Maternal sleep deprivation(MSD)is a global public health problem that affects the physical and mental development of pregnant women and their newborns.The latest research suggests that sleep deprivation(SD)disrupts th...Maternal sleep deprivation(MSD)is a global public health problem that affects the physical and mental development of pregnant women and their newborns.The latest research suggests that sleep deprivation(SD)disrupts the gut microbiota,leading to neuroinflammation and psychological disturbances.However,it is unclear whether MSD affects the establishment of gut microbiota and neuroinflammation in the newborns.In the present study,MSD was performed on pregnant SpragueDawley rats in the third trimester of pregnancy(gestational days 15-21),after which intestinal contents and brain tissues were collected from offspring at different postnatal days(P1,P7,P14,and P56).Based on microbial profiling,microbial diversity and richness increased in pregnant rats subjected to MSD,as reflected by the significant increase in the phylum Firmicutes.In addition,microbial dysbiosis marked by abundant Firmicutes bacteria was observed in the MSD offspring.Furthermore,quantitative real-time polymerase chain reaction(q RT-PCR)and enzyme-linked immunosorbent assay(ELISA)showed that the expression levels of proinflammatory cytokines interleukin 1β(IL-1β)and tumor necrosis factorα(TNF-α)were significantly higher in the MSD offspring at adulthood(P56)than in the control group.Through Spearman correlation analysis,IL-1βand TNF-αwere also shown to be positively correlated with Ruminococcus_1 and Ruminococcaceae_UCG-005 at P56,which may determine the microbiota-host interactions in MSDrelated neuroinflammation.Collectively,these results indicate that MSD changes maternal gut microbiota and affects the establishment of neonatal gut microbiota,leading to neuroinflammation in MSD offspring.Therefore,understanding the role of gut microbiota during physiological development may provide potential interventions for cognitive dysfunction in MSD-impacted offspring.展开更多
A female patient aged 3 months and 10 days was admitted to the cardiology department because of symptoms of heart failure.According to the echocardiography results,the patient received a diagnosis of primary endocardi...A female patient aged 3 months and 10 days was admitted to the cardiology department because of symptoms of heart failure.According to the echocardiography results,the patient received a diagnosis of primary endocardial fi broelastosis and was treated withγ-globulin,prednisone,digoxin,and diuretics.Coronary computed tomographic angiography and coronary angiography were performed as there was no improvement after 2 months of treatment.Finally,the patient received a diagnosis of anomalous origin of the left coronary artery from the pulmonary artery(ALCAPA).ALCAPA is a rare congenital heart defect that can cause severe heart failure during infancy,and is easily misdiagnosed clinically.In this report,we show the process of misdiagnosis of the case and consult the relevant literature,hoping to improve the understanding and early diagnosis of ALCAPA.展开更多
Objective:To investigate the etiological characteristics,clinical manifestations,and early identification methods of neonatal brain abscess.Methods:The baseline characteristics,clinical manifestations,and laboratory r...Objective:To investigate the etiological characteristics,clinical manifestations,and early identification methods of neonatal brain abscess.Methods:The baseline characteristics,clinical manifestations,and laboratory results of 12 neonatal brain abscess cases were retrospectively analyzed.Results:The clinical manifestations were fever,convulsion,and lethargy.A small number of them had respiratory and circulatory failure.The diagnosis made was based on imaging examination.All 12 cases were confirmed by cranial enhanced computed tomography(CT)or magnetic resonance imaging(MRI).Blood cultures of 9 cases were positive,with Escherichia coli in 6 cases,β-hemolytic Streptococcus in 1 case,methicillin-resistant Staphylococcus aureus in 1 case,and Enterococcus faecium in 1 case.However,only 3 of them had positive cerebrospinal fluid(CSF)cultures.All the 12 neonates were treated with antibiotic therapy upon admission,with only 3 cases treated with surgery.Among them,4 recovered and were discharged,while the remaining 8 discontinued their therapy.Conclusion:Escherichia coli is the most common pathogen of neonatal brain abscess in our study.The clinical manifestations of neonatal brain abscess are atypical,and the prognosis is poor.Respiratory and circulatory failure in children with intracranial infection may indicate the presence of brain abscess.For children with suspected brain abscess,cranial enhanced CT or MRI should be performed as soon as possible to make an early diagnosis.The prevention of brain abscess should be prioritized;neonates with sepsis or meningitis should receive prompt and strong antibiotic therapy in an effort to prevent the development of brain abscess.展开更多
Objective:To compare the effects of the use and non-use of a disinfectant on the outcomes of separation of the labia minora in infants.Methods:The patients were randomly divided into an experimental group with 24 case...Objective:To compare the effects of the use and non-use of a disinfectant on the outcomes of separation of the labia minora in infants.Methods:The patients were randomly divided into an experimental group with 24 cases and a control group with 25 cases.In the control group,1%iodophor was used to clean and disinfect the large and small labia and the surrounding skin,while normal saline was used in the experimental group.Other procedures such as the surgery and nursing method were the same in both groups.Results:There were no symptoms of urinary tract infection such as redness of the vulva,swelling,pain,and abnormal urination in the test group and control group after three days of follow-up,and no recurrence was seen at one month of follow-up.There was no statistically significant difference between the two groups(P>0.05).Conclusion:Use or non-use of a disinfectant to clean the urethral opening before separation of the labia minora has no significant effect on the outcomes,and does not cause postoperative urinary tract infection symptoms.Moreover,non-use of a disinfectant can prevent local irritation and reduce the economic burden on the patients.展开更多
Labial adhesions (LA)(also called labial agglutination) are defined as partial or complete agglutination of labia minora. The condition commonly occurs in girls during childhood with an estimated prevalence of 0.6%–5...Labial adhesions (LA)(also called labial agglutination) are defined as partial or complete agglutination of labia minora. The condition commonly occurs in girls during childhood with an estimated prevalence of 0.6%–5%and a peak incidence in the age-group of 13–24 months[1]. Over half of all patients present with symptoms related to urinary outlet obstruction[2].展开更多
