Publications by authors named "Ying Ru"

24 Publications

  • Page 1 of 1

A Review of CXCL1 in Cardiac Fibrosis.

Front Cardiovasc Med 2021 28;8:674498. Epub 2021 Apr 28.

Department of Cardiology, The First Affiliated Hospital of Nanchang University, Nanchang, China.

Chemokine C-X-C motif ligand-1 (CXCL1), principally expressed in neutrophils, macrophages and epithelial cells, is a valid pro-inflammatory factor which performs an important role in mediating the infiltration of neutrophils and monocytes/macrophages. Elevated serum level of CXCL1 is considered a pro-inflammatory reaction by the organism. CXCL1 is also related to diverse organs fibrosis according to relevant studies. A growing body of evidence suggests that CXCL1 promotes the process of cardiac remodeling and fibrosis. Here, we review structure and physiological functions of CXCL1 and recent progress on the effects and mechanisms of CXCL1 in cardiac fibrosis. In addition, we explore the role of CXCL1 in the fibrosis of other organs. Besides, we probe the possibility that CXCL1 can be a therapeutic target for the treatment of cardiac fibrosis in cardiovascular diseases.
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http://dx.doi.org/10.3389/fcvm.2021.674498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113392PMC
April 2021

The expression of mimecan in adrenal tissue plays a role in an organism's responses to stress.

Aging (Albany NY) 2021 05 10;13(9):13087-13107. Epub 2021 May 10.

The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostic and Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao tong University School of Medicine, Shanghai 200011, China.

Mimecan encodes a secretory protein that is secreted into the human serum as two mature proteins with molecular masses of 25 and 12 kDa. We found 12-kDa mimecan to be a novel satiety hormone mediated by the upregulation of the expression of interleukin (IL)-1β and IL-6 in the hypothalamus. Mimecan was found to be expressed in human pituitary corticotroph cells and was up-regulated by glucocorticoids, while the secretion of adrenocorticotropic hormone (ACTH) in pituitary corticotroph AtT-20 cells was induced by mimecan. However, the effects of mimecan in adrenal tissue on the hypothalamic-pituitary-adrenal (HPA) axis functions remain unknown. We demonstrated that the expression of mimecan in adrenal tissues is significantly downregulated by hypoglycemia and scalded stress. It was down-regulated by ACTH, but upregulated by glucocorticoids through and studies. We further found that 12-kDa mimecan fused protein increased the corticosterone secretion of adrenal cells and . Interestingly, compared to litter-mate mice, the diurnal rhythm of corticosterone secretion was disrupted under basal conditions, and the response to restraint stress was stronger in mimecan knockout mice. These findings suggest that mimecan stimulates corticosterone secretion in the adrenal tissues under basal conditions; however, the down-regulated expression of mimecan by increased ACTH secretion after stress in adrenal tissues might play a role in maintaining the homeostasis of an organism's responses to stress.
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http://dx.doi.org/10.18632/aging.202991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148509PMC
May 2021

Knockdown of dual oxidase 1 suppresses activin A-induced fibrosis in cardiomyocytes via the reactive oxygen species-dependent pyroptotic pathway.

Int J Biochem Cell Biol 2021 02 9;131:105902. Epub 2020 Dec 9.

Department of Cardiology, The First Affiliated Hospital of NanChang University, NanChang, Jiangxi Province, 330006, China. Electronic address:

Fibrotic diseases account for more than 8 million deaths worldwide annually. Reactive oxygen species (ROS) has been shown to activate pyroptosis and promote the production of interleukin (IL)-1β and IL-18, leading to fibrosis development. However, the role of dual oxidase 1 (DUOX1)-induced ROS production and pyroptosis in cardiac fibrosis remains largely unknown. Activin A was used to induce ROS and pyroptosis in cardiomyocytes. ROS level, pyroptosis, and cytokine production were detected using Active Oxygen Detection Kit, flow cytometry, and enzyme-linked immunosorbent assay, respectively. Western blotting analysis was used to measure expression changes of proteins. DUOX1 was silenced or overexpressed to investigate its role in fibrosis. We found that activin A induced ROS production and pyroptosis in cardiomyocytes, which was blocked by the ROS scavenger, N-acetyl-L-cysteine (NAC). Knockdown of DUOX1 reversed activin A-induced ROS production, pyroptosis, cytokine release, and the upregulation of proinflammatory proteins. Overexpression of DUOX1 resulted in opposite effects of knockdown DUOX1. Administration of an ROS scavenger blocked the effect of DUOX1 overexpression. Supplementation of IL-1β and IL-18 caused significant fibrosis in human cardiac fibroblasts (hCFs). The knockdown of DUOX1 protected cardiomyocytes against activin A-induced fibrosis via the inhibition of ROS, cytokine release, and pyroptosis.
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http://dx.doi.org/10.1016/j.biocel.2020.105902DOI Listing
February 2021

Single-Center Overview of Pediatric Monogenic Autoinflammatory Diseases in the Past Decade: A Summary and Beyond.

