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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.

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.

Neonatal hypoxic-ischemic encephalopathy (HIE), caused by perinatal asphyxia, is characterized by high morbidity and mortality, but there are still no effective therapeutic drugs. Mitochondrial biogenesis and apoptosis play key roles in the pathogenesis of HIE. Protopine (Pro), an isoquinoline alkaloid, has anti-apoptotic and neuro-protective effects. However, the protective roles of Pro on neonatal hypoxic-ischemic brain injury remain unclear. In this study, we established a CoCl -induced PC12 cell model in vitro and a neonatal rat hypoxic-ischemic (HI) brain damage model in vivo to explore the neuro-protective effects of Pro and try to elucidate the potential mechanisms. Our results showed that Pro significantly reduced cerebral infarct volume, alleviated brain edema, inhibited glia activation, improved mitochondrial biogenesis, relieved neuron cell loss, decreased cell apoptosis and reactive oxygen species (ROS) after HI damage. In addition, Pro intervention upregulated the levels of p-AMPK/AMPK and PGC1α as well as the downstream mitochondrial biogenesis related factors, such as nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM), but the AMPK inhibitor compound c (CC) could significantly reverse these effects of Pro. Pro may exert neuroprotective effects on neonatal hypoxic-ischemic brain damage via activation of the AMPK/PGC1α pathway, suggesting that Pro may be a promising therapeutic candidate for HIE, and our study firstly demonstrate the neuro-protective roles of Pro in HIE models.

Background Neuroinflammation and oxidative stress, mediated by microglial activation, hinder the development of oligodendrocytes (OLs) and delay myelination in preterm infants, leading to white matter injury (WMI) and long‐term neurodevelopmental sequelae. Peroxisome proliferator‐activated receptor gamma (PPAR‐γ) has been reported to inhibit inflammation and oxidative stress via modulating microglial polarization in various central nervous system diseases. However, the relationship between PPAR‐γ and microglial polarization in neonatal WMI is not well understood. Therefore, this study aimed to elucidate the role and mechanisms of PPAR‐γ in preterm infants affected by WMI. Methods In this study, an in vivo hypoxia‐ischemia (HI) induced brain WMI neonatal mouse model was established. The mice were administered intraperitoneally with either RSGI or GW9662 to activate or inhibit PPAR‐γ, respectively. Additionally, an in vitro oxygen–glucose deprivation (OGD) cell model was established and pretreated with pcDNA 3.1‐PPAR‐γ or si‐PPAR‐γ to overexpress or silence PPAR‐γ, respectively. The neuroprotective effects of PPAR‐γ were investigated in vivo. Firstly, open field test, novel object recognization test, and beam‐walking test were employed to assess the effects of PPAR‐γ on neurobehavioral recovery. Furthermore, assessment of OLs loss and OL‐maturation disorder, the number of myelinated axons, myelin thickness, synaptic deficit, activation of microglia and astrocyte, and blood–brain barrier (BBB) were used to evaluate the effects of PPAR‐γ on pathological repair. The mechanisms of PPAR‐γ were explored both in vivo and in vitro. Assessment of microglia polarization, inflammatory mediators, reactive oxygen species (ROS), MDA, and antioxidant enzymes was used to evaluate the anti‐inflammatory and antioxidative effects of PPAR‐γ activation. An assessment of HMGB1/NF‐κB and NRF2/KEAP1 signaling pathway was conducted to clarify the mechanisms by which PPAR‐γ influences HI‐induced WMI in neonatal mice. Results Activation of PPAR‐γ using RSGI significantly mitigated BBB disruption, promoted M2 polarization of microglia, inhibited activation of microglia and astrocytes, promoted OLs development, and enhanced myelination in HI‐induced WMI. Conversely, inhibition of PPAR‐γ using GW9662 further exacerbated the pathologic hallmark of WMI. Neurobehavioral tests revealed that neurological deficits were ameliorated by RSGI, while further aggravated by GW91662. In addition, activation of PPAR‐γ significantly alleviated neuroinflammation and oxidative stress by suppressing HMGB1/NF‐κB signaling pathway and activating NRF2 signaling pathway both in vivo and in vitro. Conversely, inhibition of PPAR‐γ further exacerbated HI or OGD‐induced neuroinflammation, oxidative stress via modulation of the same signaling pathway. Conclusions Our findings suggest that PPAR‐γ regulates microglial activation/polarization as well as subsequent neuroinflammation/oxidative stress via the HMGB1/NF‐κB and NRF2/KEAP1 signaling pathway, thereby contributing to neuroprotection and amelioration of HI‐induced WMI in neonatal mice. Our findings suggest that PPAR‐γ regulates microglial activation/polarization as well as subsequent neuroinflammation/oxidative stress via the HMGB1/NF‐κB and NRF2 signaling pathway, thereby contributing to myelination and amelioration of WMI after HI insult in neonatal mice.

