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1.
J Immunol Res ; 2023: 5149306, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37636861

RESUMO

White matter damage (WMD) is a primary cause of cerebral palsy and cognitive impairment in preterm infants, and no effective treatments are available. Microglia are a major component of the innate immune system. When activated, they form typical pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes and regulate myelin development and synapse formation. Therefore, they may play a pivotal role in hypoxic-ischemic (HI) WMD. Herein, we investigated neural inflammation and long-term microglia phenotypic polarization in a neonatal rat model of hypoxia-ischemia-induced WMD and elucidated the underlying pathophysiological processes. We exposed 3-day-old (P3) Sprague-Dawley rats to hypoxia (8% oxygen) for 2.5 hr after unilateral common carotid artery ligation. The activation of NLRP3 inflammatory bodies, microglia M1/M2 polarization, myelination, and synaptic development in our model were monitored 7, 14, and 21 days after birth. In addition, the Morris water maze test was performed on postnatal Day 28. We confirmed myelination disturbance in the periventricular white matter, abnormal synaptic development, and behavioral changes in the periventricular area during the development of HI WMD. In addition, we found an association between the occurrence and development of HI WMD and activation of the NLRP3 inflammasome, microglial M1/M2 polarization, and the release of inflammatory factors. NLRP3 inhibition can play an anti-inflammatory role by inhibiting the differentiation of microglia into the M1 phenotype, thereby improving myelination and synapse formation. In conclusion, microglia are key mediators of the inflammatory response and exhibit continuous phenotypic polarization 7-21 days after HI-induced WMD. This finding can potentially lead to a new treatment regimen targeting the phenotypic polarization of microglia early after HI-induced brain injury.


Assuntos
Nascimento Prematuro , Substância Branca , Animais , Feminino , Ratos , Hipóxia , Inflamassomos , Isquemia , Microglia , Doenças Neuroinflamatórias , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ratos Sprague-Dawley , Animais Recém-Nascidos
2.
Mol Med ; 29(1): 70, 2023 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-37226090

RESUMO

BACKGROUND: Bronchopulmonary dysplasia (BPD) is the most common and serious chronic lung disease in preterm infants with pathological characteristics of arrested lung development. DNA double-strand breaks (DSBs) are a serious manifestation of oxidative stress damage, but little is known about the role of DSBs in BPD. The current study set out to detect DSB accumulation and cell cycle arrest in BPD and study the expression of genes related to DNA damage and repair in BPD through DNA damage signaling pathway-based PCR array to determine a suitable target to improve arrested lung development associated with BPD. METHODS: DSB accumulation and cell cycle arrest were detected in a BPD animal model and primary cells, then a DNA damage signaling pathway-based PCR array was used to identify the target of DSB repair in BPD. RESULTS: DSB accumulation and cell cycle arrest were shown in BPD animal model, primary type II alveolar epithelial cells (AECII) and cultured cells after exposure to hyperoxia. Of the 84 genes in the DNA damage-signaling pathway PCR array, eight genes were overexpressed and 11 genes were repressed. Rad1, an important protein for DSB repair, was repressed in the model group. Real-time PCR and western blots were used to verify the microarray results. Next, we confirmed that silencing Rad1 expression aggravated the accumulation of DSBs and cell cycle arrest in AECII cells, whereas its overexpression alleviated DSB accumulation and cell cycle arrest. CONCLUSIONS: The accumulation of DSBs in AECII might be an important cause of alveolar growth arrest associated with BPD. Rad1 could be an effective target for intervention to improve this arrest in lung development associated with BPD.


Assuntos
Displasia Broncopulmonar , Exonucleases , Parada Cardíaca , Animais , Ratos , Células Epiteliais Alveolares , Displasia Broncopulmonar/genética , Pontos de Checagem do Ciclo Celular/genética , DNA , Quebras de DNA de Cadeia Dupla
3.
Front Pediatr ; 10: 946747, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36440350

RESUMO

Background: Bronchopulmonary dysplasia (BPD) is the most common neonatal chronic lung disease. However, its exact molecular pathogenesis is not understood. We aimed to identify relevant gene modules that may play crucial roles in the occurrence and development of BPD by weighted gene co-expression network analysis (WGCNA). Methods: We used RNA-Seq data of BPD and healthy control rats from our previous studies, wherein data from 30 samples was collected at days 1, 3, 7, 10, and 14. Data for preprocessing analysis included 17,613 differentially expressed genes (DEGs) with false discovery rate <0.05. Results: We grouped the highly correlated genes into 13 modules, and constructed a network of mRNA gene associations, including the 150 most associated mRNA genes in each module. Lgals8, Srpra, Prtfdc1, and Thap11 were identified as the key hub genes. Enrichment analyses revealed Golgi vesicle transport, coated vesicle, actin-dependent ATPase activity and endoplasmic reticulum pathways associated with these genes involved in the pathological process of BPD in module. Conclusions: This is a study to analyze data obtained from BPD animal model at different time-points using WGCNA, to elucidate BPD-related susceptibility modules and disease-related genes.

