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1.
EBioMedicine ; 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31474552

RESUMO

BACKGROUND: The objective of the current study was to study the molecular mechanism(s) underlying cardiac troponin I autoantibody (cTnIAAb) binding to cardiomyocyte and resultant myocardial damage/dysfunction. METHODS: cTnIAAb was purified from serum of 10 acute myocardial infarction (AMI) patients with left ventricular remodeling. Recombinant human cTnI was used to generate three mouse-derived monoclonal anti-cTnI antibodies (cTnImAb1, cTnImAb2, and cTnImAb3). The target proteins in cardiac myocyte membrane bound to cTnImAb and effect of cTnIAAb and cTnImAb on apoptosis and myocardial function were determined. FINDINGS: We found that cTnIAAb/cTnImAb1 directly bound to the cardiomyocyte membraneα-Enolase (ENO1) and triggered cell apoptosis via increased expression of ENO1 and Bax, decreased expression of Bcl2, subsequently activating Caspase8, Caspase 3, phosphatase and tensin homolog (PTEN) while inhibiting Akt activity. This cTnIAAb-ENO1-PTEN-Akt signaling axis contributed to increased myocardial apoptosis, myocardial collagen deposition, and impaired systolic dysfunction. INTERPRETATION: Results obtained in this study indicate that cTnIAAb is involved in the process of ventricular remodeling after myocardial injury. FUND: The National Natural Science Foundation of China (Grant#: 81260026).

2.
BMC Cancer ; 19(1): 777, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31387567

RESUMO

BACKGROUND: Lung cancer in young patients is rare and has unique clinicopathological features. However, the molecular features of lung cancer in these patients are unclear. In this study, we aimed to describe the molecular features and outcomes of lung adenocarcinoma in patients aged ≤35 years. METHODS: A total of 89 patients aged ≤35 years with pathologically diagnosed lung adenocarcinoma were retrospectively evaluated. Mutations in 59 cancer-associated genes and fusions of ALK and ROS1 were analyzed to understand the molecular features of young patients with lung adenocarcinoma. The clinicopathological characteristics and prognosis of each patient were reviewed. RESULTS: Of the 89 young patients, 25 (28.1%) were male, 9 (10.1%) were smokers, and the median age was 32 years (range, 18-35 years). The authors analyzed 59 genes and a total of 6 mutations and 2 fusion genes were detected. These genes were distributed among 60 patients, 12 of which had two or more mutations. ERBB2 mutations were most common (24.7%), followed by EGFR mutation (21.3%), ALK fusion (16.9%), TP53 mutation (9.0%), BRAF mutation (3.4%), PIK3CA mutation (1.1%), CTNNB1 mutation (1.1%), and ROS1 fusion (1.1%). EGFR, ERBB2, and TP53 mutations, gene abnormalities, and ALK fusions all had significant correlations with histopathological differentiation (P < 0.01). ALK fusions and EGFR mutations conferred a significantly worse prognosis than did ERBB2 mutations and tumors that contained no mutations or fusions (P < 0.01). CONCLUSIONS: The molecular features of lung adenocarcinoma in young patients are different from those of common adenocarcinoma, and the main driver genes are closely correlated with tumor differentiation and prognosis.

3.
Int J Mol Sci ; 20(16)2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31404956

RESUMO

(1) Background: Upland cotton (Gossypium hirsutum L.) is the most important natural fiber worldwide, and it is extensively planted and plentifully used in the textile industry. Major cotton planting regions are frequently affected by abiotic stress, especially drought stress. Drought resistance is a complex, quantitative trait. A genome-wide association study (GWAS) constitutes an efficient method for dissecting the genetic architecture of complex traits. In this study, the drought resistance of a population of 316 upland cotton accessions was studied via GWAS. (2) Methods: GWAS methodology was employed to identify relationships between molecular markers or candidate genes and phenotypes of interest. (3) Results: A total of 8, 3, and 6 SNPs were associated with the euphylla wilting score (EWS), cotyledon wilting score (CWS), and leaf temperature (LT), respectively, based on a general linear model and a factored spectrally transformed linear mixed model. For these traits, 7 QTLs were found, of which 2 each were located on chromosomes A05, A11, and D03, and of which 1 was located on chromosome A01. Importantly, in the candidate regions WRKY70, GhCIPK6, SnRK2.6, and NET1A, which are involved in the response to abscisic acid (ABA), the mitogen-activated protein kinase (MAPK) signaling pathway and the calcium transduction pathway were identified in upland cotton at the seedling stage under drought stress according to annotation information and linkage disequilibrium (LD) block analysis. Moreover, RNA sequencing analysis showed that WRKY70, GhCIPK6, SnRK2.6, and NET1A were induced by drought stress, and the expression of these genes was significantly different between normal and drought stress conditions. (4) Conclusions: The present study should provide some genomic resources for drought resistance in upland cotton. Moreover, the germplasm of the different phenotypes, the detected SNPs and, the potential candidate genes will be helpful for molecular marker-assisted breeding studies about increased drought resistance in upland cotton.

