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1.
Med Image Anal ; 61: 101652, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-32059169

RESUMO

Detection of early stages of Alzheimer's disease (AD) (i.e., mild cognitive impairment (MCI)) is important to maximize the chances to delay or prevent progression to AD. Brain connectivity networks inferred from medical imaging data have been commonly used to distinguish MCI patients from normal controls (NC). However, existing methods still suffer from limited performance, and classification remains mainly based on single modality data. This paper proposes a new model to automatically diagnosing MCI (early MCI (EMCI) and late MCI (LMCI)) and its earlier stages (i.e., significant memory concern (SMC)) by combining low-rank self-calibrated functional brain networks and structural brain networks for joint multi-task learning. Specifically, we first develop a new functional brain network estimation method. We introduce data quality indicators for self-calibration, which can improve data quality while completing brain network estimation, and perform correlation analysis combined with low-rank structure. Second, functional and structural connected neuroimaging patterns are integrated into our multi-task learning model to select discriminative and informative features for fine MCI analysis. Different modalities are best suited to undertake distinct classification tasks, and similarities and differences among multiple tasks are best determined through joint learning to determine most discriminative features. The learning process is completed by non-convex regularizer, which effectively reduces the penalty bias of trace norm and approximates the original rank minimization problem. Finally, the most relevant disease features classified using a support vector machine (SVM) for MCI identification. Experimental results show that our method achieves promising performance with high classification accuracy and can effectively discriminate between different sub-stages of MCI.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32034642

RESUMO

PURPOSE: Thoracic aortic dissection (TAD) is characterized by an inflammatory response. Angiopoietin-like protein 8 (ANGPTL8) is a hormone involved in the regulation of lipid metabolism and inflammation. However, the relationship between ANGPTL8 and TAD remains unknown. METHODS: This case-control study included 78 TAD patients and 72 controls. The aortic diameter was evaluated by computed tomography and used to assess TAD severity. Circulating ANGPTL8 levels were measured by enzyme-linked immunosorbent assay. Associations of ANGPTL8 with TAD were determined by multivariate logistic regression. RESULTS: Serum ANGPTL8 levels were significantly higher in TAD patients compared with controls (562.50 ± 20.84 vs. 419.70 ± 22.65 pg/mL, respectively; P < 0.001). After adjusting for confounding factors, circulating ANGPTL8 levels were an independent risk factor for TAD (odds ratio = 1.587/100 pg ANGPTL8, 95% confidence interval [CI] = 1.121-2.247, P < 0.001) and positively associated with diameter (ß = 1.081/100 pg ANGPTL8, 95% CI = 0.075-2.086, P = 0.035) and high-sensitivity C-reactive protein (hs-CRP) (ß = 0.845/100 pg ANGPTL8, 95% CI = 0.020-1.480, P = 0.009). The area under the curve (AUC) on receiver operating characteristic (ROC) analysis of the combination of ANGPTL8, hs-CRP, and D-dimer was 0.927, and the specificity and sensitivity were 98.46% and 79.49%, respectively. ANGPTL8 was significantly increased in TAD tissue compared with controls. In vitro, ANGPTL8 was increased in angiotensin II (AngII)-treated macrophages and vascular smooth muscle cells (VSMCs), while ANGPTL8 siRNA-mediated knockdown decreased inflammatory factors in AngII-treated macrophages and decreased apoptosis in AngII-treated VSMCs. CONCLUSION: ANGPTL8 is associated with TAD occurrence and development, which may involve pro-inflammatory effects on macrophages. ANGPTL8 combined with D-dimer and hs-CRP might be a useful clinical predictor of TAD. TRIAL REGISTRATION: ChiCTR-COC-17010792 http://www.chictr.org.cn/showproj.aspx?proj=18288.

