Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 384
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Cell Mol Med ; 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32126149

RESUMO

N6-Methyladenosine (m6 A) modification, the most prevalent modification of eukaryotic messenger RNA (mRNA), is involved in the progression of various tumours. However, the specific role of m6 A in bladder cancer (BCa) is still poorly understood. In this study, we demonstrated the tumour-promoting function and specific regulatory mechanism of m6 A axis, consisting of the core 'writer' protein METTL3 and the major reader protein YTHDF2. Depletion of METTL3 impaired cancer proliferation and cancer metastasis in vitro and in vivo. Through transcriptome sequencing, m6 A methylated RNA immunoprecipitation (MeRIP) and RIP, we determined that the METTL3/YTHDF2 m6 A axis directly degraded the mRNAs of the tumour suppressors SETD7 and KLF4, contributing to the progression of BCa. In addition, overexpression of SETD7 and KLF4 revealed a phenotype consistent with that induced by depletion of the m6 A axis. Thus, our findings on the METTL3/YTHDF2/SETD7/KLF4 m6 A axis provide the insight into the underlying mechanism of carcinogenesis and highlight potential therapeutic targets for BCa.

2.
BMC Urol ; 20(1): 33, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32197605

RESUMO

BACKGROUND: Sigmoid bowel perforation is a very rare and serious complication of the retropubic tension-free vaginal tape (TVT) procedure for female stress urinary incontinence. The complication can be avoided with the use of the correct manipulation technique. CASE PRESENTATION: A 75-year-old female patient underwent a retropubic TVT procedure in the local hospital for the treatment of stress urinary incontinence. The procedure was smooth. Two weeks after surgery, the patient began to complain of fever and bloody, purulent discharge from the left suprapubic skin wound. During a 4-month period after surgery, she was admitted to the local hospital 4 times for similar infection symptoms. The infections were temporarily controlled with antibiotic administration. The reason for the refractory infection of the left suprapubic skin wound was not identified until a foreign TVT mesh was found in the sigmoid colon via a colonoscopy. We diagnosed that the TVT mesh caused a sigmoid colon perforation that led to colocutaneous fistula. An exploratory laparotomy revealed that the TVT tape perforated into and out of the sigmoid colon. An 8-cm long left part of mesh was removed. Two ruptures of sigmoid colon were mended without the need for bowel resection. At the 4-years follow-up after laparotomy, the patient was doing well and still continent. CONCLUSIONS: Urologists and gynecologists should be aware of the possibility of colon bowel injury in SUI patients with prior sling surgeries. Patient having recurrent suprapubic cutaneous infection may have high degree of suspicion of colon injury after TVT sling. The passage of the retropubic space procedure should be slow and always along the pubic bone according to the anatomy.

3.
Eur J Oral Sci ; 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32154612

RESUMO

DNA damage repair is a key factor in the maintenance of cell genome stability, plays an important role in the regulation of tumour evolution, and can affect the prognosis of cancer patients. This study aimed to detect the protein expression of the DNA damage repair protein P53 and its upstream and downstream regulators, CHK1, GADD45A, and MDM2, in oral squamous cell carcinoma (OSCC), in order to analyse the association between the expression of these proteins and overall survival, and to assess their prognostic implications for OSCC patients. The expression of the above proteins was detected by immunohistochemistry in 80 human OSCC tissue samples and in non-cancerous tissue samples. Compared to that in the non-cancerous tissue, the expression of CHK1, GADD45A, and MDM2 in OSCC tissue was significantly increased. The protein expression of the tumour suppressor gene P53 was also increased. Patients with high CHK1 and MDM2 expression levels had a reduced survival time and a poor prognosis, whereas patients with high GADD45A expression levels had a good prognosis. Our results indicate that high CHK1 expression is an independent risk factor for poor OSCC prognosis, and that CHK1 may be a potential target for OSCC clinical treatment.