4.
Immunity ; 51(2): 337-350.e7, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31375460

RESUMO

Class-switch recombination (CSR) is a DNA recombination process that replaces the immunoglobulin (Ig) constant region for the isotype that can best protect against the pathogen. Dysregulation of CSR can cause self-reactive BCRs and B cell lymphomas; understanding the timing and location of CSR is therefore important. Although CSR commences upon T cell priming, it is generally considered a hallmark of germinal centers (GCs). Here, we have used multiple approaches to show that CSR is triggered prior to differentiation into GC B cells or plasmablasts and is greatly diminished in GCs. Despite finding a small percentage of GC B cells expressing germline transcripts, phylogenetic trees of GC BCRs from secondary lymphoid organs revealed that the vast majority of CSR events occurred prior to the onset of somatic hypermutation. As such, we have demonstrated the existence of IgM-dominated GCs, which are unlikely to occur under the assumption of ongoing switching.

5.
Biochem Biophys Res Commun ; 516(3): 812-818, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31256934

RESUMO

Proteinuria is an important marker and is closely related to the progressive decline of renal function. Our previous research showed that angiopoietin-like-3 (ANGPTL3) plays a crucial role in proteinuria. In this study, we prepared an antibody against ANGPTL3 coil-coiled domain (ANGPTL3-CCD) and investigated the protective effect of anti-ANGPTL3-CCD antibody in mice with adriamycin-induced nephropathy. Nephropathy was established by adriamycin injection at a dose of 25 mg per kg in 8-12 week-old male mice in the ADR group. Blockade of ANGPTL3 by anti-ANGPTL3-CCD antibody (20 mg per kg) was performed every three days nine times after adriamycin injection in the ADR plus anti-angptl3-antibody group. The anti-ANGPTL3-CCD antibody can specifically recognize ANGPTL3. After anti-ANGPTL3-CCD antibody intervention, the urinary protein level in the ADR plus anti-angptl3-antibody group was significantly lower than that in the ADR group. Serum albumin was higher and triglyceride and total cholesterol were lower in the ADR plus anti-angptl3-antibody group than in the ADR group. The levels of serum creatinine did not significantly differ among the groups. Focal sclerotic glomeruli and podocyte foot processes extensive fusion were found in the renal tissue of the ADR group, whereas no sclerotic glomeruli and only partial fusion were found in the ADR plus anti-angptl3-antibody group. This study demonstrated that the anti-ANGPTL3-CCD antibody ameliorated proteinuria and podocyte dysfunction in adriamycin-induced nephropathy in mice.

6.
Sensors (Basel) ; 19(14)2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31336876

RESUMO

Wireless visual sensor networks (WVSN) have been widely used to capture images in the fields of monitoring, intelligent transportation, and reconnaissance in recent years. Because of the wireless transmission mode and the huge amount of image data, major challenges in this application are frequent information stealing, big data problems, and harsh communication circumstances. Some encryption schemes based on compressive sensing (CS) and chaotic systems have been proposed to cope with these threats, but most of them are vulnerable against the chosen-plaintext attack (CPA). To remedy these defects, this paper designs a novel method based on non-uniform quantization (NQ). Then, in order to evaluate the true compression ratio (CR), our work takes into account limited data precision in cipher images, while most papers ignored this fact and calculated CR with the assumption of infinite data precision. Besides, to eliminate the periodic windows in the bifurcation diagram of the logistic map (LM), an optimized logistic map (OLM) is designed. Furthermore, simulation results prove that the performance of anti-jamming in the proposed cryptosystem is better than that in existing schemes under the condition of strong noise interference or severe data loss. In conclusion, the proposed method could improve the performance of security and anti-jamming for WVSN.