4.
CNS Neurosci Ther ; 28(7): 1019-1032, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35393758

RESUMO

AIM: White matter damage (WMD) is the main cause of cerebral palsy and cognitive impairment in premature infants. Although caffeine has been shown to possess neuroprotective effects in neonatal rats with hypoxic-ischemic WMD, the mechanisms underlying these protective effects are unclear. Herein, proteins modulated by caffeine in neonatal rats with hypoxic-ischemic WMD were evaluated. METHODS: We identified differential proteins and performed functional enrichment analyses between the Sham, hypoxic-ischemic WMD (HI), and HI+caffeine-treated WMD (Caffeine) groups. Confirmed the changes and effect of proteins in animal models and determined cognitive impairment via water maze experiments. RESULTS: In paraventricular tissue, 47 differential proteins were identified between the Sham, HI, and Caffeine groups. Functional enrichment analyses showed that these proteins were related to myelination and axon formation. In particular, the myelin basic protein (MBP), proteolipid protein, myelin-associated glycoprotein precursor, and sirtiun 2 (SIRT2) levels were reduced in the hypoxic-ischemic WMD group, and this effect could be prevented by caffeine. Caffeine alleviated the hypoxic-ischemic WMD-induced cognitive impairment and improved MBP, synaptophysin, and postsynaptic density protein 95 protein levels after hypoxic-ischemic WMD by preventing the HI-induced downregulation of SIRT2; these effects were subsequently attenuated by the SIRT2 inhibitor AK-7. CONCLUSION: Caffeine may have clinical applications in the management of prophylactic hypoxic-ischemic WMD; its effects may be mediated by proteins related to myelin development and synapse formation through SIRT2.


Assuntos
Hipóxia-Isquemia Encefálica , Substância Branca , Animais , Animais Recém-Nascidos , Cafeína/farmacologia , Cafeína/uso terapêutico , Modelos Animais de Doenças , Humanos , Hipóxia , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Hipóxia-Isquemia Encefálica/metabolismo , Proteômica , Ratos , Ratos Sprague-Dawley , Sirtuína 2/metabolismo , Substância Branca/metabolismo
5.
Pediatr Res ; 92(6): 1543-1554, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35220399

RESUMO

BACKGROUND: Reducing neuroinflammatory damage is an effective strategy for treating white-matter damage (WMD) in premature infants. Caffeine can ameliorate hypoxia-ischemia-induced brain WMD; however, its neuroprotective effect and mechanism against hypoxic-ischemic WMD remain unclear. METHODS: We used 3-day-old Sprague-Dawley rats to establish a model of cerebral hypoxia-ischemia-induced brain WMD after unilateral common carotid artery ligation and hypoxia exposure (8% O2 + 92% N2) for 2.5 h. Mechanism experiments were conducted to detect M1/M2 polarization and activation of microglia and NLRP3 inflammasome. RESULTS: Caffeine inhibited NLRP3 inflammasome activation, reduced microglial Iba-1 activation, inhibited microglia M1 polarization, and promoted microglia M2 polarization by downregulating CD86 and iNOS protein expression, inhibiting the transcription of the proinflammatory TNF-α and IL-1ß, upregulating CD206 and Arg-1 expression, and promoting the transcription of the anti-inflammatory factors IL-10 and TGF-ß. Importantly, we found that these caffeine-mediated effects could be reversed after inhibiting A2aR activity. CONCLUSIONS: Caffeine improved long-term cognitive function in neonatal rats with hypoxic-ischemic WMD via A2aR-mediated inhibition of NLRP3 inflammasome activation, reduction of microglial activation, regulation of the phenotypic polarization of microglia and the release of inflammatory factors, and improvement of myelination development. IMPACT: The direct protective effect of caffeine on hypoxic-ischemic white-matter damage (WMD) and its mechanism remains unclear. This study elucidated this mechanism using neonatal rats as an animal model of hypoxia-ischemia-induced cerebral WMD. The findings demonstrated caffeine as a promising therapeutic tool against immature WMD to protect neonatal cognitive function. We found that caffeine pretreatment reduced WMD in immature brains via regulation of microglial activation and polarization by adenosine A2a receptor, thereby, providing a scientific basis for future clinical application of caffeine.