Front Immunol 2020 17;11:565099. Epub 2020 Sep 17.

Department of Pediatrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.

Monogenic autoinflammatory diseases (AIDs) are inborn disorders caused by innate immunity dysregulation and characterized by robust autoinflammation. We aimed to present the phenotypes and genotypes of Chinese pediatric monogenic AID patients. A total of 288 pediatric patients clinically suspected to have monogenic AIDs at the Department of Pediatrics of Peking Union Medical College Hospital between November 2008 and May 2019 were genotyped by Sanger sequencing, and/or gene panel sequencing and/or whole exome sequencing. Final definite diagnoses were made when the phenotypes and genotypes were mutually verified. Of the 288 patients, 79 (27.4%) were diagnosed with 18 kinds of monogenic AIDs, including 33 patients with inflammasomopathies, 38 patients with non-inflammasome related conditions, and eight patients with type 1 interferonopathies. Main clinical features were skin disorders (76%), musculoskeletal problems (66%), fever (62%), growth retardation (33%), gastrointestinal tract abnormalities (25%), central nervous system abnormalities (15%), eye disorders (16%), ear problems (9%), and cardiopulmonary disorders (8%). The causative genes were , and . The present study summarized both clinical and genetic characteristics of 18 kinds of monogenic AIDs found in the largest pediatric AID center over the past decade, with fever, skin problems, and musculoskeletal system disorders being the most prevalent clinical features. Many of the mutations were newly discovered. This is by far the first and largest monogenic AID report in Chinese pediatric population and also a catalog of the phenotypic and genotypic features among these patients.
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http://dx.doi.org/10.3389/fimmu.2020.565099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527522PMC
May 2021

De Winter syndrome as an emergency electrocardiogram sign of ST-elevation myocardial infarction: a case report.

ESC Heart Fail 2020 Sep 26. Epub 2020 Sep 26.

Department of Cardiology, The First Affiliated Hospital of Nanchang University, Nanchang, China.

The case report aims to reveal de Winter's electrocardiogram (ECG) pattern as an equivalent to anterior ST-segment elevation myocardial infarction (STEMI). We report a case of a 49-year-old man with a history of smoking who presented to the emergency department with a 1 day history of chest pain that was exacerbated 5 h prior to presentation. Detailed clinical investigations and coronary angiographic characteristics were recorded. The first ECG of the patient was consistent with de Winter syndrome. Acute coronary artery angiography showed that the proximal left anterior descending coronary artery was completely occluded after the first diagonal branch artery was given off. A percutaneous coronary intervention was immediately performed. Our case indicates that early identification and diagnosis of such ECGs and timely reperfusion therapy of de Winter syndrome as a STEMI equivalent are required to improve the prognosis of such patients.
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http://dx.doi.org/10.1002/ehf2.13008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754776PMC
September 2020

C-reactive protein derived from perivascular adipose tissue accelerates injury-induced neointimal hyperplasia.

J Transl Med 2020 02 11;18(1):68. Epub 2020 Feb 11.

Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, No. 107, Yanjiang West Road, Yuexiu District, Guangzhou, 510120, People's Republic of China.

Aim: Inflammation within the perivascular adipose tissue (PVAT) in obesity plays an important role in cardiovascular disorders. C-reactive protein (CRP) level in obesity patients is significantly increased and associated with the occurrence and progression of cardiovascular disease. We tested the hypothesis CRP derived from PVAT in obesity contributes to vascular remodeling after injury.

Methods: A high-fat diet (HFD) significantly increased CRP expression in PVAT. We transplanted thoracic aortic PVAT from wild-type (WT) or transgenic CRP-expressing (CRPTG) mice to the injured femoral artery in WT mice.

Results: At 4 weeks after femoral artery injury, the neointimal/media ratio was increased significantly in WT mice that received PVAT from CRPTG mice compared with that in WT mice that received WT PVAT. Transplanted CRPTG PVAT also significantly accelerated adventitial macrophage infiltration and vasa vasorum proliferation. It was revealed greater macrophage infiltration in CRPTG adipose tissue than in WT adipose tissue and CRP significantly increased the adhesion rate of monocytes through receptor Fcγ RI. Proteome profiling showed CRP over-expression promoted the expression of chemokine (C-X-C motif) ligand 7 (CXCL7) in adipose tissue, transwell assay showed CRP increased monocyte migration indirectly via the induction of CXCL7 expression in adipocytes.

Conclusion: CRP derived from PVAT was significantly increased in HFD mice and promoted neointimal hyperplasia after vascular injury.
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http://dx.doi.org/10.1186/s12967-020-02226-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011279PMC
February 2020

Assessment of Molecular Subtypes in Thyrotoxic Periodic Paralysis and Graves Disease Among Chinese Han Adults: A Population-Based Genome-Wide Association Study.

JAMA Netw Open 2019 05 3;2(5):e193348. Epub 2019 May 3.

Department of Endocrinology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China.

