.028).

Conclusion: Repeated low-dose rhEPO treatment is beneficial against NEC in very preterm infants. Trial registration The protocol was registered retrospectively at ClinicalTrials.gov (NCT03919500) on April 18, 2019. https://clinicaltrials.gov/ct2/show/NCT03919500.
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http://dx.doi.org/10.1186/s12967-020-02459-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414749PMC
August 2020

Birth Asphyxia Is Associated With Increased Risk of Cerebral Palsy: A Meta-Analysis.

Front Neurol 2020 16;11:704. Epub 2020 Jul 16.

Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou, China.

To assess the association between birth asphyxia-as defined by the pH of umbilical cord blood-and cerebral palsy in asphyxiated neonates ≥35 weeks' gestation. Two reviewers independently selected English-language studies that included data on the incidence of cerebral palsy in asphyxiated neonates ≥35 weeks' gestation. Studies were searched from the Embase, Google Scholar, PubMed, and Cochrane Library databases up to 31 December 2019, and the references in the retrieved articles were screened. We identified 10 studies that met the inclusion criteria for our meta-analysis, including 8 randomized controlled trials and 2 observational studies. According to a random effects model, the pooled rate of cerebral palsy in the randomized controlled trials was 20.3% (95% CI: 16.0-24.5) and the incidence of cerebral palsy in the observational studies was 22.2% (95% CI: 8.5-35.8). Subgroup analysis by treatment for hypoxic ischemic encephalopathy in asphyxiated neonates showed that the pooled rates of cerebral palsy were 17.3% (95% CI: 13.3-21.2) and 23.9% (95% CI: 18.1-29.7) for the intervention group and non-intervention group, respectively. Our findings suggest that the incidence of cerebral palsy in neonates (≥35 weeks' gestation) with perinatal asphyxia is significantly higher compared to that in the healthy neonate population. With the growing emphasis on improving neonatal neurodevelopment and reducing neurological sequelae, we conclude that the prevention and treatment of perinatal asphyxia is essential for preventing the development of cerebral palsy.
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http://dx.doi.org/10.3389/fneur.2020.00704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381116PMC
July 2020

A systematic review of the clinical and genetic characteristics of Chinese patients with cystic fibrosis.

Pediatr Pulmonol 2020 11 31;55(11):3005-3011. Epub 2020 Jul 31.

Department of Neonatology, Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou, China.

Objectives: To investigate and summarize the clinical and genetic characteristics of Chinese cystic fibrosis (CF) patients to improve clinicians' understanding and decrease the rates of misdiagnosis and missed diagnoses in China.

Methods: The EMBASE, Cochrane Library, PubMed and SinoMed databases were searched for studies involving Chinese CF patients from January 1975 to August 2019.

Results: In total, 113 Chinese patients, including 53 males and 60 females, were reported. Nineteen patients had a family history of CF. The median age at diagnosis was 8.7 years. Among Chinese CF patients, 70.8% had bronchiectasis, 9.7% had a hemoptysis history, 33.6% had clubbed fingers, 17.7% had allergic bronchopulmonary aspergillosis, and 29.2% had chronic diarrhea; the incidence of malnutrition was 52.2%. Five patients had jaundice, 26 patients had hepatomegaly, and 9 patients had meconium ileus in the neonatal period, and the incidence of liver cirrhosis was 5.3%. The predominant organism in airways was Pseudomonas aeruginosa, followed by Staphylococcus aureus. Seventy-nine patients underwent the sweat test, and all of them were positive, with an average chloride ion level of 122.2 mmol/L. Eighty-eight Chinese CF patients underwent genetic testing, and 74 CF transmembrane conductance regulator (CFTR) gene mutations were reported. The most common gene mutation was c.2909G→A. One Phe508del gene mutation was observed.

Conclusion: The common clinical manifestations and CFTR gene mutations in Chinese CF patients are different from those in Caucasian patients. The age at CF diagnosis in China is relatively old, suggesting that the CF incidence in China may be seriously underestimated.
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http://dx.doi.org/10.1002/ppul.24980DOI Listing
November 2020

Early application of caffeine improves white matter development in very preterm infants.

Respir Physiol Neurobiol 2020 10 15;281:103495. Epub 2020 Jul 15.

Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital and Institute of Neuroscience, Zhengzhou University, Zhengzhou 450052, China; Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg University, Gothenburg 40530, Sweden; Department of Women's and Children's Health, Karolinska Institutet, Stockholm 17177, Sweden. Electronic address:

The aim of this study was to evaluate the effect of early prophylactic caffeine treatment on white matter development in very preterm infants using cerebral magnetic resonance imaging. A total of 194 preterm infants (≤32 weeks gestational age) were randomly assigned to the caffeine (n = 96) or placebo (n = 93) treatment group and administered with either caffeine or placebo within 72 h after birth. Cerebral magnetic resonance imaging, including diffuse tensor imaging examination, was performed at 34-36 weeks of corrected gestational age, and the fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values were measured. In total, 160 infants were included in the final analysis, including 80 cases in the placebo group and 80 cases in the caffeine group. There were fewer instances of apnea of prematurity and shorter assisted ventilation times for infants in the caffeine group compared to the placebo group (p < 0.05). Infants in the caffeine group had significantly higher FA values in white matter, including the posterior limb of the internal capsule, the corpus callosum, the frontal, occipital, and parietal white matter, the cerebellum, and the cerebral peduncle, compared to infants in the placebo group. ADC values in the above white matter areas were significantly reduced in the caffeine group. However, there were no significant differences regarding the FA and ADC in the gray matter between the two groups. These results demonstrate that early administration of caffeine improves white matter micro-structural development in preterm infants, but with no significant effect on short-term complications related to prematurity.
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http://dx.doi.org/10.1016/j.resp.2020.103495DOI Listing
October 2020

Epigenetic restoration of voltage-gated potassium channel Kv1.2 alleviates nerve injury-induced neuropathic pain.

J Neurochem 2021 02 29;156(3):367-378. Epub 2020 Jul 29.

Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.

Voltage-gated potassium channels (Kv) are important regulators of neuronal excitability for its role of regulating resting membrane potential and repolarization. Recent studies show that Kv channels participate in neuropathic pain, but the detailed underlying mechanisms are far from being clear. In this study, we used siRNA, miR-137 agomir, and antagomir to regulate the expression of Kv1.2 in spinal cord and dorsal root ganglia (DRG) of naïve and chronic constriction injury (CCI) rats. Kv currents and neuron excitability in DRG neurons were examined by patch-clamp whole-cell recording to verify the change in Kv1.2 function. The results showed that Kv1.2 was down-regulated in DRG and spinal dorsal horn (SDH) by CCI. Knockdown of Kv1.2 by intrathecally injecting Kcna2 siRNA induced significant mechanical and thermal hypersensitivity in naïve rats. Concomitant with the down-regulation of Kv1.2 was an increase in the expression of the miR-137. The targeting and regulating of miR-137 on Kcna2 was verified by dual-luciferase reporter system and intrathecal injecting miR-137 agomir. Furthermore, rescuing the expression of Kv1.2 in CCI rats, achieved through inhibiting miR-137, restored the abnormal Kv currents and excitability in DRG neurons, and alleviated mechanical allodynia and thermal hyperalgesia. These results indicate that the miR-137-mediated Kv1.2 impairment is a crucial etiopathogenesis for the nerve injury-induced neuropathic pain and can be a novel potential therapeutic target for neuropathic pain management.
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http://dx.doi.org/10.1111/jnc.15117DOI Listing
February 2021

Early prediction of adverse outcomes in infants with acute bilirubin encephalopathy.

Ann Clin Transl Neurol 2020 07 4;7(7):1141-1147. Epub 2020 Jun 4.

Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.

Objective: Acute bilirubin encephalopathy (ABE) remains one of the important causes of neonatal mortality and child disability, early identification, and intervention which could improve outcomes. The purpose of this study was to evaluate early predictors of adverse outcomes in infants with ABE.

Methods: Newborns of gestational age ≥ 35 weeks and diagnosed with ABE were included in the study. Bilirubin-induced neurological dysfunction (BIND) score, total serum bilirubin (TSB) peak value, and serum albumin levels were determined. Adverse outcomes were defined as death or survival with auditory dysfunction and/or cerebral palsy.

Results: Eighty-two infants were eligible for recruitment in the study. The outcome data from 76 ABE infants (92%) were used for analysis, of which 25 infants got adverse outcomes and 51 live a normal life. Univariate analysis for BIND score, TSB peak value, bilirubin-albumin ratio (B/A), albumin level, abnormal AABR, and neonatal sepsis was performed to elucidate the association with adverse outcomes. Bivariate logistic regression analysis showed B/A (OR 10.48, 95%CI: 1.55-70.81, P = 0.02) and BIND score (OR 3.68, 95%CI: 1.39-9.72, P = 0.01) were correlated with adverse outcomes. ROC curve analysis showed that B/A (≥8.9 mg/g), BIND score (≥6) could predict adverse outcomes of ABE separately; B/A in conjunction with BIND score could increase prediction sensitivity to 100%.

