Brain scarring in infants:immunological insights from a neonatal hypoxic-ischemic encephalopathy model

Neonatal hypoxic-ischemic encephalopathy(HIE)is a significant cause of disability in children.Improving brain function and accelerating neurological recovery may require a combination of neuroprotective and pro-regenerative treatments at different stages of HIE.While the first hours after the neonatal insult are the most critical period for neuroprotection,the existence of secondary and tertiary mechanisms of brain injury offers the possibility of preventing delayed neurodegeneration in the subsequent days,weeks,or months(Levison et al.,2022).

Spectrum of delayed post-hypoxic leukoencephalopathy syndrome:A systematic review

BACKGROUND Delayed post hypoxic leukoencephalopathy syndrome(DPHLS),also known as Grinker’s myelinopathy,is a rare but significant neurological condition that manifests days to weeks after a hypoxic event.Characterized by delayed onset of neurological and cognitive deficits,DPHLS presents substantial diagnostic and therapeutic challenges.AIM To consolidate current knowledge on pathophysiology,clinical features,diagnostic approaches,and management strategies for DPHLS,providing a comprehensive overview and highlighting gaps for future research.METHODS Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes guidelines,we systematically searched PubMed,ScienceDirect and Hinari databases using terms related to delayed post-hypoxic leukoencephalopathy.Inclusion criteria were original research articles,case reports,and case series involving human subjects with detailed clinical,neuroimaging,or pathological data on DPHLS.Data were extracted on study characteristics,participant demographics,clinical features,neuroimaging findings,pathological findings,treatment,and outcomes.The quality assessment was performed using the Joanna Briggs Institute critical appraisal checklist.RESULTS A total of 73 cases were reviewed.Common comorbidities included schizoaffective disorder,bipolar disorder,hypertension,and substance use disorder.The primary causes of hypoxia were benzodiazepine overdose,opioid overdose,polysubstance overdose,and carbon monoxide(CO)poisoning.Symptoms frequently include decreased level of consciousness,psychomotor agitation,cognitive decline,parkinsonism,and encephalopathy.Neuroimaging commonly revealed diffuse T2 hyperintensities in cerebral white matter,sometimes involving the basal ganglia and the globus pallidus.Magnetic resonance spectroscopy often showed decreased N-acetylaspartate,elevated choline,choline-to-creatinine ratio,and normal or elevated lactate.Treatment is often supportive,including amantadine,an antioxidant cocktail,and steroids.Hyperbaric oxygen therapy may be beneficial in those with CO poisoning.Parkinsonism was often treated with levodopa.Most of the patients had substantial recovery over the course of months and many cases had some residual neurocognitive deficits.CONCLUSION DPHLS remains a complex and multifaceted condition with various etiologies and clinical manifestations.Early recognition and appropriate management are crucial to improving patient outcomes.Future research should focus on standardizing diagnostic criteria,using advanced imaging techniques,and exploring therapeutic interventions to improve understanding and treatment of DPHLS.Conducting prospective cohort studies and developing biomarkers for early diagnosis and monitoring will be essential to advance patient care.

The miR-9-5p/CXCL11 pathway is a key target of hydrogen sulfide-mediated inhibition of neuroinflammation in hypoxic ischemic brain injury

We previously showed that hydrogen sulfide(H2S)has a neuroprotective effect in the context of hypoxic ischemic brain injury in neonatal mice.However,the precise mechanism underlying the role of H2S in this situation remains unclear.In this study,we used a neonatal mouse model of hypoxic ischemic brain injury and a lipopolysaccharide-stimulated BV2 cell model and found that treatment with L-cysteine,a H2S precursor,attenuated the cerebral infarction and cerebral atrophy induced by hypoxia and ischemia and increased the expression of miR-9-5p and cystathionineβsynthase(a major H2S synthetase in the brain)in the prefrontal cortex.We also found that an miR-9-5p inhibitor blocked the expression of cystathionineβsynthase in the prefrontal cortex in mice with brain injury caused by hypoxia and ischemia.Furthermore,miR-9-5p overexpression increased cystathionine-β-synthase and H2S expression in the injured prefrontal cortex of mice with hypoxic ischemic brain injury.L-cysteine decreased the expression of CXCL11,an miR-9-5p target gene,in the prefrontal cortex of the mouse model and in lipopolysaccharide-stimulated BV-2 cells and increased the levels of proinflammatory cytokines BNIP3,FSTL1,SOCS2 and SOCS5,while treatment with an miR-9-5p inhibitor reversed these changes.These findings suggest that H2S can reduce neuroinflammation in a neonatal mouse model of hypoxic ischemic brain injury through regulating the miR-9-5p/CXCL11 axis and restoringβ-synthase expression,thereby playing a role in reducing neuroinflammation in hypoxic ischemic brain injury.