Assuntos
Hipóxia-Isquemia Encefálica , Inflamassomos , Ratos , Animais , Animais Recém-Nascidos , Ratos Sprague-Dawley , Inflamassomos/metabolismo , Microglia/metabolismo , Cafeína/farmacologia , Cafeína/uso terapêutico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Hipóxia-Isquemia Encefálica/metabolismo , Isquemia
6.
Front Pediatr ; 9: 724161, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34660486

RESUMO

With the improvement in neonatal rescue technology, the survival rate of critically ill preterm infants has substantially increased; however, the incidence of brain injury and sequelae in surviving preterm infants has concomitantly increased. Although the etiology and pathogenesis of preterm brain injury, and its prevention and treatment have been investigated in recent years, powerful and effective neuroprotective strategies are lacking. Caffeine is an emerging neuroprotective drug, and its benefits have been widely recognized; however, its effects depend on the dose of caffeine administered, the neurodevelopmental stage at the time of administration, and the duration of exposure. The main mechanisms of caffeine involve adenosine receptor antagonism, phosphodiesterase inhibition, calcium ion activation, and γ-aminobutyric acid receptor antagonism. Studies have shown that there are both direct and indirect beneficial effects of caffeine on the immature brain. Accordingly, this article briefly reviews the pharmacological characteristics of caffeine, its mechanism of action in the context of encephalopathy in premature infants, and its use in the neuroprotection of encephalopathy in this patient population.

7.
Front Pediatr ; 9: 633532, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33681108

RESUMO

Objective: The clinical symptoms of neonatal Prader-Willi syndrome (PWS) are not typical and are easy to miss. The aim of the study was to investigate the clinical features and genetic characteristics of seven cases of neonatal PWS from northern China, and to improve the understanding of PWS in neonates. Methods: We retrospectively analyzed seven infants diagnosed by methylation specific multiplex ligation probe amplification technology (MS-MLPA) in the Neonatology Unit of Shengjing Hospital of China Medical University from September 2016 to July 2020. Results: All seven cases involved full term or nearly full-term infants born to mothers without a history of abnormal pregnancy or delivery. Difficulty in feeding occurred immediately after birth in infants with decreased hypotonia. Five patients had characteristic craniofacial morphology, such as a prominent forehead, narrow face, almond-shaped eyes, small mouth, and downturned mouth. Further, three of the seven infants had patent ductus arteriosus (PDA). In addition, three neonates had hyperammonemia, hypoglycemia, and idiopathic edema, respectively. PWS could be effectively diagnosed and genotyped by MS-MLPA. Conclusion: Neonates with PWS have hypotonia and feeding difficulty. Characteristic facial features and genital hypoplasia are common in neonatal PWS. Infants with PWS may be predisposed to PDA, hypoglycemia, hyperammonemia, and edema.

8.
Mol Med Rep ; 23(1)2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33179109

RESUMO

Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease in premature infants, and alveolar dysplasia and pulmonary vascular development disorders are the predominant pathological features. Apoptosis of lung epithelial cells is a key factor in the pathological process of alveolar developmental arrest. Endoplasmic reticulum stress (ERS)­associated apoptosis is a noncanonical apoptotic pathway involved in the development of several pulmonary diseases. Previous studies have demonstrated that protein kinase RNA­like endoplasmic reticulum kinase, inositol­requiring enzyme 1α (IRE1α) and activating transcription factor 6 can initiate the apoptosis signaling pathway mediated by ERS and induce apoptosis of injured cells. Among them, the IRE1α pathway is the most conservative pathway in the unfolded protein response, which serves an important role in a number of pathological environments, to the extent of determining cell fate; however, it is rarely reported in BPD. Based on the establishment of a rat BPD model, the present study verified the activation of ERS in BPD and further confirmed that prolonged ERS inhibited the protective pathway, IRE1α/X­box binding proteins, and activated the proapoptotic pathway, IRE1α/c­Jun N­terminal kinase, to induce the apoptosis of lung epitheliums.


Assuntos
Displasia Broncopulmonar/metabolismo , Endorribonucleases/genética , Endorribonucleases/metabolismo , Hiperóxia/metabolismo , Complexos Multienzimáticos/genética , Complexos Multienzimáticos/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Fator 6 Ativador da Transcrição/metabolismo , Animais , Apoptose , Displasia Broncopulmonar/genética , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático , Feminino , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Fosforilação , Ratos , Resposta a Proteínas não Dobradas , Proteína 1 de Ligação a X-Box/metabolismo
9.
Int J Mol Med ; 46(6): 2126-2136, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33125104