White matter injury (WMI), the most common type of brain damage in infants born preterm, is characterized by failure in oligodendrocyte progenitor cell maturation and myelination, thereby contributing to long-term neurological impairments. Regrettably, effective therapies for promoting remyelination and improving function are currently lacking for this growing population affected by WMI. Recombinant human fibroblast growth factor (rhFGF) 21 modulated microglial activation and then ameliorated brain damage and improved neurological deficits in several central nervous system diseases. However, the effects of rhFGF21 treatment on WMI in preterm infants remain uncertain. In this study, we established an in vivo mouse model of cerebral hypoxia–ischemia (HI)-induced brain WMI and an in vitro model using oxygen–glucose deprivation (OGD)-treated HMC3 cells to investigate the neuroprotective effects of rhFGF21 against WMI and elucidated the potential mechanism. Our findings demonstrated that administration of rhFGF21 significantly ameliorated the retardation of oligodendrocyte differentiation, promoted myelination, and mitigated axonal deficits, synaptic loss, and GFAP scarring, thereby improving lifelong cognitive and neurobehavioral dysfunction associated with WMI. Moreover, rhFGF21 modulated microglial polarization, promoted a shift from the M1 to the M2 microglial phenotype, and suppressed microglial activation, thus ameliorating inflammatory response and oxidative stress. Additionally, rhFGF21 treatment significantly inhibited the HMGB1/NF-κB pathway linked to inflammation, and activated the NRF2 pathway associated with oxidative stress through the upregulation of PPAR-γ. Importantly, the beneficial effects of rhFGF21 on HI-induced WMI and microglial activation were dramatically inhibited by PPAR-γ antagonist and its siRNA. Our findings provide compelling evidence that rhFGF21 treatment mitigated the inflammatory response and oxidative stress through the modulation of microglial polarization via the PPAR-γ-mediated HMGB1/NF-κB pathway and the NRF2 pathway, respectively, contributes to neuroprotection and the amelioration of WMI in neonatal mice. Thus, rhFGF21 represents a promising therapeutic agent for the treatment of neonatal WMI.

White matter injury (WMI) is a common complication of preterm birth, potentially resulting in long-term behavioral and motor abnormalities. The objective of this study is to investigate the neuroprotective effects of glycyrrhizin (GLY) on WMI, and try to elucidate the potential mechanisms. In vivo chronic hypoxia-induced WMI mouse model and in vitro oxygen-glucose deprivation (OGD) induced WMI cell model were established, and the effects of GLY on WMI were explored through multiple assays, such as western blotting, immunofluorescence, immunohistochemistry, behavioral experiments, real-time quantitative polymerase chain reaction (RT-qPCR), transmission electron microscope (TEM), molecular docking, and bioinformatics analysis. The results showed that GLY facilitated the maturation and differentiation of oligodendrocytes and enhanced the thickness as well as density of myelin sheaths. GLY also reduced inflammatory response, improved memory, learning, and locomotor performances, and alleviated anxiety in WMI mice. The neuroprotective effects of GLY may be involved in the down-regulation of HMGB1 and its associated proteins such as TLR4 and NF-κB. In conclusion, GLY could mitigate chronic hypoxia-induced WMI and OGD-induced oligodendrocyte injury through its anti-inflammatory effects by inhibiting the HMGB1/TLR4 pathway, suggesting a potential therapeutic avenue for WMI.

Introduction: Neonatal hypoxic-ischemic encephalopathy (HIE), caused by perinatal asphyxia, is characterized by high morbidity and mortality, but there are still no effective therapeutic drugs. Mitochondrial biogenesis and apoptosis play key roles in the pathogenesis of HIE. Protopine (Pro), an isoquinoline alkaloid, has anti-apoptotic and neuro-protective effects. However, the protective roles of Pro on neonatal hypoxic-ischemic brain injury remain unclear. Methods: In this study, we established a CoCl2-induced PC12 cell model in vitro and a neonatal rat hypoxic-ischemic (HI) brain damage model in vivo to explore the neuro-protective effects of Pro and try to elucidate the potential mechanisms. Results: Our results showed that Pro significantly reduced cerebral infarct volume, alleviated brain edema, inhibited glia activation, improved mitochondrial biogenesis, relieved neuron cell loss, decreased cell apoptosis and reactive oxygen species (ROS) after HI damage. In addition, Pro intervention upregulated the levels of p-AMPK/AMPK and PGC1[alpha] as well as the downstream mitochondrial biogenesis related factors, such as nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM), but the AMPK inhibitor compound c (CC) could significantly reverse these effects of Pro. Discussion: Pro may exert neuroprotective effects on neonatal hypoxic-ischemic brain damage via activation of the AMPK/PGC1[alpha] pathway, suggesting that Pro may be a promising therapeutic candidate for HIE, and our study firstly demonstrate the neuro-protective roles of Pro in HIE models. Keywords: neonatal hypoxic-ischemic brain damage, protopine, reactive oxygen species, apoptosis, mitochondrial biogenesis

