Neuroinflammation and angiogenesis are central to post-stroke repair. However, the cellular and molecular mechanisms regulating these events remain incompletely understood. The nuclear factor of activated T cells-1 (NFAT1) is implicated in inflammation and vascular remodeling, yet its role in ischemic stroke is unclear. We established Nfat1-deficient (Nfat1−/−) and Nfat1+/+ stroke mice to investigate the role of NFAT1 in post-stroke inflammation and repair. Neurological outcomes, infarct volume, neuronal injury, synaptic protein expression, neuroinflammation, angiogenesis, and cerebral blood flow were assessed by behavioral test, magnetic resonance imaging (MRI), Nissl staining, western blotting, ELISA, immunofluorescence, and laser speckle imaging, respectively. ChIP, dual-luciferase, and mechanistic assays identified NFAT1 downstream targets and signaling pathways. Conditioned medium experiments examined the impact of Nfat1+/+ primary microglia on endothelial cell behavior. NFAT1-overexpressing microglia were transplanted to assess therapeutic efficacy in vivo. Nfat1−/− stroke mice showed worsened neurological function, increased neuronal damage, and reduced expression of antiinflammatory and proangiogenic factors (interleukin (IL)-10, tumor growth factor (TGF)-β, VEGFA, and FGF2). NFAT1 deficiency impaired microglial polarization (CD163+ and CD206+), angiogenesis, and blood perfusion. NFAT1 upregulated HAS3 and LYVE1, promoting HA-LYVE1 autocrine/paracrine signaling and activation of the Wnt/β-catenin pathway, which facilitated antiinflammatory polarization. Conditioned medium experiments confirmed that Nfat1+/+ microglia enhanced endothelial cell proliferation, migration, and tube formation. NFAT1-overexpressing microglia therapy enhanced antiinflammatory responses and angiogenesis, improved neurological recovery (e.g. Garcia score at day 35 increased by 0.87 points versus control), and reduced infarct size (corrected infarct area decreased by 27.29 units) in stroke mice. Microglial NFAT1 drives antiinflammatory polarization and angiogenesis via the HAS3–HA–LYVE1–Wnt/β-catenin axis, ultimately improving stroke recovery. These findings reveal a previously unrecognized mechanism of neurovascular repair and highlight NFAT1+ microglia as a promising therapeutic target for ischemic stroke.

Cancer stem cells (CSCs) drive metastasis, relapse, and treatment resistance. A subpopulation of CSCs persists in a quiescent G0 state, enabling chemo- and radiotherapy evasion. Importantly, in G0 and early G1, MCM2-7 are either not loaded or not yet activated; helicase activity arises only after CMG assembly at the G1/S transition. The minichromosome maintenance (MCM) family includes the replicative helicase MCM2-7, which functions as part of the CMG (Cdc45-MCM2-7-GINS) to unwind DNA, and the MCM8/9 helicase, which acts primarily in homologous recombination (HR). Dysregulation of these complexes can potentially influence CSC therapy responses through replication stress and DNA damage response pathways. Accordingly, therapies targeting MCM2-7/CMG complexes are expected to act selectively on cells with active replicative helicases, preferentially affecting reactivated CSCs that have re-entered the cell cycle and their proliferating progeny, whereas quiescent G0 CSCs are likely refractory unless combined with strategies that induce controlled cell-cycle re-entry. This review summarizes the roles of MCM proteins in CSC phenotypes and highlights advances in MCM-targeted therapy, with particular focus on structural mechanisms of drug-target interactions to guide development of rational design and clinical translation.

