L-ascorbyl-2-phosphate alleviates white matter injury caused by chronic hypoxia through the PRMT5/P53/NF-κB pathway.

White matter injury (WMI) is one of the most serious complications associated with preterm births. Damage to oligodendrocytes, which are the key cells involved in WMI pathogenesis, can directly lead to myelin abnormalities. L-ascorbyl-2-phosphate (AS-2P) is a stable form of vitamin C. This study aimed to explore the protective effects of AS-2P against chronic hypoxia-induced WMI, and elucidate the underlying mechanisms. An in vivo chronic hypoxia model and in vitro oxygen-glucose deprivation (OGD) model were established to explore the effects of AS-2P on WMI using immunofluorescence, immunohistochemistry, western blotting, real-time quantitative polymerase chain reaction, Morris water maze test, novel object recognition test, beaming-walking test, electron microscopy, and flow cytometry. The results showed that AS-2P resulted in the increased expression of MBP, Olig2, PDGFRα and CC1, improved thickness and density of the myelin sheath, and reduced TNF-α expression and microglial cell infiltration to alleviate inflammation in the brain after chronic hypoxia. Moreover, AS-2P improved the memory, learning and motor abilities of the mice with WMI. These protective effects of AS-2P may involve the upregulation of protein arginine methyltransferase 5 (PRMT5) and downregulation of P53 and NF-κB. In conclusion, our study demonstrated that AS-2P attenuated chronic hypoxia-induced WMI in vivo and OGD-induced oligodendrocyte injury in vitro possibly by regulating the PRMT5/P53/NF-κB pathway, suggesting that AS-2P may be a potential therapeutic option for WMI.

Celastrol ameliorates hypoxic-ischemic brain injury in neonatal rats by reducing oxidative stress and inflammation.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is caused by perinatal hypoxia and subsequent reductions in cerebral blood flow and is one of the leading causes of severe disability or death in newborns. Despite its prevalence, we currently lack an effective drug therapy to combat HIE. Celastrol (Cel) is a pentacyclic triterpene extracted from Tripterygium Wilfordi that can protect against oxidative stress, inflammation, and cancer. However, whether Cel can alleviate neonatal hypoxic-ischemic (HI) brain damage remains unclear. METHODS: Here, we established both in vitro and in vivo models of HI brain damage using CoCl2-treated PC12 cells and neonatal rats, respectively, and explored the neuroprotective effects of Cel in these models. RESULTS: Analyses revealed that Cel administration reduced brain infarction size, microglia activation, levels of inflammation factors, and levels of oxidative stress markers by upregulating levels of p-AMPKα, Nrf2, HO-1, and by downregulating levels of TXNIP and NLRP3. Conversely, these beneficial effects of Cel on HI brain damage were largely inhibited by AMPKα inhibitor Compound C and its siRNA. CONCLUSIONS: We present compelling evidence that Cel decreases inflammation and oxidative stress through the AMPKα/Nrf2/TXNIP signaling pathway, thereby alleviating neonatal HI brain injury. Cel therefore represents a promising therapeutic agent for treating HIE. IMPACT: We firstly report that celastrol can ameliorate neonatal hypoxic-ischemic brain injury both in in vivo and in vitro, which represents a promising therapeutic agent for treating related brain injuries. Celastrol activates the AMPKα/Nrf2/TXNIP signaling pathway to relieve oxidative stress and inflammation and thereby alleviates neonatal hypoxic-ischemic brain injury.

Early aEEG can predict neurodevelopmental outcomes at 12 to 18 month of age in VLBWI with necrotizing enterocolitis: a cohort study.