Importance: Thyrotoxic periodic paralysis (TPP) is a potentially lethal complication of hyperthyroidism. However, only 1 specific susceptibility locus for TPP has been identified. Additional genetic determinants should be detected so that a prediction model can be constructed.

Objective: To investigate the genetic architecture of TPP and distinguish TPP from Graves disease cohorts.

Design, Setting, And Participants: This population-based case-control study used a 2-stage genome-wide association study to investigate the risk loci of TPP and weighted genetic risk score to construct a TPP prediction model with data from a Chinese Han population recruited in hospitals in China from March 2003 to December 2015. The analysis was conducted from November 2014 to August 2016.

Main Outcomes And Measures: Loci specifically associated with TPP risk and those shared with Graves disease and prediction model of joint effects of TPP-specific loci.

Results: A total of 537 patients with TPP (mean [SD] age, 35 [11] years; 458 male) 1519 patients with Graves disease and no history of TPP (mean [SD] age, 38 [13] years; 366 male), and 3249 healthy participants (mean [SD] age, 46 [10] years; 1648 male) were recruited from the Han population by hospitals throughout China. Two new TPP-specific susceptibility loci were identified: DCHS2 on 4q31.3 (rs1352714: odds ratio [OR], 1.58; 95% CI, 1.35-1.85; P = 1.24 × 10-8) and C11orf67 on 11q14.1 (rs2186564: OR, 1.50; 95% CI, 1.29-1.74; P = 2.80 × 10-7). One previously reported specific locus was confirmed on 17q24.3 near KCNJ2 (rs312729: OR, 2.08; 95% CI, 1.83-2.38; P = 8.02 × 10-29). Meanwhile, 2 risk loci (MHC and Xq21.1) were shared by Graves disease and TPP. After 2 years of treatment, the ratio of persistent thyrotropin receptor antibody positivity was higher in patients with TPP than in patients with Graves disease and no history of TPP (OR, 3.82; 95% CI, 2.04-7.16; P = 7.05 × 10-6). The prediction model using a weighted genetic risk score and 11 candidate TPP-specific single-nucleotide polymorphisms had an area under the curve of 0.80.

Conclusions And Relevance: These findings provide evidence that TPP is a novel molecular subtype of Graves disease. The newly identified loci, along with other previously reported loci, demonstrate the growing complexity of the heritable contribution to TPP pathogenesis. A complete genetic architecture will be helpful to understand the pathophysiology of TPP, and a useful prediction model could prevent the onset of TPP.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.3348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503496PMC
May 2019

Reference values for peripheral blood lymphocyte subsets of healthy children in China.

J Allergy Clin Immunol 2018 09 8;142(3):970-973.e8. Epub 2018 May 8.

Ministry of Education, Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2018.04.022DOI Listing
September 2018

Endoplasmic reticulum stress in perivascular adipose tissue promotes destabilization of atherosclerotic plaque by regulating GM-CSF paracrine.

J Transl Med 2018 04 18;16(1):105. Epub 2018 Apr 18.

Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, No.107, Yanjiang West Road, Yuexiu District, Guangzhou, 510120, China.

Background: Perivascular adipose tissue (PVAT) accelerates plaque progression and increases cardiovascular risk. We tested the hypothesis that PVAT contributed to plaque vulnerability and investigated whether endoplasmic reticulum stress (ER stress) in PVAT played an important role in vulnerable plaque.

Methods: We transplanted thoracic aortic PVAT or subcutaneous adipose tissue as a control, from donor mice to carotid arteries of recipient apolipoprotein E deficient (apoE) mice after removing carotid artery collar placed for 6 weeks. Two weeks after transplantation, ER stress inhibitor 4-phenyl butyric acid (4-PBA) was locally administrated to the transplanted PVAT and then animals were euthanized after 4 weeks. Immunohistochemistry was performed to quantify plaque composition and neovascularization. Mouse angiogenesis antibody array kit was used to test the angiogenic factors produced by transplanted adipose tissue. In vitro tube formation assay, scratch wound migration assay and mouse aortic ring assay were used to assess the angiogenic capacity of supernatant of transplanted PVAT.

Results: Ultrastructural detection by transmission electron microscopy showed transplanted PVAT was a mixed population of white and brown adipocytes with abundant mitochondria. Transplanted PVAT increased the intraplaque macrophage infiltration, lipid core, intimal and vasa vasorum neovascularization and MMP2/9 expression in plaque while decreased smooth muscle cells and collagen in atherosclerotic plaque, which were restored by local 4-PBA-treatment. Antibody array analysis showed that 4-PBA reduced several angiogenic factors [Granulocyte Macrophage Colony Stimulating Factor (GM-CSF), MCP-1, IL-6] secreted by PVAT. Besides, conditioned medium from 4-PBA treated-PVAT inhibited tube formation and migration capacity of endothelial cells and ex vivo mouse aortic ring angiogenesis compared to conditioned medium from transplanted PVAT. mRNA expression and protein levels of GM-CSF were markedly elevated in adipocytes under ER stress which would be suppressed by 4-PBA. In addition, ER stress enhanced NF-κB binding to the promoter of the mouse GM-CSF gene in adipocytes confirmed by Chromatin immunoprecipitation analyses.