There has been abundant research on the variety of programmed cell death pathways. Apoptosis, pyroptosis, and necroptosis under the action of the caspase family are essential for the innate immune response. Caspases are classified into inflammatory caspase-1/4/5/11, apoptotic caspase-3/6/7, and caspase-2/8/9/10. Although necroptosis is not caspase-dependent to transmit cell death signals, it can cross-link with pyroptosis and apoptosis signals under the regulation of caspase-8. An increasing number of studies have reiterated the involvement of the caspase family in acute lung injuries caused by bacterial and viral infections, blood transfusion, and ventilation, which is influenced by noxious stimuli that activate or inhibit caspase engagement pathways, leading to subsequent lung injury. This article reviews the role of caspases implicated in diverse programmed cell death mechanisms in acute lung injury and the status of research on relevant inhibitors against essential target proteins of the described cell death mechanisms. The findings of this review may help in delineating novel therapeutic targets for acute lung injury.

Glioma represents the most prevalent primary tumors of the central nervous system, originating from glial cells. Cancer stem cells have the ability to extensively proliferate, self-renew, and form colonies, which contribute to tumorigenesis. Studies have found a population of cells within glioblastoma exhibiting characteristics similar to those of cancer cells, termed glioma stem cells (GSCs). GSCs have two distinct phenotypes: mesenchymal subtype (MES) and proneural subtype (PN). Despite the vital role of these subtypes in glioma biology, there is a significant lack of comprehensive reviews focusing on the regulatory mechanisms underlying each phenotype.This review integrates emerging insights into the regulatory mechanisms underlying GSCs plasticity, with dedicated analysis of novel pathways governing PN and MES phenotypes and their dynamic transition. By examining these critical elements, we aim to contribute to the development of novel therapeutic strategies in the ongoing fight against gliomas.

The proneural-mesenchymal (PN-MES) transformation of glioma stem cells (GSCs) can significantly increase proliferation, invasion, chemotherapy tolerance, and recurrence. M2-like polarization of tumor-associated macrophages (TAMs) has a strong immunosuppressive effect, promoting tumor malignancy and angiogenesis. There is limited understanding on the interactions between GSCs and TAMs as well as their associated molecular mechanisms. In the present study, bioinformatics analysis, GSC and TAM co-culture, determination of TAM polarization phenotypes, and other in vitro experiments confirmed that CCL2 secreted by MES-GSCs promotes TAM-M2 polarization via the IKZF1-CD84-SHP2 pathway and PN-MES transformation of GSCs via the IKZF1-LRG1 pathway in TAMs. IKZF1 inhibitors could significantly reduce tumor volumes in animal glioma models and improve survival, as well as suppress TAM-M2 polarization and the GSC malignant phenotype. The results of this study indicate the important interaction between TAMs and GSCs in the glioma microenvironment as well as its role in tumor progression. The findings also suggest a novel target for follow-up clinical transformation research on the regulation of TAM function and GSCs malignant phenotype.

While perinatal medicine advancements have bolstered survival outcomes for premature infants, bronchopulmonary dysplasia (BPD) continues to threaten their long-term health. Gene-environment interactions, mediated by epigenetic modifications such as DNA methylation, histone modification, and non-coding RNA regulation, take center stage in BPD pathogenesis. Recent discoveries link methylation variations across biological pathways with BPD. Also, the potential reversibility of histone modifications fuels new treatment avenues. The review also highlights the promise of utilizing mesenchymal stem cells and their exosomes as BPD therapies, given their ability to modulate non-coding RNA, opening novel research and intervention possibilities.

