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Background Neonatal hypoxic-ischemic brain injury (HIE) is caused by perinatal asphyxia, which is associated with various confounding factors. Although studies on the pathogenesis and treatment of HIE have matured, sub-hypothermia is the only clinical treatment available for HIE. Previous evidence indicates that chlorogenic acid (CGA) exerts a potential neuroprotective effect on brain injury. However, the role of CGA on neonatal HI brain damage and the exact mechanism remains elusive. Here, we investigate the effects of CGA on HI models in vivo and in vitro and explore the underlying mechanism. Methods In the in vivo experiment, we ligated the left common carotid artery of 7-day-old rats and placed the rats in a hypoxic box for 2 h . We did not ligate the common carotid artery of the pups in the sham group since they did not have hypoxia. Brain atrophy and infarct size were evaluated by Nissl staining, HE staining and 2,3,5-triphenyltetrazolium chloride monohydrate (TTC) staining. Morris Water Maze test (MWM) was used to evaluate neurobehavioral disorders. Western-blotting and immunofluorescence were used to detect the cell signaling pathway. Malondialdehyde (MDA) content test, catalase (CAT) activity detection and Elisa Assay was used to detect levels of inflammation and oxidative stress. in vitro experiments were performed on isolated primary neurons. Result In our study, pretreatment with CGA significantly decreased the infarct volume of neonatal rats after HI, alleviated brain edema, and improved tissue structure in vivo. Moreover, we used the Morris water maze to verify CGA’s effects on enhancing the learning and cognitive ability and helping to maintain the long-term spatial memory after HI injury. However, Sirt1 inhibitor EX-527 partially reversed these therapeutic effects. CGA pretreatment inhibited neuronal apoptosis induced by HI by reducing inflammation and oxidative stress. The findings suggest that CGA potentially activates Sirt1 to regulate the Nrf2-NF-κB signaling pathway by forming complexes thereby protecting primary neurons from oxygen-glucose deprivation (OGD) damage. Also, CGA treatment significantly suppresses HI-induced proliferation of glial. Conclusion Collectively, this study uncovered the underlying mechanism of CGA on neonatal HI brain damage. CGA holds promise as an effective neuroprotective agent to promote neonatal brain recovery from HI-induced injury. Graphical Abstract 8NePktn-RrRjrUAHAHCXyY Video Abstract

Background Abnormal pulmonary vascular development poses significant clinical challenges for infants with bronchopulmonary dysplasia (BPD). Although numerous factors have been suggested to control the development of pulmonary blood vessels, the mechanisms underlying the role of long noncoding RNAs (lncRNAs) in this process remain unclear. Methods A lncRNA array was used to measure the differential expression of lncRNAs in premature infants with and without BPD. The expression of lncRNA-VSIG2-1:1 in patients with BPD and hyperoxia-induced human pulmonary microvascular endothelial cells (HPMECs) was assessed using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Fluorescence in situ hybridization (FISH) assay was performed to detect the subcellular localization of lncRNA-VSIG2-1:1. Pulmonary microvascular endothelial cells were stably transfected with adenoviral vectors to silence or overexpress lncRNA-VSIG2-1:1. The effects of lncRNA-VSIG2-1:1 on the proliferation, migration, and tube formation abilities of HPMECs subjected to hyperoxia were examined by performing Cell Counting Kit‐8 (CCK-8), cell migration, and tubule formation assays. RNA sequencing (RNA-seq) was performed to determine the correlation between lncRNA-VSIG2-1:1 and phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT). The protein levels of vascular endothelial growth factor (VEGF), p-PI3K, PI3K, p-AKT, and AKT were determined using western blotting. Results The expression of lncRNA-VSIG2-1:1 was upregulated in patients with BPD and hyperoxia-treated HPMECs. Inhibiting lncRNA-VSIG2-1:1 expression promoted the proliferation, migration, and tube-formation abilities of HPMECs, while significantly increasing VEGF, p-PI3K, and p-AKT levels. Conclusion Our findings reveal that the suppression of lncRNA-VSIG2-1:1 expression stimulates angiogenesis in vitro by inducing the initiation of the VEGF/PI3K/AKT signaling pathway. This observation may aid the development of novel therapeutic targets for treating BPD.