Conclusions: Our findings demonstrate that ER stress in PVAT destabilizes atherosclerotic plaque, in part through increasing GM-CSF paracrine via transcription factor NF-κB.
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http://dx.doi.org/10.1186/s12967-018-1481-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907173PMC
April 2018

Macrophage-derived foam cells impair endothelial barrier function by inducing endothelial-mesenchymal transition via CCL-4.

Int J Mol Med 2017 Aug 19;40(2):558-568. Epub 2017 Jun 19.

Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510120, P.R. China.

Recently, endothelial-mesenchymal transition (EndMT) has been demonstrated to play an important role in the development of atherosclerosis, the molecular mechanisms of which remain unclear. In the present study, scanning electron microscopy directly revealed a widened endothelial space and immunohistofluorescence demonstrated that EndMT was increased in human aorta atherosclerotic plaques. M1 macrophage-derived foam cell (M1-FC) supernatants, but not M2 macrophage-derived foam cell (M2-FC) supernatants, induced EndMT. A protein array and enzyme-linked immunosorbent assay identified that the levels of several cytokines, including C-C motif chemokine ligand 4 (CCL-4) were increased in M1-FC supernatants, in which EndMT was promoted, accompanied by increased endothelial permeability and monocyte adhesion. Furthermore, anti-CCL-4 antibody abolished the effects of M1-FC supernatants on EndMT. At the same time, CCL-4 activated its receptor, C-C motif chemokine receptor-5 (CCR-5), and upregulated transforming growth factor-β (TGF-β) expression. Further experiments revealed that EndMT induced by CCL-4 was reversed by treatment with CCR-5 antagonist and the RNA-mediated knockdown of TGF-β. On the whole, the data of the present study suggest that M1-FCs induce EndMT by upregulating CCL-4, and increase endothelial permeability and monocyte adhesion. These data may help to elucidate the important role of EndMT in the development of atherosclerosis.
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http://dx.doi.org/10.3892/ijmm.2017.3034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504989PMC
August 2017

An effective compromise between cost and referral rate: A sequential hearing screening protocol using TEOAEs and AABRs for healthy newborns.

Int J Pediatr Otorhinolaryngol 2016 Dec 26;91:141-145. Epub 2016 Oct 26.

Department of Otorhinolaryngology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China. Electronic address:

Objective: This study evaluated the efficacy of a sequential hearing screening protocol using transient evoked otoacoustic emission (TEOAE) and automated auditory brainstem response (AABR) tests in healthy newborns.

Design: A TEOAE screening was performed during the first 48-72 h of life. If the infants failed, an AABR test was performed at the same time, and they were referred for a TEOAE rescreening at six weeks old. The results of screening Protocol 1 (only TEOAE) were compared with those of screening Protocol 2 (sequential TEOAE + AABR screenings for the first screening and TEOAE for the rescreening).

Study Sample: A total of 1062 healthy newborns were enrolled in this research.

Results: For Protocol 1, the first screening and rescreening referral rates were 11.1% and 2.2%, respectively. In contrast, for Protocol 2, the referral rates were significant lower at 3.8% and 0.9%, respectively. Using the two protocols, six infants were diagnosed with hearing loss (0.57%).

Conclusions: Adding simultaneous AABR tests for infants who fail TEOAE testing at the first screening stage can significantly reduce referral rates without increasing misdiagnosis rates. Although this sequential screening process involves slightly more time and has a higher cost than TEOAE alone, its greater accuracy compensates for this difference.
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http://dx.doi.org/10.1016/j.ijporl.2016.10.025DOI Listing
December 2016

Hydrogen sulfide suppresses endoplasmic reticulum stress-induced endothelial-to-mesenchymal transition through Src pathway.

Life Sci 2016 Jan 2;144:208-17. Epub 2015 Dec 2.

Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, People's Republic of China; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou 510120, People's Republic of China. Electronic address:

Aims: Hydrogen sulfide (H2S) ameliorates cardiac fibrosis in several models by suppressing endoplasmic reticulum (ER) stress. Endothelial-to-mesenchymal transition (EndMT) is implicated in the development of cardiac fibrosis. Therefore, we investigated whether H2S could attenuate EndMT by suppressing ER stress.

Main Methods: ER stress was induced by tunicamycin (TM) and thapsigargin (TG) and inhibited by 4-phenylbutyrate (4-PBA) in human umbilical vein endothelial cells (HUVECs). ER stress and EndMT were measured by Western blot, Real-Time PCR and immunofluorescence staining. Inhibition Smad2 and Src pathway were performed by specific inhibitors and siRNA. Ultrastructural examination was detected by transmission electron microscope. The functions of HUVECs were investigated by cell migration assay and tube formation in vitro.