RESUMO

Bronchopulmonary dysplasia (BPD), also known as chronic lung disease, is one of the most common respiratory diseases in premature new­born humans. Mitochondria are not only the main source of reactive oxygen species but are also critical for the maintenance of homeostasis and a wide range of biological activities, such as producing energy, buffering cytosolic calcium and regulating signal transduction. However, as a critical quality control method for mitochondria, little is known about the role of mitophagy in BPD. The present study assessed mitochondrial function in hyperoxia­exposed alveolar type II (AT­II) cells of rats during lung development. New­born Sprague­Dawley rats were divided into hyperoxia (85% oxygen) and control (21% oxygen) groups. Histopathological and morphological properties of the lung tissues were assessed at postnatal days 1, 3, 7 and 14. Ultrastructural mitochondrial alteration was observed using transmission electron microscopy and the expression of the mitophagy proteins putative kinase (PINK)1, Parkin and Nip3­like protein X (NIX) in the lung tissues was evaluated using western blotting. Immunofluorescence staining was used to determine the co­localisation of PINK1 and Parkin. Real­time analyses of extracellular acidification rate and oxygen consumption rate were performed using primary AT­II cells to evaluate metabolic changes. Mitochondria in hyperoxia­exposed rat AT­II cells began to show abnormal morphological and physiological features. These changes were accompanied by decreased mitochondrial membrane potential and increased expression levels of PINK1­Parkin and NIX. Increased binding between a mitochondria marker (cytochrome C oxidase subunit IV isoform I) and an autophagy marker (microtubule­associated protein­1 light chain­3B) was observed in primary AT­II cells and was accompanied by decreased mitochondrial metabolic capacity in model rats. Thus, mitophagy mediated by PINK1, Parkin and NIX in AT­II cells occurred in hyperoxia­exposed new­born rats. These findings suggested that the accumulation of dysfunctional mitochondria may be a key factor in the pathogenesis of BPD and result in attenuated alveolar development.


Assuntos
Hiperóxia/metabolismo , Proteínas de Membrana/metabolismo , Mitofagia , Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Alvéolos Pulmonares/patologia , Ubiquitina-Proteína Ligases/metabolismo , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Células Epiteliais Alveolares/ultraestrutura , Animais , Animais Recém-Nascidos , Displasia Broncopulmonar/complicações , Displasia Broncopulmonar/patologia , Modelos Animais de Doenças , Feminino , Hiperóxia/complicações , Hiperóxia/patologia , Potencial da Membrana Mitocondrial , Mitocôndrias/patologia , Mitocôndrias/ultraestrutura , Alvéolos Pulmonares/metabolismo , Ratos Sprague-Dawley
10.
Biomed Res Int ; 2020: 7176169, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33083482

RESUMO

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a common and serious complication in premature infants. Lung fibroblasts (LFs) are present in the extracellular matrix and participate in pulmonary development in response to BPD. The aim of this study was to investigate the effect of extracellular signal-regulated kinase (ERK) on LFs cultured from newborn rats. Material and Methods. Primary LFs were isolated and treated with epidermal growth factor (EGF, 20 ng/mL) in the presence or absence of an ERK inhibitor, PD98059 (10 µmol/L). Phosphorylated ERK1/2 (p-ERK1/2) protein levels were determined using immunocytochemistry, western blotting, and real-time reverse transcription quantitative (RT-q)PCR. LF proliferation was examined by flow cytometry and a cell counting kit-8 assay. LF transdifferentiation was examined by protein and mRNA expression of α-smooth muscle actin (α-SMA) by immunocytochemistry, western blotting, and RT-qPCR. LF migration was examined by the transwell method. RESULTS: Phosphorylated ERK1/2, which was activated by EGF, promoted LF proliferation by accelerating cell-cycle progression from the G1 to S phase. After treatment with PD98059, the expression of p-ERK1/2 in LFs, cellular proliferation, and the percentage of cells in S phase were significantly decreased. Phosphorylated ERK1/2 also promoted the differentiation of LFs into myofibroblasts through increased α-SMA synthesis and migration. CONCLUSION: The activation of ERK promotes proliferation, transdifferentiation, and migration of lung fibroblasts from newborn rats.


Assuntos
Movimento Celular/genética , Proliferação de Células/genética , Transdiferenciação Celular/genética , Fator de Crescimento Epidérmico/genética , Fibroblastos/fisiologia , Pulmão/fisiologia , Sistema de Sinalização das MAP Quinases/genética , Actinas/genética , Animais , Animais Recém-Nascidos , Diferenciação Celular/genética , Matriz Extracelular/genética , Miofibroblastos/fisiologia , Fosforilação/genética , RNA Mensageiro/genética , Ratos
11.
J Health Econ ; 72: 102317, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32497954

RESUMO

The relationship between social capital and health has received extensive attention in fields such as public health, medicine, epidemiology, gerontology and other health-related disciplines. In contrast, the economics literature on this subject is relatively small. To address this research gap, we investigate the cross-disciplinary empirical literature using meta-analysis. We analyze 12,778 estimates from 470 studies. Our analysis finds that social capital is significantly related to a variety of positive health outcomes. However, the effect sizes are consistently very small. This finding is robust across different types of social capital (e.g., cognitive, structural, bonding, bridging, linking), and for many different measures of health outcomes (e.g., mortality, disease/illnesses, depression). The small effects that we estimate cast doubt on recent initiatives to promote health through social capital such as those by the WHO, the OECD, and US Healthy People 2020.