BACKGROUND: Studies have shown that neurological damage is common in necrotizing enterocolitis (NEC) survivors. The purpose of the study was to investigate the predictive value of amplitude-integrated electroencephalogram (aEEG) for neurodevelopmental outcomes in preterm infants with NEC. METHODS: Infants with NEC were selected, and the control group was selected based on 1:1-2 pairing by gestational age. We performed single-channel (P3-P4) aEEG in the two groups. The Burdjalov scores were compared between the two groups. Cranial magnetic resonance imaging (MRI) was performed several months after birth. The neurological outcomes at 12 to 18 months of age were compared with the Gesell Developmental Schedules (GDS). The predictive value of aEEG scores for neurodevelopmental delay was calculated. RESULTS: There was good consistency between the two groups regarding general conditions. In the 1st aEEG examination, the patients in NEC group had lower Co (1.0 (0.0, 2.0) vs. 2.0 (2.0, 2.0), P = 0.001), Cy (1.0 (0.0, 2.0) vs. 3.0 (3.0, 4.0), P < 0.001), LB (1.0 (0.0, 2.0) vs. 2.0 (2.0, 2.0), P < 0.001), B (1.0 (1.0, 2.0) vs. 3.0 (3.0, 3.5), P < 0.001) and T (3.0 (2.0, 8.0) vs. 10.0 (10.0, 11.5), P < 0.001), than the control group. Cranial MRI in NEC group revealed a widened interparenchymal space with decreased myelination. The abnormality rate of cranial MRI in the NEC group was higher than that in the control group (P = 0.001). The GDS assessment indicated that NEC children had inferior performance and lower mean scores than the control group in the subdomains of gross motor (71 (SD = 6.41) vs. 92 (SD = 11.37), P < 0.001), fine motor (67 (SD = 9.34) vs. 96 (SD = 13.69), adaptive behavior (76 (SD = 9.85) vs. 95 (SD = 14.38), P = 0.001), language (68 (SD = 12.65) vs. 95 (SD = 11.41), P < 0.001), personal-social responses (80 (SD = 15.15) vs. 93(SD = 14.75), P = 0.037) and in overall DQ (72 (SD = 8.66) vs. 95 (SD = 11.07), P < 0.001). The logistic binary regression analysis revealed that the NEC patients had a significantly greater risk of neurodevelopmental delay than the control group (aOR = 27.00, 95% CI = 2.561-284.696, P = 0.006). Confirmed by Spearman's rank correlation analysis, neurodevelopmental outcomes were significantly predicted by the 1st aEEG Burdjalov score (r = 0.603, P = 0.001). An abnormal 1st Burdjalov score has predictive value for neurodevelopmental delay with high specificity (84.62%) and positive predictive value (80.00%). CONCLUSIONS: Children with NEC are more likely to develop neurodevelopmental delay. There is high specificity and PPV of early aEEG in predicting neurodevelopmental delay.

[Expression rhythm of autophagic gene in neurons of neonatal rats with hypoxia/ischemia and its regulatory mechanism].

OBJECTIVE: To investigate the expression of autophagic gene and circadian gene in the neurons of neonatal rats after hypoxic-ischemic brain damage and the mechanism of nerve injury induced by hypoxia/ischemia. METHODS: Twelve Sprague-Dawley (SD) rats were randomly divided into hypoxic-ischemic (HI) group and sham-operation group, with 6 rats in each group. Ligation of the right common carotid artery and hypoxic treatment were performed to establish a model of hypoxic-ischemic brain damage. Western blot was used to measure the expression of the circadian protein Clock in the cortex and hippocampus. The neurons of the rats were cultured in vitro and randomly divided into oxygen glucose deprivation (OGD) group and control group. The neurons in the OGD group were treated with DMEM medium without glucose or serum to simulate ischemic state, and hypoxic treatment was performed to establish an in vitro model of hypoxic-ischemic brain damage. Western blot was used to measure the expression of autophagy-related proteins Beclin1 and LC3 and Clock protein at different time points. The changes in the expression of Beclin1 and LC3 were measured after the expression of Clock protein in neurons was inhibited by small interfering RNA technique. RESULTS: The expression of autophagy-related proteins Beclin1 and LC3Ⅱ in neurons cultured in vitro displayed a rhythmic fluctuation; after OGD treatment, the expression of Beclin1 and LC3Ⅱ gradually increased over the time of treatment and no longer had a rhythmic fluctuation. Compared with the sham-operation group, the HI group had a significant reduction in the expression of Clock protein in the cortex and hippocampus (P<0.05). After OGD treatment, the neurons cultured in vitro had a significant reduction in the expression of Clock protein (P<0.05). Compared with the negative control group, the Clock gene inhibition group had significant reductions in the expression of Beclin1 and LC3Ⅱ (P<0.05). CONCLUSIONS: Hypoxia/ischemia induces the disorder in the expression rhythm of autophagy-related proteins Beclin1 and LC3, and the mechanism may be associated with the fact that the circadian protein Clock participates in the regulation of the expression of Beclin1 and LC3.