Interpretation: Both B/A and BIND score can be used to predict adverse outcomes of ABE, and the combination of the two parameters can increase prediction sensitivity significantly.
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http://dx.doi.org/10.1002/acn3.51077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359120PMC
July 2020

Inhibiting the interaction between apoptosis-inducing factor and cyclophilin A prevents brain injury in neonatal mice after hypoxia-ischemia.

Neuropharmacology 2020 07 8;171:108088. Epub 2020 Apr 8.

Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden; Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China; Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Centre of Perinatal Medicine and Health, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Electronic address:

The interaction between apoptosis-inducing factor (AIF) and cyclophilin A (CypA) has been shown to contribute to caspase-independent apoptosis. Blocking the AIF/CypA interaction protects against glutamate-induced neuronal cell death in vitro, and the purpose of this study was to determine the in vivo effect of an AIF/CypA interaction blocking peptide (AIF(370-394)-TAT) on neonatal mouse brain injury after hypoxia-ischemia (HI). The pups were treated with AIF (370-394)-TAT peptide intranasally prior to HI. Brain injury was significantly reduced at 72 h after HI in the AIF(370-394)-TAT peptide treatment group compared to vehicle-only treatment for both the gray matter and the subcortical white matter, and the neuroprotection was more pronounced in males than in females. Neuronal cell death was evaluated in males at 8 h and 24 h post-HI, and it was decreased significantly in the CA1 region of the hippocampus and the nucleus habenularis region after AIF(370-394)-TAT treatment. Caspase-independent apoptosis was decreased in the cortex, striatum, and nucleus habenularis after AIF(370-394)-TAT treatment, but no significant change was found on caspase-dependent apoptosis as indicated by the number of active caspase-3-labeled cells. Further analysis showed that both AIF and CypA nuclear accumulation were decreased after treatment with the AIF(370-394)-TAT peptide. These results suggest that AIF(370-394)-TAT inhibited AIF/CypA translocation to the nucleus and reduced HI-induced caspase-independent apoptosis and brain injury in young male mice, suggesting that blocking AIF/CypA might be a potential therapeutic target for neonatal brain injury.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108088DOI Listing
July 2020

Prognostic value of amplitude-integrated EEG in neonates with high risk of neurological sequelae.

Ann Clin Transl Neurol 2020 02 7;7(2):210-218. Epub 2020 Feb 7.

Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital and Institute of Neuroscience, Zhengzhou University, Zhengzhou, 450052, China.

Objective: To determine the efficacy and the prognostic value of amplitude-integrated electroencephalography (aEEG) in term and near-term neonates with high risk of neurological sequelae.

Methods: Infants of ≥35 weeks of gestation diagnosed with neonatal encephalopathy or with high risk of brain injury were included. All eligible infants underwent aEEG within 6 h after clinical assessment. The infants were followed up 12 months to evaluate neurological development.

Results: A total of 250 infants were eligible, of which 85 had normal aEEG, 81 had mildly abnormal aEEG, and 84 had severely abnormal aEEG. Of these infants, 168 were diagnosed with different neonatal encephalopathies, 27 with congenital or metabolic diseases, and 55 with high risk of brain injury. In all, 22 infants died, 19 were lost to follow-up, and 209 completed the follow-up at 12 months, of which 62 were diagnosed with a neurological disability. Statistical analysis showed that severely abnormal aEEG predicted adverse neurological outcome with a sensitivity of 70.2%, a specificity of 87.1%, a positive predictive value of 75.6%, and a negative predictive value of 83.7%.

Interpretation: aEEG can predict adverse outcomes in high-risk neonates and is a useful method for monitoring neonates with high risk of adverse neurological outcomes.
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http://dx.doi.org/10.1002/acn3.50989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034499PMC
February 2020

Overexpression of apoptosis inducing factor aggravates hypoxic-ischemic brain injury in neonatal mice.

Cell Death Dis 2020 01 30;11(1):77. Epub 2020 Jan 30.

Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.