7.
Clin Genet ; 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31328266

RESUMO

To explore the approaches and diagnostic yield of genetic testing for renal disease in children, we describe the genotype and phenotype of the national cohort of children with renal disease from 13 different regions of China recruited from 2014 to 2018 by building up the multicenter registration system (Chinese Children Genetic Kidney Disease Database, CCGKDD). Genetic diagnosis was confirmed in 42.1% of our cohort of 1001 pediatric patients with clinical suspicion of a genetic renal disease. Of the 106 distinct monogenetic disorders detected, 15 accounted for 60.7% of genetic diagnoses. The diagnostic yield was 29.1% in steroid resistant nephritic syndrome (SRNS), 61.4% in cystic renal disease, 17.0% in congenital anomalies of the kidney and urinary tract (CAKUT), 62.3% in renal tubular disease/renal calcinosis, and 23.9% for chronic kidney disease (CKD) 3 to 5 stage with unknown origin. Genetic approaches of target gene sequence (TGS), singleton whole-exome sequencing (WES) and trio-WES were performed with diagnostic rates of 44.8%, 36.2%, and 42.6%, respectively. The early use of trio-WES could improve the diagnostic rate especially in renal tubular disease and calcinosis. We report the genetic spectrum of Chinese children with renal disease. Establishment of the CCGKDD will improve the genetic work on renal disease.

8.
Zhongguo Zhong Yao Za Zhi ; 44(10): 2051-2058, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31355560

RESUMO

To establish ultra performance liquid chromatography( UPLC) fingerprint of Puerariae Lobatae Radix from different habitats and simultaneously determine the contents of six isoflavonoids. The UPLC fingerprint analysis and content determination were performed on a Waters ACQUITY UPLC BEH C_(18)( 2. 1 mm×50 mm,1. 7 µm) chromatographic column,with acetonitrile-0. 05% formic acid as mobile phase for gradient elution. The detection wavelength was set at 250 nm; the flow rate was 0. 2 mL·min~(-1); the column temperature was 30 ℃ and the injection volume was 2 µL. Similarity evaluation system for chromatographic fingerprint of traditional Chinese medicine( TCM) was adopted; principal component analysis( PCA) and discriminant analysis by partial least square method( PLS-DA) in Simca-P software were used to identify the differential components in samples from three habitats. The similarity was over 0. 90 in 29 batches of samples,indicating good consistency of the samples. The samples were clustered into 3 categories by PCA and PLS-DA,and six differential components such as puerarin apioside,daidzin,and isoflavoues aglycone were found. The determination results of 6 isoflavones,including 3'-hydroxy puerarin,puerarin,3'-methoxy puerarin,puerarin apioside,daidzin,and isoflavoues aglycone,showed that the content of the same component and the fluctuation range between different components were all different among different habitats. The total content of 6 isoflavones from different regions was Anhui 11. 21% >Henan 10. 97% >Shannxi 9. 38%. The establishment of UPLC fingerprint combined with simultaneous determination of 6 active components provides a more comprehensive reference for quality control and quality evaluation of Puerariae Lobatae Radix.

9.
Midwifery ; 78: 32-41, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31349182

RESUMO

OBJECTIVE: The objective of this study is to understand the perceived needs for information on maternal and infant healthcare during the puerperium among the fathers of newborns in China, and to examine factors that are associated with the patterns of perceived needs. DESIGN: A cross-sectional study was conducted. METHODS: A survey was conducted in the obstetrics department of the First Affiliated Hospital of Soochow University in Suzhou, China. A total of 206 fathers of newborns were interviewed with a response rate of 98.1%. Latent class analysis (LCA) was used to identify a priori unknown patterns of perceived needs for information (knowledge/skills) on maternal and infant healthcare during the puerperium period. Chi-square tests were applied to examine factors associated with such patterns of needs. RESULTS: The majority of the participants perceived strong needs for information on maternal and infant healthcare during the puerperium. LCA identified three latent classes on perceived needs for information on maternal healthcare among Chinese fathers of newborns: Class 1 - Low: Some Infant Health Related Needs; Class 2 - Moderate: Lower Physical Recovery Needs; and Class 3 - High: Enthusiastic Needs. Similarly, three latent classes were identified for perceived needs for information on infant health care: Class 1 - Low: Some Medical Needs; Class 2 - Moderate: Lower Breastfeeding Needs; and Class 3 - High: Enthusiastic Needs. Fathers aged 30 to 35, urban residents, and those with higher education were more likely to be in the Enthusiastic Needs groups for information needs for both maternal and infant healthcare. CONCLUSIONS: Perceived needs for information on maternal and infant healthcare are widespread among fathers of newborns in China. Three distinct latent classes for perceived needs for information (knowledge/skills) on maternal and infant health were identified in this population. Socio-demographics, such as age, residence, and education, were significantly associated with such patterns of needs. The findings have implications for the development of interventions to improve maternal and infant healthcare in China.