[Effects of PINK1 gene on cell apoptosis and cell autophagy in neonatal mice with hypoxic-ischemic brain damage].

OBJECTIVE: To study the effect of PINK1 (phosphatase and tensin homolog deleted on chromosome ten induced putative kinase 1) gene on cell apoptosis and cell autophagy in neonatal mice with hypoxic-ischemic brain damage (HIBD). METHODS: Seventy-two wild-type C57BL/6 mice and 72 PINK1 gene knockout neonatal C57BL/6 mice were randomly divided into four groups: sham-operated wild-type (SWT), HIBD model wild-type (MWT), sham-operated knockout (SKO) and HIBD model knockout (MKO). HIBD model was prepared by low oxygen exposure for 2.5 hours after right carotid artery ligation. After 24 hours of hypoxia-ischemia treatment, TTC (2,3,5-triphenyl four azole nitrogen chloride) staining was used to measure brain infarct volume. The immunohistochemical staining was used to measure the expression of cell apoptosis protein cleaved-caspase-3 (CC3) in brain tissues. The TUNEL method was used to measure cell apoptosis. The immunofluorescence staining and Western blot were used to measure the expression of cell autophagy protein LC3. RESULTS: Compared with the MWT group, the infarct volume of brain tissues was markedly reduced in the MKO group (P<0.05), the number of apoptotic cells and the cell apoptosis index were markedly decreased in the MKO group (P<0.05), the expression of apoptosis protein CC3 was significantly reduced in the MKO group (P<0.05), the expression of cell autophagy protein LC3 was significantly decreased in the MKO group, and the autophagy indicator LC3II/LC3I was also markedly reduced in the MKO group (P<0.05). CONCLUSIONS: PINK1 gene knockout can protect neonatal mice from HIBD.

Metformin attenuates white matter injury in neonatal mice through activating NRF2/HO-1/NF-κB pathway.

White matter injury (WMI) is a major form of brain injury that occurs in preterm infants and develops into lifelong disabilities, including cerebral palsy, impaired cognitive function, and psychiatric disorders. Metformin (MET) has been reported to have neuroprotective effects. However, whether MET is responsible for neuroprotection against WMI remains unclear. In this study, we established a WMI model in neonatal mice to explore the neuroprotective effects of MET and attempted to elucidate its potential mechanisms. Our results showed that MET increased the expression of myelin basic protein (MBP), oligodendrocyte transcription factor 2 (Olig2), and CC1, improved the thickness and density of the myelin sheath, and reduced oxidative stress and microglial infiltration after chronic hypoxia induction. Moreover, MET improved memory, learning, and motor abilities as well as relieved anxiety-like behaviors in mice with WMI. These protective effects of MET may involve the upregulation of the nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1(HO-1)/NF-κB pathway related protein expressions. In addition, the NRF2 inhibitor ML385 could significantly reverse the effects of MET. In conclusion, this study suggested that MET attenuated chronic hypoxia-induced WMI through activating the NRF2/HO-1/NF-κB pathway, indicating that MET might be a promising therapeutic option for WMI.

A New Approach for Exploring Reperfusion Brain Damage in Hypoxic Ischemic Encephalopathy.