新生儿脑病有多种类型,如缺氧缺血性脑病、胆红素脑病、低血糖脑病、早产儿脑病、脓毒症相关脑病、遗传代谢性脑病及线粒体脑病等.磁共振成像(magnetic resonance imaging,MRI)技术可以用于诊断及评估病情,是新生儿脑病较理想的影像检查方法.常规MRI虽应用最普遍,但往往难以达到早期诊断及精准识别的目的,也不能评估脑功能情况.目前多模态MRI技术,包括弥散加权成像、弥散张量成像、磁敏感加权成像、氢质子磁共振波谱成像、流体衰减反演恢复等,具有灵敏度高、特异性强、信号对比度高、反映脑组织代谢水平等优势,可以弥补常规MRI技术的不足,对早期诊断及鉴别新生儿脑病,以及评估脑功能和判断预后具有广泛的应用前景.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is a serious disorder, which may comprise diabetes, thyroid disease, enteropathy, cytopenias, eczema, and other multi-system autoimmune dysfunction features. IPEX syndrome is caused by mutations in the forkhead box P3 (FOXP3) gene. Here, we report the clinical manifestations of a patient with IPEX syndrome onset in the neonatal period. A de novo mutation at exon 11 of the FOXP3 gene (c.1190G > A, p.R397Q) was found, and its main clinical manifestations included hyperglycemia and hypothyroidism. Subsequently, we comprehensively reviewed the clinical characteristics and FOXP3 mutations of 55 reported neonatal IPEX cases. The most frequent clinical presentation included symptoms of gastrointestinal involvement (n = 51, 92.7

This paper reports a case of neonatal lupus syndrome manifested by metabolic disease. A male neonate was admitted to the Children's Hospital of Soochow University due to poor response and vomiting for 1 day. Based on the clinical symptoms, including the patterned skin and a full anterior fontanelle, and a result of leukocytosis, neonatal sepsis was considered. Lysinuric protein intolerance was not excluded from the genetic metabolic disorders screening. The patient was positive for lupus-related autoantibodies and antinuclear antibodies, which were also found in his mother and elder sister. He had no functional variant of the SCL7A7 gene, a gene related to lysinuric protein intolerance, thereby the diagnosis of neonatal lupus syndrome manifested by metabolic disorders was confirmed. After treatment with methylprednisolone, the patient recovered well with no specific change in blood genetic metabolism at re-examination. Monthly follow-up after discharge found decreased antibody titers.

The nuclear factor of activated T cells (NFAT) was first identified as a transcriptional regulator of activated T cells. The NFAT family is involved in the development of tumors. Furthermore, recent evidence reveals that NFAT proteins regulate the development of inflammatory and immune responses. New discoveries have also been made about the mechanisms by which NFAT regulates cancer progression through cancer stem cells (CSC). Here, we discuss the role of the NFAT family in the immune system and various cancer types.

ObjectiveTo investigate the levels of tumor-infiltrating CD8(+) lymphocytes (CD8(+) TILs) and the expression of programmed cell death receptor ligand 1 (PD-L1) in the tumor microenvironment (TME) of pediatric and adolescent pituitary adenomas (PAPAs) and analyze the correlation between their levels and the clinical characteristics. MethodsA series of 43 PAPAs cases were enrolled over a period of 5 years. To compare the TME of PAPAs and adult PAs, 43 PAPAs cases were matched with 60 adult PAs cases (30 cases were between 20 and 40 years old, and 30 cases were older than 40 years) for main clinical characteristics. The expression of immune markers in PAPAs was detected by immunohistochemistry, and their correlation with the clinical outcomes was analyzed using statistical methods. ResultsIn the PAPAs group, CD8(+) TILs level was significantly lower (3.4 (5.7) vs. 6.1 (8.5), p = 0.001), and PD-L1 expression (0.040 (0.022) vs. 0.024 (0.024), p < 0.0001) was significantly higher as compared with the older group. The level of CD8(+) TILs was negatively correlated with the expression of PD-L1 (r = -0.312, p = 0.042). Moreover, CD8(+) TILs and PD-L1 levels were associated with Hardy (CD8, p = 0.014; PD-L1, p = 0.018) and Knosp (CD8, p = 0.02; PD-L1, p = 0.017) classification. CD8(+) TILs level was associated with high-risk adenomas (p = 0.015), and it was associated with the recurrence of PAPAs (HR = 0.047, 95% CI 0.003-0.632, p = 0.021). ConclusionCompared with the TME in adult PAs, the TME in PAPAs was found to express a significantly altered level of CD8(+) TILs and PD-L1. In PAPAs, CD8(+) TILs and PD-L1 levels were associated with clinical characteristics.