Cancer cell genomes originate from single-cell mutation with sequential clonal and subclonal expansion of somatic mutation acquisition during pathogenesis,thus exhibiting a Darwinian evolutionary process(Gerstung et a...Cancer cell genomes originate from single-cell mutation with sequential clonal and subclonal expansion of somatic mutation acquisition during pathogenesis,thus exhibiting a Darwinian evolutionary process(Gerstung et al.,2020;Nik-Zainal et al.,2012).Through next-generation sequencing of tumor tissue,this evolutionary process can be characterized by statistical modelling,which can identify the clonal state,somatic mutation order,and evolutionary process(Gerstung et al.,2020;Mcgranahan&Swanton,2017).Inference of clonal and subclonal structure from bulk or single-cell tumor genomic sequencing data has a huge impact on studying cancer evolution.Clonal state and mutation order can provide detailed insight into tumor origin and future development.In the past decade,various methods for subclonal reconstruction using bulk tumor sequencing data have been developed.However,these methods had different programming languages and data input formats,which limited their use and comparison.Therefore,we established a web server for Clonal and Subclonal Structure Inference and Evolution(COSINE)of cancer genomic data,which incorporated twelve popular subclonal reconstruction methods.We deconstructed each method to provide a detailed workflow of single processing steps with a user-friendly interface.To the best of our knowledge,this is the first web server providing online subclonal inference based on the integration of most popular subclonal reconstruction methods.COSINE is freely accessible at www.clab-cosine.net.展开更多
BACKGROUND Juvenile dermatomyositis(JDM)is an idiopathic inflammatory myopathy that occurs in childhood.It is characterized by muscle weakness and a characteristic rash.Previous literature reports have rarely describe...BACKGROUND Juvenile dermatomyositis(JDM)is an idiopathic inflammatory myopathy that occurs in childhood.It is characterized by muscle weakness and a characteristic rash.Previous literature reports have rarely described JDM with severe skin ulcers and infections.CASE SUMMARY Herein,we describe a case of a 2-year-old female patient who suffered from JDM,whose myositis-specific autoantibodies were positive for anti-nuclear matrix protein 2 antibody,with progressively worsening skin ulcers and severe infections.The patient was treated with glucocorticoids and various immunosuppressants.Nevertheless,further progression of the disease and the combination of primary disease and severe infection in the later period were fatal.CONCLUSION In children,anti-nuclear matrix protein 2+JDM combined with skin ulcers often indicates severe disease.In such cases,personalized treatment for the primary disease and infection prevention and control are essential.展开更多
Objective:To summarize the clinical features and therapeutic effects of transcatheter embolotherapy for congenital pulmonary arteriovenous fi stulas(PAVFs)in children,and to explore the method and therapeutic principl...Objective:To summarize the clinical features and therapeutic effects of transcatheter embolotherapy for congenital pulmonary arteriovenous fi stulas(PAVFs)in children,and to explore the method and therapeutic principle of transcatheter embolotherapy for congenital PAVFs in children.Method:We retrospectively reviewed nine patients with PAVF who underwent transcatheter embolotherapy in the Children’s Hospital of Chongqing Medical University from July 2004 to July 2019,including the demographic characteristics,clinical manifestations,effi ciency of closure,and follow-up.Results:Transcatheter embolotherapy was successful in all cases,and the symptom remission rate was 100%during the follow-up.No residual shunts or other complications occurred during the follow-up period.Compared with before embolotherapy,there were signifi cant changes in the percentage of saturated oxyhemoglobin and total hemoglobin level at the last follow-up(t=10.06,P=0.000;t=3.055,P=0.0076).No signifi cant difference was observed in pulmonary artery pressure before and after embolotherapy(t=0.13,P=0.90).Conclusions:Transcatheter embolotherapy offers the advantages of safety,with a decreased risk of trauma and a specifi c effect of treatment,and therefore is recommended as the fi rst-line treatment for congenital PAVFs in children.However,continued research is necessary to understand the full potential of transcatheter embolotherapy.展开更多
Tetralogy of Fallot(TOF)is the most common cyanotic congenital heart disease and the incidence of late cardiac death in long-term survivors continues to increase.1 So,there is an urgent need to explore the etiology an...Tetralogy of Fallot(TOF)is the most common cyanotic congenital heart disease and the incidence of late cardiac death in long-term survivors continues to increase.1 So,there is an urgent need to explore the etiology and pathogenesis of TOF.The precise cause of TOF is currently unclear,and exploration of the pathogenesis has focused increasingly in recent years on the roles of noncoding gene products,especially long noncoding RNAs(lncRNAs).展开更多
As a widely used plasticizer,di-(2-ethylhexyl)phthalate(DEHP)is known to induce significant testicular injury.However,the potential mechanism and effects of pubertal exposure to DEHP on testis development remain uncle...As a widely used plasticizer,di-(2-ethylhexyl)phthalate(DEHP)is known to induce significant testicular injury.However,the potential mechanism and effects of pubertal exposure to DEHP on testis development remain unclear.In vivo,postnatal day(PND)21 male rats were gavaged with 0,250,and 500 mg/kg DEHP for ten days.Damage to the seminiferous epithelium and disturbed spermatogenesis were observed after DEHP exposure.Meanwhile,oxidative stress-induced injury and pyroptosis were activated.Both endoplasmic reticulum(ER)stress and mitophagy were involved in this process.Monoethylhexyl phthalate(MEHP)was used as the biometabolite of DEHP in vitro.The GC-1 and GC-2 cell lines were exposed to 0,100μM,200μM,and 400μM MEHP for 24 h.Reactive oxygen species(ROS)generation,oxidative stress damage,ER stress,mitophagy,and pyroptosis were significantly increased after MEHP exposure.The ultrastructure of the ER and mitochondria was destroyed.X-box binding protein 1(XBP1)was observed to be activated and translocated into the nucleus.ROS generation was inhibited by acetylcysteine.The levels of antioxidative stress,ER stress,mitophagy,and pyroptosis were decreased as well.After the administration of the ER stress inhibitor 4-phenyl-butyric acid,both mitophagy and pyroptosis were inhibited.Toyocamycin-induced XBP1 down-regulation decreased the levels of mitophagy and pyroptosis.The equilibrium between pyroptosis and mitophagy was disturbed by XBP1 accumulation.In summary,our findings confirmed that DEHP induced a ROS-mediated imbalance in pyroptosis and mitophagy in immature rat testes via XBP1.Moreover,XBP1 might be the key target in DEHP-related testis dysfunction.展开更多