Reperfusion is an essential pathological stage in hypoxic ischemic encephalopathy (HIE). Although the Rice-Vannucci model is widely used in HIE research, it remains difficult to replicate HIE-related reperfusion brain injury. The purpose of this study is to establish a rat model of hypoxia ischemia reperfusion brain damage (HIRBD) using a common carotid artery (CCA) muscle bridge in order to investigate the mechanisms of cerebral resistance to hypoxic-ischemic and reperfusion brain damage. Random assignment of Sprague-Dawley (SD) rats to the Sham, HIRBD, and Rice-Vannucci groups. Changes in body weight, mortality rate, spontaneous alternation behavior test (SAB test), and dynamic changes in cerebral blood flow (CBF) were detected. The damaged cerebral cortices were extracted for morphological comparison, transcriptomic analysis, and quantitative real-time PCR. Harvesting the hippocampus for transmission electron microscopy (TEM) detection. As a result, CCA muscle bridge could effectively block CBF, which recovered after the muscle bridge detachment. Pathological comparison, the SAB test, and TEM analysis revealed that brain damage in Rice-Vannucci was more severe than HIRBD. Gpx1, S100a6, Cldn5, Esr1, and Gfap were highly expressed in both HIRBD and Rice-Vannucci. In conclusion, the CCA muscle bridge-established HIRBD model could be used as an innovative and dependable model to simulate pathological process of HIRBD.

CRISPR/Cas9 system and its applications in nervous system diseases.

The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system is an acquired immune system of many bacteria and archaea, comprising CRISPR loci, Cas genes, and its associated proteins. This system can recognize exogenous DNA and utilize the Cas9 protein's nuclease activity to break DNA double-strand and to achieve base insertion or deletion by subsequent DNA repair. In recent years, multiple laboratory and clinical studies have revealed the therapeutic role of the CRISPR/Cas9 system in neurological diseases. This article reviews the CRISPR/Cas9-mediated gene editing technology and its potential for clinical application against neurological diseases.

Corrigendum to 'CRISPR/Cas9 system and its applications in nervous system diseases' [Genes & Diseases 11 (2024) 675-686].

[This corrects the article DOI: 10.1016/j.gendis.2023.03.017.].

[Clinical features and homological analysis of Pichia ohmeri-caused hospital-acquired fungemia in premature infants].

OBJECTIVE: To analyze the clinical features of fungemia caused by Pichia ohmeri (P. ohmeri) in neonate intensive care unit and explore its molecular biological characteristics so as to improve its diagnosis and treatment level. METHODS: The clinical data of 6 infected infants were retrospectively analyzed. The strains obtained from them were identified and homological analysis was performed through randomly amplified polymorphic assay to explore the epidemiological characteristics of this nosocomial infection. RESULTS: Before the isolation of P. ohmeri, they received intravenous antibacterial therapy for 13 - 45 days. Among them, 4 received mechanical ventilation and 5 had a peripheral insertion of central venous catheters. Five infants were healed after a therapy of caspofungin for 15 - 30 days. One neonate recurred after a 30-day administration of fluconazole. The strain was identified and confirmed as P. ohmeri. RAPD genotyping results showed that all 6 strains were from the same clone. No similar cases occurred after positive control measures despite a negative epidemiological sampling. CONCLUSIONS: P. ohmeri may cause premature infant fungemia and lead to its spread in hospital. Hospital infection control is a key point. And caspofungin is both safe and effective in the therapy of neonate fungemia.

Chloroquine Protects Hypoxia/Ischemia-Induced Neonatal Brain Injury in Rats by Mitigating Blood-Brain Barrier Disruption.