Key Findings: Under ER stress, the expression of endothelial marker CD31 significantly decreased while mesenchymal markers α-SMA, vimentin and collagen 1 increased which could be inhibited by 4-PBA. Moreover, HUVECs changed into a fibroblast-like appearance with the activation of Smad2 and Src kinase pathway. After inhibiting Src pathway, EndMT would be significantly inhibited. TM reduced H2S levels in cell lysate and H2S pretreatment could preserve endothelial cell appearance with decreased ER stress and ameliorated dilation of ER. H2S could also downregulate the mesenchymal marker expression, and upregulate the endothelial markers expression, accompanied with the suppression of Src pathway. Moreover, H2S partially restored the capacity of migration and tube formation in HUVECs.

Significance: These results revealed that H2S could protect against ER stress-induced EndMT through Src pathway, which may be a novel role for the cardioprotection of H2S.
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http://dx.doi.org/10.1016/j.lfs.2015.11.025DOI Listing
January 2016

Validation of the Ability of SYNTAX and Clinical SYNTAX Scores to Predict Adverse Cardiovascular Events After Stent Implantation: A Systematic Review and Meta-Analysis.

Angiology 2016 10 26;67(9):820-8. Epub 2015 Nov 26.

Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China

To compare the predicative ability of SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) and clinical SYNTAX scores for major adverse cardiac events (MACEs) after stent implantation in patients with coronary artery disease (CAD). Studies were identified by electronic and manual searches. Twenty-six studies were included in the meta-analysis. The pooled C-statistics of SYNTAX score for 1- and 5-year all-cause mortality (ACM) were 0.65 (95% confidence interval [CI]: 0.61-0.68) and 0.62 (95% CI: 0.59-0.65), respectively, with weak heterogeneity. The 1- and 5-year ACM pooled C-statistics for clinical SYNTAX scores were significantly higher at 0.77 and 0.71, respectively (Ps < .05). Both scoring systems predicted 1- and 5-year MACE equally well. The pooled risk ratio of the SYNTAX score for predicting 1-year ACM per unit was 1.04 (95% CI: 1.03-1.05). Calibration analysis indicated SYNTAX scores overestimated the risk of major adverse cardiac and cerebrovascular events in each risk stratum. The SYNTAX score demonstrated minimal discrimination in predicting 1- or 5-year adverse cardiovascular events after percutaneous coronary intervention in patients with CAD. The clinical SYNTAX score could further improve the predictive capability for ACM but not MACE.
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http://dx.doi.org/10.1177/0003319715618803DOI Listing
October 2016

Disease-associated variants in different categories of disease located in distinct regulatory elements.

BMC Genomics 2015 18;16 Suppl 8:S3. Epub 2015 Jun 18.

Background: The invention of high throughput sequencing technologies has led to the discoveries of hundreds of thousands of genetic variants associated with thousands of human diseases. Many of these genetic variants are located outside the protein coding regions, and as such, it is challenging to interpret the function of these genetic variants by traditional genetic approaches. Recent genome-wide functional genomics studies, such as FANTOM5 and ENCODE have uncovered a large number of regulatory elements across hundreds of different tissues or cell lines in the human genome. These findings provide an opportunity to study the interaction between regulatory elements and disease-associated genetic variants. Identifying these diseased-related regulatory elements will shed light on understanding the mechanisms of how these variants regulate gene expression and ultimately result in disease formation and progression.

Results: In this study, we curated and categorized 27,558 Mendelian disease variants, 20,964 complex disease variants, 5,809 cancer predisposing germline variants, and 43,364 recurrent cancer somatic mutations. Compared against nine different types of regulatory regions from FANTOM5 and ENCODE projects, we found that different types of disease variants show distinctive propensity for particular regulatory elements. Mendelian disease variants and recurrent cancer somatic mutations are 22-fold and 10- fold significantly enriched in promoter regions respectively (q<0.001), compared with allele-frequency-matched genomic background. Separate from these two categories, cancer predisposing germline variants are 27-fold enriched in histone modification regions (q<0.001), 10-fold enriched in chromatin physical interaction regions (q<0.001), and 6-fold enriched in transcription promoters (q<0.001). Furthermore, Mendelian disease variants and recurrent cancer somatic mutations share very similar distribution across types of functional effects. We further found that regulatory regions are located within over 50% coding exon regions. Transcription promoters, methylation regions, and transcription insulators have the highest density of disease variants, with 472, 239, and 72 disease variants per one million base pairs, respectively.

Conclusions: Disease-associated variants in different disease categories are preferentially located in particular regulatory elements. These results will be useful for an overall understanding about the differences among the pathogenic mechanisms of various disease-associated variants.
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http://dx.doi.org/10.1186/1471-2164-16-S8-S3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480828PMC
March 2016

The combination of L-4F and simvastatin stimulate cholesterol efflux and related proteins expressions to reduce atherosclerotic lesions in apoE knockout mice.

Lipids Health Dis 2013 Dec 8;12:180. Epub 2013 Dec 8.