4.
Sci Adv ; 6(4): eaay9819, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32010791

RESUMO

Disassembly of intercellular junctions is a hallmark of epithelial-mesenchymal transition (EMT). However, how the junctions disassemble remains largely unknown. Here, we report that E3 ubiquitin ligase Smurf1 targets p120-catenin, a core component of adherens junction (AJ) complex, for monoubiquitination during transforming growth factor ß (TGFß)-induced EMT, thereby leading to AJ dissociation. Upon TGFß treatment, activated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylates T900 of p120-catenin to promote its interaction with Smurf1 and subsequent monoubiquitination. Inhibition of T900 phosphorylation or ubiquitination of p120-catenin abrogates TGFß-induced AJ dissociation and consequent tight junction (TJ) dissociation and cytoskeleton rearrangement, hence markedly blocking lung metastasis of murine breast cancer. Moreover, the T900 phosphorylation level of p120-catenin is positively correlated with malignancy of human breast cancer. Hence, our study reveals the underlying mechanism by which TGFß induces dissociation of AJs during EMT and provides a potential strategy to block tumor metastasis.

6.
Cell Prolif ; 53(2): e12751, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31971654

RESUMO

OBJECTIVES: Downregulation of miR-502-5p has emerged as a critical factor in tumour progression in several cancers. Herein, we elucidated the role of miR-502-5p in bladder cancer. MATERIALS AND METHODS: RT-qPCR was performed to examine the expression of miR-502-5p in bladder cancer. And DNA methylation analysis showed that epigenetic mechanisms may contribute to the downregulation of miR-502-5p. Then, wound-healing assay, transwell assay, colony formation assay, CCK8 assay and flow cytometry analysis were applied to evaluate the function of miR-502-5p in bladder cancer cell lines. Western blot was conducted to measure the protein levels of related genes. Furthermore, dual-luciferase reporter assay, in vivo tumorigenesis assay and immunohistochemical staining were also conducted as needed. RESULTS: MiR-502-5p is frequently downregulated in BCa. Meanwhile, hypermethylation of CpG islands contributes to the downregulation of miR-502-5p. Functionally, overexpression of miR-502-5p inhibited cell proliferation and migration in vitro and repressed tumour growth in vivo. CCND1, DNMT3B and NOP14 were identified as direct targets of miR-502-5p. Interestingly, DNMT3B and miR-502-5p established a positive feedback loop in the regulation of bladder cancer. In addition, rescue experiments further validated the direct molecular interaction between miR-502-5p and its targets. CONCLUSIONS: Our study proposed and demonstrated that the miR-502-5p-mediated regulatory network is critical in bladder cancer; this network may be useful in the development of more effective therapies against bladder cancer.


Assuntos
Movimento Celular/genética , Proliferação de Células/genética , Ciclina D1/genética , DNA (Citosina-5-)-Metiltransferases/genética , MicroRNAs/genética , Proteínas Nucleares/genética , Neoplasias da Bexiga Urinária/genética , Animais , Linhagem Celular , Linhagem Celular Tumoral , Ilhas de CpG/genética , Metilação de DNA/genética , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica/genética , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias da Bexiga Urinária/patologia
7.
Int J Biol Markers ; 35(1): 57-64, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31973613

RESUMO

BACKGROUND: Changes in circulating adiponectin have been related to the risks of various cancers. However, the association between circulating adiponectin and the risk of renal cell carcinoma has not been fully determined. A meta-analysis was performed to evaluate the relationship between circulating adiponectin and renal cell carcinoma risk. METHODS: Observational studies that evaluated the association between circulating adiponectin and renal cell carcinoma risk were identified via a systematic search of PubMed and Embase databases. The difference between circulating adiponectin in renal cell carcinoma cases and healthy controls, and the multivariable adjusted association between circulating adiponectin and renal cell carcinoma risk were evaluated. A random effects model was used if significant heterogeneity existed; otherwise a fixed effects model was applied. RESULTS: Eight case-control studies with 2624 renal cell carcinoma cases and 2904 healthy controls were included. Pooled results showed that circulating adiponectin was significantly lower in renal cell carcinoma cases than in healthy controls (mean difference = -1.08 ug/mL; 95% confidence interval (CI) -1.62, -0.54; P < 0.001). Higher circulating adiponectin was independently associated with a significantly lowered risk of renal cell carcinoma (adjusted odds ratio for 1 SD increment of adiponectin = 0.78; 95% CI: 0.63, 0.96; P = 0.02). Subgroup analyses according to characteristics including study design, ethnics of participants, blood samples, numbers of participants, mean ages of participants, and study quality showed consistent results. CONCLUSIONS: Lower circulating adiponectin is associated with increased risk of renal cell carcinoma. The potential pathophysiological mechanisms underlying the role of circulating adiponectin in the pathogenesis of renal cell carcinoma deserve further investigation.