Neonatal hypoxic-ischemic (H/I) brain damage (HIBD) is a devastating condition for which there are presently no effective therapeutic strategies against its severe neurological deficits in neonates and young children. Traditionally, H/I induces the compromise of the blood-brain barrier (BBB), which causes neuronal cell death, eventually resulting in brain secondary injury. In addition to neonatal HIBD, chloroquine (CQ) has been proved to exert a protective effect on BBB disruption in several brain injury models. The main purpose of this research was to study whether CQ protects the BBB from H/I insult and confers beneficial neuroprotection in the neonatal Rice-Vannucci rat model. Herein, we reported that CQ administration significantly reduced brain damage and improved behavioral dysplasia after H/I injury. Moreover, we demonstrated the protective effects of CQ on BBB integrity, evidenced by ameliorating brain edema and Evans blue extravasation, inhibiting the degeneration of the tight junction and adherens junction proteins, and improving pericyte survival in neonatal rats after HIBD. These findings indicated that CQ administration protected the BBB against H/I injury, thereby ameliorating brain damage and promoting neurofunctional recovery. Collectively, our data demonstrated that CQ played a crucial role in BBB integrity after neonatal H/I injury, which sheds light on the development of therapeutic agents to treat HIBD.

Ginsenoside Rb1 inhibits ferroptosis to ameliorate hypoxic-ischemic brain damage in neonatal rats.

Hypoxic ischemic encephalopathy (HIE) is among the leading causes of neonatal mortality, and currently there is no effective treatment. Ginsenoside Rb1 (GsRb1) is one of the principal active components of ginseng, and has protective benefits against oxidative stress, inflammation, hypoxic injury, and so on. However, the role and underlying mechanism of GsRb1 on HIE are unclear. Here, we established the neonatal rat hypoxic-ischemic brain damage (HIBD) model in vivo and the PC12 cell oxygen-glucose deprivation (OGD) model in vitro to investigate the neuroprotective effects of GsRb1 on HIE, and illuminate the potential mechanism. Our results showed that GsRb1 and the ferroptosis inhibitor liproxstatin-1 (Lip-1) could significantly restore System Xc activity and antioxidant levels as well as inhibit lipid oxidation levels and inflammatory index levels of HIBD and OGD models. Taken together, GsRb1 might inhibit ferroptosis to exert neuroprotective effects on HIE through alleviating oxidative stress and inflammation, which will set the foundation for future research on ferroptosis by reducing hypoxic-ischemic brain injury and suggest that GsRb1 might be a promising therapeutic agent for HIE.

Diallyl disulfide attenuates pyroptosis via NLRP3/Caspase-1/IL-1ß signaling pathway to exert a protective effect on hypoxic-ischemic brain damage in neonatal rats.

Hypoxic-ischemic encephalopathy (HIE) is a perinatal brain disease caused by hypoxia in neonates. It is one of the leading causes of neonatal death in the perinatal period, as well as disability beyond the neonatal period. Due to the lack of a unified and comprehensive treatment strategy for HIE, research into its pathogenesis is essential. Diallyl disulfide (DADS) is an allicin extract, with detoxifying, antibacterial, and cardiovascular disease protective effects. This study aimed to determine whether DADS can alleviate HIE induced brain damage in rats and oxygen-glucose deprivation (OGD)-induced pyroptosis in PC12 cells, as well as whether it can inhibit pyroptosis via the NLRP3/Caspase-1/IL-1ß signaling pathway. In vivo, DADS significantly reduced the cerebral infarction volume, alleviated inflammatory reaction, reduced astrocyte activation, promoted tissue structure recovery, improved pyroptosis caused by HIE and improved the prognosis following HI injury. In vitro findings indicated that DADS increased cell activity, decreased LDH activity and reduced the expression of pyroptosis-related proteins, including IL-1ß, IL-18, and certain inflammatory factors in PC12 cells caused by OGD. Mechanistically, DADS inhibited pyroptosis and protected against HIE via the NLRP3/Caspase-1/IL-1ß pathway. The specific inhibitor of caspase-1, VX-765, inhibited caspase-1 activation, and IL-1ß expression was determined. Additionally, the overexpression of NLRP3 reversed the protective effect of allicin against OGD-induced pyroptosis. In conclusion, these findings demonstrated that DADS inhibits the NLRP3/Caspase-1/IL-1ß signaling pathway and decreases HI brain damage.