Does MgSO_(4) protect the preterm brain?Dissecting its role in the pathophysiology of hypoxic ischemic encephalopathy

Mitigating preterm encephalopathy continues to be one of the greatest challenges in perinatal medicine.Preterm encephalopathy is associated with high mortality,serious morbidity,and significant socio-economic impacts on the individuals,their families,and public health sectors and welfare systems that last a lifetime.The cost of disability associated with preterm brain injury continues to rise.Prevention of this injury,and disability,would significantly reduce this socioeconomic burden.

Sodium Sulfite as a Novel Hypoxia Revulsant Involved in Hypoxic Regulation in Escherichia coli

As a reducing salt,sodium sulfite could deprive oxygen in solution,which could mimic hypoxic stress in Caenorhabditis elegans.In this study,the wildtype Escherichia coli strain MG1655 was used to examine the inhibition of sodium sulfite-induced hypoxia by observing the bacterial growth curves.

Dunbar Syndrome and Hypoxic Hepatitis: An Unusual Presentation

Hypoxic hepatitis, also known as ischemic hepatitis, is characterized by acute hepatocellular injury due to inadequate oxygen delivery to the liver. Celiac trunk stenosis can lead to hepatic ischemia and subsequent liver damage. We present the case of an 81-year-old patient with a history of hypertension, ischemic heart disease, hypothyroidism, and biliary lithiasis, who developed hypoxic hepatitis secondary to Dunbar syndrome and a stenosis of the superior mesenteric artery. The patient improved symptoms and liver function tests with conservative management, including intravenous fluids and supportive care. Long-term management involved continued antiplatelet therapy and statins, with consideration of further interventions for celiac trunk stenosis. This case underscores the importance of recognizing Dunbar syndrome as well as superior mesentery trunk stenosis as a potential cause of hypoxic hepatitis. It highlights the need for multidisciplinary management in such cases.

Hypoxic Preconditioning Eliminates Differences in the Innate Resistance of Rats to Severe Hypoxia

Hypoxic preconditioning is able to increase the body’s resistance to hypoxic/ischemic stress. Understanding how to apply the hypoxic response to initiate the protective mechanism of ischemic preconditioning is a high priority. However, the relationship between innate resistance to hypoxic stress and preconditioning efficiency of moderate hypoxia has been poorly studied. In our work, the efficiency of single moderate hypobaric hypoxia (HBH) for resistance to severe hypobaric hypoxia (SHBH) was studied on intact rats and those pre-tested under SHBH with low, intermediate and high resistance to hypoxia. HBH has a significant preconditioning action on the resistance to hypoxia over a wide range from 270 to 1464 s (4.5 to 24.5 min) and at the same time eliminates the differences in the endurance under SHBH between all rat groups. It is concluded that 1) HBH preconditioning efficiency does not depend on an innate resistance to SHBH and prior hypoxic experience of rats;and 2) the pretesting to severe hypoxia has no value for predicting the hypoxic preconditioning efficiency and study of adaptive mechanisms.

Hypoxic preconditioning stimulates angiogenesis in ischemic penumbra after acute cerebral infarction

Previous studies have demonstrated the protective effect of hypoxic preconditioning on acute cerebral infarction, but the mechanisms underlying this protection remain unclear. To investigate the protective mechanisms of hypoxic preconditioning in relation to its effects on angiogenesis, we in- duced a photochemical model of cerebral infarction in an inbred line of mice （BALB/c）. Mice were then exposed to hypoxic preconditioning 30 minutes prior to model establishment. Results showed significantly increased vascular endothelial growth factor and CD31 expression in the ischemic penumbra at 24 and 72 hours post infarction, mainly in neurons and vascular endothelial cells. Hypoxic preconditioning increased vascular endothelial growth factor and CD31 expression in the ischemic penumbra and the expression of vascular endothelial growth factor was positively related to that of CD31. Moreover, hypoxic preconditioning reduced the infarct volume and improved neu- rological function in mice. These findings indicate that the protective role of hypoxic preconditioning in acute cerebral infarction may possibly be due to an increase in expression of vascular endothelial growth factor and CD31 in the ischemic penumbra, which promoted angiogenesis.