Neonatal cerebral infaraction(NCI)is the brain injury caused by cerebrovascular disease in neonates within 28 days, which can lead to poor outcome.At present, the etiology of NCI is still unclear, which may involve a variety of risk factors concerning maternal, placental and neonatal issues.The risk of developing NCI increases when risk factors increase.In order to indentify neonates with risk factors and diagnose NCI early, this review summarized the high-risk factors of NCI from three aspects, involving prenatal, intrapartum and postpartum stages.Timely intervention need to be given to improve the prognosis of neonates with NCI.

With the progress of perinatal medicine, the survival rate of premature infants has been greatly improved, but the incidence of preterm related complications has also increased, including growth retardation, premature brain injury, retinopathy of prematurity, bronchopulmonary dysplasia and necrotizing enterocolitis.Insulin-like growth factor-1(IGF-1)specifically binds to IGF-1 receptor to activate intracellular signaling pathways, so that can promote cell growth, proliferation and differentiation, and inhibit apoptosis.IGF-1 is involved in the development of the heart, brain, lung, and other important organs and promotes tissue growth, so it plays an important role in fetal intrauterine development and neonatal extrauterine growth.At present, some clinical trials have found that recombinant IGF-1 and its binding protein-3 can play a role in the prevention and treatment of retinopathy of prematurity and bronchopulmonary dysplasia, bringing hope for the prevention and treatment of these refractory complications of prematurity.In this review, the function of IGF-1 and its role in preterm related complications are reviewed.

Mitochondrial disease refers to an energy metabolic disorder caused by dysfunction of oxidative phosphorylation system or pyruvate dehydrogenase complex as a result of mitochondrial DNA or nuclear DNA mutation.It can occur at any age arranging from newborn to adult, which is often presented as clinical syndromes.Common clinical manifestations in neonatal period include premature delivery, intrauterine growth restriction, hypotonia, dyspnea, convulsions, feeding difficulties, hyperlactic acid, etc, lacking of specificity.Neonatal onset syndromes include Leigh syndrome, mitochondrial encephalomyopathy-lactic acidosis and stroke-like episodes syndrome, Alpers syndrome, myocerebrohepatopathy spectrum disorder, Barth syndrome and Pearson syndrome.The diagnosis depends on the comprehensive analysis of clinical symptoms, biochemical tests, neuroimaging, histological tests and genetic tests.In most cases, there are few effective drugs.Gene therapy and exogenous mitochondrial transplantation are the directions of future exploration.

Background: Although pericardial effusion/cardiac tamponade (PCE/CT) is a rare complication of peripherally inserted central catheters (PICCs), with an incidence of 0. 07-2%, it is associated with high mortality and is often life threatening. We sought to improve understanding of PICC-induced PCE/CT among pediatricians. Case presentation: The clinical data of PICC-associated PCE/CT in a very low birth weight (VLBW) infant were summarized, and the relevant literature was also reviewed. Conclusions: In VLBW infants with a PICC, if unstable respiratory circulatory system states are observed that cannot be explained, such as tachycardia, bradycardia, apnea, hypotension, and metabolic acidosis, PICC-induced PCE/CT should be considered. Early diagnosis and pericardial puncture are key to saving infants' lives.