Assuntos
Capital Social , Promoção da Saúde , Humanos
12.
Int J Mol Med ; 46(2): 773-781, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32467992

RESUMO

Supplemental oxygen therapy can be life­saving for premature infants. Our previous study revealed a defect in the autophagic flux in the lung tissues of neonatal rats with hyperoxia­induced bronchopulmonary dysplasia (BPD), but the underlying mechanism remains unknown. Moreover, there are few innovative treatments that can completely alter the course of BPD. The present study examined the expression of Syntaxin 17 (STX17), a protein necessary for autophagosome­lysosome binding, in alveolar type II (AT­II) epithelial cells of neonatal rats with BPD. Neonatal Sprague­Dawley rats were randomly exposed to elevated O2 levels [fraction of inspired oxygen (FiO2), 0.8; model group] or normal room air (FiO2, 0.21; control group), and the expression levels of STX17, autophagy­related [Microtubule­associated protein 1A/1B­light chain 3B (LC3B)­II, p62, lysosomal­associated membrane protein 1)] and apoptosis­related (cleaved caspase3) mRNA and proteins were examined in lung tissues. Moreover, the expression levels of the aforementioned proteins were measured in isolated primary AT­II cells cultured in vitro under hyperoxic conditions in the presence or absence of pharmacological modulators of autophagy. Transmission electron microscopy identified that AT­II cell apoptosis and autophagosome aggregation were elevated in the lungs of BPD rats compared with control rats on postnatal day 7. STX17 mRNA and protein expression levels were decreased in lung tissue and isolated AT­II cells as early as postnatal day 3 in BPD rats, while the expression levels of LC3B­II, p62 and cleaved caspase3 were increased, reaching a peak on postnatal day 7. This early reduction in STX17 expression, followed by increased expression in autophagy­ and apoptosis­related proteins, was also observed in isolated AT­II cells exposed to hyperoxia in vitro. However, treatment with the autophagy inducers rapamycin or LiCl eliminated the hyperoxia­induced reduction in STX17, partially restored the autophagy flux and increased the survival of AT­II cells exposed to hyperoxia. Collectively, these results indicated that STX17 expression in AT­II cells was reduced in the early stages of BPD in neonatal rats and may be related to the subsequent hyperoxia­induced block in autophagic flux.


Assuntos
Células Epiteliais Alveolares/metabolismo , Autofagia/fisiologia , Displasia Broncopulmonar/metabolismo , Proteínas Qa-SNARE/metabolismo , Animais , Animais Recém-Nascidos , Autofagia/genética , Western Blotting , Displasia Broncopulmonar/genética , Modelos Animais de Doenças , Feminino , Imunofluorescência , Humanos , Hiperóxia/genética , Hiperóxia/metabolismo , Pulmão/metabolismo , Masculino , Microscopia Eletrônica de Transmissão , Proteínas Qa-SNARE/genética , Ratos , Ratos Sprague-Dawley
13.
Life Sci ; 252: 117662, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32298739

RESUMO

AIMS: Bronchopulmonary dysplasia (BPD) is a severe respiratory complication in preterm infants. This study reveals the molecular mechanism of autophagic agonists regulating the Nrf2-ARE pathway via p62 to improve alveolar development in BPD rats. MAIN METHODS: Newborn Sprague-Dawley rats were randomly exposed to a hyperoxic environment (FiO2 = 0.85) for 14 days and rapamycin (RAPA) was intraperitoneally injected on alternate days into hyperoxia-exposed mice. Alveolar development was assessed using HE and RAC values. Markers associated with the p62-Keap1-Nrf2-ARE pathway were detected by western blot, immunohistochemistry, and RT-PCR. Co-localization of proteins was determined using double immunofluorescence staining. KEY FINDINGS: At the levels of lung tissue and primary type II alveolar epithelial cells, the enhanced binding between phosphorylated p62 and Keap1 disrupted the nuclear transport of Nrf2. The activated Nrf2 was insufficient to reverse alveolar simplification. The autophagy agonist was able to inhibit p62 phosphorylation, promote Keap1 degradation, increase Nrf2 nuclear transport, augment downstream antioxidant enzyme expression, and enhance antioxidant capacity, thereby improving the simplification of alveolar structure in BPD rats. SIGNIFICANCE: The use of autophagy agonists to enhance the Nrf2-ARE pathway activity and promote alveolar development could be a novel target in antioxidant therapy for BPD.