Impact of hypoxic preconditioning on apoptosis and its possible mechanism in orthotopic liver autotransplantation in rats

BACKGROUND: Hepatocyte apoptosis is a severe form of cell death after hepatic ischemia-reperfusion injury (HIRI), and its relief is an important issue in liver transplantation. Hypoxic preconditioning (HP) is considered to have protective effects on HIRI. This study was designed to explore the impact of HP on apoptosis and its possible mechanism during orthotopic liver autotransplantation. METHODS: A modified orthotopic liver autotransplantation model was used to simulate HIRI. Sprague-Dawley rats were randomly divided into normal control, autotransplantation (AT) and HP groups. The HP group was subjected to an 8% oxygen atmosphere for 90 minutes before surgery. At 1, 6 and 24 hours after surgery, the rats were killed and their liver tissue was sampled to assess the expression of Bcl-2 protein. The samples were subjected to blood chemistry study, morphological study under a light or transmission electron microscope, and quantitative study of mitochondria. RESULTS: The serum levels of ALT and AST in the HP group were lower than those in the AT group at 1, 6 and 24 hours after orthotopic liver autotransplantation (P < 0.05). Bcl-2 protein expression was increased in the HP group at each measurement point (P < 0.05). Light microscopy showed that hepatic injury in the AT group was much more severe than in the HP group. Hepatocytes in the AT group showed typical apoptosis signs under a transmission electron microscope. The ultrastructural appearance of hepatocytes in the HP group was much better than in the AT group, and the area, perimeter and diameter of the mitochondria were smaller in the HP group than in the AT group (P < 0.05). CONCLUSIONS: Hepatocytes sense and respond to decreased tissue oxygenation. Stimulation by HP relieves apoptosis by upregulating expression of Bcl-2 protein and its protection of mitochondria after orthotopic liver autotransplantation.

Effect of Hypoxic Preconditioning on Neural Cell Apoptosis and Expression of Bcl-2 and Bax in Cerebral Ischemia-Reperfusion in Rats

In order to investigate the protective effect of hypoxic preconditioning on the cerebral ischemia-reperfusion injury, the expression of Bcl-2 and Bax was detected by using immunohistochemical staining after 3 h cerebral ischemia followed by 1, 6, 12, 24 and 48 h reperfusion respectively in rats treated with or without hypoxic preconditioning before cerebral ischemia. In addition, the apoptosis of neural cells and the behavioral scores for neurological functions recovery were evaluated by TUNEL staining and ＂crawling method＂, respectively. Compared with control group （cerebral ischemia-reperfusion without hypoxic preconditioning）, the expression of Bcl-2 was significantly increased, but that of Bax decreased in the hypoxic preconditioning group （cerebral ischemiareperfusion with hypoxie preconditioning）, both P〈0.05. The pre-treatment with hypoxic preconditioning could reduce the apoptosis of neural cells and promote the neurological function recovery as compared to control group. It was suggested that hypoxic preconditioning may have protective effects on the cerebral ischemia-reperfusion injury by inhibiting the apoptosis of neural cells, increase the expression of Bcl-2 and decrease the expression of Bax.

Hypoxic preconditioning reduces NLRP3 inflammasome expression and protects against cerebral ischemia/reperfusion injury

Hypoxic preconditioning can protect against cerebral ischemia/reperfusion injury. However, the underlying mechanisms that mediate this effect are not completely clear. In this study, mice were pretreated with continuous, intermittent hypoxic preconditioning;1 hour later, cerebral ischemia/reperfusion models were generated by middle cerebral artery occlusion and reperfusion. Compared with control mice, mice with cerebral ischemia/reperfusion injury showed increased Bederson neurological function scores, significantly increased cerebral infarction volume, obvious pathological damage to the hippocampus, significantly increased apoptosis;upregulated interleukin-1β, interleukin-6, and interleukin-8 levels in brain tissue;and increased expression levels of NOD-like receptor family pyrin domain containing 3(NLRP3), NLRP inflammasome-related protein caspase-1, and gasdermin D. However, hypoxic preconditioning significantly inhibited the above phenomena. Taken together, these data suggest that hypoxic preconditioning mitigates cerebral ischemia/reperfusion injury in mice by reducing NLRP3 inflammasome expression. This study was approved by the Medical Ethics Committee of the Fourth Hospital of Baotou, China(approval No. DWLL2019001) in November 2019.