目的 探讨连接蛋白(Cx)47在缺氧缺血(HI)致新生大鼠脑室周围白质软化(PVL)发生、发展中表达,阐明Cx47对少突胶质细胞(OLs)髓鞘化的影响.方法 将120只出生3 d的新生大鼠随机分为HI组和对照组,每组各60只.采用右侧颈总动脉结扎后低氧2 h建立PVL动物模型,在手术后l、3、7、14 d分别留取脑组织标本,采用HE染色、透射电镜观察脑组织形态学改变,免疫组化、Western blotting和实时 PCR方法检测2组Cx47蛋白和基因表达.结果 光镜下可见对照组脑组织结构致密,神经胶质细胞形态完整,排列均匀,胞核大,染色清晰.HI组手术后1 d细胞间隙增宽,细胞肿胀、变形、细胞核固缩;手术后3 d可见侧脑室旁白质细胞大量坏死,神经纤维走行紊乱,脑组织结构疏松模糊呈囊性及筛网状坏死;手术后7 d脑室旁白质坏死区域更为广泛,呈簇状及点状坏死,水肿减轻,出现不同程度胶质增生;手术后14 d脑白质胼胝体变薄,纤维走向紊乱,呈网状或条索状,部分出现囊腔病变侧脑室扩大.透射电镜下对照组呈现完整的细胞形态,细胞间缝隙连接紧密;HI组可见OLs出现溶解碎裂,细胞之间缝隙连接开放.免疫组化可见Cx47与髓鞘碱性蛋白(MBP)表达定位于OLs,与对照组比较,HI组Cx47与MBP表达均减少(P < 0.01).2组Cx47蛋白及基因表达水平随大鼠日龄增加而增加;与对照组比较,HI组各时间Cx47表达均较降低(P <0.01).结论 在HI致PVL新生大鼠模型中存在OLs损伤、髓鞘化障碍、缝隙连接开放,在此过程中Cx47表达显著降低,提示Cx47可能参与髓鞘化障碍及缝隙连接开放.

Background: Probiotics are gradually being used as a supplementation to prevent necrotizing enterocolitis (NEC) and reduce mortality in neonates. We performed an updated meta-analysis to systematically evaluate the efficacy and safety of prophylactic probiotic supplementation for preventing NEC. Methods: The databases including PubMed, EMbase, and China National Knowledge Infrastructure were used to search the relevant articles. The latest retrieval date was up to May 2019. Two reviewers independently screened literature, extracted data, and assessed the risk of bias of the included studies. The meta-analysis was performed using Stata version 10.0. Results: Finally, a total of 74 studies containing – cases and – controls were included. The results showed that the probiotics could significantly reduce the incidence of NEC (stage II or more) (OR=0.435, 95% CI=0.357-0.530, p<0.001), the overall mortality (OR=0.630, 95% CI=0.491-0.808, p<0.001), and NEC-related mortality (OR=0.639, 95% CI=0.423-0.966, p=0.034). Conclusion: This meta-analysis indicates that the use of probiotics can effectively reduce the occurrence of NEC and mortality in neonates. These data provide the possible information for the clinical treatment.

Objective Previous studies have found abnormal proliferation and transdifferentiation of alveolar epithelial cells(AECs) in hyperoxic lung injury of neonatal rats. The purpose of this study was to clarify the expression of zonula occludens 1(ZO-1) and ZO-1 related nucleic acid binding protein(ZONAB) in AECs in hyperoxic lung injury model,in order to investigate its effect on the proliferation and transdiffer-entiation of AECs in the injured lung tissue. Methods Full-term neonatal Wistar rats were randomly divided into two groups within 12 h after birth,model group( inhaled oxygen concentration 85%) and control group ( inhaled air). Lung specimens were collected at 7,14 and 21 days after exposure. The expression of ZONAB in typeⅡalveolar epithelial cells(AECⅡ)was observed by double immunofluorescence staining. At the same time,AEC Ⅱ was isolated from lung tissues of animal models at these time points,and the expression levels of ZO-1,ZONAB protein and mRNA in lung tissues and AECⅡof the two groups were detected by Western blot and Real-Time PCR. In addition,AECⅡwas isolated from lung tissue of normal newborn rats and then divided into model group(85% oxygen concentration)and control group(21% oxygen concentration). After 48 hours of culture in vitro,the expression levels of ZO-1,ZONAB protein and mRNA were detected,and the expression level and location of ZONAB were observed by immunofluorescence staining. Results Double immunofluorescence staining showed that the expression of ZONAB in AECⅡin model group was signifi-cantly lower than that in control group. The protein and mRNA expression levels of ZO-1 and ZONAB in AECⅡisolated from lung tissue of model group were both significantly lower than those from control group, starting from 7 d after hyperoxia exposure. AECⅡisolated from lung tissue of normal newborn rats,were then incubated for 48 hours under hyperoxia or normoxia in vitro,the protein and mRNA expression levels of ZO-1 and ZONAB significantly decreased in model group compared with those in control group. The results of im-munofluorescence staining showed that the expression of ZONAB was higher in AECⅡof the control group, and ZONAB was mostly located in the junction and nucleus of cells,while the expression of ZONAB in the model group significantly decreased than that in the control group,and the expression sites were clustered in the cytoplasm,with little expression in the junction and nucleus. Conclusion ZO-1,as a tight junction-relat-ed protein,is down-regulated in hyperoxic lung injury model. In addition to destroying pulmonary epithelial barrier to mediate pulmonary edema,it also participated in the regulation of proliferation and differentiation of AECs by regulating transcription factor ZONAB, suggesting that this may be another pathway leading to hyperoxic lung injury.