Effect of arctigenin on neurological diseases: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: Arctium lappa L. is a common specie of Asteraceae. Its main active ingredient, Arctigenin (AG), in mature seeds exerts pharmacological effects on the Central Nervous System (CNS). AIM OF THE STUDY: To review studies on the specific effects of the AG mechanism on various CNS diseases and elucidate signal transduction mechanisms and their pharmacological actions. MATERIALS AND METHODS: This investigation reviewed the essential role of AG in treating neurological disorders. Basic information on Arctium lappa L. was retrieved from the Pharmacopoeia of the People's Republic of China. The related articles from 1981 to 2022 on the network database (including CNKI, PubMed, and Wan Fang and so on) were reviewed using AG and CNS diseases-related terms such as Arctigenin and Epilepsy. RESULTS: It was confirmed that AG has a therapeutic effect on Alzheimer's disease, Glioma, infectious CNS diseases (such as Toxoplasma and Japanese Encephalitis Virus), Parkinson's disease, Epilepsy, etc. In these diseases, related experiments such as a Western blot analysis revealed that AG could alter the content of some key factors (such as the reduction of Aß in Alzheimer's disease). However, in-vivo AG's metabolic process and possible metabolites are still undetermined. CONCLUSION: Based on this review, the existing pharmacological research has indeed made objective progress to elucidate how AG prevents and treats CNS diseases, especially senile degenerative disease such as Alzheimer's diseases. It was revealed that AG could be used as a potential nervous system drug as it has a wide range of effects in theory with markedly high application value, especially in the elder group. However, the existing studies are limited to in-vitro experiments; therefore, little is known about how AG metabolizes and functions in-vivo, limiting its clinical application and requiring further research.

Myricetin attenuates hypoxic-ischemic brain damage in neonatal rats via NRF2 signaling pathway.

Introduction: Hypoxic-ischemic encephalopathy (HIE) is a crucial cause of neonatal death and neurological sequelae, but currently there is no effective therapy drug for HIE. Both oxidative stress and apoptosis play critical roles in the pathological development of HIE. Myricetin, a naturally extracted flavonol compound, exerts remarkable effects against oxidative stress, apoptosis, and inflammation. However, the role and underlying molecular mechanism of myricetin on HIE remain unclear. Methods: In this study, we established the neonatal rats hypoxic-ischemic (HI) brain damage model in vivo and CoCl2 induced PC12 cell model in vitro to explore the neuroprotective effects of myricetin on HI injury, and illuminate the potential mechanism. Results: Our results showed that myricetin intervention could significantly reduce brain infarction volume, glia activation, apoptosis, and oxidative stress marker levels through activating NRF2 (Nuclear factor-E2-related factor 2) and increase the expressions of NRF2 downstream proteins NQO-1 and HO-1. In addition, the NRF2 inhibitor ML385 could significantly reverse the effects of myricetin. Conclusion: This study found that myricetin might alleviate oxidative stress and apoptosis through NRF2 signaling pathway to exert the protective role for HI injury, which suggested that myricetin might be a promising therapeutic agent for HIE.

Reperfusion after hypoxia-ischemia exacerbates brain injury with compensatory activation of the anti- ferroptosis system: based on a novel rat model.