Assuntos
Autofagia/efeitos dos fármacos , Displasia Broncopulmonar/fisiopatologia , Alvéolos Pulmonares/metabolismo , Sirolimo/farmacologia , Animais , Animais Recém-Nascidos , Elementos de Resposta Antioxidante , Antioxidantes/metabolismo , Modelos Animais de Doenças , Humanos , Hiperóxia/complicações , Recém-Nascido , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Sprague-Dawley
14.
Biomed Res Int ; 2019: 5249675, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31687391

RESUMO

The broad spectrum of disabilities caused by white matter injury (WMI) cannot be explained simply by hypomyelination. Synaptic injury in the thalamus may be related to disabilities in WMI survivors. Neuronal injury in the thalamus has been found most commonly in autopsy cases of preterm WMI. We hypothesized that hypoxia/ischemia (HI) in neonatal rats results in synaptic abnormalities in the thalamus that contribute to disabilities in WMI survivors. We examined changes in synapses in a neonatal rat model of HI-induced WMI. Right common carotid artery ligation and hypoxia (8% oxygen for 2.5 hours (h)) were performed in three-day-old Sprague-Dawley rats. We found HI rats performed worse in the Morris water maze test than sham rats, suggesting long-term cognition impairment after HI injury. A loss of synapses in the thalamus accompanied by hypomyelination and oligodendrocytes (OLs) reduction was observed. At the ultrastructural level, reductions in active zone (AZ) length and postsynaptic density (PSD) thickness were detected at 2 weeks after HI exposure. Furthermore, increased expression of synaptophysin and PSD-95 in both groups was observed from 3 days (d) to 21 d after hypoxic/ischemic (HI) injury. PSD-95 expression was significantly lower in HI rats than in sham rats from 14 d to 21 d after HI injury, and synaptophysin expression was significantly lower in HI rats from 7 d to 14 d after HI injury. However, no significant difference in synaptophysin expression was observed between HI rats and sham rats at 21 d after HI injury. The results demonstrated synaptic abnormalities in the thalamus accompanied by hypomyelination in WMI in response to HI exposure, which may contribute to the diverse neurological defects observed in WMI patients. Although synaptic reorganization occurred as a compensatory response to HI injury, the impairments in synaptic transmission were not reversed.


Assuntos
Lesões Encefálicas/patologia , Hipóxia-Isquemia Encefálica/patologia , Hipóxia/patologia , Sinapses/patologia , Tálamo/patologia , Substância Branca/patologia , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Aprendizagem em Labirinto/fisiologia , Oligodendroglia/patologia , Densidade Pós-Sináptica/patologia , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica/fisiologia
15.
Ital J Pediatr ; 45(1): 140, 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31706331

RESUMO

BACKGROUND: Preterm infants have immature gastrointestinal tracts and poor immunity. In this study, the effects of Lactobacillus reuteri DSM 17938 first on early feeding tolerance, growth, and second on infection prevention in preterm infants were evaluated. METHODS: One hundred fourteen formula-fed preterm infants with a gestational age between 30 weeks and 37 weeks, and a birth weight between 1500 and 2000 g were enrolled; 57 in the intervention and 57 in the control group:the intervention group was given a dose of 1 × 108 colony-forming units (5 drops) of L. reuteri DSM 17938 once daily, beginning with the first feeding until discharge. The control group did not receive probiotics. Early feeding tolerance (as time to full enterla feeding and number of reflux), growth, incidences of sepsis, localized infection, NEC, and adverse effects were recorded for both groups. RESULTS: The number of Daily reflux episodes (times/d) was lower (2.18 ± 0.83 vs. 3.77 ± 0.66, P < 0.01) and time to full enteral feedings (120 mL/kg/d) (9.95 ± 2.46 d vs. 13.80 ± 3.47 d, P < 0.05) was shorter in the intervention group. Average daily weight gain (14.55 ± 3.07 g/d vs. 10.12 ± 2.80 g/d), head circumference increas e(0.0760 ± 0.0157 cm/d vs. 0.0681 ± 0.0108 cm/d), and body length increase (0.1878 ± 0.0151 cm/d vs. 0.1756 ± 0.0166 cm/d) of the intervention group were higher (P < 0.01). There were no significant differences in the incidences of sepsis (4.44% vs. 8.33%), localized infection (6.67% vs. 8.33%), or NEC (2.22% vs. 10.42%) between the 2 groups (P > 0.05). The number of daily defecations (times/d) in the intervention group was higher (3.08 ± 0.33 vs. 2.29 ± 0.20, P < 0.01) and the length of hospital stay was shorter than that in the control group (20.60 ± 5.36 d vs. 23.75 ± 8.57 d, P < 0.05). No adverse effects were noted among the infants receiving L. reuteri. CONCLUSION: L. reuteri may be an useful tool in improving early feeding tolerance in preterm infants, promoting growth, increasing the frequency of defecation, and shortening the length of hospital stay. TRIAL REGISTRATION: ChiCTR, ChiCTR1900025590. Registered 1 February 2019- Retrospectively registered, http://www.chictr.org.cn/listbycreater.aspx.