10.
Acta Pharmacol Sin ; 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171828

RESUMO

Deregulated Polycomb repressive complex 2 (PRC2) is intimately involved in tumorigenesis and progression, making it an invaluable target for epigenetic cancer therapy. Disrupting the EZH2-EED interaction, which is required for PRC2 enzymatic activity, is a promising strategy for cancer treatment. However, this kind of inhibitors are still limited. The in-cell protein-protein interaction screening was conducted for approximately 1300 compounds by NanoBRET technology. Co-immunoprecipitation (Co-IP), protein thermal shift assay (PTSA), and cellular thermal shift assay (CETSA) were performed to investigate the regulation of PRC2 by AZD9291. The anti-tumor effects of AZD9291 on breast cancer (BC) cells and diffuse large B-cell lymphoma (DLBCL) cells were detected. MicroRNA array assay, luciferase reporter assay, and qRT-PCR were conducted to identify the interaction and regulation among AZD9291, EZH2, and miR-34a. We discovered that, AZD9291, a potent and selective EGFR inhibitor, disrupted the interaction of EZH2-EED, leading to impairment of PRC2 activity and downregulation of EZH2 protein. In addition, AZD9291 declined EZH2 mRNA expression via upregulating the expression of a tumor suppressor, miR-34a. Our results suggest that AZD9291 can serve as a lead compound for further development of antagonist of PRC2 protein-protein interactions and EZH2 mRNA may be a direct target of miR-34a through non-canonical base pairing.

11.
ACS Appl Mater Interfaces ; 11(20): 18858-18864, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31037945

RESUMO

Recently, single-layer CrI3, a member of the chromium trihalides CrX3 (where X = Cl, Br, or I), has been exfoliated and experimentally demonstrated as an atomically thin material suitable for two-dimensional spintronics. Valley splitting due to the magnetic proximity effect has been demonstrated in a WSe2/CrI3 van der Waals heterojunction. However, the understanding of the mechanisms behind the favorable performance of CrI3 is still limited. Here, we systematically study the carrier mobility and the intrinsic point defects in CrX3 and assess their influence on valley splitting in WSe2/CrI3 by first-principles calculations. The flat-band nature induces extremely large carrier mass and ultralow carrier mobility. In addition, intrinsic point defects-localized states in the middle of the band gap-show deep transition energy levels and act as carrier recombination centers, further lowering the carrier mobility. Moreover, vacancies in CrI3 can enhance ferromagnetism and valley splitting in a WSe2/CrI3 heterojunction, proving that chromium trihalides are excellent ferromagnetic insulators for spintronic and valleytronic applications.