Bronchopulmonary dysplasia (BPD) is a common, chronic lung disease of infants. Presently, high oxygen exposure and mechanical ventilation considerably influence the development of BPD. To clarify the pathological mechanisms of this disease, we developed a hyperoxia-induced BPD rat model and investigated the role of CDKN1A in the pathogenesis of BPD. Newborn rats were randomly assigned to the hyperoxia (85% O2) and control (normoxia, 21% O2) groups. Lung tissues were collected on days 1, 3, 7, 14, or 21 after the start of hyperoxia or normoxia exposure. The expression of CDKN1A was detected by immunohistochemistry, western blot, and real-time PCR. Starting from day 3, CDKN1A mRNA expression was higher in the hyperoxia group. From day 7, the radial alveolar count was significantly different between the two groups, and on day 14, the hyperoxia group had high CDKN1A protein expression compared to the control group. These results suggest that increased CDKN1A expression may be involved in the pathogenesis of BPD through alveolarization and lung retardation.

Previous studies by our group have confirmed excessive transdifferentiation of alveolar epithelial cells (AECs) in a hyperoxia‑induced bronchopulmonary dysplasia (BPD) model, but the underlying mechanism have remained elusive. The transcription factor zonula occludens 1‑associated nucleic acid binding protein (ZONAB) has the biological functions of inhibition of epithelial cell differentiation and promotion of epithelial cell proliferation. The aim of the present study was to explore the regulatory effect of ZONAB on the transdifferentiation and proliferation of AECs in a model of hyperoxia‑induced lung injury. Newborn Wistar rats were randomly allocated to a model group (inhalation of 85% O2) or a control group (inhalation of normal air), and ZONAB expression in lung tissues was detected at different time‑points. Type II AECs (AEC II) isolated from normal newborn rats were primarily cultured under an atmosphere of 85 or 21% O2, and ZONAB expression in the cells was examined. The primary cells were further transfected with ZONAB plasmid or small interfering (si)RNA and then exposed to hyperoxia, and the indicators for transdifferentiation and proliferation were measured. The present study indicated that ZONAB expression in AEC II of the BPD rats was significantly decreased from 7 days of exposure to hyperoxia onwards. In the AEC II isolated from normal neonatal rats, ZONAB expression in the model group was also reduced compared with that in the control group. After transfection with the plasmid pCMV6‑ZONAB, the expression of aquaporin 5 (type I alveolar epithelial cell marker) decreased and the expression of surfactant protein C (AEC II marker), proliferating‑cell nuclear antigen and cyclin D1 increased, which was opposite to the effects of ZONAB siRNA. Transfection with pCMV6‑ZONAB also alleviated excessive transdifferentiation and inhibited proliferation of AEC II induced by hyperoxia treatment. These results suggest that ZONAB expression in AEC II decreases under hyperoxia conditions, which promotes transdifferentiation and inhibits proliferation of AECs. This may, at least in part, be the underlying mechanism of lung epithelial injury in the hyperoxia-induced BPD model.