Assuntos
Fenômenos Fisiológicos da Nutrição do Lactente , Limosilactobacillus reuteri , Probióticos/uso terapêutico , Desenvolvimento Infantil , Defecação , Método Duplo-Cego , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Tempo de Internação , Masculino
16.
Exp Ther Med ; 17(1): 701-708, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30651853

RESUMO

Bronchopulmonary dysplasia (BPD) is a common, serious complication occurring in premature infants. Although clinical characteristics and pathologic changes are well described, the pathogenesis of alveolar dysplasia and interstitial fibrosis is less clear. Lung fibroblasts (LFs) are present in the extracellular matrix and serve essential roles during pulmonary epithelial injury and in response to fibrosis development in BPD. The current study investigated hyperoxia-induced proliferation of primary LFs in vitro and mechanisms that may be involved. Newborn rats were exposed to 90% oxygen, while control rats were kept in normal atmosphere. Primary LFs were isolated on postnatal day 3, 7 and 14. Hyperoxia-induced proliferation of LFs isolated on day 7 and 14 by accelerating the cell cycle progression from G1 to S phase. Collagen type I protein secretion and mRNA expression on day 7 and 14 were increased by hyperoxia compared with the controls. Hyperoxia significantly increased the phosphorylation of extracellular signal-regulated kinase (ERK) and significantly increased collagen type I expression compared with the room air control group. The findings indicated that an increase in LF proliferation in response to hyperoxia was associated with ERK1/2 phosphorylation. This mechanism may contribute to over-proliferation of LFs leading to disturbed formation of normal alveoli.

17.
Pediatr Pulmonol ; 53(8): 1053-1066, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29893049

RESUMO

AIM: Autophagy is a common process during development. Abnormal autophagy can impact cell apoptosis. Previous studies have shown that apoptosis is present during bronchopulmonary dysplasia (BPD). However, there is no consensus on the level of coexisting autophagy. This study was designed to investigate the role of autophagy and the effects of autophagy inducers in a BPD model. METHOD: A total of 100 newborn Sprague-Dawley rats were randomly assigned to model and control groups. BPD models were established by hyperoxic induction(FiO2 0.80). Some of them were treated with autophagy-inducing agents. RESULT: As compared to the control group, more autophagic bodies were found within Type II alveolar epithelial cells (AT-II cells) under transmission electron microscopy (TEM) in the model group at 3 d . These autophagic bodies were also accompanied by apoptotic bodies and expression of both bodies peaked at 7 d. As shown by TdT-mediated dUTP nick end labeling (TUNEL), there were more apoptotic cells in the model group than in the control group. Protein expression levels of LC3B-II, p62, Lamp1, and cleaved Caspase-3 increased with increased hyperoxic exposure time. No significant differences were observed in the mRNA expression levels of LC3B, p62, and Lamp1. After introducing an autophagy inducer, either rapamycin or lithium chloride, the radial alveolar count (RAC) value of BPD model group increased as compared with placebo group, the thickness of alveolar septum decreased, while apoptosis decreased. CONCLUSION: Reduced autophagy resulting from blocked autophagy flow may be a key link in the pathogenesis of BPD. By enhancing repressed autophagy, apoptosis could be reduced and alveolar development improved.


Assuntos
Células Epiteliais Alveolares/metabolismo , Apoptose/fisiologia , Autofagia/fisiologia , Displasia Broncopulmonar/metabolismo , Hiperóxia/metabolismo , Pulmão/metabolismo , Células Epiteliais Alveolares/patologia , Animais , Animais Recém-Nascidos , Displasia Broncopulmonar/patologia , Caspase 3/metabolismo , Modelos Animais de Doenças , Humanos , Hiperóxia/patologia , Recém-Nascido , Pulmão/patologia , Ratos , Ratos Sprague-Dawley
18.
Int J Mol Med ; 42(3): 1653-1665, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29901175

RESUMO

Bronchopulmonary dysplasia (BPD) seriously affects the health and prognosis of children, but the efficacy of treatments is poor. The present study aimed to examine the effects of C/EBP homologous protein (CHOP), activating transcription factor 4 (ATF4) and microtubule­associated protein light chain 3ß (LC3B), and the interaction between CHOP and LC3B, in newborn rats with BPD. At 1, 7, 14 and 21 days, the rats in the model [fraction of inspired oxygen (FiO2)=80­85%] and control groups (FiO2=21%) were randomly sacrificed, and lung samples were collected. Alveolar development was evaluated according to the radial alveolar count (RAC) and alveolar septum thickness. Ultrastructural changes were observed by transmission electron microscopy (TEM), the expression levels of CHOP, ATF4 and LC3B were determined by immunohistochemistry, and western blot and reverse transcription­quantitative polymerase chain reaction analyses. The co­localization of CHOP and LC3B in lung tissues was determined by immunofluorescence. The results showed that, compared with the control group, alveolarization arrest was present in the model group. The TEM observations revealed that, at 14 days, type II alveolar epithelial cell (AECII) lamellar bodies were damaged, with an apparent dilation of the endoplasmic reticulum (ER) and autophagy in cells within the model group. Between days 7 and 14, the protein levels of ATF4, CHOP and LC3B were significantly increased in the model group. The mRNA levels of CHOP and LC3B were lower at days 7­21. CHOP and LC3B were co­localized in the cells of the lung tissues at day 14 in the model group. Pearson's correlation analysis showed that the protein levels of CHOP and LC3B­II were positively correlated in the model groups. As in previous studies, the present study demonstrated that BPD damaged the AECII cells, which exhibited detached and sparse microvilli and the vacuolization of lamellar bodies. In addition, it was found that the ER was dilated, with autophagosomes containing ER and other organelles in AECII cells; the expression levels of CHOP and LC3B­II were upregulated. CHOP and LC3B­II may have joint involvement in the occurrence and development of BPD.