Hypoxic-ischemic encephalopathy, which predisposes to neonatal death and neurological sequelae, has a high morbidity, but there is still a lack of effective prevention and treatment in clinical practice. To better understand the pathophysiological mechanism underlying hypoxic-ischemic encephalopathy, in this study we compared hypoxic-ischemic reperfusion brain injury and simple hypoxic-ischemic brain injury in neonatal rats. First, based on the conventional Rice-Vannucci model of hypoxic-ischemic encephalopathy, we established a rat model of hypoxic-ischemic reperfusion brain injury by creating a common carotid artery muscle bridge. Then we performed tandem mass tag-based proteomic analysis to identify differentially expressed proteins between the hypoxic-ischemic reperfusion brain injury model and the conventional Rice-Vannucci model and found that the majority were mitochondrial proteins. We also performed transmission electron microscopy and found typical characteristics of ferroptosis, including mitochondrial shrinkage, ruptured mitochondrial membranes, and reduced or absent mitochondrial cristae. Further, both rat models showed high levels of glial fibrillary acidic protein and low levels of myelin basic protein, which are biological indicators of hypoxic-ischemic brain injury and indicate similar degrees of damage. Finally, we found that ferroptosis-related Ferritin (Fth1) and glutathione peroxidase 4 were expressed at higher levels in the brain tissue of rats with hypoxic-ischemic reperfusion brain injury than in rats with simple hypoxic-ischemic brain injury. Based on these results, it appears that the rat model of hypoxic-ischemic reperfusion brain injury is more closely related to the pathophysiology of clinical reperfusion. Reperfusion not only aggravates hypoxic-ischemic brain injury but also activates the anti-ferroptosis system.

Ferrostatin-1 attenuates hypoxic-ischemic brain damage in neonatal rats by inhibiting ferroptosis.

Background: Hypoxic-ischemic brain damage (HIBD) is a type of brain damage that is caused by perinatal asphyxia and serious damages the central nervous system. At present, there is no effective drug for the treatment of this disease. Besides, the pathogenesis of HIBD remains elusive. While studies have shown that ferroptosis plays an important role in HIBD, its role and mechanism in HIBD are yet to be fully understood. Methods: The HIBD model of neonatal rats was established using the Rice-Vannucci method. A complete medium of PC12 cells was adjusted to a low-sugar medium, and the oxygen-glucose deprivation model was established after continuous hypoxia for 12 h. Laser Doppler blood flow imaging was used to detect the blood flow intensity after modeling. 2,3,5-triphenyl tetrazolium chloride staining was employed to detect ischemic cerebral infarction in rat brain tissue, and hematoxylin and eosin staining and transmission electron microscopy were used to observe brain injury and mitochondrial damage. Immunofluorescence was applied to monitor the expression of GFAP. Real-time quantitative polymerase chain reaction, western blot, and immunofluorescence were utilized to detect the expression of messenger RNA and protein. The level of reactive oxygen species (ROS) in cells was detected using the ROS detection kit. Results: The results showed that ferrostatin-1 (Fer-1) significantly alleviated the brain injury caused by hypoxia and ischemia. Fer-1 significantly increased the expression of SLC3A2, SLC7A11, ACSL3, GSS, and GPX4 (P<0.05) and dramatically decreased the expressions of GFAP, ACSL4, TFRC, FHC, FLC, 4-HNE, HIF-1α, and ROS (P<0.05). Conclusions: Fer-1 inhibits ferroptosis and alleviates HIBD by potentially targeting the GPX4/ACSL3/ACSL4 axis; however, its specific mechanism warrants further exploration.

[Clinical analysis of 31 cases of neonatal purulent meningitis caused by Escherichia coli].

OBJECTIVE: Neonatal purulent meningitis is a severe infection responsible for high mortality and disabling sequelae. Escherichia coli is the main pathogen of neonatal purulent meningitis. This study explored the clinical characteristics and antibiotic resistance of Escherichia coli-induced neonatal meningitis. METHODS: A retrospective chart review was performed. A total of 31 cases of neonatal purulent meningitis caused by Escherichia coli were identified in the neonatal intensive care unit between January 1, 2001 and December 31, 2011. The clinical characteristics and antibiotic sensitivity test results were analyzed. RESULTS: Fever, poor feeding, lethargy and seizure were common clinical signs of neonatal purulent meningitis caused by Escherichia coli. Acute complications mainly included hyponatremia (17 cases), hydrocephalus (8 cases), subdural collection (2 cases), ventriculitis (2 cases) and cerebral infarction (1 case). Thirty neonates (97%) had increased CRP levels. Of the 31 patients, 14 cases were cured and 12 had adverse outcomes (5 patients died during hospitalization). Escherichia coli strains were resistant (>50%) to commonly used penicillins and cephalosporins between 2007 and 2011, presenting significantly higher resistance rates than between 2001 and 2006. The detection rate of extended spectrum ß-lactamases (ESBLs)-producing strains between 2007 and 2011 increased significantly compared with between 2001 and 2006 (57% vs 0). CONCLUSIONS: The clinical manifestations of neonatal purulent meningitis caused by Escherichia coli are non specific. The outcome is poor. Monitoring of CRP levels is valuable for the early diagnosis of neonatal purulent meningitis. The antimicrobial resistance rates of Escherichia coli are increasing, especially to cephalosporins. The percentage of ESBLs-producing strains is increasing over the years.