Apoptosis inducing factor (AIF) has been shown to be a major contributor to neuron loss in the immature brain after hypoxia-ischemia (HI). Indeed, mice bearing a hypomorphic mutation causing reduced AIF expression are protected against neonatal HI. To further investigate the possible molecular mechanisms of this neuroprotection, we generated an AIF knock-in mouse by introduction of a latent transgene coding for flagged AIF protein into the Rosa26 locus, followed by its conditional activation by a ubiquitously expressed Cre recombinase. Such AIF transgenic mice overexpress the pro-apoptotic splice variant of AIF (AIF1) at both the mRNA (5.9 times higher) and protein level (2.4 times higher), but not the brain-specific AIF splice-isoform (AIF2). Excessive AIF did not have any apparent effects on the phenotype or physiological functions of the mice. However, brain injury (both gray and white matter) after neonatal HI was exacerbated in mice overexpressing AIF, coupled to enhanced translocation of mitochondrial AIF to the nucleus as well as enhanced caspase-3 activation in some brain regions, as indicated by immunohistochemistry. Altogether, these findings corroborate earlier studies demonstrating that AIF plays a causal role in neonatal HI brain injury.
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http://dx.doi.org/10.1038/s41419-020-2280-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992638PMC
January 2020

MiR-424 overexpression protects alveolar epithelial cells from LPS-induced apoptosis and inflammation by targeting FGF2 via the NF-κB pathway.

Life Sci 2020 Feb 24;242:117213. Epub 2019 Dec 24.

Department of Pediatric, Henan Provincial People's Hospital, Zhengzhou 450000, PR China; Department of Pediatric, People's Hospital of Zhengzhou University, Zhengzhou 450000, PR China.

Acute respiratory distress syndrome (ARDS) is a multifactorial, inflammatory lung injury disease with high morbidity and mortality. However, the underlying pathogenic mechanism remains unknown. In this study, lipopolysaccharide (LPS)-stimulated alveolar epithelial cells were used to mimic the inflammatory pathogenesis of ARDS in vitro. We here investigated the role of miR-424 in LPS-stimulated alveolar epithelial cells and found it to be substantially downregulated. Overexpression of miR-424 inhibited apoptosis and inflammation in LPS-stimulated alveolar epithelial cells, and the miR-424 inhibitor exhibited the opposite effect. A bioinformatic analysis revealed a potential binding site of miR-424 in the 3'-UTR of fibroblast growth factor 2 (FGF2). A luciferase reporter assay suggested that miR-424 targeted FGF2 in alveolar epithelial cells. The level of FGF2 protein was inhibited by miR-424 mimic, whereas was significantly upregulated after miR-424 suppression in LPS-stimulated alveolar epithelial cells. MiR-424 also exhibited the protective role in LPS-induced apoptosis and inflammation by directly targeting FGF2 via the NF-κB pathway. In conclusion, our results demonstrate that miR-424 had a protective role in LPS-induced apoptosis and inflammation of alveolar epithelial cells by targeting FGF2 via regulating NF-κB pathway. This might contribute novel evidence to help identify a therapeutic target for treating ARDS.
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http://dx.doi.org/10.1016/j.lfs.2019.117213DOI Listing
February 2020

Folic Acid and Risk of Preterm Birth: A Meta-Analysis.

Front Neurosci 2019 28;13:1284. Epub 2019 Nov 28.

Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou, China.

The results from epidemiologic studies linking blood folate concentrations, folic acid supplementation, or dietary folate to the risk of preterm birth are inconsistent. In this study, we aimed to summarize the available evidence on these associations. A systematic search of the PubMed/MEDLINE, Google Scholar, Web of Science, and Cochrane Library databases up to October 20, 2018 was performed and reference lists of retrieved articles were screened. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for the highest vs. the lowest levels of folate concentrations, folic acid supplementation, and dietary folate were calculated using random-effects models. Subgroup analyses and univariate meta-regression were performed to explore the sources of heterogeneity. Ten studies (six prospective cohort studies and four case-control studies) were included on folate concentrations, 13 cohort studies were included about folic acid supplementation, and 4 cohort studies were included regarding dietary folate intake. Higher maternal folate levels were associated with a 28% reduction in the risk of preterm birth (OR 0.72, 95% CI 0.56-0.93). Higher folic acid supplementation was associated with 10% lower risk of preterm birth (OR 0.90, 95% CI 0.85-0.95). In addition, a significant negative association was observed between dietary folate intake and the risk of preterm birth (OR 0.68, 95% CI 0.55-0.84), but no significant relation was seen between dietary folate and the risk of spontaneous preterm birth (OR 0.89, 95% CI 0.57-1.41). In the subgroup analysis, higher maternal folate levels in the third trimester were associated with a lower risk of preterm birth (OR 0.58, 95% CI 0.36-0.94). To initiate taking folic acid supplementation early before conception was adversely associated with preterm birth risk (OR 0.89, 95% CI 0.83-0.95). In conclusion, higher maternal folate levels and folic acid supplementation were significantly associated with a lower risk of preterm birth. The limited data currently available suggest that dietary folate is associated with a significantly decreased risk of preterm birth.
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http://dx.doi.org/10.3389/fnins.2019.01284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892975PMC
November 2019