Assuntos
Displasia Broncopulmonar/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Fator de Transcrição CHOP/metabolismo , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Células Epiteliais Alveolares/ultraestrutura , Animais , Displasia Broncopulmonar/patologia , Feminino , Pulmão/metabolismo , Pulmão/patologia , Pulmão/ultraestrutura , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley
19.
Mol Med Rep ; 17(5): 6277-6284, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29512787

RESUMO

The present study investigated the expression of bone morphogenetic protein (BMP) 7 in a newborn rat model of bronchopulmonary dysplasia (BPD) and the biological effects of BMP7 on newborn rat lung fibroblast (LF) cells. For this purpose, a total of 196 newborn rats were randomly and equally assigned to a model group and a control group. Lung tissue was collected at days 3, 7, 14 and 21 for histological analysis. The location and expression of BMP7 was examined by immunohistochemical staining and reverse transcription­quantitative polymerase chain reaction (RT­qPCR) analysis. A total of 38 full­term newborn rats on the day of birth were sacrificed and LF cells were isolated and treated with BMP7. The biological effects of BMP7 on LF cells were assessed by cell proliferation and cell cycle analysis. The findings demonstrated that abnormal alveolar development due to BPD was gradually intensified in the model group over time. Immunohistochemical staining revealed that the location of BMP7 in lung tissue was altered. Immunohistochemistry and RT­qPCR assays demonstrated a gradual decrease in BMP7 expression in the model group induced by hyperoxia. MTT assays demonstrated that BMP7 inhibited LF cells and the inhibitory effect was dose­dependent and time­dependent. Flow cytometry revealed that the inhibitory effect of BMP7 in LF cells was causing cell cycle arrest at the G1 phase. The present study demonstrated that BMP7 may serve an important role in alveolar development in a BPD model. BMP7 may be involved in abnormal alveolar development through the regulation of LF proliferation.


Assuntos
Proteína Morfogenética Óssea 7/biossíntese , Displasia Broncopulmonar/metabolismo , Fibroblastos/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular , Alvéolos Pulmonares/metabolismo , Animais , Animais Recém-Nascidos , Displasia Broncopulmonar/patologia , Fibroblastos/patologia , Regulação da Expressão Gênica , Alvéolos Pulmonares/patologia , Ratos , Ratos Wistar
20.
Mol Med Rep ; 17(4): 5940-5949, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29436652

RESUMO

As research into periventricular leukomalacia (PVL) gradually increases, concerns are emerging about long­term neuron injury. The present study aimed to investigate neuronal injury and the relevant alterations in apoptosis and autophagy in a PVL model established previously. A rat model of hypoxia­ischemia­induced PVL was established. In the model group, Sprague­Dawley (SD) rats [postnatal day 3 (P3)] were subjected to right common carotid artery ligation followed by suturing and exposed to 6­8% oxygen for 2 h; in the control group, SD rats (P3) were subjected to right common carotid artery dissection followed by suturing, without ligation and hypoxic exposure. At 1, 3, 7 and 14 days following modeling, brain tissue samples were collected and stained with hematoxylin and eosin. Cellular apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and the protein and mRNA expression alterations of neuronal nuclei (NeuN), caspase­3 and Beclin 1 in the model group were detected by western blot analysis and reverse transcription­quantitative polymerase chain reaction (RT­qPCR) analyses. Compared with the control group, the protein and mRNA expression levels of NeuN (a marker of mature neurons) were markedly reduced, the number of positive cells was increased as detected by TUNEL, and the protein and mRNA expression levels of caspase­3 and Beclin 1 were elevated in the model group. In the rat model of hypoxia­ischemia­induced PVL, oligodendrocyte injury and myelinization disorders were observed, in addition to neuron injury, a decrease in mature neurons and the co­presence of apoptosis and autophagy. However, apoptosis and autophagy exist in different phases: Apoptosis is involved in neuron injury, while autophagy is likely to have a protective role.


Assuntos
Apoptose , Autofagia , Hipóxia-Isquemia Encefálica/complicações , Leucomalácia Periventricular/etiologia , Leucomalácia Periventricular/metabolismo , Neurônios/metabolismo , Animais , Animais Recém-Nascidos , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Biomarcadores , Biópsia , Caspase 3/genética , Caspase 3/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Imuno-Histoquímica , Leucomalácia Periventricular/patologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/patologia , Ratos
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