Department of Cardiology, Zhongshan hospital, Sun Yat- Sen University, Zhongshan, Guang Dong, China.

Background: Both L-4F, one apolipoprotein A-1 mimetic peptide, and statins can reduce progression of atherosclerosis by different mechanisms. The combination of the two drugs can cause lesion regression by rendering HDL anti-inflammatory. We postulated that combination of L-4F and simvastatin may stimulate cholesterol efflux and related proteins expressions to alleviate atherosclerosis.

Methods: Thirty male wild-type (W-T) C57 BL/6 mice and apo E(-/-) mice were divided into five groups: W-T group, atherosclerosis (AS) group, simvastatin group, L-4F group and the combination of simvastatin and L-4F group. After 16 weeks, serum lipids, atherosclerotic lesion areas, cholesterol efflux and the expressions of related proteins including ABCA1, SR-BI, ABCG1, LXRα and PPARγ were evaluated.

Results: The aortic atherosclerotic lesion areas were reduced more significantly by combination of both drugs than single agent, and cholesterol efflux was promoted more in combination group than simvastatin and L-4F group. Besides, the combination group promoted expressions of cholesterol efflux related proteins.

Conclusions: The combination of L-4F and simvastatin reduced atherosclerotic lesions, which stimulates cholesterol efflux by promoting the expressions of related proteins. In addition, these results help us further understand that the regression of the atherosclerosis would be assessed by reduction in LDL-C with increase of cholesterol efflux.
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http://dx.doi.org/10.1186/1476-511X-12-180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3866605PMC
December 2013

Refined association of TSH receptor susceptibility locus to Graves' disease in the Chinese Han population.

Eur J Endocrinol 2014 Jan 1;170(1):109-19. Epub 2014 Jan 1.

State Key Laboratory of Medical Genomics, Shanghai Institute of Endocrinology and Metabolism, Molecular Medicine Center, Ruijin Hospital Affiliated to Shanghai Jiaotong University (SJTU) School of Medicine, Shanghai 200025, China.

Background: Convincing evidence has demonstrated the association of TSH receptor (TSHR) with Graves' disease (GD) in the Chinese Han population.

Objective: The aim of this study was to identify the causal variants for GD in the region encompassing TSHR by a refining association study.

Design And Methods: GD patients (1536) and 1516 sex-matched controls were recruited in the first stage, and an additional 3832 GD patients and 3426 sex-matched controls were recruited in the replication stage. Genotyping was performed using Illumina Human660-Quad BeadChips or TaqMan single nucleotide polymorphism (SNP) Genotyping Assays and the Fluidigm EP1 platform.

Results: When the results of regression analysis for 74 genotyped SNPs and 922 imputed SNPs in the first-stage cohort were combined, rs179243 and rs3783949 were the probable susceptibility SNPs associated with GD in TSHR. Eleven SNPs, including rs179243 and rs3783949, were selected to further refine the association in the replication study. Finally, rs12101261 and rs179243 were confirmed as independent GD susceptibility variants in the replication and combined populations. Further, we also found that the rate of persistent TSHR autoantibody positivity (pTRAb+) was significantly higher in the GD patients with the susceptible genotypes rs12101261 or rs179243 than in the GD patients carrying the protective genotypes, after the GD patients had been treated for more than 1 year.

Conclusions: These findings indicate that rs12101261 and rs179243 are the possible causal SNPs for GD susceptibility in the TSHR gene and could serve as genetic markers to predict the outcome of pTRAb+ in GD patients.
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http://dx.doi.org/10.1530/EJE-13-0517DOI Listing
January 2014

Expanding ART for treatment and prevention of HIV in South Africa: estimated cost and cost-effectiveness 2011-2050.

PLoS One 2012 13;7(2):e30216. Epub 2012 Feb 13.

HIV/AIDS Department, World Health Organization, Geneva, Switzerland.

Background: Antiretroviral Treatment (ART) significantly reduces HIV transmission. We conducted a cost-effectiveness analysis of the impact of expanded ART in South Africa.

Methods: We model a best case scenario of 90% annual HIV testing coverage in adults 15-49 years old and four ART eligibility scenarios: CD4 count <200 cells/mm(3) (current practice), CD4 count <350, CD4 count <500, all CD4 levels. 2011-2050 outcomes include deaths, disability adjusted life years (DALYs), HIV infections, cost, and cost per DALY averted. Service and ART costs reflect South African data and international generic prices. ART reduces transmission by 92%. We conducted sensitivity analyses.