8.
Circulation ; 141(12): 984-1000, 2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-31902237

RESUMO

BACKGROUND: S-nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in the pathogenesis of cardiovascular disease. The aim of this study was to determine the role of SNO of MLP (muscle LIM protein) in myocardial hypertrophy, as well as the mechanism by which SNO-MLP modulates hypertrophic growth in response to pressure overload. METHODS: Myocardial samples from patients and animal models exhibiting myocardial hypertrophy were examined for SNO-MLP level using biotin-switch methods. SNO sites were further identified through liquid chromatography-tandem mass spectrometry. Denitrosylation of MLP by the mutation of nitrosylation sites or overexpression of S-nitrosoglutathione reductase was used to analyze the contribution of SNO-MLP in myocardial hypertrophy. Downstream effectors of SNO-MLP were screened through mass spectrometry and confirmed by coimmunoprecipitation. Recruitment of TLR3 (Toll-like receptor 3) by SNO-MLP in myocardial hypertrophy was examined in TLR3 small interfering RNA-transfected neonatal rat cardiomyocytes and in a TLR3 knockout mouse model. RESULTS: SNO-MLP level was significantly higher in hypertrophic myocardium from patients and in spontaneously hypertensive rats and mice subjected to transverse aortic constriction. The level of SNO-MLP also increased in angiotensin II- or phenylephrine-treated neonatal rat cardiomyocytes. S-nitrosylated site of MLP at cysteine 79 was identified by liquid chromatography-tandem mass spectrometry and confirmed in neonatal rat cardiomyocytes. Mutation of cysteine 79 significantly reduced hypertrophic growth in angiotensin II- or phenylephrine-treated neonatal rat cardiomyocytes and transverse aortic constriction mice. Reducing SNO-MLP level by overexpression of S-nitrosoglutathione reductase greatly attenuated myocardial hypertrophy. Mechanistically, SNO-MLP stimulated TLR3 binding to MLP in response to hypertrophic stimuli, and disrupted this interaction by downregulating TLR3-attenuated myocardial hypertrophy. SNO-MLP also increased the complex formation between TLR3 and RIP3 (receptor-interacting protein kinase 3). This interaction in turn induced NLRP3 (nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3) inflammasome activation, thereby promoting the development of myocardial hypertrophy. CONCLUSIONS: Our findings revealed a key role of SNO-MLP in myocardial hypertrophy and demonstrated TLR3-mediated RIP3 and NLRP3 inflammasome activation as the downstream signaling pathway, which may represent a therapeutic target for myocardial hypertrophy and heart failure.

9.
Blood ; 135(11): 826-833, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-31914172

RESUMO

Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a life-threatening hyperinflammatory syndrome triggered by EBV infection. It often becomes relapsed or refractory (r/r), given that etoposide-based regimens cannot effectively clear the virus. r/r EBV-HLH is invariably lethal in adults without allogeneic hematopoietic stem cell transplantation. Here, we performed a retrospective analysis of 7 r/r EBV-HLH patients who were treated with nivolumab on a compassionate-use basis at West China Hospital. All 7 patients tolerated the treatment and 6 responded to it. Five of them achieved and remained in clinical complete remission with a median follow-up of 16 months (range, 11.4-18.9 months). Importantly, both plasma and cellular EBV-DNAs were completely eradicated in 4 patients. Single-cell RNA-sequencing analysis showed that HLH syndrome was associated with hyperactive monocytes/macrophages and ineffective CD8 T cells with a defective activation program. Nivolumab treatment expanded programmed death protein-1-positive T cells and restored the expression of HLH-associated degranulation and costimulatory genes in CD8 T cells. Our data suggest that nivolumab, as a monotherapy, provides a potential cure for r/r EBV-HLH, most likely by restoring a defective anti-EBV response.

