ABSTRACT
Objective:To investigate the prognosis of childhood adrenoleukodystrophy (ALD) with cognitive disorder after haploidentical allogenic hematopoietic stem cell transplantation (haplo-HSCT), and to identify risk factors affecting the prognosis.Methods:It was a single-center retrospective study involving 31 ALD children receiving haplo-HSCT in Peking University People′s Hospital from January 2014 to October 2022.Survival analysis was performed by Kaplan-Meier method. Cox regression analysis was performed to identify risk factors for the prognosis of childhood ALD following haplo-HSCT. Results:Among the 31 children with ALD, 1 case died of cardiogenic shock during the transplantation, and the remaining had a successful haplo-HSCT.Ten children with ALD had cognitive disorder before haplo-HSCT, including 3 cases with the minimal LOES score ≥10 points and 8 cases with the Neurologic Function Score (NFS)>0 point before haplo-HSCT.Six children had major functional disability (MFD) and 2 cases died due to progression of ALD after haplo-HSCT.Twenty children did not have cognitive disorder before haplo-HSCT, of whom 3 cases had the LOES score≥10 points and 6 cases had NFS>0 before haplo-HSCT.Four children had MFD and 2 cases died due to progression of ALD after haplo-HSCT.For ALD patients without cognitive disorder after haplo-HSCT, the 3-year and 5-year survival rate were 100.0% and 72.9%, respectively, and the 5-year MFD-free survival was 61.6%.For ALD patients with cognitive disorder after haplo-HSCT, the 3-year survival rate was 83.3%.Compared with ALD patients with the LOES score<10 points before haplo-HSCT, those with the LOES score≥10 points had 9.243 times the risk of developing MFD after haplo-HSCT ( P=0.024, 95% CI: 1.332-64.127). Compared with ALD patients without cognitive disorder before haplo-HSCT, ALD patients with cognitive disorder had 9.749 times the risk of developing MFD after haplo-HSCT ( P=0.023, 95% CI: 1.358-66.148). Conclusions:Cognitive disorder and LOES score≥10 points before haplo-HSCT are risk factors for developing MFD in children with ALD following haplo-HSCT.
ABSTRACT
Objective@#To investigate the significance of endoplasmic reticulum stress-associated gene tri-bbles pseudokinase 3 (TRIB3) in the long-term brain injury in rats with developing epilepy.@*Methods@#Thirty male SD rats aged 21 days were randomly divided into the control group and the epilepsy group, 15 rats in each group.The rats in the epilepsy group were intraperitoneally injected with kainic acid (10 mg/kg) to induce seizures, while the rats in the control group were injected with the equal volume of 9 g/L saline.The rats in two groups were euthanized at 30 d after kainic acid administration.The damage to the ultrastructure of the cortex were observed by using transmission electron microscopy.Neuronal apoptosis in the cortex of rats was detected by terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) assay.The expression and localization of glucose regulated protein 78 (GRP78), CCAAT/enhancer binding protein-homologous protein (CHOP), TRIB3, and the activation of protein kinase B (AKT) in the cortex were examined by using Western blot analysis and immunohistochemistry.@*Results@#Compared with the control group, the different ultrastructural changes were observed in the cortex in the epilepsy group rats.TUNEL assay indicated that the number of apoptosis cells of cortex in the epilepsy group was increased.The protein levels of GRP78 and TRIB3 were upregulated in the cortex of the epileptic rats (1.280±0.272, 1.725±0.570), compared with the control group (1.000±0.000, 1.000±0.000), and the differences were statistically significant (all P<0.05). There was no significant change in CHOP protein between the control group and the epilepsy group.The level of phosphorylated AKT(p-AKT) was decreased in the cortex of the epilepsy group (0.150±0.047), compared with the control group (1.000±0.000), and the difference was statistically significant (P<0.05).@*Conclusions@#The brain injury caused by epilepsy in the developing rats can sustain to the stage of mature rats, and the endoplasmic reti-culum stress-associated gene TRIB3 is involved in the pathogenesis of long-term brain damage in the rats with deve-loping epilepsy.
ABSTRACT
Objective To investigate the significance of endoplasmic reticulum stress _associated gene tri_bbles pseudokinase 3(TRIB3)in the long_term brain injury in rats with developing epilepy. Methods Thirty male SD rats aged 21 days were randomly divided into the control group and the epilepsy group,15 rats in each group. The rats in the epilepsy group were intraperitoneally injected with kainic acid(10 mg/kg)to induce seizures,while the rats in the control group were injected with the equal volume of 9 g/L saline. The rats in two groups were euthanized at 30 d after kainic acid administration. The damage to the ultrastructure of the cortex were observed by using transmission elec_tron microscopy. Neuronal apoptosis in the cortex of rats was detected by terminal_deoxynucleoitidyl transferase media_ted nick end labeling( TUNEL)assay. The expression and localization of glucose regulated protein 78( xRP78), CCAAT/enhancer binding protein _ homologous protein( CHOP ),TRIB3,and the activation of protein kinase B (AKT)in the cortex were examined by using Western blot analysis and immunohistochemistry. Results Compared with the control group,the different ultrastructural changes were observed in the cortex in the epilepsy group rats. TUNEL assay indicated that the number of apoptosis cells of cortex in the epilepsy group was increased. The protein levels of xRP78 and TRIB3 were upregulated in the cortex of the epileptic rats(1. 280 ± 0. 272,1. 725 ± 0. 570),com_pared with the control group(1. 000 ± 0. 000,1. 000 ± 0. 000),and the differences were statistically significant( all P<0. 05). There was no significant change in CHOP protein between the control group and the epilepsy group. The level of phosphorylated AKT(p_AKT)was decreased in the cortex of the epilepsy group(0. 150 ± 0. 047),compared with the control group(1. 000 ± 0. 000),and the difference was statistically significant(P<0. 05). Conclusions The brain injury caused by epilepsy in the developing rats can sustain to the stage of mature rats,and the endoplasmic reti_culum stress_associated gene TRIB3 is involved in the pathogenesis of long_term brain damage in the rats with deve_loping epilepsy.
ABSTRACT
Study of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway has been becoming more and more popular.This pathway widely exists in kinds of cells of human being.As one main anti-apoptic and enhancing survival pathway in cells, it plays an important role in cellular growth (increased cell size), proliferation (increased cell number), apoptosis, cell survival and migration.At the same time,the pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration disease, epilepsy.In recent years,many studies have shown that the dysfunction of PI3K/Akt/mTOR signaling pathway can lead to neurodevelopmental disease.Loss of tuberous sclerosis complex (TSC)1/2 or phosphatase ad tensin homologue deleted on chromosome 10 (PTEN), or environmental stimuli such as inflammation, epilepsy, or hypoxia may stimulate mTOR-dependent protein synthesis,resulting in a host of cellular, structural, and physiological responses that culminate in clinical symptoms.Study the role of mTOR signaling pathway in early-onset epileptic encephalopathy, discuss the intervention and therapy in early-onset epileptic encephalopathy have important clinical meanings.In this article, the components, physiological functions,information were elucidated relative to the PI3 K/Akt/mTOR signaling pathway, and the interaction of the signaling pathway and epilepsy was discussed.