12.
BMC Nephrol ; 20(1): 185, 2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31126248

RESUMO

BACKGROUND: Angiopoietin-like-3 (Angptl3) knockout is known for its protective effects on podocyte injury and proteinuria in the early stage of adriamycin (ADR) nephropathy. The current study re-evaluated the renoprotective effect of Angptl3 knockout in chronic ADR nephropathy and attempted to explore the mechanism underlying the effect associated with Angptl3 knockout in glomerulosclerosis. METHODS: B6; 129S5 mice were injected with ADR to induce nephropathy. Kidney structure and serum and urine parameters were observed during long-term follow-up. Cultured primary mouse podocytes were exposed to ADR and analyzed for the expression of some relative proteins. Podocyte loss was analyzed in both in vivo and in vitro experiments. RESULTS: Angptl3 knockout attenuated proteinuria and hypoproteinemia, protected renal structure and function, and improved the survival of mice over the whole process of ADR nephropathy. Furthermore, Angptl3 knockout reduced the numbers of the detached and apoptotic cells in the renal tissue and alleviated podocyte loss in mice with ADR chronic nephropathy, thereby, delaying the glomerulosclerosis formation. Additional results in vitro showed that Angptl3 knockout attenuated ADR-induced primary podocyte loss, including podocyte detachment and apoptosis. CONCLUSION: In addition to serving a renoprotective role in the early stage of ADR nephropathy, Angptl3 knockout contributed to disease amelioration throughout the ADR nephropathy process. Angptl3 knockout effectively delayed glomerulosclerosis formation by attenuating podocyte loss through rescuing podocytes from detachment and apoptosis. Angptl3 antagonists or inhibitors might have therapeutic potential in the occurrence and progression of nephropathy.

13.
Mol Cancer Ther ; 18(8): 1439-1450, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31142662

RESUMO

DNA replication and repair proteins play an important role in cancer initiation and progression by affecting genomic instability. The DNA endonuclease Mus81 is a DNA structure-specific endonuclease, which has been implicated in DNA replication and repair. In this study, we found that Mus81 promotes gastric metastasis by controlling the transcription of ZEB1, a master regulator of the epithelial-mesenchymal transition (EMT). Our results revealed that Mus81 is highly expressed in gastric cancer samples from patients and cell lines compared with their normal counterparts. Particularly, Mus81 expression positively correlated with ZEB1 expression and Mus81 overexpression was significantly associated with higher incidence of lymph node metastasis in patients. Furthermore, Mus81 promoted migration of gastric cancer cells both in vitro and in vivo We conducted a drug screen using a collection of preclinical and FDA-approved drugs and found that the BRD4 inhibitor AZD5153 inhibited the expression of Mus81 and ZEB1 by regulating the epigenetic factor Sirt5. As expected, AZD5153 treatment significantly reduced the migration of gastric cancer cells overexpressing Mus81 in vitro and in vivo Collectively, we show that Mus81 is a regulator of ZEB1 and promotes metastasis in gastric cancer. Importantly, we demonstrate that the BRD4 inhibitor AZD5153 can potentially be used as an effective antimetastasis drug because of its effect on Mus81.

14.
J Exp Bot ; 70(15): 3969-3979, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31120500

RESUMO

Artemisinin is a sesquiterpene lactone produced by the Chinese traditional herb Artemisia annua and is used for the treatment of malaria. It is known that salicylic acid (SA) can enhance artemisinin content but the mechanism by which it does so is not known. In this study, we systematically investigated a basic leucine zipper family transcription factor, AaTGA6, involved in SA signaling to regulate artemisinin biosynthesis. We found specific in vivo and in vitro binding of the AaTGA6 protein to a 'TGACG' element in the AaERF1 promoter. Moreover, we demonstrated that AaNPR1 can interact with AaTGA6 and enhance its DNA-binding activity to its cognate promoter element 'TGACG' in the promoter of AaERF1, thus enhancing artemisinin biosynthesis. The artemisinin contents in AaTGA6-overexpressing and RNAi transgenic plants were increased by 90-120% and decreased by 20-60%, respectively, indicating that AaTGA6 plays a positive role in artemisinin biosynthesis. Importantly, heterodimerization with AaTGA3 significantly inhibits the DNA-binding activity of AaTGA6 and plays a negative role in target gene activation. In conclusion, we demonstrate that binding of AaTGA6 to the promoter of the artemisinin-regulatory gene AaERF1 is enhanced by AaNPR1 and inhibited by AaTGA3. Based on these findings, AaTGA6 has potential value in the genetic engineering of artemisinin production.