Comprehensive analysis of coding and non-coding RNA transcriptomes related to hypoxic adaptation in Tibetan chickens

Background:Tibetan chickens,a unique native breed in the Qinghai-Tibet Plateau of China,possess a suite of adaptive features that enable them to tolerate the high-altitude hypoxic environment.Increasing evidence suggests that long non-coding RNAs(lncRNAs)and microRNAs(miRNAs)play roles in the hypoxic adaptation of high-altitude animals,although their exact involvement remains unclear.Results:This study aimed to elucidate the global landscape of mRNAs,lncRNAs,and miRNAs using transcriptome sequencing to construct a regulatory network of competing endogenous RNAs(ceRNAs)and thus provide insights into the hypoxic adaptation of Tibetan chicken embryos.In total,354 differentially expressed genes(DE genes),389 differentially expressed lncRNAs(DE lncRNAs),and 73 differentially expressed miRNAs(DE miRNAs)were identified between Tibetan chickens(TC)and control Chahua chickens(CH).GO and KEGG enrichment analysis revealed that several important DE miRNAs and their target DE lncRNAs and DE genes are involved in angiogenesis(including blood vessel development and blood circulation)and energy metabolism(including glucose,carbohydrate,and lipid metabolism).The ceRNA network was then constructed with the predicted DE gene-DE miRNA-DE lncRNA interactions,which further revealed the regulatory roles of these differentially expressed RNAs during hypoxic adaptation of Tibetan chickens.Conclusions:Analysis of transcriptomic data revealed several key candidate ceRNAs that may play high-priority roles in the hypoxic adaptation of Tibetan chickens by regulating angiogenesis and energy metabolism.These results provide insights into the molecular mechanisms of hypoxic adaptation regulatory networks from the perspective of coding and non-coding RNAs.

Resting-state network complexity and magnitude changes in neonates with severe hypoxic ischemic encephalopathy

Resting-state functional magnetic resonance imaging has revealed disrupted brain network connectivity in adults and teenagers with cerebral palsy. However, the specific brain networks implicated in neonatal cases remain poorly understood. In this study, we recruited 14 termborn infants with mild hypoxic ischemic encephalopathy and 14 term-born infants with severe hypoxic ischemic encephalopathy from Changzhou Children's Hospital, China. Resting-state functional magnetic resonance imaging data showed efficient small-world organization in whole-brain networks in both the mild and severe hypoxic ischemic encephalopathy groups. However, compared with the mild hypoxic ischemic encephalopathy group, the severe hypoxic ischemic encephalopathy group exhibited decreased local efficiency and a low clustering coefficient. The distribution of hub regions in the functional networks had fewer nodes in the severe hypoxic ischemic encephalopathy group compared with the mild hypoxic ischemic encephalopathy group. Moreover, nodal efficiency was reduced in the left rolandic operculum, left supramarginal gyrus, bilateral superior temporal gyrus, and right middle temporal gyrus. These results suggest that the topological structure of the resting state functional network in children with severe hypoxic ischemic encephalopathy is clearly distinct from that in children with mild hypoxic ischemic encephalopathy, and may be associated with impaired language, motion, and cognition. These data indicate that it may be possible to make early predictions regarding brain development in children with severe hypoxic ischemic encephalopathy, enabling early interventions targeting brain function. This study was approved by the Regional Ethics Review Boards of the Changzhou Children's Hospital(approval No. 2013-001) on January 31, 2013. Informed consent was obtained from the family members of the children. The trial was registered with the Chinese Clinical Trial Registry(registration number: ChiCTR1800016409) and the protocol version is 1.0.