10.
Arterioscler Thromb Vasc Biol ; 40(1): 175-188, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31694393

RESUMO

OBJECTIVE: Thoracic aortic dissection (TAD) is a fatal disease that leads to aortic rupture and sudden death. However, little is known about the effect and molecular mechanism of S-nitrosylation (SNO) modifications in TAD formation. Approach and Results: SNO levels were higher in aortic tissues from TAD patients than in those from healthy controls, and PLS3 (plastin-3) SNO was identified by liquid chromatography-tandem mass spectrometry analysis. Furthermore, tail vein administration of endothelial-specific adeno-associated viruses of mutant PLS3-C566A (denitrosylated form) suppressed the development of TAD in mice, but the wild-type PLS3 (S-nitrosylated form) virus did not. Mechanistically, Ang II (angiotensin II)-induced PLS3 SNO enhanced the association of PLS3 with both plectin and cofilin via an iNOS (inducible nitric oxide synthase)-dependent pathway in endothelial cells. The formation of PLS3/plectin/cofilin complex promoted cell migration and tube formation but weakened adherens junction formation in Ang II-treated endothelial cells. Interestingly, denitrosylated form of PLS3 partially mitigated Ang II-induced PLS3/plectin/cofilin complex formation and cell junction disruption. Additionally, the inhibition of iNOS attenuated PLS3 SNO and the association of PLS3 with plectin and cofilin, thereby modulating endothelial barrier function. CONCLUSIONS: Our data indicate that protein SNO modification in endothelial cells modulates the progression of aortic aneurysm and dissection. The iNOS-mediated SNO of PLS3 at the Cys566 site promoted its interaction with cofilin and plectin, thus contributing to endothelial barrier disruption and pathological angiogenesis in TAD.

11.
12.
J Antibiot (Tokyo) ; 73(3): 189-193, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31827255

RESUMO

A new p-terphenyl derivative aspergicandidusin A (1), a new cleistanthane diterpenoid 6-deoxyaspergiloid C (13), and 12 known compounds (2-12, and 14) were isolated from the mold Aspergillus candidus. The structures of the new compounds were elucidated by spectral analysis of NMR and MS data. The absolute configuration of C-1 in 13 was determined via the circular dichroism data of the [Rh2(OCOCF3)4] complex. Compounds 2-8 and 11 showed moderate inhibitory activity against K562 cell lines with the IC50 value in the range from 17.9 to 46.3 µM. Compound 13 exhibited moderate cytotoxicity against HepG2 cells with the IC50 value of 47.7 µM. Compounds 11 and 12 exhibited moderate activity against the growth of S. aureus with MIC value of 6.25 µM, respectively.

13.
Chem Biodivers ; 17(1): e1900436, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31705573

RESUMO

A facile method was developed for synthesis of boronic acid-functionalized silica nanocomposites (SiO2 -BA) by 'thiol-ene' click reaction, where silica nanoparticles were synthesized by using tetraethoxysilane (TEOS) and γ-mercaptopropyl trimethoxysilane (γ-MPTS) as precursors. The morphology and structure properties of the resultant SiO2 -BA were characterized by transmission electronic microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), and Brunner-Emmet-Teller measurements (BET). The adsorption behavior of the SiO2 -BA for glycoproteins was evaluated. Under the optimized conditions, the SiO2 -BA exhibited higher adsorption capacity towards glycoproteins (ovalbumin, OVA, 7.64 µmol/g) than non-glycoproteins (bovine serum albumin, BSA, 0.83 µmol/g). In addition, the practicality of the SiO2 -BA was further assessed by selective enrichment of glycoproteins from egg white samples.


Assuntos
Ácidos Borônicos/química , Glicoproteínas/química , Nanocompostos/química , Dióxido de Silício/química , Adsorção , Clara de Ovo/química , Estrutura Molecular , Tamanho da Partícula , Dióxido de Silício/síntese química , Propriedades de Superfície
14.
J Hazard Mater ; : 121785, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31818667

RESUMO

Acrylamide (ACR), a neurotoxicity and carcinogenic chemical, has attracted considerable attention since it is present at high concentrations in thermally cooked carbohydrate-rich foods. ACR exposure significantly increased rate of fetal resorption, and decreased fetal body weights in mice. However, no detailed information is available about the effect of ACR on uterine decidualization, which is a vital process in the establishment of successful pregnancy. Thus, our aim of this study was to explore the effect and mechanism of ACR on uterine decidualization in vivo during mice pregnancy. Mice were gavaged with 0, 10, and 50 mg ACR /kg/day from gestational days (GD) 1 until GD 8, whereas pseudopregnant mice from pseudopregnant day (PPD) 4 until PPD 8. Results indicated ACR treatment dramatically reduced numbers of implanted embryos, and decreased the weights of implantation site and oil-induced uterus. Nevertheless, no significant difference was observed in the weights of no oil-induced uterus between control and ACR-treated group. Furthermore, ACR significantly reduced numbers of polyploidy and PCNA-positive decidual cells and expression of cyclin D3 and p21 proteins, and induced apoptosis of decidua, as presented by up-regulation of Bax and cleaved-caspase-3, and decreased Bcl-2 protein during normal pregnant and pseudopregnant process. In summary, ACR exposure significantly inhibited uterine endometrial decidualization via the apoptosis and suppression of cyclin D3/p21 in mice.