Disrupting the balance of neuronal excitation and inhibition (E/I) is an important pathogenic mechanism of anxiety and depression. Interferon regulatory factor 3 (IRF3) plays a key role in the innate immune response, ...Disrupting the balance of neuronal excitation and inhibition (E/I) is an important pathogenic mechanism of anxiety and depression. Interferon regulatory factor 3 (IRF3) plays a key role in the innate immune response, and activation of IRF3 triggers the expression of type I interferons and downstream interferon-stimulated genes, which are associated with anxiety and depression. However, whether IRF3 participates in the pathogenesis of anxiety/depression by regulating E/I balance remains poorly understood. Here, we reported that global knockout (KO) of IRF3 (IRF3^(−/−)) significantly increased anxiety/depression-like behaviors, but did not affect normal spatial learning and memory. Compared with wild type (WT) control mice, the E/I balance was disrupted, as reflected by enhanced glutamatergic transmission and decreased GABAergic transmission in the neurons of hippocampal CA1 and medial prefrontal cortex (mPFC) in IRF3-KO mice. Importantly, genetic rescue of IRF3 expression by adeno-associated virus (AAV) was sufficient to alleviate anxiety/depression-like behaviors and restore the neuronal E/I balance in IRF3-KO mice. Taken together, our results indicate that IRF3 is critical in maintaining neuronal E/I balance, thereby playing an essential role in ensuring emotional stability.展开更多
The aim of this phase I study is to evaluate,for the first time,the safety and efficacy of sintilimab in pediatric patients diagnosed with advanced or recurrent malignancies.During the dose escalation phase,patients r...The aim of this phase I study is to evaluate,for the first time,the safety and efficacy of sintilimab in pediatric patients diagnosed with advanced or recurrent malignancies.During the dose escalation phase,patients received a single intravenous infusion of sintilimab at varying doses of 1,3,and 10 mg/kg.The primary endpoints included the identification of dose-limiting toxicities(DLTs)as well as the evaluation of safety and tolerance.Secondary endpoints focused on assessing objective response rate(ORR),progression-free survival(PFS),and overall survival(OS).A total of 29 patients were enrolled,including 10 individuals diagnosed with Hodgkin lymphoma(HL)and 19 patients with various other tumor categories.Notably,diverse pathological types such as thymoma,choroid plexus carcinoma,and NK/T-cell lymphoma were also included in the study cohort.By the safety data cutoff,most adverse events were grade 1 or 2,with grade 3 or higher treatment-related adverse events(TRAE)occurring in 10%of patients.Among the 27 evaluated subjects,four achieved confirmed complete response(CR)while seven patients exhibited confirmed partial response(PR).Additionally,seven patients maintained disease(SD)during the study period.Notably,sintilimab demonstrated remarkable tolerability without DLTs and exhibited promising anti-tumor effects in pediatric HL.Whole-exome sequencing(WES)was conducted in 15 patients to assess the mutational landscape and copy number variation(CNV)status.The completion of this phase I study establishes the foundation for potential combination regimens involving sintilimab in childhood cancer treatment.The trial is registered on ClinicalTrials.gov with the identifier NCT04400851.展开更多
We investigated the associations of clinical and socioeconomic factors with delayed orchidopexy for cryptorchidism in China. A retrospective study was conducted on cryptorchid boys who underwent orchidopexy at Childre...We investigated the associations of clinical and socioeconomic factors with delayed orchidopexy for cryptorchidism in China. A retrospective study was conducted on cryptorchid boys who underwent orchidopexy at Children's Hospital at Chongqing Medical University in China from January 2012 to December 2017. Of 2423 patients, 410 (16.9%) received timely repair by 18 months of age, beyond which surgery was considered delayed. Univariate analysis suggested that the laterality of cryptorchidism (P = 0.001), comorbidities including inguinal hernia/scrotal hydrocele (P < 0.001) or urinary tract disease (P = 0.016), and whether patients lived in a poverty county (P < 0.001) could influence whether orchidopexy was timely or delayed. Logistic regression analysis suggested that the following factors were associated with delayed repair: unilateral rather than bilateral cryptorchidism (odds ratio [OR]= 1.752, P < 0.001), absence of inguinal hernia or hydrocele (OR = 2.027, P = 0.019), absence of urinary tract disease (OR = 3.712, P < 0.001), and living in a poverty county (OR = 2.005, P < 0.001). The duration of postoperative hospital stay and hospital costs increased with the patient's age at the time of surgery.展开更多
We aimed to explore the associations between the age at which children undergo surgery for hypospadias and a range of social and clinical factors in a single center.Our aim was to promote the early surgical treatment ...We aimed to explore the associations between the age at which children undergo surgery for hypospadias and a range of social and clinical factors in a single center.Our aim was to promote the early surgical treatment of children with hypospadias.For a 6-year period,social and clinical data were collected from all children undergoing surgery to repair hypospadias in Children’s Hospital of Chongqing Medical University(Chongqing,China),located in southwest of China.We analyzed the correlations between age at surgery and a range of social and clinical factors.A total of 1611 eligible cases were recruited,with a mean age of 54.3 months and a median age of 42 months:234 cases(14.5%)were classified into a“timely operation”group,419(26.0%)cases into a“subtimely operation”group,and 958(59.5%)cases into a“delayed operation”group.According to multivariate regression analyses,the higher the regional economic level,the closer the urethral opening to the perineum,and the higher the educational level of the guardians was,the younger the children were when they underwent the initial surgery for hypospadias;this was also the case for families without other children.Our subgroup analysis showed that the primary educational level of the guardians was a risk factor for subtimely surgery in their children(odds ratio[OR]=1.52,95%confidence interval[CI]:1.08-2.15,P<0.05).A lower regional economic level(OR=1.87,95%CI:1.26-2.78,P<0.01),a lower educational level of the guardians(OR=3.84,95%CI:2.31-6.41,P<0.01),and an anterior-segment urethral opening(OR_(1)[vs middle hypospadias]=2.07,95%CI:1.42-3.03;0R_(2)[vs posterior hypospadias]=2.63,95%CI:1.75-3.95;P<0.01)were all risk factors for delayed surgery in children.展开更多
We describe and summarize the diagnosis,treatment,and reasons for delayed treatment of children with cryptorchidism torsion in Children's Hospital of Chongqing Medical University.The study included 19 cases of cry...We describe and summarize the diagnosis,treatment,and reasons for delayed treatment of children with cryptorchidism torsion in Children's Hospital of Chongqing Medical University.The study included 19 cases of cryptorchidism torsion.The age of the children ranged from 16 days to 12 years(median:6 years).The interval from diagnosis to surgery varied from 4 h to 16 days(median:3 days).Ultrasound was performed in all cases.Fifteen cases had cryptorchidism torsion,2 cases had a soft tissue mass in the inguinal region,and 2 cases had an inguinal/abdominal teratoma.Five cases were treated with an orchidopexy,12 cases were treated with orchiectomy,and 2 cases received resection of a testicular tumor.The 5 children with an orchidopexy were followed up from 1 month to 7 years(median:3 years),with 1 child having a testis retraction and no blood supply.Of the 12 children who had an orchiectomy,three had delayed diagnosis due to family unawareness of the condition,while other delays were due to delayed referral from primary care facilities.The relative rarity and insufficient awareness of cryptorchidism torsion resulted in a low rate of testicular salvage.Therefore,hospitals of all levels should be fully aware of cryptorchidism with torsion and ensure a male child's genital system and inguinal region are examined to improve the success rate of testicular salvage.展开更多
