Publications by authors named "Fengyu Che"

12 Publications

  • Page 1 of 1

[Analysis of a novel JAG1 variant and clinical phenotype in a family affected with Alagille syndrome].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2021 Jun;38(6):545-548

The Third Department of Children's Infectious and Liver Diseases, Xi'an Children's Hospital, Xi'an, Shaanxi 710003, China.

Objective: To explore the genetic basis of a pedigree affected with Alagille syndrome (ALGS).

Methods: Targeted capture and next generation sequencing was carried out for the proband. Candidate variants were verified by Sanger sequencing among his family members. Their pathogenicity of the variant was predicted with bioinformatic analysis. Clinical characteristics and genotype-phenotype correlation were analyzed.

Results: The proband, his elder sister and mother were found to carry a heterozygous c.1270dupG (p.Ala424Glyfs*5) variant of the JAG1 gene, which may lead to premature termination of translation and a truncated protein with loss of function. The variant was unreported previously. The phenotypes of the proband (cholestasis, pulmonary artery stenosis and peculiar faces) have differed from those of his elder sister (cholestasis with pruritus, posterior embryonic ring of cornea) and mother (with no clinical manifestation). Cholestasis and peculiar face of the proband became insignificant with age.

Conclusion: The c.1270dupG (p.Ala424Glyfs*5) variant of the JAG1 gene probably underlay the ALGS in this pedigree with incomplete penetrance.
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http://dx.doi.org/10.3760/cma.j.cn511374-20200410-00249DOI Listing
June 2021

Novel Compound Heterozygous Pathogenic Variants in Cause Isolated Sulfite Oxidase Deficiency in a Chinese Han Family.

Front Genet 2021 7;12:607085. Epub 2021 May 7.

Shaanxi Institute for Pediatric Diseases, Xi'an Children's Hospital, Xi'an, China.

Aim: To explore the clinical imaging, laboratory and genetic characteristics of a newborn boy with isolated sulfite oxidase deficiency (ISOD) in a Chinese mainland cohort.

Methods: Homocysteine and uric acid in plasma and cysteine and total homocysteine in the blood spot were assessed in a Chinese newborn patient with progressive encephalopathy, tonic seizures, abnormal muscle tone, and feeding difficulties. Whole exome sequencing and Sanger sequencing facilitated an accurate diagnosis. The pathogenicity predictions and conservation analysis of the identified mutations were conducted by bioinformatics tools.

Results: Low total homocysteine was detected in the blood spot, while homocysteine and uric acid levels were normal in the plasma. -sulfocysteine was abnormally elevated in urine. A follow-up examination revealed several progressive neuropathological findings. Also, intermittent convulsions and axial dystonia were observed. However, the coordination of sucking and swallowing was slightly improved. A novel paternal nonsense variant c.475G > T (p.Glu159) and a novel maternal missense variant c.1201A > G (p.Lys401Glu) in were identified in this case by co-segregation verification.

Conclusion: This is the second report of early-onset ISOD case in a non-consanguineous Chinese mainland family. Combined with the clinical characteristics and biochemical indexes, we speculated that these two novel pathogenic variants of the gene underlie the cause of the disease in this patient. Next-generation sequencing (NGS) and Sanger sequencing provided reliable basis for clinical and prenatal diagnoses of this family, it also enriched the mutation spectrum of the gene.
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http://dx.doi.org/10.3389/fgene.2021.607085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139553PMC
May 2021

A Novel pH-Sensitive Multifunctional DNA Nanomedicine: An Enhanced and Harmless GD2 Aptamer-Mediated Strategy for Guiding Neuroblastoma Antitumor Therapy.

Int J Nanomedicine 2021 10;16:3217-3240. Epub 2021 May 10.

Department of Neonatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.

Background: GD2 is a mainstream biomarker for neuroblastoma (NB)-targeted therapy. Current anti-GD2 therapeutics exhibit several side effects since GD2 is also expressed at low levels on normal cells. Thus, current anti-GD2 therapeutics can be compromised by the coexistence of the target receptor on both cancer cells and normal cells.

Propose: Aptamers are promising and invaluable molecular tools. Because of the pH difference between tumor and normal cells, in this study, we constructed a pH-sensitive aptamer-mediated drug delivery system (IGD-Targeted).