15.
Biol Pharm Bull ; 42(11): 1789-1798, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31685763

RESUMO

Autophagy plays key roles in the development of acute pancreatitis (AP) and the regulation of impaired autophagy has therapeutic potential. The objective of the present study was to investigate whether pharmacological inhibition of autophagy could ameliorate AP in mice and examine the underlying mechanisms. In current study, by imaging-based high-throughput screening, a novel spautin-1 derivative spautin-A41 was identified as a potent autophagy inhibitor. Mice treated with spautin-A41 were resistant to the cerulein-induced elevation of serum pancreatic enzyme activities and pancreatic apoptosis. Mechanistically, spautin-A41 effectively reduced the expression levels of Class III phosphatidylinositol 3 (PI3) kinase complexes and subsequently ameliorated pancreatitis by inhibiting the formation of autophagosome. Therefore, pharmacological inhibition of autophagy by spautin-A41 may serve as new target for treating or lessening the severity of AP.

16.
J Biomed Res ; 0(0): 1-9, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31741464

RESUMO

Cardiac fibrosis is a common pathological change of many cardiovascular diseases. ß-catenin has been shown to promote fibrosis. However, the precise role of its homolog γ-catenin in the process of fibrosis remains largely unclear. In this study, we found that the expression of γ-catenin was significantly decreased in angiotensin Ⅱ (Ang Ⅱ)-induced cardiac fibrosis model, contrary to most reports of ß-catenin. Overexpression of γ-catenin in cardiac fibroblasts (CFs) significantly inhibited the expression of α-smooth muscle actin (α-SMA), whereas knocking down the expression of γ-catenin with siRNA promoted the occurrence of cardiac fibrosis. Mechanistically, γ-catenin could bind to GSK-3ß to inhibit the phosphorylation of GSK-3ß, therefore preventing cardiac fibrosis. Our study shows that γ-catenin is an important protective factor in cardiac fibrosis, which provides a new potential target for the treatment of cardiac fibrosis.

17.
Mol Ther Nucleic Acids ; 18: 916-926, 2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31760376

RESUMO

The linear mRNAs transcribed under alternative RNA splicing and overexpression/amplification of the androgen receptor (AR) gene are poor prognostic biomarkers of castrate-resistant prostate cancer (PCa). Whether the AR gene also transcribes non-coding circular RNAs that are associated with PCa development and tumor progression remains unclear. Here, we identified and characterized an AR circular RNA, called circAR3, that is widely expressed in PCa cell models and prostate tumors. circAR3 can be secreted into culture media of PCa cell lines and is detectable in the serum from mice bearing PCa xenografts. In PCa patient tissues, circAR3 is highly expressed in benign prostate and hormone naive PCa but downregulated when tumors were treated with neoadjuvant hormone therapy and further reduced when tumors progressed to the castrate-resistant stage. However, circAR3 levels in plasma are extremely low in patients with benign prostate, are upregulated in PCa patients with high Gleason scores and lymph node metastasis, and become undetectable in men after radical prostatectomy. circAR3 does not affect AR signaling, PCa cell proliferation, and invasion rates. Our results demonstrated that the origin of the detectable plasma circAR3 is from the prostate/PCa. Plasma circAR3 may be developed to be a PCa biomarker to monitor PCa development and tumor progression.