BACKGROUND Few studies have addressed the effects of human leukocyte antigen(HLA)alleles on different clinical sub-phenotypes in childhood steroid-sensitive nephrotic syndrome(SSNS),including SSNS without recurrence(S...BACKGROUND Few studies have addressed the effects of human leukocyte antigen(HLA)alleles on different clinical sub-phenotypes in childhood steroid-sensitive nephrotic syndrome(SSNS),including SSNS without recurrence(SSNSWR)and steroid-dependent nephrotic syndrome/frequently relapse nephrotic syndrome(SDNS/FRNS).In this study,we investigated the relationship between HLA system and children with SSNSWR and SDNS/FRNS and clarified the value of HLA allele detection for precise typing of childhood SSNS.METHODS A total of 241 Chinese Han individuals with SSNS were genotyped using GenCap-WES Capture Kit,and four-digit resolution HLA alleles were imputed from available Genome Wide Association data.The distribution and carrying frequency of HLA alleles in SSNSWR and SDNS/FRNS were investigated.Additionally,logistic regression and mediating effects were used to examine the relationship between risk factors for disease process and HLA system.RESULTS Compared with SSNSWR,significantly decreased serum levels of complement 3(C3)and complement 4(C4)at onset were detected in SDNS/FRNS(C3,P<0.001;C4,P=0.018).The average time to remission after sufficient initial steroid treatment in SDNS/FRNS was significantly longer than that in SSNSWR(P=0.0001).Low level of C4 was further identified as an independent risk factor for SDNS/FRNS(P=0.008,odds ratio=0.174,95% confidence interval 0.048-0.630).The HLA-A*11:01 allele was independently associated with SSNSWR and SDNS/FRNS(P=0.0012 and P=0.0006,respectively).No significant HLA alleles were detected between SSNSWR and SDNS/FRNS.In addition,a mediating effect among HLA-I alleles(HLA-B*15:11,HLA-B*44:03 and HLA-C*07:06),C4 level and SDNS/FRNS was identified.CONCLUSIONS HLA-I alleles provide novel genetic markers for SSNSWR and SDNS/FRNS.HLA-I antigens may be involved in steroid dependent or frequent relapse in children with SSNS as mediators of immunoregulation.展开更多
To the Editor:Off-label drug use(OLDU)refers to the use of a drug outside of the age,indication,weight,dose,formulation,or route of administration indicated on the label.It is a major concern and a common practice for...To the Editor:Off-label drug use(OLDU)refers to the use of a drug outside of the age,indication,weight,dose,formulation,or route of administration indicated on the label.It is a major concern and a common practice for clinicians around the globe,especially for pediatricians,owing to the lack of pediatric-specific drug information.[1]Research showed that US office-based physicians had ordered 41.2 million off-label orders per year for children and the trend had been increasing from 2006 to 2015.展开更多
Although it is widely accepted that human induced pluripotent stem cell-derived cardiomyocytes(hiPSC-CMs)are readily available,robustly reproducible,and physiologically appropriate human cells for clinical application...Although it is widely accepted that human induced pluripotent stem cell-derived cardiomyocytes(hiPSC-CMs)are readily available,robustly reproducible,and physiologically appropriate human cells for clinical applications and research in the cardiovascular field,hiPSC-CMs cultured in vitro retain an immature metabolic phenotype that limits their application,and little is known about the underlying molecular mechanism controlling mitochondrial metabolic maturation during human induced pluripotent stem cells(hiPSCs)differentiation into cardiomyocytes.In this study,we found that peroxisome proliferator-activated receptor g coactivator-1α(PGC-1α)played an important role in inducing mitochondrial biogenesis and establishing oxidative phosphorylation(OXPHOS)during the cardiac differentiation of hiPSCs.Knocking down PGC-1α by siRNA impaired mitochondrial respiration,while upregulating PGC-1α by ZLN005 promoted mitochondrial biosynthesis and function by regulating the expression of downstream genes involved in mitochondrial dynamics and oxidative metabolism in hiPSCCMs.Furthermore,we found that estrogen-related receptor a(ERRa)was required for the induction of PGC-1α stimulatory effects in hiPSC-CMs.These findings provide key insights into the molecular control of mitochondrial metabolism during cardiac differentiation and may be used to generate more metabolically mature cardiomyocytes for application.展开更多
GATA4 is a particularly important cardiogenic transcription factor and serves as a potent driver of cardiogenesis.Recent progress in the field has made it clear that histone acetylation can influence gene expression t...GATA4 is a particularly important cardiogenic transcription factor and serves as a potent driver of cardiogenesis.Recent progress in the field has made it clear that histone acetylation can influence gene expression through changing the structure of chromatin.Our previous research had revealed that hypo-acetylation could repress gata4 expression in cardiocytes,however the underlying mechanism by which this occurred was still unclear.To reveal the mechanism of histone acetylation involved in the regulation of gata4 transcription,we concentrated on P300,one of the important histone acetyltransferase associated with cardiogenesis.We found that P300 participated in gata4 expression through regulating histone acetylation in embryonic mouse hearts.RNAi-mediated downregulation of P300 modulated the global acetylation of H3 and the acetylation of H3K4,H3K9,and H3K27 in gata4 and Tbx5 promoters.Interestingly,there was an obvious inhibition of gata4 transcription,whereas Tbx5 was not influenced.Furthermore,SGC-CBP30,the selective inhibitor of the bromodomain in CBP/P300,downregulated gata4 transcription by repressing the acetylation of H3K4,H3K9,and H3K27 in the gata4 promoters.Taken together,our results identified that acetylation of H3K4,H3K9,and H3K27 mediated by P300 plays an important role in regulation of gata4 expression in cardiogenesis.展开更多
Alveolar epithelial cells(AECs)injury and failed reconstitution of the AECs barrier are both integral to alveolar flooding and subsequent pulmonary fibrosis(PF).Nevertheless,the exact mechanisms regulating the regener...Alveolar epithelial cells(AECs)injury and failed reconstitution of the AECs barrier are both integral to alveolar flooding and subsequent pulmonary fibrosis(PF).Nevertheless,the exact mechanisms regulating the regeneration of AECs post-injury still remain unclear.SMARCA4 is a part of the large ATP-dependent chromatin remodelling complex SWI/SNF,which is essential for kidney and heart fibrosis.We investigates SMARCA4 function in lung fibrosis by establishing PF mice model with bleomycin firstly and found that the expression of SMARCA4 was mainly enhanced in alveolar type II(ATII)cells.Moreover,we established an alveolar epithelium-specific SMARCA4-deleted SP-C-rtTA/(tetO)7-Cre/SMARCA4f/f mice(SOSM4D/D)model,as well as a new SMARCA4-deleted alveolar type II(ATII)-like mle-12 cell line.We found that the bleomycin-induced PF was more aggressive in SOSM4D/D mice.Also,the proliferation of ATII cells was decreased with the loss of SMARCA4 in vivo and in vitro.In addition,we observed increased proliferation of ATII cells accompanied by abnormally high expression of SMARCA4 in human PF lung sections.These data uncovered the indispensable role of SMARCA4 in the proliferation of ATII cells,which might affect the progression of PF.展开更多