Methods: In vivo Systematic Evolution of Ligands by Exponential Enrichment (SELEX) was used to generate a novel GD2 aptamer. Flow cytometry and molecular docking were applied to assess the binding specificities, affinities abilities of the aptamers. Confocal microscope, CCK8 assay, and BrdU assay were utilized to evaluate whether IGD-Targeted could only bind with GD2 at acidic environment. To evaluate whether IGD-Targeted could inhibit GD2-positive tumor and protect normal cells, in vivo living imaging, histomorphological staining, blood test, and RNA-sequencing were observed in animal model.

Results: GD2 aptamer termed as DB67 could bind with GD2-positive cells with high specificity, while has minimal cross-reactivities to other negative cells. It has been validated that the i-motif in IGD-Targeted facilitates the binding specificity and affinity of the GD2 aptamer to GD2-positive NB tumor cells but does not interfere with GD2-positive normal cells at the pH of the cellular microenvironment. In addition, IGD-Targeted is capable of delivering Dox to only GD2-positive NB tumor cells and not to normal cells in vivo and in vitro, resulting in precise inhibition of tumor cells and protection of normal cells.

Conclusion: This study suggests that IGD-Targeted as a promising platform for NB therapy which could show greater tumor inhibition and fewer side effects to normal cells, regardless of the existence of the same receptor on the target and nontarget cells.
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http://dx.doi.org/10.2147/IJN.S302450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121684PMC
May 2021

[Isovaleric acidemia due to compound heterozygous variants of IVD gene in a case].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2021 Feb;38(2):150-153

Shaanxi Provincial Institute of Pediatrics, Xi'an Children's Hospital, Xi'an, Shaanxi 710002, China. com.

Objective: To analyze the clinical features, biochemical characteristics and molecular pathogenesis of a girl with isovaleric acidemia.

Methods: Clinical features, blood spot amino acid profiles and urinary organic acid profiles of the patient were analyzed. Targeted capture, next generation sequencing and Sanger sequencing were carried out to detect potential variant of the IVD gene.

Results: The patient presented with poor weight gain, poor feeding, lethargy, and a "sweaty feet" odor 10 days after birth. Biochemical test suggested hyperammonemia. Blood spot amino acid profiles displayed a dramatic increase in isovalerylcarnitine (C5: 3. 044, reference range 0.04 - 0.4 μmol/L). Organic acid analysis of her urine sample revealed a high level of isovaleric glycine (669. 53, reference range 0 - 0.5). The child was ultimately diagnosed with isovaleric acidemia, and was found to harbor a paternally derived heterozygous variant c.149G>A (p.R50H) and a maternally derived heterozygous variant c.1123G>A (p.G375S) of the IVD gene. Her elder brother was a heterozygous carrier of c.1123G>A (p.G375S) variant. The c.149G>A (p.R50H) was a known pathogenic variant, while the c.1123G>A (p.G375S) variant was previously unreported.

Conclusion: The pathogenesis of the patient was delineated from the perspective of genetics, which has provided a basis for clinical diagnosis, treatment as well as genetic counseling.
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http://dx.doi.org/10.3760/cma.j.cn511374-20200415-00271DOI Listing
February 2021

CD123 thioaptamer protects against sepsis via the blockade between IL-3/CD123 in a cecal ligation and puncture rat model.

Nucleosides Nucleotides Nucleic Acids 2021 28;40(1):16-31. Epub 2020 Sep 28.

Shaanxi Institute of Pediatric Diseases, Xi'an Children's Hospital, Xi'an, Shaanxi, People's Republic of China.

Sepsis is one of the most common causes of death in ICU and especially is a harmful and a life-threatened disease to pediatrics in the world. It has been demonstrated that IL-3 plays an essential role in the processing of sepsis and the inhibition of IL-3 may alleviate sepsis progress. In our previous study, we selected a novel CD123 aptamer successfully which could inhibit the interaction of CD123 and IL-3. The aim of this study is to explore the protection ability of the first thioaptamer SS30 against sepsis in a cecal ligation and puncture (CLP) rat model. Serum IL-3 level of sepsis patients was assessed by ELISA. CLP rat model was applied in all experimental groups. CD123 thioaptamer SS30 and CD123 antibody were used to block the recognition between IL-3 and CD123. Body weight, temperature, blood gas, MAP, and serum cytokines of four grouped rats were assessed. Flow cytometry was utilized to evaluate JAK2 and STAT5 proteins. After the administration of SS30 or CD123 antibody, the rats in SS30 and CD123 antibody group had lower cytokines values(lactate, TNF-α, IL-1β, and IL-6), whereas exhibited higher value of core temperature, MAP, PO/FiO, and ETCO than those in the CLP group. The expression level of phosphorylated JAK2 and STAT5 was declined and the survival rate of rats was increased. In addition, the protection ability of SS30 was better than CD123 antibody. Therefore, CD123 thioaptamer SS30 could reduce mortality by down-regulating the phosphorylated JAK2/STAT5 signaling pathway, and reduce serum cytokines which involving in sepsis development in CLP rat model.
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http://dx.doi.org/10.1080/15257770.2020.1815770DOI Listing
June 2021

mGluR5 mediates ketamine antidepressant response in susceptible rats exposed to prenatal stress.

J Affect Disord 2020 07 1;272:398-408. Epub 2020 May 1.

Shaanxi Institute of Pediatric Diseases, Xi'an Key Laboratory of Children's Health and Diseases, Xi'an Children's Hospital (The Affiliated Children's Hospital of Xi'an Jiaotong University), Xi'an, Shaanxi, 86-710003, P.R. China; Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 86-710061, P.R. China. Electronic address:

Background: New insights have recently been gained into ketamine's potential anti-depressive effects. However, the mechanisms that underlie ketamine's rapid antidepressant activity still remain a mystery.

Methods: We used a rat prenatal stress (PS) model of depression to explore the functional role of mGluR5 in ketamine's rapidly induced antidepressant activity. Effects of the antidepressants imipramine, escitalopram, ketamine, and fluoxetine were compared. AAV-mGluR5 and AAV-shRNA-mGluR5 were constructed to overexpress and knockdown hippocampal mGluR5 respectively.

Results: This study shows that mGluR5, which is associated with depression-like behaviors, is increased in susceptible rats exposed to prenatal stress, and that ketamine could significantly alleviate these stress-induced effects. RU-38486 down-regulated expression of mGluR5 and up-regulated NR1. MPEP and CHPG also altered expression of both mGluR5 and NR1. Notably, hippocampal overexpression of mGluR5 in wild type rats changed NR1 and PSD-95 expression and induced depression-like behavior that could be blocked by ketamine activity. Further, knockdown of hippocampal mGluR5 in PS-S rats restored normal levels of mGluR5, NR1, and PSD-95, and alleviated depression-like behavior.

Limitations: The entire rat hippocampus was used for this study, but the role of mGluR5 may vary by sub-region.

Conclusion: These results suggest that hippocampal mGluR5 may play a key role in mediating the rapid antidepressant effects of ketamine in a prenatal stress model of depression. This provides a novel therapeutic target in clinical treatment of depression.
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http://dx.doi.org/10.1016/j.jad.2020.03.104DOI Listing
July 2020

[Clinical phenotype and variantal analysis of a pedigree affected with hereditary coagulation factor V deficiency].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2020 Apr;37(4):427-430

Shaanxi Institute of Pediatric Diseases, Xi'an Children's Hospital, Xi'an, Shaanxi 710002, China.

Objective: To explore the molecular basis for a pedigree affected with coagulation factor V (FV) deficiency.

Methods: Clinical data of the patient and his family members was analyzed. Targeted capture and next-generation sequencing (NGS) and Sanger sequencing were carried out to detect potential variant of the FV gene.

Results: The patient presented with jaundice and prolonged prothrombin time (PT) and activated partial thromboplastic time (APTT). V factor activity measured only 0.1% of the normal level, though the patient had no sign of bleeding. A paternal heterozygous variant c.653T>C (p.F218S) and a maternal heterozygous variant c.3642_3643del (p.P1215Rfs*175) were identified in the FV gene of the patient. His elder brother was a heterozygous carrier of the c.653T>C (p.F218S) variant. c.653T>C(p.F218S) was a known pathogenic variant, while the c.3642_3643del (p.P1215Rfs*175) variant was unreported previously.

Conclusion: Mutations of the FV gene probably underlie the hereditary coagulation factor V deficiency in this patient. NGS combined with Sanger sequencing has detected potential variant with efficiency and provided a reliable basis for clinical and prenatal diagnosis for this family.
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http://dx.doi.org/10.3760/cma.j.issn.1003-9406.2020.04.015DOI Listing
April 2020

Novel Aptamer-Functionalized Nanoparticles Enhances Bone Defect Repair By Improving Stem Cell Recruitment.

Int J Nanomedicine 2019 6;14:8707-8724. Epub 2019 Nov 6.

Shaanxi Institute of Pediatric Diseases, Xi'an Children's Hospital, Xi'an, Shaanxi 86-710003, People's Republic of China.

Background: The restoration and repair method in the clinic of delayed fracture healing and non-union after comminuted fractures are urgently needed to improve the prognosis of patients. The recruitment of endogenous stem cells has been considered a promising approach in bone defect repair.

Propose: The aim of this study was to generate a de novel MSCs aptamer and developed the first, feasible, economical, bio-compatible, and functional MSCs aptamer-directed nanoparticles without complex manufacture to recruit mesenchymal stem cells (MSCs) for bone defect regeneration.

Methods: Whole-cell SELEX was used to generate a de novel MSCs aptamer. Flow cytometry was applied to assess the binding specificities, affinities and sorting abilities of the aptamers. Nano-Aptamer Ball (NAB) was constructed by NHS/EDC reaction. The diameter and zeta of NAB were assessed by dynamic light scattering. CCK8 assay was utilized to evaluate whether NAB could cause non-specific cytotoxicity and induce cell proliferation. To evaluate the bone repair capacity of NAB, histomorphological staining, alizarin red and micro X-ray were used to observe the repair degree of defect in vivo. ELISA was used to detect osteopontin (OPN), osteocalcin (BGP) by, and alkaline phosphatase (ALP) in peripheral blood.

Results: MSCs aptamer termed as HM69 could bind with MSCs with high specificity and Kd of 9.67 nM, while has minimal cross-reactivities to other negative cells. HM69 could capture MSCs with a purity of >89%. In vitro, NAB could bind and capture MSCs effectively, whereas did not cause obvious cytotoxicity. In vivo, serum OPN, BGP, and ALP levels in the NAB group of rats were increased at both 2 and 4 weeks, indicating the repair and osteogenesis generation. The healing of bone defects in the NAB group was significantly better than control groups, the defects became blurred, and local trabecular bone growth could be observed in X-ray. The organized hematoma and cell growth in the bone marrow of the NAB group were more vigorous in bone sections staining.

Conclusion: These suggested that HM69 and HM69-functionalized nanoparticles NAB exhibited the ability to recruit MSCs both in vitro and in vivo and achieved a better outcome of bone defect repair in a rat model. The findings demonstrate a promising strategy of using aptamer-functionalized bio-nanoparticles for the restoration of bone defects via aptamer-introduced homing of MSCs.
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http://dx.doi.org/10.2147/IJN.S223164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6847998PMC
March 2020

Corrigendum to "SS30, a novel thioaptamer targeting CD123, inhibits the growth of acute myeloid leukemia cells" [Life Sci. 232 (2019) 116663].

Life Sci 2020 Jan 30;240:117111. Epub 2019 Nov 30.

Shaanxi Institute of Pediatric Diseases, Xi'an Children's Hospital, Xi'an, Shaanxi 0086-710003, PR China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 0086-710061, PR China. Electronic address:

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http://dx.doi.org/10.1016/j.lfs.2019.117111DOI Listing
January 2020

SS30, a novel thioaptamer targeting CD123, inhibits the growth of acute myeloid leukemia cells.

Life Sci 2019 Sep 16;232:116663. Epub 2019 Jul 16.

Shaanxi Institute of Pediatric Diseases, Xi'an Children's Hospital, Xi'an, Shaanxi 0086-710003, PR China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 0086-710061, PR China. Electronic address:

Aims: CD123 represents an important acute myeloid leukemia (AML) therapeutic target. CD123 aptamers may potentially serve as tumor-homing ligands with excellent affinity and specificity for AML targeted therapy, but their complexity, laborious preparation and nuclease digestion limited pharmacological application. The aim of this study was to develop the first CD123 thioaptamer to overcome these obstacles.

Main Methods: Flow cytometry was utilized to assess the binding specificity, affinity and anti-nuclease ability of thioaptamer. CCK8, Annexin-V/DAPI, and colony forming assays were used to evaluate the anti-cancer ability of thioaptamer in vitro. The tumor volume, weights, survival rate, H&E staining of organs, and serum level of organ damage biomarkers of animal model were applied to investigate the anti-cancer ability of thioaptamer in vivo. Furthermore, we explored the binding mechanism between thioaptamer and CD123.

Key Findings: CD123 thioaptamer SS30 was able to bind to CD123 structure with high specificity in complex nuclease environment, the dissociation constant of 39.1 nM for CD123 peptide and 287.6 nM for CD123 AML cells, while exhibiting minimal cross-reactivity to albumin. Furthermore, SS30 inhibited the proliferation and survival of AML cell lines and human AML blasts selectively in vitro (P < 0.01). In addition, SS30 prolonged the survival and inhibited tumor growth in a mouse xenograft tumor model in vivo. Of note, SS30 blocked the interaction between IL-3 and CD123, and decreased expression of p-STAT5 and p-AKT.

Significance: The proliferation inhibition and nuclease resistance ability of SS30 made it as a more promising functional molecule for AML targeted therapy.
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http://dx.doi.org/10.1016/j.lfs.2019.116663DOI Listing
September 2019

Mutational Analysis of TYR, OCA2, and SLC45A2 Genes in Chinese Families with Oculocutaneous Albinism.

Mol Genet Genomic Med 2019 07 14;7(7):e00687. Epub 2019 Jun 14.

Department of Biochemistry and Molecular Biology, Center for DNA Typing, Air Force Medical University, Xi'an, Shaanxi, P.R. China.

Background: Oculocutaneous albinism (OCA) is a group of heterogeneous autosomal recessive genetic disorder of melanin synthesis results in hypopigmented hair, skin, and eyes. OCA type 1, OCA type 2, and OCA type 4, which are respectively caused by mutations in TYR, OCA2, and SLC45A2 have high morbidity rates in Asia.

Methods: TYR, OCA2, and SLC45A2 mutation analysis was carried out on 18 nonconsanguineous OCA patients and four fetuses were included for prenatal diagnose. Three genes of all individuals were amplified by polymerase chain reaction and examined by Sanger sequencing. The pathogenicity of the detected mutations were analyzed by Mutation Taster, PolyPhen 2, and SIFT software, and the conservation of the substituted amino acids were analyzed by MEGA software.

Results: Eleven TYR mutations, three OCA2 mutations, and two SLC45A2 mutations were identified in 14 OCA type 1 patients, two OCA type 2 patients, and two OCA type 4 patients. c.1021A>G, p.R341G in TYR, c.1096_1104del, p.V366*, and c.1079C>T, p.S360F in OCA2 were novel. One of the four fetuses carried compound heterozygous mutation of TYR and became spontaneous abortion, the other three carried no mutations and appeared normal at birth.

Conclusion: In this study, specific clinical characteristics of OCA patients were described. Three novel pathogenic mutations were identified which will enrich the mutation spectrum of OCA, and the prenatal genetic screening in fetus at risk of OCA can provide vital information for genetic counseling.
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http://dx.doi.org/10.1002/mgg3.687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625147PMC
July 2019

A Newly Identified Missense Mutation in FARS2 Causes Autosomal-Recessive Spastic Paraplegia.

Hum Mutat 2016 Feb 10;37(2):165-9. Epub 2015 Dec 10.

Department of Biochemistry and Molecular Biology, Xi'an, Shaanxi, 710032, China.

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by spasticity of the lower limbs due to pyramidal tract dysfunction. Here, we report that a missense homozygous mutation c.424G>T (p.D142Y) in the FARS2 gene, which encodes a mitochondrial phenylalanyl tRNA synthetase (mtPheRS), causes HSP in a Chinese consanguineous family by using combination of homozygous mapping and whole-exome sequencing. Immunohistochemical experiments were performed showing that the FARS2 protein was highly expressed in the Purkinje cells of rat cerebellum. The aminoacylation activity of mtPheRS was severely disrupted by the p.D142Y substitution in vitro not only in the first aminoacylation step but also in the last transfer step. Taken together, our results indicate that a missense mutation in FARS2 contributes to HSP, which has the clinical significance of the regulation of tRNA synthetases in human neurodegenerative diseases.
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http://dx.doi.org/10.1002/humu.22930DOI Listing
February 2016
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