Gene expression of vascular endothelial growth factor A and hypoxic adaptation in Tibetan pig

Background： Vascular endothelial growth factor A （VEGFA） can induce endothelial cell proliferation, promote cell migration, and inhibit apoptosis. These processes play key roles in physiological blood vessel formation and pathological angiogenesis. Methods： In this study, we examined VEGFA gene expression in the heart, liver, and kidney of Tibetan pigs （-I-P）, Yorkshire pigs that migrated to high altitudes （YH）, and Yorkshire pigs that lived at low altitudes （YL）. We used PCR and Sanger sequencing to screen for single nucleotide polymorphisms （SNPs） in 5＇-flanking DNA and exons of the VEGFA gene. Quantitative real-time PCR and western blots were used to measure expression levels and PCR products were sequenced. Results： Results showed that the VEGFA mRNA and protein expression in heart, liver and kidney of TP was higher than that in YH and YL. In addition, the mRNA sequence of the pig VEGFA gene was conserved among pig breeds, and only five SNPs were found in the 5＇-flanking region of the VEGFA gene, the allele frequency distributions of the 5 SNPs were not significantly different between the TP, Yorkshire （YL）, and Diannan small-ear （DN） pig populations. Conclusion： In conclusion, the Tibetan pig showed high tissues, which suggests that the VEGFA gene may play a levels of VEGFA gene expression in several hypoxic major functional role in hypoxic adaptation.

Low serum albumin predicts early mortality in patients with severe hypoxic hepatitis

To evaluate the incidence, etiology, and predictors of mortality of severe hypoxic hepatitis. METHODSWe used computerized patient records to identify consecutive cases of severe hypoxic hepatitis admitted to a tertiary hospital in Singapore over a one-year period. We defined severe hypoxic hepatitis as elevation of serum transaminases more than 100 times upper limit of normal in the clinical setting of cardiac, circulatory or respiratory failure after exclusion of other causes of hepatitis. We used multivariable regression analysis to determine predictors for mortality. RESULTSWe identified 75 cases of severe hypoxic hepatitis out of 71380 hospital admissions over one year, providing an incidence of 1.05 cases per 1000 admissions. Median age was 65 years (range 19-88); 57.3% males. The most common etiologies of severe hypoxic hepatitis were acute myocardial infarction and sepsis. Fifty-three patients (71%) died during the hospitalization. The sole independent predictive factor for mortality was serum albumin measured at the onset of severe hypoxic hepatitis. Patients with low serum albumin of less than 28 g/L have more than five-fold increase risk of death (OR = 5.39, 95%CI: 1.85-15.71). CONCLUSIONSevere hypoxic hepatitis is uncommon but has a high mortality rate. Patients with low serum albumin are at highest risk of death.

Gene expression changes after hypoxic preconditioning in rat hepatocytes

BACKGROUND: Hypoxic preconditioning can protect hepatocytes against hypoxic injury, but its mechanism has not been elucidated. The aim of this study was to profile gene expression patterns involved in hypoxic preconditioning and probable mechanism at the level of gene expression. METHODS: Hepatocytes were divided into 2 groups: control group and hypoxic preconditioning group. Biotinlabeled cRNA from the control group and the hypoxic preconditioning group was hybridized by oligonucleotide microarray. Genes that were significantly associated with hypoxic preconditioning were filtered, and validated at the level of transcript expression. RESULTS: Forty-three genes with significantly altered expression patterns were discovered and most of them had not been previously reported. Among these genes,genes encoding superoxide dismutase 2 (SOD2)and interleukin 10 (IL-10) in the hypoxic preconditioning group were confirmed to be up-regulated with real-time quantitative PCR. CONCLUSIONS: Many cytokines are involved in hypoxic preconditioning and protect hepatocytes from hypoxiareoxygenation injury, and the increase of oxygen freeradical scavengers and anti-inflammatory factors may play a key role in this phenomenon. Diverse signal pathways are probably involved.

Vascular endothelial growth factor: an attractive target in the treatment of hypoxic/ischemic brain injury

Cerebral hypoxia or ischemia results in cell death and cerebral edema, as well as other cellular reactions such as angiogenesis and the reestablishment of functional microvasculature to promote recovery from brain injury. Vascular endothelial growth factor is expressed in the central nervous system after hypoxic/ischemic brain injury, and is involved in the process of brain repair via the regulation of angiogenesis, neurogenesis, neurite outgrowth, and cerebral edema, which all require vascular endothelial growth factor signaling. In this review, we focus on the role of the vascular endothelial growth factor signaling pathway in the response to hypoxic/ischemic brain injury, and discuss potential therapeutic interventions.