基金supported by the National Natural Science Foundation of China(82071395,91749116)Natural Science Foundation of Chongqing(cstc2021ycjh-bgzxm0186,cstc2020jcyjzdxm X0004)+1 种基金Science and Technology Research Program of Chongqing Municipal Education Commission(KJZD-K201900403)Innovation Research Group at Institutions of Higher Education in Chongqing(CXQTP19034)。
文摘Maternal sleep deprivation(MSD)is a global public health problem that affects the physical and mental development of pregnant women and their newborns.The latest research suggests that sleep deprivation(SD)disrupts the gut microbiota,leading to neuroinflammation and psychological disturbances.However,it is unclear whether MSD affects the establishment of gut microbiota and neuroinflammation in the newborns.In the present study,MSD was performed on pregnant SpragueDawley rats in the third trimester of pregnancy(gestational days 15-21),after which intestinal contents and brain tissues were collected from offspring at different postnatal days(P1,P7,P14,and P56).Based on microbial profiling,microbial diversity and richness increased in pregnant rats subjected to MSD,as reflected by the significant increase in the phylum Firmicutes.In addition,microbial dysbiosis marked by abundant Firmicutes bacteria was observed in the MSD offspring.Furthermore,quantitative real-time polymerase chain reaction(q RT-PCR)and enzyme-linked immunosorbent assay(ELISA)showed that the expression levels of proinflammatory cytokines interleukin 1β(IL-1β)and tumor necrosis factorα(TNF-α)were significantly higher in the MSD offspring at adulthood(P56)than in the control group.Through Spearman correlation analysis,IL-1βand TNF-αwere also shown to be positively correlated with Ruminococcus_1 and Ruminococcaceae_UCG-005 at P56,which may determine the microbiota-host interactions in MSDrelated neuroinflammation.Collectively,these results indicate that MSD changes maternal gut microbiota and affects the establishment of neonatal gut microbiota,leading to neuroinflammation in MSD offspring.Therefore,understanding the role of gut microbiota during physiological development may provide potential interventions for cognitive dysfunction in MSD-impacted offspring.
基金The project was funded by the Natural Science Foundation of Chongqing Science and Technology Commission(cstc2019jcyj-msxmX0866).
文摘A female patient aged 3 months and 10 days was admitted to the cardiology department because of symptoms of heart failure.According to the echocardiography results,the patient received a diagnosis of primary endocardial fi broelastosis and was treated withγ-globulin,prednisone,digoxin,and diuretics.Coronary computed tomographic angiography and coronary angiography were performed as there was no improvement after 2 months of treatment.Finally,the patient received a diagnosis of anomalous origin of the left coronary artery from the pulmonary artery(ALCAPA).ALCAPA is a rare congenital heart defect that can cause severe heart failure during infancy,and is easily misdiagnosed clinically.In this report,we show the process of misdiagnosis of the case and consult the relevant literature,hoping to improve the understanding and early diagnosis of ALCAPA.
文摘Objective:To investigate the etiological characteristics,clinical manifestations,and early identification methods of neonatal brain abscess.Methods:The baseline characteristics,clinical manifestations,and laboratory results of 12 neonatal brain abscess cases were retrospectively analyzed.Results:The clinical manifestations were fever,convulsion,and lethargy.A small number of them had respiratory and circulatory failure.The diagnosis made was based on imaging examination.All 12 cases were confirmed by cranial enhanced computed tomography(CT)or magnetic resonance imaging(MRI).Blood cultures of 9 cases were positive,with Escherichia coli in 6 cases,β-hemolytic Streptococcus in 1 case,methicillin-resistant Staphylococcus aureus in 1 case,and Enterococcus faecium in 1 case.However,only 3 of them had positive cerebrospinal fluid(CSF)cultures.All the 12 neonates were treated with antibiotic therapy upon admission,with only 3 cases treated with surgery.Among them,4 recovered and were discharged,while the remaining 8 discontinued their therapy.Conclusion:Escherichia coli is the most common pathogen of neonatal brain abscess in our study.The clinical manifestations of neonatal brain abscess are atypical,and the prognosis is poor.Respiratory and circulatory failure in children with intracranial infection may indicate the presence of brain abscess.For children with suspected brain abscess,cranial enhanced CT or MRI should be performed as soon as possible to make an early diagnosis.The prevention of brain abscess should be prioritized;neonates with sepsis or meningitis should receive prompt and strong antibiotic therapy in an effort to prevent the development of brain abscess.
文摘Objective:To compare the effects of the use and non-use of a disinfectant on the outcomes of separation of the labia minora in infants.Methods:The patients were randomly divided into an experimental group with 24 cases and a control group with 25 cases.In the control group,1%iodophor was used to clean and disinfect the large and small labia and the surrounding skin,while normal saline was used in the experimental group.Other procedures such as the surgery and nursing method were the same in both groups.Results:There were no symptoms of urinary tract infection such as redness of the vulva,swelling,pain,and abnormal urination in the test group and control group after three days of follow-up,and no recurrence was seen at one month of follow-up.There was no statistically significant difference between the two groups(P>0.05).Conclusion:Use or non-use of a disinfectant to clean the urethral opening before separation of the labia minora has no significant effect on the outcomes,and does not cause postoperative urinary tract infection symptoms.Moreover,non-use of a disinfectant can prevent local irritation and reduce the economic burden on the patients.
基金supported by National Natural Science Foundation of China [NO.81873828] in the document search and data analysis
文摘Labial adhesions (LA)(also called labial agglutination) are defined as partial or complete agglutination of labia minora. The condition commonly occurs in girls during childhood with an estimated prevalence of 0.6%–5%and a peak incidence in the age-group of 13–24 months[1]. Over half of all patients present with symptoms related to urinary outlet obstruction[2].
基金supported by the CAS Pioneer Hundred Talents Program and National Natural Science Foundation of China(32070683)to Y.P.C.the Science and Technology Planning Project of XI'AN(GXYD6.2)National Natural Science Foundation of China(61771369)to X.G.Y.