Results: Expanding ART to CD4 count <350 cells/mm(3) prevents an estimated 265,000 (17%) and 1.3 million (15%) new HIV infections over 5 and 40 years, respectively. Cumulative deaths decline 15%, from 12.5 to 10.6 million; DALYs by 14% from 109 to 93 million over 40 years. Costs drop $504 million over 5 years and $3.9 billion over 40 years with breakeven by 2013. Compared with the current scenario, expanding to <500 prevents an additional 585,000 and 3 million new HIV infections over 5 and 40 years, respectively. Expanding to all CD4 levels decreases HIV infections by 3.3 million (45%) and costs by $10 billion over 40 years, with breakeven by 2023. By 2050, using higher ART and monitoring costs, all CD4 levels saves $0.6 billion versus current; other ART scenarios cost $9-194 per DALY averted. If ART reduces transmission by 99%, savings from all CD4 levels reach $17.5 billion. Sensitivity analyses suggest that poor retention and predominant acute phase transmission reduce DALYs averted by 26% and savings by 7%.

Conclusion: Increasing the provision of ART to <350 cells/mm3 may significantly reduce costs while reducing the HIV burden. Feasibility including HIV testing and ART uptake, retention, and adherence should be evaluated.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0030216PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278413PMC
July 2012

[Stimulatory effect of TNF-α on differentiation and maturation of dendritic cells].

Zhongguo Shi Yan Xue Ye Xue Za Zhi 2010 Oct;18(5):1265-8

Department of Pediatrics, Peking Union Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.

The study was aimed to explore the stimulatory effect of tumor necrosis factorα (TNF-α) on differentiation and maturation of human peripheral blood mononuclear cell-derived dendritic cells (PBMNCDC). 30 ml of peripheral blood from healthy volunteers were collected, the PBMNC were isolated according to Thomas' method and were cultured with incubation of granulocyte/macrophage colony stimulating factor (GM-CSF), interleukin-4 (IL-4) for 8 day, and TNF-α was added on day 5. The expression of HLA-DR, CD83 and CD1a on surface of DC were detected by flow cytometry, the ability of DC to stimulate the proliferation of allogenic T cells was evaluated by MTT assay. The results showed that the TNF-α could up-regulate the expression of HLA-DR, CD83 and CD1a and activated DC could enhance the proliferation of allogenic T cells. Furthermore, the TNF-α at the concentration of 20 ng/ml was more effective. It is concluded that the TNF-α can effectively enhance the functional differentiation and maturation of the PBMNCDC and TNF-α at the concentration of 20 ng/ml is most effective to enhance differentiation and maturation of DC.
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October 2010

Glucocorticoid up-regulates mimecan expression in corticotroph cells.

Mol Cell Endocrinol 2010 Jun 21;321(2):239-44. Epub 2010 Feb 21.

Ruijin Hospital, Shanghai Institute of Endocrinology, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University (SJTU) School of Medicine, Shanghai, China.

Mimecan is a protein of unknown function that is expressed in the pituitary. The aim of this study is to clarify the regulation and intracellular localisation of mimecan gene expression in the pituitary. With immunohistochemistry, we observed that mimecan protein was co-expressed with ACTH in pituitary corticotroph cells. Northern and Western blot analyses revealed that mimecan expression and secretion in corticotroph cells were up-regulated by treating AtT-20 cells with glucocorticoid. Meanwhile, mimecan expression in rat primary culture pituitary cells was also promoted by glucocorticoid. Co-incubation of AtT-20 cells with RU486 and glucocorticoid completely reversed the induction of mimecan gene expression by glucocorticoid. In addition, luciferase reporter assays showed that the -1474/+43 promoter region of mimecan was sufficient for glucocorticoid-responsive mimecan expression. These data collectively suggest that mimecan expressed in pituitary corticotroph cells is increased by glucocorticoid and that the up-regulation may be mediated by the classical GR pathways.
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http://dx.doi.org/10.1016/j.mce.2010.02.021DOI Listing
June 2010

[Progress in the research on the role of mesangial remodeling in glomerualr diseases].

Zhongguo Dang Dai Er Ke Za Zhi 2009 Oct;11(10):866-8

Department of Pediatrics, Peking Union Medical College, Beijing 100730, China.

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October 2009

Effect of dietary phytate and phytase on proteolytic digestion and growth regulation of broilers.

Arch Anim Nutr 2009 ;63(4):292-303

b School of Livestock Science and Technology, Henan University of Science and Technology , Luoyang , China.

This study was designed to investigate the effect of dietary phytate and phytase on proteolytic digestion and growth signalling in the gastrointestinal tract of broilers. Diets containing phytate phosphorus (2.2 or 4.4 g/kg) with phytase dose rates of 0, 500, or 1,000 FTU/kg were fed to 504 female Cobb chicks for three weeks. Diets containing high phytate reduced the activity of pepsin and trypsin, whereas the inclusion of microbial phytase increased the activity of pepsin, H(+)K(+)-ATPase, trypsin and alanyl aminopeptidase. In the intestine, phytate upregulated the mRNA expression of somatostatin, and down-regulated the mRNA expressions of ghrelin and target of rapamycin (TOR). Phytase down regulated the somatostatin gene, and upregulated the genes of ghrelin, TOR, p70 S6 kinase (S6K) and methionyl aminopeptidase. Significant interactions between phytate and phytase on the mRNA expressions of ghrelin, somatostatin and S6K in the jejunum were detected. The results suggest that dietary phytate and phytase can influence the gastrointestinal endocrine and exocrine systems, as well as the peripherally regulatory network of growth in broilers.
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http://dx.doi.org/10.1080/17450390903020422DOI Listing
December 2016

A splice site mutation combined with a novel missense mutation of LHCGR cause male pseudohermaphroditism.

