Objective:To investigate the relationship of single nucleotide polymorphism (SNP) of high mobi-lity group protein A2 ( HMGA2) gene with prepubertal idiopathic short stature (ISS) and the efficacy of recombinant human growth hormone (rhGH) in Han population of Henan Province. Methods:A total of 120 children who were diagnosed with prepubertal ISS and treated with rhGH standards for at least one year from July 2017 to September 2019 at the Children′s Endocrinology Clinic of the Third Affiliated Hospital of Zhengzhou University were enrolled in the ISS group of this study.Meanwhile, 120 healthy children (control group) of the same age and gender whose height was within the normal range were selected as controls.Their peripheral blood was collected, and the polymorphism distributions of SNP loci(rs1042725 and rs7968682)were determined by molecular biology.Analysis was carried out to specify the annual growth rate, height standard deviation score (HtSDS), and insulin-like growth factor-1(IGF-1) of ISS children with different genotypes (before and after treatment )and those in the control group.Results:(1)In both ISS group and control group, children with CC and CT alleles at rs1042725 locus of HMGA2 had higher growth rate than those with TT allele before treatment[(4.33±0.64) cm/year, (3.95±0.45) cm/year; (6.35±0.41) cm/year, (6.12±0.32) cm/year vs.(3.76±0.52) cm/year, (5.96±0.42) cm/ year], therefore the difference were statistically significant (all P<0.05). (2)After treatment with GT genotype at the HMGA2 rs7968682 locus in children with ISS, the growth rate of age and bone HtSDS was higher than that of TT genotype [(0.74±0.30) cm/year vs. (0.63±0.24) cm/year, (0.16±0.05) cm/year vs.(0.14±0.05) cm/year], therefore the differences were statistically significant(all P<0.05). Conclusions:The polymorphism of the HMGA2 SNP locus (rs1042725) in the Han population of Henan province may be related to ISS level, while the polymorphism of the SNP locus (rs7968682) may be related to rhGH efficacy.

Traumatic brain injury (TBI)-induced coagulopathy has increasingly been recognized as a significant risk factor for poor outcomes, but the pathogenesis remains poorly understood. In this study, we aimed to investigate the causal role of acrolein, a typical lipid peroxidation product, in TBI-induced coagulopathy, and further explore the underlying molecular mechanisms. We found that the level of plasma acrolein in TBI patients suffering from coagulopathy was higher than that in those without coagulopathy. Using a controlled cortical impact mouse model, we demonstrated that the acrolein scavenger phenelzine prevented TBI-induced coagulopathy and recombinant ADAMTS-13 prevented acrolein-induced coagulopathy by cleaving von Willebrand factor (VWF). Our results showed that acrolein may contribute to an early hypercoagulable state after TBI by regulating VWF secretion. mRNA sequencing (mRNA-seq) and transcriptome analysis indicated that acrolein over-activated autophagy, and subsequent experiments revealed that acrolein activated autophagy partly by regulating the Akt/mTOR pathway. In addition, we demonstrated that acrolein was produced in the perilesional cortex, affected endothelial cell integrity, and disrupted the blood-brain barrier. In conclusion, in this study we uncovered a novel pro-coagulant effect of acrolein that may contribute to TBI-induced coagulopathy and vascular leakage, providing an alternative therapeutic target.

Traumatic brain injury (TBI) triggers the activation of the endogenous coagulation mechanism, and a large amount of thrombin is released to curb uncontrollable bleeding through thrombin receptors, also known as protease-activated receptors (PARs). However, thrombin is one of the most critical factors in secondary brain injury. Thus, the PARs may be effective targets against hemorrhagic brain injury. Since the PAR1 antagonist has an increased bleeding risk in clinical practice, PAR4 blockade has been suggested as a more promising treatment. Here, we explored the expression pattern of PAR4 in the brain of mice after TBI, and explored the effect and possible mechanism of BMS-986120 (BMS), a novel selective and reversible PAR4 antagonist on secondary brain injury. Treatment with BMS protected against TBI in mice. mRNA-seq analysis, Western blot, and qRT-PCR verification in vitro showed that BMS significantly inhibited thrombin-induced inflammation in astrocytes, and suggested that the Tab2/ERK/NF-κB signaling pathway plays a key role in this process. Our findings provide reliable evidence that blocking PAR4 is a safe and effective intervention for TBI, and suggest that BMS has a potential clinical application in the management of TBI.

Clinical advances in the treatment of intracranial hemorrhage (ICH) are restricted by the incomplete understanding of the molecular mechanisms contributing to secondary brain injury. Acrolein is a highly active unsaturated aldehyde which has been implicated in many nervous system diseases. Our results indicated a significant increase in the level of acrolein after ICH in mouse brain. In primary neurons, acrolein induced an increase in mitochondrial fragmentation, loss of mitochondrial membrane potential, generation of reactive oxidative species, and release of mitochondrial cytochrome c. Mechanistically, acrolein facilitated the translocation of dynamin-related protein1 (Drp1) from the cytoplasm onto the mitochondrial membrane and led to excessive mitochondrial fission. Further studies found that treatment with hydralazine (an acrolein scavenger) significantly reversed Drp1 translocation and the morphological damage of mitochondria after ICH. In parallel, the neural apoptosis, brain edema, and neurological functional deficits induced by ICH were also remarkably alleviated. In conclusion, our results identify acrolein as an important contributor to the secondary brain injury following ICH. Meanwhile, we uncovered a novel mechanism by which Drp1-mediated mitochondrial oxidative damage is involved in acrolein-induced brain injury.