文摘Cancer cell genomes originate from single-cell mutation with sequential clonal and subclonal expansion of somatic mutation acquisition during pathogenesis,thus exhibiting a Darwinian evolutionary process(Gerstung et al.,2020;Nik-Zainal et al.,2012).Through next-generation sequencing of tumor tissue,this evolutionary process can be characterized by statistical modelling,which can identify the clonal state,somatic mutation order,and evolutionary process(Gerstung et al.,2020;Mcgranahan&Swanton,2017).Inference of clonal and subclonal structure from bulk or single-cell tumor genomic sequencing data has a huge impact on studying cancer evolution.Clonal state and mutation order can provide detailed insight into tumor origin and future development.In the past decade,various methods for subclonal reconstruction using bulk tumor sequencing data have been developed.However,these methods had different programming languages and data input formats,which limited their use and comparison.Therefore,we established a web server for Clonal and Subclonal Structure Inference and Evolution(COSINE)of cancer genomic data,which incorporated twelve popular subclonal reconstruction methods.We deconstructed each method to provide a detailed workflow of single processing steps with a user-friendly interface.To the best of our knowledge,this is the first web server providing online subclonal inference based on the integration of most popular subclonal reconstruction methods.COSINE is freely accessible at www.clab-cosine.net.
文摘BACKGROUND Juvenile dermatomyositis(JDM)is an idiopathic inflammatory myopathy that occurs in childhood.It is characterized by muscle weakness and a characteristic rash.Previous literature reports have rarely described JDM with severe skin ulcers and infections.CASE SUMMARY Herein,we describe a case of a 2-year-old female patient who suffered from JDM,whose myositis-specific autoantibodies were positive for anti-nuclear matrix protein 2 antibody,with progressively worsening skin ulcers and severe infections.The patient was treated with glucocorticoids and various immunosuppressants.Nevertheless,further progression of the disease and the combination of primary disease and severe infection in the later period were fatal.CONCLUSION In children,anti-nuclear matrix protein 2+JDM combined with skin ulcers often indicates severe disease.In such cases,personalized treatment for the primary disease and infection prevention and control are essential.
文摘Objective:To summarize the clinical features and therapeutic effects of transcatheter embolotherapy for congenital pulmonary arteriovenous fi stulas(PAVFs)in children,and to explore the method and therapeutic principle of transcatheter embolotherapy for congenital PAVFs in children.Method:We retrospectively reviewed nine patients with PAVF who underwent transcatheter embolotherapy in the Children’s Hospital of Chongqing Medical University from July 2004 to July 2019,including the demographic characteristics,clinical manifestations,effi ciency of closure,and follow-up.Results:Transcatheter embolotherapy was successful in all cases,and the symptom remission rate was 100%during the follow-up.No residual shunts or other complications occurred during the follow-up period.Compared with before embolotherapy,there were signifi cant changes in the percentage of saturated oxyhemoglobin and total hemoglobin level at the last follow-up(t=10.06,P=0.000;t=3.055,P=0.0076).No signifi cant difference was observed in pulmonary artery pressure before and after embolotherapy(t=0.13,P=0.90).Conclusions:Transcatheter embolotherapy offers the advantages of safety,with a decreased risk of trauma and a specifi c effect of treatment,and therefore is recommended as the fi rst-line treatment for congenital PAVFs in children.However,continued research is necessary to understand the full potential of transcatheter embolotherapy.
基金supported by grants from the National Key R&D Program of China(No.2021YFC2701101)the National Natural Science Foundation of China(No.81930036 and 82150008)the Commission for Science and Technology of Shanghai Municipality(China)(No.20ZR1404800).
文摘Tetralogy of Fallot(TOF)is the most common cyanotic congenital heart disease and the incidence of late cardiac death in long-term survivors continues to increase.1 So,there is an urgent need to explore the etiology and pathogenesis of TOF.The precise cause of TOF is currently unclear,and exploration of the pathogenesis has focused increasingly in recent years on the roles of noncoding gene products,especially long noncoding RNAs(lncRNAs).
基金supported by the National Natural Science Foundation of China(No.81771566,82071632)the Postgraduate Research Innovation Project of Chongqing Medical University(China)(No.CYB22210)the Youth Basic Research Project from the Ministry of Education Key Laboratory of Child Development and Disorders(China)(No.YBRP-202114).
文摘As a widely used plasticizer,di-(2-ethylhexyl)phthalate(DEHP)is known to induce significant testicular injury.However,the potential mechanism and effects of pubertal exposure to DEHP on testis development remain unclear.In vivo,postnatal day(PND)21 male rats were gavaged with 0,250,and 500 mg/kg DEHP for ten days.Damage to the seminiferous epithelium and disturbed spermatogenesis were observed after DEHP exposure.Meanwhile,oxidative stress-induced injury and pyroptosis were activated.Both endoplasmic reticulum(ER)stress and mitophagy were involved in this process.Monoethylhexyl phthalate(MEHP)was used as the biometabolite of DEHP in vitro.The GC-1 and GC-2 cell lines were exposed to 0,100μM,200μM,and 400μM MEHP for 24 h.Reactive oxygen species(ROS)generation,oxidative stress damage,ER stress,mitophagy,and pyroptosis were significantly increased after MEHP exposure.The ultrastructure of the ER and mitochondria was destroyed.X-box binding protein 1(XBP1)was observed to be activated and translocated into the nucleus.ROS generation was inhibited by acetylcysteine.The levels of antioxidative stress,ER stress,mitophagy,and pyroptosis were decreased as well.After the administration of the ER stress inhibitor 4-phenyl-butyric acid,both mitophagy and pyroptosis were inhibited.Toyocamycin-induced XBP1 down-regulation decreased the levels of mitophagy and pyroptosis.The equilibrium between pyroptosis and mitophagy was disturbed by XBP1 accumulation.In summary,our findings confirmed that DEHP induced a ROS-mediated imbalance in pyroptosis and mitophagy in immature rat testes via XBP1.Moreover,XBP1 might be the key target in DEHP-related testis dysfunction.
基金supported by grants from the National Natural Science Foundation of China(No.82071395 and 82001158)the Natural Science Foundation of Chongqing,China(No.cstc2021ycjh-bgzxm0186 and cstc2020jcyj-zdxmX0004)+2 种基金the Science and Technology Research Program of Chongqing Municipal Education Commission,China(No.KJZD-K201900403)Innovation Research Group at Institutions of Higher Education in Chongqing,China(No.CXQTP19034)CQMU Program for Youth Innovation in Future Medicine,China(No.W0044).