Hum Mutat 2009 Sep;30(9):E855-65

Department of Endocrinology, Research Center of Tissue Engineering, Department of Plastic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Leydig cell hypoplasia (LCH) is a rare form of male pseudohermaphroditism caused by inactivating mutations in the luteinizing hormone receptor gene (LHCGR). The majority of LHCGR mutations are located in the coding sequence, resulting in impairment of either LH/CG binding or signal transduction. We report a Chinese family with two siblings (46, XY and 46, XX) carrying a missense mutation (c. 455 T>C, p. Ile152Thr) and a splice site mutation (c. 537-3 C>A). Computational analysis of the missense mutation in the three-dimensional structural model predicted it might influence the distribution of hydrogen bonds and intermolecular contacts between the hormone and receptor. Consistent with these findings, in vitro mutant analysis revealed a marked impairment of human chorionic gonadotropin binding and signal transduction. The splice-acceptor mutation (c. 537-3 C>A) resulted in abnormal splicing of LHCGR mRNA, skipping exon 7. This report expands the genotypic spectrum of LHCGR mutations, with relevant implications for the molecular analysis of this gene.
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http://dx.doi.org/10.1002/humu.21072DOI Listing
September 2009

[Clinical and molecular genetic analysis for 7 patients from 5 pedigrees with 17a-hydroxylase/17, 20 lyase deficiency].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2009 Jun;26(3):282-7

Molecular Medical Center, Shanghai Institute of Endocrinology, the Affiliated Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 PR China.

Objective: To investigate the clinical and genetic characteristics of 7 patients from 5 families with 17a-hydroxylase/17,20 lyase deficiency (17OHD) and the CYP17A1 mutation in Chinese.

Methods: Clinical features and laboratory data were collected from 5 families with 17OHD. PCR direct sequencing was performed to screen the mutation of CYP17A1 gene of the patients. Polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) and sequencing were performed to screen the mutations of CYP17A1 gene in 288 healthy individuals from Shandong province.

Results: Seven patients (5 of them were 46,XX; 2 were 46,XY) had typical clinical presentation of sexual infantilism, hypertension and hypokalemia. Hormone profile indicated decreased plasma cortisol and sex hormones, and elevated blood adrenocorticotrophic hormone (ACTH). TAC329AA and H373L in exon 6 and D487_F489del in exon 8 were identified from the patients. One heterozygote for D487_F489del was identified in 288 healthy controls.

Conclusion: The TAC329AA and D487_F489del of the CYP17A1 gene were the most frequent mutations in Chinese with 17OHD.There might be certain frequency of heterozygotes for D487_F489del in Chinese population.
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http://dx.doi.org/10.3760/cma.j.issn.1003-9406.2009.03.010DOI Listing
June 2009

[Association of SNP276 in adiponectin gene with type 2 diabetes mellitus and insulin sensitivity].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2005 Dec;22(6):698-701

Department of Pediatrics, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, P. R. China.

Objective: To investigate the distribution of SNP276 in adiponectin gene in Chinese Hans and its impact on type 2 diabetes mellitus and insulin sensitivity.

Methods: The study population consisted of 417 Chinese Hans residents in Anhui province, including 141 subjects with normal glucose tolerance (NGT) and 276 with type 2 diabetes (T2DM). The islet beta-cell insulin secretion and tissue insulin sensitivity were assessed by formulae of homeostasis model assessment (HOMA-IR & HOMA beta). Firstly, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) was used to determine whether variation exists in APM1. Then, exact variation was detected by automated DNA direct sequencing.

Results: The genotypes of APM1 SNP276 were 0.489 GG, 0.418 GT and 0.092 TT and the major allele was G (frequency=0.699) in subjects with NGT. The distributions of genotypes and alleles of SNP276 both displayed significant difference between NGT and T2DM groups (P=0.031 and 0.013). The SNP276 non-TT (TG+GG) genotype was associated with increased risk of T2DM (OR=2.447, 95%CI: 1.067-5.612, P=0.035). In T2DM group, the subjects with SNP276 GG or GT genotype had higher body mass index, body fat content, fasting plasma glucose and HOMA-IR than did those with TT genotype (P < 0.05 or P < 0.01). Besides, GG genotype had higher systolic blood pressure (P=0.021). In NGT group, SNP276 non-TT carrier had increased body mass index, body fat content, waist hip ratio, fasting plasma insulin, oral glucose tolerance test 2 h plasma insulin and HOMA-IR when compared with TT genotype (P < 0.05 or 0.01).

Conclusion: SNP276 in APM1 was associated with T2DM and insulin sensitivity.
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December 2005