15.
Plant Cell Physiol ; 60(8): 1747-1760, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31076768

RESUMO

Artemisinin, the frontline drug against malaria, is a sesquiterpenoid extracted from Artemisia annua. Light has been proposed to play an important role in the activation of artemisinin biosynthesis. Here, we report the basic leucine zipper transcription factor (TF) AaHY5 as a key regulator of light-induced biosynthesis of artemisinin. We show that AaHY5 transcription overlaps with that of artemisinin biosynthesis genes in response to light and in A. annua tissues. Analysis of AaHY5 overexpression and RNAi-suppression lines suggests that AaHY5 is a positive regulator of the expression of artemisinin biosynthesis genes and accumulation of artemisinin. We show that AaHY5 complements the hy5 mutant in Arabidopsis thaliana. Our data further suggest that AaHY5 interacts with AaCOP1, the ubiquitin E3 ligase CONSTITUTIVE PHOTOMORPHOGENIC1 in A. annua. In yeast one-hybrid and transient expression assays, we demonstrate that AaHY5 acts via the TF GLANDULAR TRICHOME-SPECIFIC WRKY 1 (AaGSW1) in artemisinin regulation. In summary, we present a novel regulator of artemisinin gene expression and propose a model in which AaHY5 indirectly controls artemisinin production in response to changing light conditions.


Assuntos
Artemisia annua/metabolismo , Artemisininas/metabolismo , Luz , Artemisia annua/efeitos da radiação , Regulação da Expressão Gênica de Plantas/efeitos da radiação , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas/metabolismo , Plantas Geneticamente Modificadas/efeitos da radiação , Fatores de Transcrição
16.
Clin Nephrol ; 92(2): 89-94, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31131822

RESUMO

OBJECTIVE: Nephronophthisis (NPH) is an autosomal recessive cystic kidney disease. Its onset is obscure, and its early clinical manifestations and pathological changes lack specificity, which makes clinical diagnosis difficult. At present, as many as 90 genetic alterations can result in NPH, which exhibits significant genetic heterogeneity. Therefore, high-throughput sequencing technology provides an effective method to identify and characterize novel NPH pathogenic genes when compared to Sanger sequencing. This study summarizes the gene mutations and clinical data of whole exome sequencing, which was used to diagnose 5 NPH patients to improve the understanding of the causative genes and clinical phenotypes of NPH. MATERIALS AND METHODS: The clinical manifestations, laboratory examination indexes, and imaging data of 5 patients of NPH were reported. Whole exome sequencing was performed in 5 children, and the causative genes and mutation sites were analyzed by bioinformatics and genetics. The mutation sites were verified in children and their parents using Sanger direct sequencing. RESULTS: Among the 5 patients (3 male and 2 female), 2 patients had infantile NPH, and 3 patients had juvenile NPH. The 2 infantile NPH patients were characterized by the onset of liver dysfunction accompanied by hypertension and left ventricular change, and the renal function progressed to end-stage renal disease (ESRD) after 7 months and 9 months, respectively. The 2 cases of infantile NPH had NPHP3 mutations, with one carrying compound heterozygous mutations (c.1358A>G, c.2369A>G) and the other simultaneously carrying a c.1174C>T IVS26-3A>G cleavage site mutation from the father and a nonsense mutation (p.392R>X, 939) from the mother. The 2 juvenile NPH children had entered ESRD at the onset of the disease, including 1 patient with Joubert syndrome. The 2 patients with juvenile NPH had frameshift mutations (c.1583 to 1596: deletion) and homozygous point mutations (7 c.640G>T) of the NPHP1 gene. In addition, another patient with frequent urination and nocturia resulting in stage CKD3 renal function had a complex heterozygous mutation of the NPHP2 gene (c.2686G>A, c.1943A>G). The urine A1MU/creatinine and urinary transferrin increased in all 5 patients without hematuria. CONCLUSION: Whole exome sequencing identified the causative genes of NPH in 5 children. In NPH children with NPHP3 gene mutations, renal functional damage was characterized by early onset and rapid progression to ESRD, often accompanied by liver dysfunction and hypertension.

17.
Biochem Biophys Res Commun ; 513(3): 732-739, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-30987821

RESUMO

Intrauterine low-protein diet can affect kidney development and hence final nephron number. In this study, we reported that intrauterine low-protein diet can cause congenital anomalies of the kidney and urinary tract (CAKUT) phenotypes, which was dominated by the duplicated collecting system phenotype. At the same time, ectopic ureteric buds were increased under intrauterine low-protein diet and the number of UB branches was reduced in the serum-free culture. Intrauterine low-protein diet can change metanephric gene expression. Slit2/Robo2 and Spry1 expression levels were decreased, Ret expression was increased, and downstream p-Akt activity enhanced with apoptosis abnormal in ureteric bud tissue, which may be the mechanisms that intrauterine low-protein diet causes increased incidence of CAKUT in offspring. Thus, we showed correlation between intrauterine low-protein diet and CAKUT in offspring.