文摘Disrupting the balance of neuronal excitation and inhibition (E/I) is an important pathogenic mechanism of anxiety and depression. Interferon regulatory factor 3 (IRF3) plays a key role in the innate immune response, and activation of IRF3 triggers the expression of type I interferons and downstream interferon-stimulated genes, which are associated with anxiety and depression. However, whether IRF3 participates in the pathogenesis of anxiety/depression by regulating E/I balance remains poorly understood. Here, we reported that global knockout (KO) of IRF3 (IRF3^(−/−)) significantly increased anxiety/depression-like behaviors, but did not affect normal spatial learning and memory. Compared with wild type (WT) control mice, the E/I balance was disrupted, as reflected by enhanced glutamatergic transmission and decreased GABAergic transmission in the neurons of hippocampal CA1 and medial prefrontal cortex (mPFC) in IRF3-KO mice. Importantly, genetic rescue of IRF3 expression by adeno-associated virus (AAV) was sufficient to alleviate anxiety/depression-like behaviors and restore the neuronal E/I balance in IRF3-KO mice. Taken together, our results indicate that IRF3 is critical in maintaining neuronal E/I balance, thereby playing an essential role in ensuring emotional stability.
基金The National Natural Science Foundation of China(No.82002835)The National Key Research and Development Project(No.2022YFC2705005)Guangzhou Science and Technology project(No.202201011572).
文摘The aim of this phase I study is to evaluate,for the first time,the safety and efficacy of sintilimab in pediatric patients diagnosed with advanced or recurrent malignancies.During the dose escalation phase,patients received a single intravenous infusion of sintilimab at varying doses of 1,3,and 10 mg/kg.The primary endpoints included the identification of dose-limiting toxicities(DLTs)as well as the evaluation of safety and tolerance.Secondary endpoints focused on assessing objective response rate(ORR),progression-free survival(PFS),and overall survival(OS).A total of 29 patients were enrolled,including 10 individuals diagnosed with Hodgkin lymphoma(HL)and 19 patients with various other tumor categories.Notably,diverse pathological types such as thymoma,choroid plexus carcinoma,and NK/T-cell lymphoma were also included in the study cohort.By the safety data cutoff,most adverse events were grade 1 or 2,with grade 3 or higher treatment-related adverse events(TRAE)occurring in 10%of patients.Among the 27 evaluated subjects,four achieved confirmed complete response(CR)while seven patients exhibited confirmed partial response(PR).Additionally,seven patients maintained disease(SD)during the study period.Notably,sintilimab demonstrated remarkable tolerability without DLTs and exhibited promising anti-tumor effects in pediatric HL.Whole-exome sequencing(WES)was conducted in 15 patients to assess the mutational landscape and copy number variation(CNV)status.The completion of this phase I study establishes the foundation for potential combination regimens involving sintilimab in childhood cancer treatment.The trial is registered on ClinicalTrials.gov with the identifier NCT04400851.
基金the National Natural Science Foundation of China (Grant No. 81571425).
文摘We investigated the associations of clinical and socioeconomic factors with delayed orchidopexy for cryptorchidism in China. A retrospective study was conducted on cryptorchid boys who underwent orchidopexy at Children's Hospital at Chongqing Medical University in China from January 2012 to December 2017. Of 2423 patients, 410 (16.9%) received timely repair by 18 months of age, beyond which surgery was considered delayed. Univariate analysis suggested that the laterality of cryptorchidism (P = 0.001), comorbidities including inguinal hernia/scrotal hydrocele (P < 0.001) or urinary tract disease (P = 0.016), and whether patients lived in a poverty county (P < 0.001) could influence whether orchidopexy was timely or delayed. Logistic regression analysis suggested that the following factors were associated with delayed repair: unilateral rather than bilateral cryptorchidism (odds ratio [OR]= 1.752, P < 0.001), absence of inguinal hernia or hydrocele (OR = 2.027, P = 0.019), absence of urinary tract disease (OR = 3.712, P < 0.001), and living in a poverty county (OR = 2.005, P < 0.001). The duration of postoperative hospital stay and hospital costs increased with the patient's age at the time of surgery.
基金the National Natural Science Foundation of China(No.81970571)。
文摘We aimed to explore the associations between the age at which children undergo surgery for hypospadias and a range of social and clinical factors in a single center.Our aim was to promote the early surgical treatment of children with hypospadias.For a 6-year period,social and clinical data were collected from all children undergoing surgery to repair hypospadias in Children’s Hospital of Chongqing Medical University(Chongqing,China),located in southwest of China.We analyzed the correlations between age at surgery and a range of social and clinical factors.A total of 1611 eligible cases were recruited,with a mean age of 54.3 months and a median age of 42 months:234 cases(14.5%)were classified into a“timely operation”group,419(26.0%)cases into a“subtimely operation”group,and 958(59.5%)cases into a“delayed operation”group.According to multivariate regression analyses,the higher the regional economic level,the closer the urethral opening to the perineum,and the higher the educational level of the guardians was,the younger the children were when they underwent the initial surgery for hypospadias;this was also the case for families without other children.Our subgroup analysis showed that the primary educational level of the guardians was a risk factor for subtimely surgery in their children(odds ratio[OR]=1.52,95%confidence interval[CI]:1.08-2.15,P<0.05).A lower regional economic level(OR=1.87,95%CI:1.26-2.78,P<0.01),a lower educational level of the guardians(OR=3.84,95%CI:2.31-6.41,P<0.01),and an anterior-segment urethral opening(OR_(1)[vs middle hypospadias]=2.07,95%CI:1.42-3.03;0R_(2)[vs posterior hypospadias]=2.63,95%CI:1.75-3.95;P<0.01)were all risk factors for delayed surgery in children.
基金supported by the Basic Research and Frontier Exploration Project of Chongqing Science and Technology Bureau of Yuzhong District(No.20200151).
文摘We describe and summarize the diagnosis,treatment,and reasons for delayed treatment of children with cryptorchidism torsion in Children's Hospital of Chongqing Medical University.The study included 19 cases of cryptorchidism torsion.The age of the children ranged from 16 days to 12 years(median:6 years).The interval from diagnosis to surgery varied from 4 h to 16 days(median:3 days).Ultrasound was performed in all cases.Fifteen cases had cryptorchidism torsion,2 cases had a soft tissue mass in the inguinal region,and 2 cases had an inguinal/abdominal teratoma.Five cases were treated with an orchidopexy,12 cases were treated with orchiectomy,and 2 cases received resection of a testicular tumor.The 5 children with an orchidopexy were followed up from 1 month to 7 years(median:3 years),with 1 child having a testis retraction and no blood supply.Of the 12 children who had an orchiectomy,three had delayed diagnosis due to family unawareness of the condition,while other delays were due to delayed referral from primary care facilities.The relative rarity and insufficient awareness of cryptorchidism torsion resulted in a low rate of testicular salvage.Therefore,hospitals of all levels should be fully aware of cryptorchidism with torsion and ensure a male child's genital system and inguinal region are examined to improve the success rate of testicular salvage.
基金funded by the China National Natural Science Foundation(No.81770713)China National Clinical Research Center Foundation(No.YBXM-2019-002).