Single-nucleotide polymorphism screening and RNA sequencing of key messenger RNAs associated with neonatal hypoxic-ischemia brain damage

A single-nucleotide polymorphism(SNP)is an alteration in one nucleotide in a certain position within a genome.SNPs are associated with disease susceptibility.However,the influences of SNPs on the pathogenesis of neonatal hypoxic-ischemic brain damage remain elusive.Seven-day-old rats were used to establish a hypoxic ischemic encephalopathy model.SNPs and expression profiles of mRNAs were analyzed in hypoxic ischemic encephalopathy model rats using RNA sequencing.Genes exhibiting SNPs associated with hypoxic ischemic encephalopathy were identified and studied by gene ontology and pathway analysis to identify their possible involvement in the disease mechanism.We identified 89 up-regulated genes containing SNPs that were mainly located on chromosome 1 and 2.Gene ontology analysis indicated that the up-regulated genes containing SNPs are mainly involved in angiogenesis,wound healing and glutamatergic synapse and biological processing of calcium-activated chloride channels.Signaling pathway analysis indicated that the differentially expressed genes play a role in glutamatergic synapses,long-term depression and oxytocin signaling.Moreover,intersection analysis of high throughput screening following PubMed retrieval and RNA sequencing for SNPs showed that CSRNP1,DUSP5 and LRRC25 were most relevant to hypoxic ischemic encephalopathy.Significant up-regulation of genes was confirmed by quantitative real-time polymerase chain reaction analysis of oxygen-glucose-deprived human fetal cortical neurons.Our results indicate that CSRNP1,DUSP5 and LRRC25,containing SNPs,may be involved in the pathogenesis of hypoxic ischemic encephalopathy.These findings indicate a novel direction for further hypoxic ischemic encephalopathy research.This animal study was approved on February 5,2017 by the Animal Care and Use Committee of Kunming Medical University,Yunnan Province,China(approval No.kmmu2019038).Cerebral tissue collection from a human fetus was approved on September 30,2015 by the Ethics Committee of Kunming Medical University,China(approval No.2015-9).

Xuefuzhuyu decoction and astragalus prevent hypoxic-ischemic brain injury

Hypoxic-ischemic brain injury models were generated by bilateral carotid artery ligation in Sprague-Dawley rats. Successful models were treated with a combination of Xuefuzhuyu decoction and 10g of astragalus. The experimental results showed that neuronal morphology and structure recovered, nerve growth factor mRNA expression increased in brain tissues, and neurological function signifi-cantly improved. There was no significant difference in these measures compared with rats treated with Xuefuzhuyu decoction alone or a combined treatment of Xuefuzhuyu decoction with 40 g as-tragalus. These experimental findings revealed that, Xuefuzhuyu decoction combined with astra-galus may up-regulate the expression of nerve growth factor mRNA and accordingly exert a neu-roprotective effect; however, this protection is not dependent on astragalus dosage.

Cerebrospinal fluid from rats given hypoxic preconditioning protects neurons from oxygen-glucose deprivation-induced injury

Hypoxic preconditioning activates endogenous mechanisms that protect against cerebral isch- emic and hypoxic injury. To better understand these protective mechanisms, adult rats were housed in a hypoxic environment （8% 02/92% N2） for 3 hours, and then in a normal oxygen environment for 12 hours. Their cerebrospinal fluid was obtained to culture cortical neurons from newborn rats for 1 day, and then the neurons were exposed to oxygen-glucose deprivation for 1.5 hours. The cerebrospinal fluid from rats subjected to hypoxic preconditioning reduced oxygen-glucose deprivation-induced injury, increased survival rate, upregulated Bcl-2 expression and downregulated Bax expression in the cultured cortical neurons, compared with control. These results indicate that cerebrospinal fluid from rats given hypoxic preconditioning protects against oxygen-glucose deprivation-induced injury by affecting apoptosis-related protein expres- sion in neurons from newborn rats.