Background Neonatal hypoxic-ischemic brain damage (HIBD) is a leading cause of neurological deficits and death in neonates. In HIBD, the death of endothelial cells and disruption of the blood–brain barrier (BBB) are closely related to the severity of brain damage and long-term clinical outcomes. There is increasing evidence that a glycolytic enzyme, pyruvate kinase M2 (PKM2), is essential for managing metabolic processes in endothelial cells, but its role (and underlying molecular mechanism) in hypoxic-ischemic (HI)-associated endothelial cell metabolism, cell survival, and BBB function remains unknown. Methods We established an in vivo HI-induced brain injury rat model and an in vitro model in which human cerebral microvascular endothelial cells (hCMECs) underwent oxygen-glucose deprivation (OGD). Infarct volume was measured and neurobehavioral tests were conducted to assess brain damage, and Evans blue extravasation and FITC-dextran were used to evaluate the BBB. RNA sequencing, qRT–PCR, western blotting, and immunofluorescence labeling were conducted to identify the molecular mechanisms underlying HIBD. Results PKM2 expression was upregulated in the brains of HIBD rats and in OGD-treated hCMECs. The inhibition of PKM2 greatly upregulated the expression of pyroptosis-associated proteins, including NLRP3, cleaved caspase-1, GSDMD, IL-1β, and IL-18. In contrast, the activation of PKM2 preserved junctional proteins and maintained the integrity of the BBB, which together improved functional recovery in HIBD rats. Mechanistically, preconditioning of PKM2 contributed to lactate-mediated cellular defense mechanisms, including the activation of nuclear factor erythroid 2-related factor 2 (NRF2) and thioredoxin (TRX), and to the downregulation of thioredoxin-interacting protein (TXNIP) via a modest increase in reactive oxygen species. Conclusions Our analyses provide compelling evidence that PKM2 preconditioning attenuates endothelial cell pyroptosis and BBB disruption in neonatal HIBD by causing oxidative stress resistance and activating the NRF2/TRX/TXNIP pathway. Therefore, PKM2 represents a promising pharmacological target for treating HIBD.

Ferroptosis is a novel regulated cell death characterized by metabolic disorders and iron-dependent oxidative destruction of the lipid bilayer. It is primarily caused by the imbalance of oxidation and anti-oxidation in the body and is precisely regulated by numerous factors and pathways inside and outside the cell. Recent studies have indicated that ferroptosis plays a vital role in the pathophysiological process of multiple systems of the body including the nervous system. Ferroptosis may be closely linked to the occurrence and development of neurodegenerative diseases, strokes, and brain tumors. It may also be involved in the development, maturation, and aging of the nervous system. Therefore, this study aims to investigate ferroptosis's occurrence and regulatory mechanism and summarize its research progress in the pathogenesis and treatment of neurological diseases. This would allow for novel ideas for basic and clinical research of neurological diseases.

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 CoCl 2 induced PC1 2 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.

Background Neonatal Hypoxic-Ischemic Encephalopathy (HIE) is a critical lifelong disabling neonatal disease with insufficient effective therapies. Signaling molecules derived from Astrocyte-Neuron Crosstalk have the potential to improve the prognosis, but relevant HIE research is limited. Methods We established hypoxic–ischemic brain damage (HIBD) in postnatal day 7 rat pups using the Rice–Vannucci model, and verified the injury both structurally and hemodynamically by histopathology and laser speckle contrast imaging. Whole-brain single-cell RNA sequencing was performed at P10, and proteomic profiling was conducted on astrocytes subjected to oxygen–glucose deprivation. We charted astrocyte diversity in situ using multiplex immunofluorescence. Thyroid hormones and signaling pathways were quantified by ELISA and Western blotting. Therapeutic efficacy was assessed by histopathology and the Morris water maze. Results A brain-wide single-cell transcriptomic atlas revealed a strong transcriptional coupling between astrocytes and neurons. Among astrocytes, we identified and functionally characterized a Dio2⁺Slc1a2⁺ subpopulation with metabolic and neuroprotective features, which was markedly depleted after HIBD. Pseudotime trajectories showed dynamic astrocyte state transitions over time, contextualizing the loss and reparative potential of the Dio2⁺ subpopulation. In vivo and in vitro, boosting astrocytic Dio2 or delivering exogenous Triiodothyronine(T3) enhanced neural repair and improved behavior across both early and long-term stages. Conclusions We defined a previously unrecognized neuroprotective astrocyte subpopulation and revealed temporal heterogeneity in astrocytic inflammatory responses in HIE. We also identified a T3-mediated astrocyte–neuron crosstalk mechanism that mitigated HIBD, highlighting a tractable therapeutic avenue.

Background Neonatal hypoxic-ischemic encephalopathy (HIE) affects as many as 100,000 infants each year in China. Therapeutic hypothermia reduces HIE related mortality and long-term neurodevelopmental disabilities. National guidelines for HIE management were published a decade ago. This study aimed to investigate the current status of HIE diagnosis and treatment in China. Method This prospective cross-sectional national survey used a questionnaire evaluating practices related to HIE management. Descriptive statistics and Chi-square or Fisher’s exact test were used, and a p -value of < 0.05 was considered significant. Results The 273 hospitals that completed the survey were located in 31 of the 34 provincial districts in China. Eighty-eight percent of the hospitals were Level III hospitals, and 74% treated 10 or more HIE cases annually. Awareness rates of the national guidelines for HIE diagnosis, HIE treatment, and therapeutic hypothermia protocol were 85, 63, and 78%, respectively. Neurological manifestations and blood gas were used as HIE diagnostic criteria by 96% (263/273) and 68% (186/273) of the hospitals, respectively. Therapeutic hypothermia was used in 54% (147/273) of hospitals. The percentage of general hospitals that implemented therapeutic hypothermia (43%, 71/165) was significantly lower than that in maternity and infant hospitals (67%, 49/73) ( χ 2  = 11.752, p  = 0.001) and children’s hospitals (77%, 27/35) ( χ 2  = 13.446, p  < 0.001). Reasons for not providing therapeutic hypothermia included reduction of HIE cases in recent years (39%), high cost of cooling devices and treatment (31%), lack of training (26%), and safety concerns (4%). Among the hospitals that provided therapeutic hypothermia, 27% (39/147) were in full compliance with the recommended protocol. Eighty-one percent (222/273) of the hospitals treated HIE infants with putative neuroprotective agents alone or in combination with cooling. Ninety-one percent of the hospitals had long-term neurodevelopmental follow-up programs for infants with HIE. Conclusions There is significant heterogeneity in HIE diagnosis and treatment in China. Therapeutic hypothermia has not become a standard of care for neonatal HIE nationwide. Unproven agents are widely used for HIE treatment. Nationwide standardization of HIE management and dissemination of therapeutic hypothermia represent the opportunities to reduce mortality and improve long-term neurodevelopmental outcomes of children affected by HIE.

Neonatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of neurological disability and mortality in newborns, with limited therapeutic options beyond hypothermia. Bromodomain and extra-terminal domain (BET) proteins function as epigenetic readers that regulate gene expression by recognizing acetylated lysine residues on histones. Among BET inhibitors, (+)-JQ1 (JQ1) has recently garnered attention due to its potent anti-inflammatory and antioxidant properties. This study aims to investigate the neuroprotective effects of JQ1 and elucidate the underlying mechanisms in the context of HIE brain injury. We established an in vivo model via the modified Rice-Vannucci method, alongside an in vitro model using oxygen-glucose deprivation (OGD) in HT22 cells. Transcriptomic changes in cortical tissues during the acute phase after HIE were profiled through RNA sequencing. Western blot, immunofluorescence, immunohistochemistry, and transmission electron microscopy were employed to measure the levels of neuroinflammation and ferroptosis. Furthermore, SIRT3-knockdown HT22 cells under OGD conditions were used to validate the JQ1-mediated protective mechanisms. JQ1 treatment significantly reduced cerebral infarction, edema, and neuronal loss, while improving emotional behavior and cognitive functions after HIE. It inhibited the cGAS-STING pathway, and alleviated ferroptosis by restoring GPX4 and system Xc⁻ activity while reducing iron overload. These effects were reversed by the SIRT3 inhibitor 3-TYP or SIRT3 siRNA. JQ1 exerts neuroprotective effects in neonatal hypoxic-ischemic encephalopathy by attenuating neuroinflammation and suppressing ferroptosis. We demonstrate that SIRT3 upregulation in the brain underlies the neuroprotective role of JQ1.

Background Brain abscesses are uncommon but life-threatening in extremely preterm (EP, Gestational Age < 28 weeks) infants. The information of long-time follow-up is rare, but very few cases presented almost intact neural function after injury. Case presentation We report the clinical course and the outcome of a 27-week preterm infant with multiple brain abscesses. The brain abscesses were detected by cranial magnetic resonance imaging (MRI) and were treated with surgical aspiration twice and a 7-week course of intravenous antibiotics. The patient had two episodes of seizure like activities at 8 and 11 years old respectively, whereas she had normal results of electroencephalogram (EEG). MRI showed encephalomalacia and periventricular leukomalacia. Otherwise, she had no obvious neurological deficits based on multiple physical examination and her intellectual quotient (IQ) was in normal range in the long-time follow-up. Conclusions Early diagnosis of brain abscesses and appropriate therapy can improve the prognosis. Furthermore, this case report provides an example of the possible neuroplasticity of brain in EP infants.

Neonatal meningitis (NM) caused by remains a major health problem in industrialized countries. Currently, information on the epidemiology and antimicrobial susceptibility patterns of NM in developing countries such as China is relatively scarce. Therefore, the present study investigated changes in the antimicrobial susceptibility of causing NM in a perinatal center in eastern China over the past 20 years. This survey was conducted during three periods: 2001-2006, 2007-2012, and 2013-2020. NM was diagnosed according to the number of white blood cells in the cerebrospinal fluid (CSF) and the presence of a single potential pathogenic bacterium in the culture prepared from the blood or CSF of a newborn baby. Changes in the antimicrobial susceptibility of were analyzed. In total, 182 NM cases were identified. was identified in 69 of these cases, and in 21 of these cases, extended-spectrum beta-lactamase (ESBL) production was detected. was the main cause of NM identified in this study. The overall susceptibility of to third-generation cephalosporins such as cefotaxime decreased from 100% during 2001-2006 to 50% during 2007-2012 and, subsequently, increased to 71.0% during 2013-2020. This pattern of change is correlated with bacterial ESBL production. Only 8.3% of found in samples collected from infants with early onset meningitis (EOM) produced ESBL, while 37.3% of isolated from children with late-onset meningitis (LOM) produced ESBL. remains the primary pathogen of NM. Compared with that isolated from infants with LOM, the percentage of ESBL-producing multidrug-resistant isolated from infants with EOM is significantly lower. Clinicians should consider this trend when determining appropriate and effective antibiotics as empirical treatment for NM.