文摘BACKGROUND Few studies have addressed the effects of human leukocyte antigen(HLA)alleles on different clinical sub-phenotypes in childhood steroid-sensitive nephrotic syndrome(SSNS),including SSNS without recurrence(SSNSWR)and steroid-dependent nephrotic syndrome/frequently relapse nephrotic syndrome(SDNS/FRNS).In this study,we investigated the relationship between HLA system and children with SSNSWR and SDNS/FRNS and clarified the value of HLA allele detection for precise typing of childhood SSNS.METHODS A total of 241 Chinese Han individuals with SSNS were genotyped using GenCap-WES Capture Kit,and four-digit resolution HLA alleles were imputed from available Genome Wide Association data.The distribution and carrying frequency of HLA alleles in SSNSWR and SDNS/FRNS were investigated.Additionally,logistic regression and mediating effects were used to examine the relationship between risk factors for disease process and HLA system.RESULTS Compared with SSNSWR,significantly decreased serum levels of complement 3(C3)and complement 4(C4)at onset were detected in SDNS/FRNS(C3,P<0.001;C4,P=0.018).The average time to remission after sufficient initial steroid treatment in SDNS/FRNS was significantly longer than that in SSNSWR(P=0.0001).Low level of C4 was further identified as an independent risk factor for SDNS/FRNS(P=0.008,odds ratio=0.174,95% confidence interval 0.048-0.630).The HLA-A*11:01 allele was independently associated with SSNSWR and SDNS/FRNS(P=0.0012 and P=0.0006,respectively).No significant HLA alleles were detected between SSNSWR and SDNS/FRNS.In addition,a mediating effect among HLA-I alleles(HLA-B*15:11,HLA-B*44:03 and HLA-C*07:06),C4 level and SDNS/FRNS was identified.CONCLUSIONS HLA-I alleles provide novel genetic markers for SSNSWR and SDNS/FRNS.HLA-I antigens may be involved in steroid dependent or frequent relapse in children with SSNS as mediators of immunoregulation.
文摘To the Editor:Off-label drug use(OLDU)refers to the use of a drug outside of the age,indication,weight,dose,formulation,or route of administration indicated on the label.It is a major concern and a common practice for clinicians around the globe,especially for pediatricians,owing to the lack of pediatric-specific drug information.[1]Research showed that US office-based physicians had ordered 41.2 million off-label orders per year for children and the trend had been increasing from 2006 to 2015.
基金This work was supported by the National Natural Science Foundation of China[grant numbers 81670270,81970244,81700250].
文摘Although it is widely accepted that human induced pluripotent stem cell-derived cardiomyocytes(hiPSC-CMs)are readily available,robustly reproducible,and physiologically appropriate human cells for clinical applications and research in the cardiovascular field,hiPSC-CMs cultured in vitro retain an immature metabolic phenotype that limits their application,and little is known about the underlying molecular mechanism controlling mitochondrial metabolic maturation during human induced pluripotent stem cells(hiPSCs)differentiation into cardiomyocytes.In this study,we found that peroxisome proliferator-activated receptor g coactivator-1α(PGC-1α)played an important role in inducing mitochondrial biogenesis and establishing oxidative phosphorylation(OXPHOS)during the cardiac differentiation of hiPSCs.Knocking down PGC-1α by siRNA impaired mitochondrial respiration,while upregulating PGC-1α by ZLN005 promoted mitochondrial biosynthesis and function by regulating the expression of downstream genes involved in mitochondrial dynamics and oxidative metabolism in hiPSCCMs.Furthermore,we found that estrogen-related receptor a(ERRa)was required for the induction of PGC-1α stimulatory effects in hiPSC-CMs.These findings provide key insights into the molecular control of mitochondrial metabolism during cardiac differentiation and may be used to generate more metabolically mature cardiomyocytes for application.
基金The study was supported by research grants from the National Natural Science Foundation of China(Grant Number:81300129).
文摘GATA4 is a particularly important cardiogenic transcription factor and serves as a potent driver of cardiogenesis.Recent progress in the field has made it clear that histone acetylation can influence gene expression through changing the structure of chromatin.Our previous research had revealed that hypo-acetylation could repress gata4 expression in cardiocytes,however the underlying mechanism by which this occurred was still unclear.To reveal the mechanism of histone acetylation involved in the regulation of gata4 transcription,we concentrated on P300,one of the important histone acetyltransferase associated with cardiogenesis.We found that P300 participated in gata4 expression through regulating histone acetylation in embryonic mouse hearts.RNAi-mediated downregulation of P300 modulated the global acetylation of H3 and the acetylation of H3K4,H3K9,and H3K27 in gata4 and Tbx5 promoters.Interestingly,there was an obvious inhibition of gata4 transcription,whereas Tbx5 was not influenced.Furthermore,SGC-CBP30,the selective inhibitor of the bromodomain in CBP/P300,downregulated gata4 transcription by repressing the acetylation of H3K4,H3K9,and H3K27 in the gata4 promoters.Taken together,our results identified that acetylation of H3K4,H3K9,and H3K27 mediated by P300 plays an important role in regulation of gata4 expression in cardiogenesis.
基金This work was supported by the National Natural Science Foundation Committee of China[grant numbers 81373444,81570142,81670018]the Chinese Ministry of Science and Technology[grant number 2016YFA0101300]the Key Grant from the Chongqing Science and Technology Commission[grant number cstc2014yykfC10003].
文摘Alveolar epithelial cells(AECs)injury and failed reconstitution of the AECs barrier are both integral to alveolar flooding and subsequent pulmonary fibrosis(PF).Nevertheless,the exact mechanisms regulating the regeneration of AECs post-injury still remain unclear.SMARCA4 is a part of the large ATP-dependent chromatin remodelling complex SWI/SNF,which is essential for kidney and heart fibrosis.We investigates SMARCA4 function in lung fibrosis by establishing PF mice model with bleomycin firstly and found that the expression of SMARCA4 was mainly enhanced in alveolar type II(ATII)cells.Moreover,we established an alveolar epithelium-specific SMARCA4-deleted SP-C-rtTA/(tetO)7-Cre/SMARCA4f/f mice(SOSM4D/D)model,as well as a new SMARCA4-deleted alveolar type II(ATII)-like mle-12 cell line.We found that the bleomycin-induced PF was more aggressive in SOSM4D/D mice.Also,the proliferation of ATII cells was decreased with the loss of SMARCA4 in vivo and in vitro.In addition,we observed increased proliferation of ATII cells accompanied by abnormally high expression of SMARCA4 in human PF lung sections.These data uncovered the indispensable role of SMARCA4 in the proliferation of ATII cells,which might affect the progression of PF.