18.
BMC Infect Dis ; 19(1): 878, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640590

RESUMO

BACKGROUND: The purpose of this study was to prospectively investigate the value of real-time ultrasound elastography (RTE) for the diagnosis of liver fibrosis (LF) in patients with chronic hepatitis B (CHB), to correlate the elastography findings with the histologic stage of LF and to compare RTE findings with those from noninvasive tests of LF calculated using laboratory blood parameters. METHODS: Liver biopsies, laboratory blood testing, and RTE were performed in 91 patients with CHB. The LF index (LFI) was calculated using a multiple linear regression equation involving 11 parameters, which represented the degree of LF. The higher the LFI is, the greater the degree of LF. RESULTS: The mean aspartate aminotransferase-to-platelet ratio index (APRI) and the mean fibrosis index based on four factors (FIB-4) were significantly different for the 5 stages of LF, respectively. The APRI (r = 0.43, P = 0.006), FIB-4 (r = 0.51, P = 0.012) and LFI (r = 0.562, P = 0.004) were correlated with the stages of LF. For discriminating stage F0 from F1, only the LFI had significant power (P = 0.026) for predicting stage F1. For discriminating stage F4 from F3, only the LFI had statistically significant power (P = 0.024) in predicting stage F4. The areas under the receiver operating characteristic curves (AUCs) of the LFI for diagnosing significant, advanced LF and liver cirrhosis were significantly higher than those of the APRI and FIB-4, and the LFI had better sensitivity and specificity. CONCLUSIONS: The LFI calculated by RTE is reliable for the assessment of LF in patients with CHB and has better discrimination power than the APRI and FIB-4.


Assuntos
Hepatite B Crônica/patologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Adulto , Grupo com Ancestrais do Continente Asiático , Aspartato Aminotransferases/sangue , Biópsia , Técnicas de Imagem por Elasticidade/métodos , Feminino , Hepatite B Crônica/complicações , Humanos , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Estudos Prospectivos , Curva ROC , Sensibilidade e Especificidade
19.
J Epidemiol ; 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31548437

RESUMO

BACKGROUND: To investigate epidemiologic features of Kawasaki disease (KD) in Shanghai from 2013 through 2017 and identify risk factors for coronary artery lesions (CAL). METHODS: As in our previous three surveys, a set of questionnaires and diagnostic guidelines for KD were sent to 50 hospitals providing pediatric medical care in Shanghai. Medical records of KD patients diagnosed from January 2013 through December 2017 were retrospectively analyzed. Multivariate logistic regression analysis was performed to identify risk factors for CAL. RESULTS: A total of 4452 cases were enrolled. Male-to-female ratio was 1.7:1. The incidence of KD was 68.8 to 107.3 per 100,000 children aged <5 years from 2013 to 2017. Age at onset ranged from 15 days to 14.0 years (median: 1.8 years). KD occurred more frequently in spring and summer. Of 4325 patients (97.0%) receiving intravenous immunoglobulin (IVIG), 362 (8.4%) were resistant to initial IVIG. CAL occurred in 406 (9.1%) patients, including 118 (2.7%) with medium aneurysms and 31 (0.7%) with giant aneurysms. Recurrent cases were 60 (1.3%). No death was found in this survey. Higher platelet levels, lower albumin levels, male sex, incomplete KD, IVIG resistance, and receiving initial IVIG ≤4 days or >10 days, were independently associated with CAL. CONCLUSIONS: The incidence of KD in Shanghai had substantially increased while the proportion of CAL had substantially decreased as compared with our previous surveys. Higher platelet levels, lower albumin levels, male sex, incomplete KD, IVIG resistance, and receiving initial IVIG ≤4 days or >10 days, were risk factors for CAL.

20.
Sci Transl Med ; 11(510)2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31534017

RESUMO

Transforming growth factor-ß1 (TGFß1) has been identified as a major pathogenic factor underlying the development of diabetic nephropathy (DN). However, the current strategy of antagonizing TGFß1 has failed to demonstrate favorable outcomes in clinical trials. To identify a different therapeutic approach, we designed a mass spectrometry-based DNA-protein interaction screen to find transcriptional repressors that bind to the TGFB1 promoter and identified Yin Yang 1 (YY1) as a potent repressor of TGFB1. YY1 bound directly to TGFB1 promoter regions and repressed TGFB1 transcription in human renal mesangial cells. In mouse models, YY1 was elevated in mesangial cells during early diabetic renal lesions and decreased in later stages, and knockdown of renal YY1 aggravated, whereas overexpression of YY1 attenuated glomerulosclerosis. In addition, although their duration of diabetic course was comparable, patients with higher YY1 expression developed diabetic nephropathy more slowly compared to those who presented with lower YY1 expression. We found that a small molecule, eudesmin, suppressed TGFß1 and other profibrotic factors by increasing YY1 expression in human renal mesangial cells and attenuated diabetic renal lesions in DN mouse models by increasing YY1 expression. These results suggest that YY1 is a potent transcriptional repressor of TGFB1 during the development of DN in diabetic mice and that small molecules targeting YY1 may serve as promising therapies for treating DN.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA