Publications by authors named "Qiuxia Yu"

22 Publications

  • Page 1 of 1

Anti-Hyperuricemic and Nephroprotective Effects of Dihydroberberine in Potassium Oxonate- and Hypoxanthine-Induced Hyperuricemic Mice.

Front Pharmacol 2021 20;12:645879. Epub 2021 Apr 20.

School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.

Phellodendri Chinese Cortex has long been used to treat hyperuricemia and gout. Berberine (BBR), its characteristic ingredient, has also been shown to be effective in alleviating monosodium urate crystals-triggered gout inflammation and . Dihydroberberine (DHB) is a hydrogenated derivative of BBR that showed improved efficacy on many metabolic disorders. However, its anti-hyperuricemia effect remains underexplored. In the present work, the hypouricemic and renoprotective effects of DHB on hyperuricemic mice were investigated. The hyperuricemic mice model was induced by intraperitoneal injection of potassium oxonate (PO, 300 mg/kg) combined with intragastric administration of hypoxanthine (HX, 300 mg/kg) for 7 days. Different dosages of DHB (25, 50 mg/kg), BBR (50 mg/kg) or febuxostat (Feb, 5 mg/kg) were orally given to mice 1 h after modeling. The molecular docking results showed that DHB effectively inhibited xanthine oxidase (XOD) by binding with its active site. , DHB exhibited significant XOD inhibitory activity (IC value, 34.37 μM). The results showed that DHB had obvious hypouricemic and renoprotective effects in hyperuricemic mice. It could not only lower the uric acid and XOD levels in serum, but also suppress the activities of XOD and adenosine deaminase (ADA) in the liver. Furthermore, DHB noticeably down-regulated the renal mRNA and protein expression of XOD. Besides, DHB remarkably and dose-dependently ameliorated renal damage, as evidenced by considerably reducing serum creatinine and blood urea nitrogen (BUN) levels, inflammatory cytokine (TNF-α, IL-1β, IL-6 and IL-18) levels and restoring kidney histological deteriorations. Further mechanistic investigation showed that DHB distinctly down-regulated renal mRNA and protein levels of URAT1, GLUT9, NOD-like receptor 3 (NLRP3), apoptosis-associated speck-like (ASC), caspase-1 and IL-1β. Our study revealed that DHB had outstanding hypouricemic and renoprotective effects via suppressing XOD, URAT1, GLUT9 and NLRP3 inflammasome activation in the kidney.
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http://dx.doi.org/10.3389/fphar.2021.645879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093860PMC
April 2021

Abnormal Expression of Dysferlin in Blood Monocytes Supports Primary Dysferlinopathy in Patients Confirmed by Genetic Analyses.

Front Neurol 2020 4;11:540098. Epub 2021 Feb 4.

Department of Neurology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.

Dysferlin deficiency causes dysferlinopathy. This study aimed to expand the mutational spectrum of dysferlinopathies, to further study one case with diagnostic ambiguity, and to identify the diagnostic value of dysferlin expression in total peripheral blood mononuclear cells (PBMC). The clinical and molecular profiles of dysferlinopathies in eight Chinese patients were evaluated. We also conducted magnetic resonance imaging (6/8) and determined dysferlin protein expression in muscle (7/8) and PBMC (3/8). Nine of the 13 mutations identified were novel. One patient was homozygous for the Gln111Ter mutation by genomic DNA sequencing but was found to be heterozygous by sequencing of cDNA from total PBMC. A daughter of this patient did not carry any Gln111Ter mutation. Abnormal muscle MRI with predominant involvement of the medial gastrocnemius and soleus muscle was observed in 5/6 patients. Dysferlin levels were significantly reduced (immunohistochemistry/immunoblot) or absent (immunohistochemistry) in muscle and total PBMC (26-39%) for most patients. Sarcoplasmic accumulation of dysferlin was detected in one patient. Genomic DNA sequencing detects frequent homozygous mutations, while fewer heterozygous mutations in cDNA are detected after posttranscription. Total PBMC may serve as an alternative to confirm diagnosis and to guide further testing in dysferlinopathies. Our results contribute to the mutational spectrum of dysferlinopathies.
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http://dx.doi.org/10.3389/fneur.2020.540098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890250PMC
February 2021

Evaluation of the Z-score accuracy of noninvasive prenatal testing for fetal trisomies 13, 18 and 21 at a single center.

Prenat Diagn 2021 May 11;41(6):690-696. Epub 2021 Feb 11.

Department of Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, P.R. China.

Objective: To assess the correlation between Z-scores of positive noninvasive prenatal testing (NIPT) results and the positive predictive value (PPV) of NIPT.

Methods: Pregnancies with positive NIPT results at Guangzhou Women and Children's Medical Centre between July 2017 and May 2020 were included in this study. Fetal karyotyping or microarray analysis was provided to patients with abnormal NIPT results for confirmatory testing. Logistic regression analyses was applied to study the relationship between the Z scores and the PPV performance. The optimal cutoff values for indicating fetal common trisomies were obtained based on receiver operating characteristic (ROC) curve analysis, and then the PPV were calculated in pregnancies with positive NIPT results at Z-score greater than or equal to cutoff value and in patients with a Z-score between 3 and cutoff value respectively.

Results: A total of 214 pregnancies with positive NIPT results for fetal common trisomies were validated by invasive prenatal diagnosis and follow up in this study. Of these, NIPT indicated trisomy 13 in 25 cases, trisomy 18 in 54 cases and trisomy 21 in 135 patients. Logistic regression analyses showed a significant association (p < 0.05) between the Z-scores and true positive results for T21 and T18. For T13, the significant association was not observed (p > 0.05). The ROC curve analysis showed that the optimal cutoff Z-score for indicating fetal trisomies 13, 18, and 21 were 6.889, 7.574 and 6.612 respectively, and the corresponding area under curve were 0.706, 0.916, and 0.954. In this cohort with abnormal NIPT results, the cutoff values revealed a sensitivity of 96.8% and a specificity of 90% for indicating trisomies 21, and a sensitivity of 88.9% and a specificity of 92.6% for trisomies 18. However, probably due to the sample size, the sensitivity and specificity for indicating trisomy 13 were lower (85.7% and 61.1%) than that for trisomies 21 and 18. The PPVs in pregnancies with positive NIPT results at Z-score greater than or equal to cutoff value were 99.18% (121/122) for trisomy 21, 92.31% (24/26) for trisomy 18 and 46.15% (6/13) for trisomy 13. In patients with a Z-score between 3 and cutoff Z-score, the PPV of NIPT for trisomies 21, 18, and 13 were 30.77% (4/13), 10.71% (3/28), and 8.33% (1/12) respectively. Moreover, by classifying Z scores as 3 ≤ Z < 5, 5 ≤ Z < 10, and Z ≥ 10, the majority of Z scores were above 10 with a PPV of 99% for T21 and just 5.2% were between 3 and 5 with a PPV of 14.3%. In contrast for T18, over a third of tests had Z scores between 3 and 5. The PPV in this group is just over 5%.

Conclusions: The present results show that the PPV performance of NIPT for fetal trisomies 13, 18, and 21 are closely associated with Z-score. The higher the Z-score, the greater the likelihood that the aneuploidy result is correct. Our experience in evaluating the Z-score accuracy of NIPT in this study could be of use in similar work.
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http://dx.doi.org/10.1002/pd.5908DOI Listing
May 2021

A novel splicing mutation in F8 causes various aberrant transcripts in a hemophilia A patient and identifies a new transcript from healthy individuals.

Blood Coagul Fibrinolysis 2020 Dec;31(8):506-510

Laboratory of Genetics and Metabolism, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning.

: Hemophilia A is an X-linked hemorrhagic disorder caused by deficiency or dysfunction of the coagulation factor VIII (FVIII), and a great variety of mutations in the factor VIII gene (F8) are identified. We aimed to identify the genetic defects of the F8 gene in a Chinese patient with moderate hemophilia A. We have identified a novel intronic variant in the hemophilia A patient by DNA sequence analysis, cDNA sequencing, and TA clone sequencing. An intronic variant, c.5816-1G>A, was identified and the cDNA sequencing confirmed the pathogenicity of the transition. TA clone sequencing showed that the splicing mutation produced two aberrant premRNA skipping exons (18 and exon 18 + 19, respectively). These aberrant mRNA forms maintain the reading frame and are predicted to code for deleted FVIII isoforms and the shorter abnormal transcript accounted for one-eighth of the total mRNA. There was a new unreported transcript with E22 spliced out in healthy individuals and our patient, whose specific functions need to be determined in further studies. Our study widens the mutation spectrum of the F8 gene. In addition, the study findings could provide the opportunity to reveal alternative splicing patterns.
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http://dx.doi.org/10.1097/MBC.0000000000000952DOI Listing
December 2020

A novel splicing mutation of is associated with nonsyndromic cleft lip with or without cleft palate.

J Matern Fetal Neonatal Med 2020 Jul 22:1-8. Epub 2020 Jul 22.

Department of Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, P. R. China.

Background: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common birth defects, and occurs in approximately 1/700 live births worldwide. The correlation between the region and NSCL/P was first identified by genome-wide association studies (GWAS), but few reports have examined NSCL/P caused by mutations in the Chinese population.

Methods: We performed chromosome microarray analysis (CMA) for two consecutive abnormal fetuses and whole exome sequencing (WES) for the family, including 3 patients and 2 normal family members, Sanger sequencing and RT-PCR were used to confirm the mutation.

Results: We identified a novel splice donor mutation ( c.1920 + 1G > A) in two consecutive NSCL/P fetuses, and the variant was inherited from the mother and grandfather. The mutation caused abnormal skipping of exon 17, and the mRNA level of was significantly decreased compared to the wild type.

Conclusions: In this study, we successfully diagnosed the genetic cause of NSCL/P in a family and first report that the c.1920 + 1G > A mutation in is associated with NSCL/P. Our study enriches the genetic landscape of NSCL/P, extends the mutation spectrum of , and provides a new direction for the diagnosis of NSCL/P in patients and its prenatal diagnosis in fetuses.
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http://dx.doi.org/10.1080/14767058.2020.1786523DOI Listing
July 2020

Corrigendum to "A systematic comparison of exercise training protocols on animal models of cardiovascular capacity" [Life Sci. 217 (2019) 128-140].

Life Sci 2020 Aug 4;254:117757. Epub 2020 Jun 4.

National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China/CGDB, Shaanxi Normal University College of Life Sciences, Xi'an 710119, China. Electronic address:

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http://dx.doi.org/10.1016/j.lfs.2020.117757DOI Listing
August 2020

Prenatal exome sequencing in fetuses with congenital heart defects.

Clin Genet 2020 09 9;98(3):215-230. Epub 2020 Jun 9.

Department of Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.

The genetic diagnosis of congenital heart defects (CHDs) is challenging because of genetic and phenotypic heterogeneity. The aim of our study was to evaluate the clinical value of whole exome sequencing (WES) in the prenatal diagnosis of CHDs in a large cohort. Trio-based WES was performed in 260 fetuses with CHDs negative for karyotype and chromosome microarray analysis results. WES produced a diagnostic yield of 10% (26/260) in the entire cohort. Relative high diagnostic rate was observed in cases with cardiac rhabdomyoma (60%), complex CHDs (16.7%), septal defect (14.0%), and conotruncal defect (9.9%). There was no significant difference between the diagnostic yields in simple and complex CHDs groups (9.9% vs 16.7%), and in non-isolated and isolated CHDs groups (15.7% vs 7.9%). The diagnostic yields in cases with CHDs with soft markers, CHDs with fetal growth restriction, and CHDs with other structural anomalies (syndromic CHDs) were 0 (0/13), 50% (1/2) and 18.2% (10/55), respectively. Variants of unknown significance were detected in 16 (6.2%) fetuses, and secondary findings in 7 (2.7%) cases. Variants in 14 candidate genes were identified. Our study demonstrates an incremental diagnostic yield by trio-based WES in the prenatal diagnosis of CHDs after routine tests, not as high as expected.
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http://dx.doi.org/10.1111/cge.13774DOI Listing
September 2020

Genetic tests aid in counseling of fetuses with cerebellar vermis defects.

Prenat Diagn 2020 09 28;40(10):1228-1238. Epub 2020 May 28.

Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.

Objective: To assess the value of chromosome microarray analysis (CMA) and whole exome sequencing (WES) in fetuses with cerebellar vermis defects (CVD).

Methods: From 2013 to 2019, we performed CMA on 43 fetuses with CVD, who were divided into cerebellar vermis hypoplasia (CVH) group and Dandy-Walker malformation (DWM) group according to morphological subtypes. Subsequently, WES was performed on 19 fetuses with normal CMA results to identify diagnostic genetic variants (DGVs).

Results: Chromosome aneuploidies and clinically significant copy number variants were identified in 23.3% (10/43) of fetuses, and a significantly higher positive rate was found in fetuses with multiple compared with isolated malformations (36% vs 5.6%, P = .028). STAG2 genes related to Xq25 duplication syndrome was possibly a novel candidate gene for CVD. WES detected eight DGVs in seven genes among the 19 fetuses tested. Autosomal recessive ciliopathies (4/8) caused by TMEM231, CSPP1, and CEP290 mutations, were the most frequent monogenetic diseases, followed by Opitz GBBB syndrome (2/8) caused by MID1 and SPECC1L variants.

Conclusion: The combined use of CMA and WES has the potential to provide genetic diagnoses in 42% (18/43) of fetal CVD. WES should be offered when CMA results are normal.
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http://dx.doi.org/10.1002/pd.5732DOI Listing
September 2020

Nonalcoholic fatty liver disease experiences accumulation of hepatic liquid crystal associated with increasing lipophagy.

Cell Biosci 2020 6;10:55. Epub 2020 Apr 6.

Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, Xi'an, 710062 China.

Background: In the past 30 years, incidences of non-alcoholic fatty liver disease (NAFLD) has risen by 30%. However, there is still no clear mechanism or accurate method of anticipating liver failure. Here we reveal the phase transitions of liquid crystalline qualities in hepatic lipid droplets (HLDs) as a novel method of anticipating prognosis.

Methods: NAFLD was induced by feeding C57BL/6J mice on a high-fat (HiF) diet. These NAFLD livers were then evaluated under polarized microscopy, X-ray diffraction and small-angle scattering, lipid component chromatography analysis and protein expression analysis. Optically active HLDs from mouse model and patient samples were both then confirmed to have liquid crystal characteristics. Liver MAP1LC3A expression was then evaluated to determine the role of autophagy in liquid crystal HLD (LC-HLD) formation.

Results: Unlike the normal diet cohort, HiF diet mice developed NAFLD livers containing HLDs exhibiting Maltese cross birefringence, phase transition, and fluidity signature to liquid crystals. These LC-HLDs transitioned to anisotropic crystal at 0 °C and remain crystalline. Temperature increase to 42 °C causes both liquid crystal and crystal HLDs to convert to isotropic droplet form. These isotropic HLDs successfully transition to anisotropic LC with fast temperature decrease and anisotropic crystal with slow temperature decrease. These findings were duplicated in patient liver. Patient LC-HLDs with no inner optical activity were discovered, hinting at lipid saturation as the mechanism through which HLD acquire LC characteristics. Downregulation of MAP1LC3A in conjunction with increased LC-HLD also implicated autophagy in NAFLD LC-HLD formation.

Conclusions: Increasing concentrations of amphiphilic lipids in HLDs favors organization into alternating hydrophilic and hydrophobic layers, which present as LC-HLDs. Thus, evaluating the extent of liquid crystallization with phase transition in HLDs of NAFLD patients may reveal disease severity and predict impending liver damage.
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http://dx.doi.org/10.1186/s13578-020-00414-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137450PMC
April 2020

Nonimmune hydrops fetalis: Genetic analysis and clinical outcome.

Prenat Diagn 2020 06 3;40(7):803-812. Epub 2020 May 3.

Department of Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.

Objective: To investigate the genetic causes and clinical outcomes of nonimmune hydrops fetalis (NIHF).

Methods: Cohort of cases of NIHF between July 2013 and December 2018. Initial genetic testing included quantitative fluorescence polymerase chain reaction for aneuploidies, karyotyping and chromosomal microarray analysis (CMA). In negative results, whole exome sequencing (WES) of the fetuses and parents was performed. Clinical post-natal follow-up assessments were conducted.

Results: One hundred and nine patients fulfilled the study inclusion criteria and were sequentially genetically assessed by karyotype, CMA and WES. Among them, 24.8% (27/109) had a clinically significant genetic abnormality: 21 (19%) had abnormal karyotypes; 3/72 had pathogenic/likely pathogenic copy number variants (additional yield = 4.2%); and 3 had single gene disorders. The pregnancy termination and live birth rates of the cases with positive genetic testing results were significantly different from those with negative results (92.6% vs 53.7% and 3.7% vs 31.7%, respectively, P < .05 for both). During clinical follow-up of the survivors, 3/23 (13.0%) children developed an additional phenotype.

Conclusion: This study improves our understanding of the diagnostic yield of CMA and WES for NIHF. A genetic diagnosis of NIHF can help determine the fetal prognosis and recurrence risk and influence pregnancy decision-making.
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http://dx.doi.org/10.1002/pd.5691DOI Listing
June 2020

Dynamics expression of during embryonic early development of .

Cell Biosci 2019 8;9. Epub 2019 Jan 8.

1National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China/CGDB, Shaanxi Normal University College of Life Sciences, Xi'an, 710062 China.

Background: Calcium signaling are conserved from invertebrates to vertebrates and plays critical roles in many molecular mechanisms of embryogenesis and postnatal development. As a critical component of the signaling pathway, the RyR medicated calcium-induced calcium release signaling system, has been well studied along with their regulator FK506-binding protein 12 (FKBP12/Calstabin). Lack of FKBP12 is known to result in lethal cardiac dysfunction in mouse. However, precisely how FKBP12 is regulated and effects calcium signaling in remains largely unknown.

Results: In this study, we identified both temporal and localization changes in expression of a translational and transcriptional regulator of RyR (DmRyR) and FKBP12, through embryonic development. is first expressed at the syncytial blastoderm stage and undergoes increased expression during the cellular blastoderm and early gastrulation stages. At late gastrulation, expression begins to decline until it reaches homeostasis, which it then maintains throughout the rest of development. Throughout these described changes in expression, DmFKBP12 mRNA remain stable, which indicates that protein dynamics are attributed to regulation at the mRNA to protein translation level. In addition to temporal changes in expression, dynamic expression profiles during development also revealed DmFKBP12 localization. Although DmFKBP12 is distributed evenly between the anterior to posterior poles of the blastoderm egg, the protein is expressed more strongly in the cortex of the early gastrula with the highest concentration found in the basement membrane of the cellular blastoderm. Fertilized egg, through the profile as under-membrane cortex distribution concentering onto basement at cellular blastoderm, to the profile as three-gem layer localization in primitive neuronal and digestion architecture of early gastrula. By late gastrulation, DmFKBP12 is no longer identified in the yolk or lumen of duct structures and has relocated to the future brain (suboesophageal and supraesophageal ganglions), ventral nervous system, and muscular system. Throughout these changes in distribution, in situ mRNA monitoring detected equal distribution of mRNA, once again indicating that regulation of occurs at the translational level in development.

Conclusion: As a critical regulator of the DmRyR-FKBP complex, DmFKBP12 expression in fluctuates temporally and geographically with the formation of organ systems. These finding indicate that and RyR associated calcium signaling plays an essential role in the successful development of . Further study on the differences between mammalian RyR-FKBP12 and DmRyR-FKBP12 can be exploited to develop safe pesticides.
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http://dx.doi.org/10.1186/s13578-019-0270-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325743PMC
January 2019

A systematic comparison of exercise training protocols on animal models of cardiovascular capacity.

Life Sci 2019 Jan 3;217:128-140. Epub 2018 Dec 3.

National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China/CGDB, Shaanxi Normal University College of Life Sciences, Xi'an 710119, China. Electronic address:

Cardiovascular disease (CVD) is a major global cause of mortality, which has prompted numerous studies seeking to reduce the risk of heart failure and sudden cardiac death. While regular physical activity is known to improve CVD associated morbidity and mortality, the optimal duration, frequency, and intensity of exercise remains unclear. To address this uncertainty, various animal models have been used to study the cardioprotective effects of exercise and related molecular mechanism such as the mice training models significantly decrease size of myocardial infarct by affecting Kir6.1, VSMC sarc-K channels, and pulmonary eNOS. Although these findings cement the importance of animal models in studying exercise induced cardioprotection, the vast assortment of exercise protocols makes comparison across studies difficult. To address this issue, we review and break down the existent exercise models into categories based on exercise modality, intensity, frequency, and duration. The timing of sample collection is also compared and sorted into four distinct phases: pre-exercise (Phase I), mid-exercise (Phase II), exercise recovery (Phase III), and post-exercise (Phase IV). Finally, because the life-span of animals so are limited, small changes in animal exercise duration can corresponded to untenable amounts of human exercise. To address this limitation, we introduce the Life-Span Relative Exercise Time (RET) as a method of accurately defining short-term, medium-term and long-term exercise relative to the animal's life expectancy. Systematic organization of existent protocols and this new system of defining exercise duration will allow for a more solid framework from which researchers can extrapolate animal model data to clinical application.
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http://dx.doi.org/10.1016/j.lfs.2018.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320317PMC
January 2019

Altered expression of circular RNAs in human placental chorionic plate-derived mesenchymal stem cells pretreated with hypoxia.

J Clin Lab Anal 2019 Mar 28;33(3):e22825. Epub 2018 Nov 28.

Guangzhou Women and Children's Medical Center, Sun Yat-sen University, Guangzhou, China.

Background: Hypoxic preconditioning alters the biological properties of mesenchymal stem cells (MSCs). It is not known whether this process has an effect on circular RNAs (circRNAs) in MSCs.

Methods: Human placental chorionic plate-derived MSCs (hpcpMSCs) isolated from the same placentae were classed into two groups: hypoxic pretreated (hypoxia) group and normally cultured (normoxia) group. The comparative circRNA microarray analysis was used to determine circRNAs expression and verified by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) in the two groups.

Results: One hundred and two differentially expressed circRNAs in the hypoxia group were found compared to that in the normoxia group (fold change >1.5-fold and P < 0.05). The expression levels of circRNAs by qRT-PCR were consistent with those evaluated by microarray analysis. Gene ontology (GO) analysis showed that the putative function of their target genes for those differentially expressed circRNAs was primarily involved in cell development and its differentiation and regulation. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that transcriptional misregulation in cancer and mitogen-activated protein kinase (MAPK) signaling pathway were the most significant. MAPK signaling pathway was found to be the core regulatory pathway triggered by hypoxia.

Conclusions: The results indicate that the altered expression of specific circRNAs in MSCs is associated with hypoxic preconditioning. This finding provides further exploration of underlying mechanisms of the characteristic changes of MSCs with hypoxic preconditioning.
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http://dx.doi.org/10.1002/jcla.22825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818546PMC
March 2019

Pregnancy outcome of autosomal aneuploidies other than common trisomies detected by noninvasive prenatal testing in routine clinical practice.

Prenat Diagn 2018 10 6;38(11):849-857. Epub 2018 Sep 6.

Department of Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, P.R. China.

Objective: The objective of the study is to report the incidence and pregnancy outcome of autosomal aneuploidies other than common trisomies 21, 18, and 13 detected by noninvasive prenatal testing (NIPT) at a single center.

Methods: Pregnant women undergoing NIPT from February 2015 to January 2018 in our center were offered expanded screening to include rare autosomal aneuploidies. Aneuploidies included extra copy chromosomes (most likely trisomies) and decreased copy chromosomes (most likely monosomies). The pregnancy outcomes of women consenting to the expanded NIPT screen were recorded.

Results: Expanded NIPT was performed in 15 362 pregnancies. A total of 59 autosomal aneuploidies other than the 3 common trisomies were detected, with a positive screening rate of 0.38% (59/15 362). The screen positive rate was higher in women aged above 35 years than in those younger (0.44% vs 0.32%, P < .05). Of the screen positive results, 30.5% (18/59) were because of extra copies for chromosomes trisomy 7, 10.2% (6/59) for chromosome 22, and 8.5% (5/59) for chromosomes 8 and 16 respectively, while other choromosomes were less frequently involved. Decreased copy chromosomes were less common: 6.8% (4/59) for chromosomes 14 and 13. Mixed aneuploidies with increased copies for some chromosomes and decreased copies for others were also noted. Invasive prenatal diagnosis was performed in 61% (36/59) of the cases. Invasive test results and clinical follow-ups demonstrated that most (94.9%, 56/59) of the rare aneuploidies were false positives, probably resulting from confined placental mosaicism. Only 1 case (1.7%, 1/59) with NIPT report of extra copies of chromosome 7 and without ultrasound evidence of fetal abnormality was confirmed to be fetal mosaicism by microarray test. Uniparental disomy of whole chromosome 2 was identified by microarray analysis in 1 case with extra copy chromosome 2 detected by NIPT. Loss of heterozygocity of chromosome 7q11.23-q21.11 was detected in another case with extra copy chromosome 7. Fortunately, pregnancy outcomes of both cases were normal. Two fetal deaths attributed to severe fetal growth restriction were associated with extra copies of chromosome 16 at expanded NIPT.

Conclusions: Autosomal aneuploidies other than trisomies 21, 18, and 13 are not uncommon in routine clinical NIPT practice. Extra copies of chromosomes in rare cases can be associated with uniparental disomy. Most rare aneuploidies at NIPT have good pregnancy outcomes. Thus, invasive testing should be used with caution for these aneuploidies in routine clinical practice.
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http://dx.doi.org/10.1002/pd.5340DOI Listing
October 2018

Mutation in SSUH2 Causes Autosomal-Dominant Dentin Dysplasia Type I.

Hum Mutat 2017 01 19;38(1):95-104. Epub 2016 Oct 19.

Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.

Dentin dysplasia type I (DDI) is an autosomal-dominant genetic disorder resulting from dentin defects. The molecular basis of DDI remains unclear. DDI exhibits unique characteristics with phenotypes featuring obliteration of pulp chambers and diminutive root, thus providing a useful model for understanding the genetics of tooth formation. Using a large Chinese family with 14 DDI patients, we mapped the gene locus responsible for DDI to 3p26.1-3p24.3 and further identified a missense mutation, c.353C>A (p.P118Q) in the SSUH2 gene on 3p26.1, which co-segregated with DDI. We showed that SSUH2 (p.P118Q) perturbed the structure and significantly reduced levels of mutant (MT) protein and mRNA compared with wild-type SSUH2. Furthermore, MT P141Q knock-in mice (+/- and -/-) had a unique partial obliteration of the pulp cavity and upregulation or downregulation of six major genes involved in odontogenesis: Dspp, Dmp1, Runx2, Pax9, Bmp2, and Dlx2. The phenotype of missing teeth was determined in zebrafish with morpholino gene knockdowns and rescued by injection of normal human mRNA. Taken together, our observations demonstrate that SSUH2 disrupts dental formation and that this novel gene, together with other odontogenesis genes, is involved in tooth development.
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http://dx.doi.org/10.1002/humu.23130DOI Listing
January 2017

A splicing mutation in VPS4B causes dentin dysplasia I.

J Med Genet 2016 09 31;53(9):624-33. Epub 2016 May 31.

Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China Guangdong Genetic Testing Engineering Research Center, Guangzhou, China.

Background: Dentin dysplasia I (DDI) is a genetically heterogeneous autosomal-dominant disorder characterised by rootless teeth with abnormal pulpal morphology, the aetiology of which presents as genetically heterogeneous.

Methods And Results: Using a cohort of a large Chinese family with 10 patients with DDI, we mapped to a 9.63 Mb candidate region for DDI on chromosome 18q21.2-q21.33. We then identified a mutation IVS7+46C>G which resulted in a novel donor splice site in intron 7 of the VPS4B gene with co-segregation of all 10 affected individuals in this family. The aberrant transcripts encompassing a new insert of 45 bp in size were detected in gingival cells from affected individuals. Protein structure prediction showed that a 15-amino acid insertion altered the ATP-binding cassette of VPS4B. The mutation resulted in significantly reduced expression of mRNA and protein and altered subcellular localisation of VPS4B, indicating a loss of function of VPS4B. Using human gingival fibroblasts, the VPS4B gene was found to act as an upstream transducer linked to Wnt/β-catenin signalling and regulating odontogenesis. Furthermore, knockdown of vps4b in zebrafish recapitulated the reduction of tooth size and absence of teeth similar to the tooth phenotype exhibited in DDI index cases, and the zebrafish mutant phenotype could be partially rescued by wild-type human VPS4B mRNA. We also observed that vps4b depletion in the zebrafish negatively regulates the expression of some major genes involved in odontogenesis.

Conclusions: This study identifies VPS4B as a disease-causing gene for DDI, which is one of the important contributors to tooth formation, through the Wnt/β-catenin signalling pathway.
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http://dx.doi.org/10.1136/jmedgenet-2015-103619DOI Listing
September 2016

Association between vaspin level and coronary artery disease in patients with type 2 diabetes.

Diabetes Res Clin Pract 2016 Mar 28;113:26-32. Epub 2016 Jan 28.

Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin 150001, Heilongjiang, PR China.

Aim: Adipokines contribute to the atherosclerotic process, connecting obesity and diabetes to cardiovascular disease. Vaspin is a recently discovered adipokine, so data about the relationship of vaspin to coronary artery disease in type-2 diabetes mellitus (T2DM) is limited. The current study was designed to evaluate the association of vaspin with the presence of coronary artery disease in T2DM.

Methods: We enrolled 228 patients with T2DM, with or without CAD, between March 2010 and July 2011, and 120 healthy control participants. Serum vaspin, homeostasis model assessment of insulin resistance (HOMA-IR) and other cardiovascular risk factors were assayed.

Results: Vaspin levels were significantly increased in patients with T2DM compared to healthy individuals, and were further increased in patients with both T2DM and CAD compared to those with T2DM but without CAD. Moreover, vaspin correlated positively with body mass index, fasting plasma glucose, insulin and HOMA-IR in all patients with T2DM (P<0.05). Furthermore, in multivariate logistic regression analysis, vaspin level was associated with the presence of CAD in patients with T2DM.

Conclusions: Vaspin correlates with CAD in T2DM.
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http://dx.doi.org/10.1016/j.diabres.2015.12.001DOI Listing
March 2016

A Double Heterozygous Mutation of TNNI3 Causes Hypertrophic Cardiomyopathy in a Han Chinese Family.

Cardiology 2016 28;133(2):91-6. Epub 2015 Oct 28.

Department of Cardiovascular Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Objectives: To investigate the variations in the TNNI3 gene in a Chinese Han family affected by hypertrophic cardiomyopathy (HCM) and the potential molecular mechanism linking these mutations with disease.

Methods: Peripheral venous blood was acquired from family members, and TNNI3 mutations were identified by DNA sequencing. The pathophysiology of TNNI3 mutations was investigated using bioinformatics, subcellular localization determination and Western blotting.

Results: Sanger sequencing revealed that the proband possessed 2 heterozygous mutations, c.235C>T and c.470C>T, located at exons 4 and 6 of the TNNI3 gene. The proband (II-2) and her brother (II-1), who had been previously diagnosed with HCM, harbored both mutations whereas their healthy parents harbored only 1. Alignment of the TNNI3 amino acid sequence indicated that the two Pro residues were highly conserved across species. Subcellular localization showed that both wild-type (WT) and mutant TNNI3 proteins were localized at the cell nucleus. Western blot analysis of expression in human embryonic kidney 293T cells showed that the intracellular levels of the mutant proteins were significantly decreased compared to WT TNNI3 (p < 0.01).

Conclusions: Our findings showed that a double heterozygous mutation in the TNNI3 gene is involved in the pathogenesis of HCM via haploinsufficiency. These results will inspire further studies to investigating the link between the TNNI3 gene and HCM.
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http://dx.doi.org/10.1159/000440877DOI Listing
September 2016

Analysis of human upstream open reading frames and impact on gene expression.

Hum Genet 2015 Jun 24;134(6):605-12. Epub 2015 Mar 24.

Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.

The upstream open reading frame (uORF) is a post-transcriptional regulatory element in the 5' untranslated region (5'UTR), which modulates the translation levels of main open reading frame (mORF). Earlier studies showed that disturbed uORF-mediated translation control can result in drastic changes in translation levels of mORF, leading to genetic disorders. To date, there has been no systematic investigation into the relationship between variations in patients and uORF status. Here, taking the advantage of several datasets, including gene ontology (GO) annotations and sequence feature analysis, we have examined uORF impacts in human transcripts. GO annotations indicate that uORF-containing genes are enriched in certain features such as oncogenes and transcription factors. Sequence feature analysis reveals that uORF is a factor for determination of the translation initiation site (TIS) in human transcripts. We show that genes with uORFs have lower protein expression levels than genes without uORFs in multiple human tissues. Moreover, by examining three disease variation databases, we identified uORF-altering mutations from a total of 3,740,225 variations, which are highly suspected to be associated with changed levels of gene expression. For an experimental validation, we found four mutations with significant effects on protein expression but with only modest changes in transcription levels. These findings will provide researchers on related diseases with new insights into the importance of known mutations.
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http://dx.doi.org/10.1007/s00439-015-1544-7DOI Listing
June 2015

Primary gastrointestinal stromal tumor of the prostate: A case report and literature review.

Oncol Lett 2014 Jun 12;7(6):1925-1929. Epub 2014 Mar 12.

Department of Anesthesia, The Affiliated Tumor Hospital of Xiangya Medical School, The Central South University, Changsha, Hunan 410008, P.R. China.

Extragastrointestinal stromal tumors (EGISTs) are relatively rare soft tissue neoplasms arising from the extra gastrointestinal tract. The current study presents a case of primary EGIST of the prostate observed in a 55-year-old male. Imaging studies showed a 10×10.5×9.5-cm prostate mass. On histological observation, the mass was separated from the rectum serosa and exhibited a high mitotic count (8/50 high-power fields). The results of immunohistochemical staining showed positive immunoreactivity for cluster of differentiation (CD)117 (c-kit), CD34 and DOG1 in the tumor. On mutation analysis, loss of heterozygosity of the c-kit gene was observed in the prostatic EGIST; however, the platelet-derived growth factor receptor-α (PDGFRA) gene was considered to be normal. Therefore, as EGIST of the prostate is rare, there is a requirement for the confirmation of the diagnosis to be based on immunohistochemistry and mutation analysis (of c-kit and PDGFRA).
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http://dx.doi.org/10.3892/ol.2014.1968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049718PMC
June 2014

Survivin and HLA-I expression predicts survival of patients with clear cell renal cell carcinoma.

Tumour Biol 2014 Aug 23;35(8):8281-8. Epub 2014 May 23.

Department of Urology, Xiangya Hospital, The Central South University, 87 Xiangya Road, 410008, Changsha, Hunan, China.

Altered expression of survivin and leukocyte antigen class I (HLA-I) proteins is associated with tumor progression. This study investigated their expressions in clear cell renal cell carcinoma (ccRCC) tissues for association with a clinical significance of ccRCC patients. Ninety ccRCC and 20 normal tissue samples (i.e., control) were immunohistochemically stained for survivin and HLA-I expression for an association with clinicopathological data and survival of ccRCC patients. Survivin protein was expressed in 82.2 % (74/90) of ccRCC tissue samples compared to 0 % in the normal tissues, and HLA-I protein was expressed in 90 % (18/20) of the normal tissues vs. 67.8 % (61/90) in ccRCC samples. Survivin expression was associated with tumor grade, stage, and lymph node metastasis (p = 0.000, p = 0.016, and p = 0.001, respectively). Conversely, lost HLA-I expression did not have any associations with clinicopathological data (p > 0.05). Survivin-negative patients had a higher tumor-free survival rate than patients with survivin expression (p = 0.037). Patients with normal HLA-I levels had a higher tumor-free survival rate than those with reduced HLA-I levels (p = 0.02). The uni- and multivariate analyses indicated that expression of survivin and HLA-I, individually and in combination, was an independent predictor for survival of ccRCC patients. Overexpression of survivin but reduced HLA-I expression is useful in the prediction of tumor-free survival of ccRCC patients.
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http://dx.doi.org/10.1007/s13277-014-2058-yDOI Listing
August 2014

Down-regulation of human leukocyte antigen class I (HLA-I) is associated with poor prognosis in patients with clear cell renal cell carcinoma.

Acta Histochem 2013 Jun 12;115(5):470-4. Epub 2012 Dec 12.

Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, People's Republic of China.

Human leukocyte antigen class I (HLA-I) molecules are transmembrane glycoproteins that have been reported to be down-regulated in multiple types of human malignancies, including clear cell renal cell carcinoma (CCRCC). However, only one study has investigated its prognostic value in CCRCC. In the present study, HLA-I protein expression was analyzed in 120 archived, paraffin-embedded CCRCC samples and 10 adjacent normal tissues using immunohistochemistry. The correlation between HLA-I expression and clinicopathological factors was evaluated by the χ(2) test. Patients' overall survival was analyzed by the Kaplan-Meier method. HLA-I down-regulation was observed in 38.3% (46/120) of renal tumor samples, but only in 10% (1/10) of adjacent normal tissues. Statistical analysis showed a significant correlation of HLA-I expression with TNM stage, lymph node metastasis, and Fuhrman grade. Patients with tumors displaying down-regulation of HLA-I showed significantly shorter overall survival (P=0.021, log-rank test). More importantly, multivariate analysis indicated that down-regulation of HLA-I was an independent prognostic factor for CCRCC patients (P=0.033). Overall, our data suggest that HLA-I down-regulation is associated with tumor progression and a poor prognosis in CCRCC patients, and emphasize the importance of HLA-I in natural and therapeutic immune surveillance of patients with CCRCC.
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http://dx.doi.org/10.1016/j.acthis.2012.11.002DOI Listing
June 2013