18.
J Matern Fetal Neonatal Med ; : 1-6, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-30983458

RESUMO

OBJECTIVE: The aim of this prospective observational study was to establish a suitable model for the postnatal follow-up and management of prenatal renal and urinary tract anomalies in Shanghai, China. METHODS: Minhang and Changning maternal child health care hospitals were selected to establish the integrated management model. Newborns with prenatal renal and urinary tract anomalies in these two centers were eligible to participate in the study from 2015 to 2017. All newborns were classified into three groups based on prenatal findings: (1) severe/complex urinary tract dilatation (UTD) with ureterectasia, (2) other renal and urinary tract abnormalities, and (3) isolated mild to moderate UTD. The newborns underwent their first postnatal ultrasound and follow-up according to the presumed management strategy. Demographic and clinical data were collected from all institutes. RESULTS: A total of 129 newborns fulfilled the study criteria, and 121 completed the postnatal evaluation. Ten newborns in group 1 (n = 13) were diagnosed with obstructive uropathy, including 9 with ureteropelvic junction obstruction (UPJO) and one with megaureter. All 13 newborns in group 2 had consistent postnatal results and were followed under previously established procedures. Sixty-seven cases in group 3 (n = 95) had a UTD at their first scan at 42 postnatal days, and two were diagnosed with UPJO. A total of 2 infants with UPJO underwent surgery, and 71 (65.7%, 71/108) of the UTD cases were resolved. CONCLUSIONS: The majority of the patients had a favorable outcome. Close multidisciplinary collaboration among obstetricians, neonatologists, pediatricians, and pediatric nephrologists and urologists is mandatory.

19.
iScience ; 13: 173-189, 2019 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-30849621

RESUMO

Epithelial morphogenesis is a common feature in various organs and contributes to functional formation. However, the molecular mechanisms behind epithelial morphogenesis remain largely unknown. Mammary gland is an excellent model system to investigate the molecular mechanisms of epithelial morphogenesis. In this study, we found that cysteine dioxygenase (CDO), a key enzyme in cysteine oxidative metabolism, was involved in mammary epithelial morphogenesis. CDO knockout (KO) females exhibited severe defects in mammary branching morphogenesis and ductal elongation, resulting in poor lactation. CDO contributes to the luminal epithelial cell differentiation, proliferation, and apoptosis mainly through its downstream product cysteine sulfinic acid (CSA). Exogenous supplementation of CSA not only rescued the defects in CDO KO mouse but also enhanced ductal growth in wild-type mouse. It suggests that CDO regulates luminal epithelial differentiation and regeneration via CSA and consequently contributes to mammary development, which raises important implications for epithelial morphogenesis and pathogenesis of breast cancer.

20.
World J Pediatr ; 15(3): 262-269, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30864060

RESUMO

BACKGROUND: Mizoribine (MZR) is an immunosuppressant used to treat adult nephropathy. There is little experience with the drug in treating Chinese children with frequently relapsing nephrotic syndrome (FRNS). We investigated the efficacy and safety for treating MZR with FRNS. Furthermore, the relationship between efficacy and serum concentration was investigated. METHODS: A prospective multicenter observational 12-month study was performed for evaluating the usefulness of MZR with FRNS. Serum MZR concentration was measured, and the relationships between pharmacokinetic parameters (Cmax, AUC), number of relapses, and urinary protein were evaluated. RESULTS: Eighty-two pediatric patients from four hospitals were treated with MZR and prednisone. MZR treatment significantly reduced the number of relapses and steroid doses. A correlation between pharmacokinetic parameters and relapses was observed, which fits well with the sigmoidal Emax model. Even in the relationship between pharmacokinetic parameters and urinary proteins, it was recognized that there was a threshold in the pharmacokinetic parameters for the therapeutic effect similar to the results obtained with the sigmoidal Emax model. Eleven patients (13.4%) experienced mild adverse events. CONCLUSIONS: MZR therapy was effective in reducing the number of relapses and steroid doses. No severe adverse reactions were observed. Therapeutically effective serum concentrations were estimated to be Cmax ≥ about 2 µg/mL or AUC ≥ about 10 µg h/mL. MZR and steroid treatment were effective and safe for pediatric FRNS.

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