Objective: Rice-Vannucci model has been widely used as HIE（Hypoxic ischemic encephalopathy ） animal model in the past forty years, but it does not mimic reperfusion injury that occurs during HIE. The aim of the present study was to establish a new neonatal rat model by simulating hypoxia ischemia reperfusion brain damage (HIRBD) through \"common carotid artery (CCA) muscle bridge\". Methods: Sixty 7-day-old male Sprague-Dawley rats were randomly assigned to group A (HIRBD groups, n=36), group B (Rice-Vannucci group, n=12), and group C (sham-operated group, n=12). Rats in group A were assigned to 3 subgroups (A1-A3, 12 animals/subgroup). Dynamic changes in cerebral blood flow (CBF) were evaluated by the laser speckle imaging system. The status of the CCA was observed under a stereomicroscope. Changes in body weight, gross morphology as well as pathological sections of brain tissue were examined to evaluate the feasibility of the model. Results: The results indicated that CCA muscle bridge successfully blocked the CBF. CBF was restored after removal of the CCA muscle bridge in HIRBD groups. The CCA was in good condition after removing the muscle bridge, and blood supply was not affected. Changes in body weight, gross morphology and pathological sections of brain tissue indicated that ischemia reperfusion induced by the CCA muscle bridge method caused varying degrees of brain damage. Conclusion: CCA muscle bridge method is effective for establishing a reliable, stable, and reproducible neonatal rat model for study of HIRBD. Competing Interest Statement The authors have declared no competing interest.

The aim of this study is to investigate the trajectory of medial longitudinal fasciculus (MLF) and explore its anatomical relationship with the oculomotor nerve using tractography technique. The MLF and oculomotor nerve were reconstructed at the same time with preset three region of interests (ROIs): one set at the area of rostral midbrain, one placed on the MLF area at the upper pons, and one placed at the cisternal part of the oculomotor nerve. This mapping protocol was tested in an HCP‐1065 template, 35 health subjects from Massachusetts General Hospital (MGH), 20 healthy adults and 6 brainstem cavernous malformation (BCM) patients with generalized q‐sampling imaging (GQI)‐based tractography. Finally, the 200 μm brainstem template from Center for In Vivo Microscopy, Duke University (Duke CIVM), was used to validate the trajectory of reconstructed MLF. The MLF and oculomotor nerve were reconstructed in the HCP‐1065 template, 35 MGH health subjects, 20 healthy adults and 6 BCM patients. The MLF was in conjunction with the ipsilateral mesencephalic part of the oculomotor nerve. The displacement of MLF was identified in all BCM patients. Decreased QA, RDI and FA were found in the MLF of lesion side, indicating axonal loss and/or edema of displaced MLF. The reconstructed MLF in Duke CIVM brainstem 200 μm template corresponded well with histological anatomy. The MLF and oculomotor nerve were visualized accurately with our protocol using GQI‐based fiber tracking. This GQI‐based tractography is an important tool in the reconstruction and evaluation of MLF. The mapping protocol of medial longitudinal fasciculus using the generalized q‐sampling imaging based tractography.

Purpose Obstructive sleep apnea (OSA) is a common sleep-breathing disorder. Numerous investigations have found a strong inherent relationship between OSA and hypothyroidism. Studies suggest that lymphocytes may be involved in the development of hypothyroidism in patients with OSA. This study aimed to assess the association between lymphocytes and hypothyroidism in OSA patients. Patients and methods This study involved 920 patients with OSA who underwent nocturnal sleep monitoring, thyroid function testing, and routine blood tests. In patients with OSA, logistic regression analysis indicated independent predictors of hypothyroidism. The cutoff level of lymphocyte count was determined using a receiver operating characteristic (ROC) analysis to predict the occurrence of hypothyroidism in individuals with OSA. Results This study comprised 920 OSA patients (617 males and 303 women), 879 with normal thyroid function, and 41 with hypothyroidism, with a hypothyroidism incidence of 4.46%. In the entire OSA population and male OSA patients, the number of lymphocytes was significantly higher in the hypothyroid group than in the control group ( p  = 0.002 and 0.020, respectively). In addition, among the OSA population younger than 60 years old and patients with mild to moderate OSA, lymphocytes were found to be considerably more in the hypothyroid group than in the euthyroid group. Lymphocyte count, ESS, and sex were all independent predictors of hypothyroidism development in OSA patients. According to ROC curve analysis, the risk of hypothyroidism increases with increasing lymphocyte count in the total patient population, with an optimal diagnostic cutoff point of 2.5 (× 10*9/L). Conclusions The prevalence of hypothyroidism in patients with OSA increases as the number of lymphocytes increases. Lymphocyte count can be used as an independent predictor of the occurrence of hypothyroidism, and it has a diagnostic value for OSA combined with hypothyroidism.