Indole-3-propionic Acid Attenuates HI-Related Blood-Brain Barrier Injury in Neonatal Rats by Modulating the PXR Signaling Pathway.

The blood-brain barrier (BBB) is an important physiological barrier of the human body contributing to maintaining brain homeostasis and normal function. Hypoxic-ischemic (HI)-related brain injury is one of the main causes of neonatal acute morbidity and chronic disability. The previous research of our group confirmed that there was serious BBB destruction during HI brain injury. However, at present, the protection strategy of BBB is very limited, and further research on the protection mechanism is warranted. Indole-3-propionic acid (IPA) is a bacterial metabolism with anti-inflammatory and antioxidant properties, having neuroprotective effects and protective effects on the mucosal barrier. However, the role of IPA in BBB is not clear. In this research, we demonstrated the protective effect of IPA on BBB disruption from HI brain injury and hypothesized that it involves the amelioration of inflammation, oxidative stress, and MMP activation, thereby inhibiting apoptosis of rat brain microvascular endothelial cells (rBMECs). We demonstrated that expression levels of several inflammatory markers, including iNOS, TNF-α, IL-6, and IL-1ß, were significantly increased from HI damage or OGD injury. However, IPA treatment inhibited the increase significantly. Moreover, we demonstrated that IPA reduced intracellular ROS levels and MMP activation in rBMECs from OGD injury. Further research on the underlying detailed molecular mechanisms suggested that IPA attenuates inflammation by inhibiting NF-κB signaling. Finally, we investigated the mechanism of the relationship between PXR activation and NF-κB inhibition. The results suggested overexpression of PXR in rBMECs could significantly counteract the decrease of junction proteins and downregulate the increased p-IκB-α and p-NF-κB from OGD injury. However, the protective effects of IPA were reversed by antagonists of the PXR. Taken together, IPA might mitigate HI-induced damage of the BBB and the protective effect may be exerted through modulating the PXR signaling pathway.

A neonate with molybdenum cofactor deficiency type B.

Molybdenum cofactor deficiency (MoCD) is an autosomal recessive disease which leads to a combined deficiency of molybdenum cofactor dependent enzymes. There are four different genes in molybdenum cofactor biosynthesis, MOCS1, MOCS2, MOCS3, GEPH. The patients with MOCS2 homozygous mutation who onset in the neonatal period always have severe seizures, feeding difficulties, progressive neurological deterioration. The incidence of the disease is low, and certain types have never been reported in China. Here, we present a Chinese term infant with MOCS2 who presented seizure, intolerance to feed and hypotonia on the third day after birth. Treatment included intravenous nutrition, antibiotic, and anticonvulsant therapy. The seizure can't be controlled and her encephalopathy progressed. A homozygous mutation in exon 4 in MOSC2 gene was found and the mutation of the patient has not been reported before. In conclusion, the patients with MOCS2 who onset in neonatal period often shows uncontrolled seizure, feeding difficulties, hypotonia and early death. And the MRI of them shows severe encephalomalacia. There is no treatment for the disease by now, but early diagnosis and genetic detection can give the family genetic counseling.