3.
Sci Rep ; 10(1): 301, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31942011

RESUMO

MicroRNA-27a/b are small non-coding RNAs which are reported to regulate inflammatory response and cell proliferation. Although some studies have demonstrated that miR-27b is down-regulated in the oral specimens of patients suffering with oral lichen planus (OLP), the molecular mechanism of miR-27b decrease remains a large mystery, and the expression of miR-27a in OLP is not well explored. Here, we demonstrated both miR-27a and miR-27b, compared with healthy controls, were reduced in the oral biopsies, serum and saliva samples derived from OLP patients. The reductions of miR-27a/b were also confirmed in the lipopolysaccharide (LPS)- or activated CD4+ T cell-treated human oral keratinocytes (HOKs). Furthermore, we found vitamin D receptor (VDR) binding sites in the promoters of miR-27a/b genes and verified this finding. We also tested miR-27a/b levels in the oral epithelium from paricalcitol-treated, vitamin D deficient or VDR knockout mice. In the rescue experiments, we confirmed vitamin D and VDR inhibited LPS- or activated CD4+ T cell-induced miR-27a/b reductions in HOKs. In sum, our results show that vitamin D/VDR signaling induces miR-27a/b in oral lichen planus.

4.
Cell Death Dis ; 11(1): 15, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31907356

RESUMO

Oral lichen planus (OLP) is a kind of oral epithelial disorder featured with keratinocyte apoptosis and inflammatory reaction. The pathogenesis of OLP remains an enigma. Herein, we showed that the levels of miR-26a/b were robustly down-regulated in oral mucosal biopsies, serum and saliva in OLP patients compared with healthy control. Moreover, we found the binding sites of vitamin D receptor (VDR) in the promoter regions of miR-26a/b genes and proved that the induction of miR-26a/b was VDR dependent. The reduction of miR-26a/b expression was also detected in the oral epithelium of vitamin D deficient or VDR knockout mice. miR-26a/b inhibitors enhanced apoptosis and Type 1T helper (Th1) cells-related cytokines production in oral keratinocytes, whereas miR-26a/b mimics were protective. Mechanistically, we analyzed miRNA target genes and confirmed that miR-26a/b blocked apoptosis by directly targeting Protein Kinase C δ (PKCδ) which promotes cellular apoptotic processes. Meanwhile, miR-26a/b suppressed Th1-related cytokines secretion through targeting cluster of the differentiation 38 (CD38). In accordant with miR-26a/b decreases, PKCδ and CD38 levels were highly elevated in OLP patients' samples. Taken together, our present investigations suggest that vitamin D/VDR-induced miR-26a/b take protective functions in OLP via both inhibiting apoptosis and impeding inflammatory response in oral keratinocytes.

5.
Biol Trace Elem Res ; 193(2): 422-433, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31054068

RESUMO

Osteoarthritis (OA), a common degenerative disease affecting articular cartilage, is caused by multiple factors, and currently, there are few approaches to effectively delay its progression. This study aimed to evaluate whether a strontium compound (in the form of strontium gluconate, Glu-Sr) could reduce OA pathology severity in osteoarthritic rat models by directly targeting chondrocytes, including catabolic/anabolic activities and/or chondrogenic differentiation. Glu-Sr was administered to OA rats by oral gavage beginning during OA induction and continuing for 8 weeks. Glu-Sr treatment was found to significantly reduce cartilage degeneration and delay OA progression. Further examination showed that collagen II, Sox9, and aggrecan (ACAN) genes were up-regulated whereas IL-1ß was down-regulated in chondrocytes isolated from Glu-Sr-treated rats. Glu-Sr also antagonized the catabolic effects of IL-1ß on chondrocytes. Furthermore, Glu-Sr was shown to promote the chondrogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs), possibly through promoting chondrogenic gene expression, including CTGF and FGF1, as revealed by RNA-sequencing (RNA-seq). These results suggest that systemic administration of Glu-Sr may be useful in prophylactic and therapeutic treatment of chronic cartilage degradation through affecting multiple steps from chondrogenic differentiation of progenitors to matrix formation in mature chondrocytes.

6.
Cardiovasc Res ; 116(1): e19-e20, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31850501
7.
Small ; 16(4): e1905925, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31880079

RESUMO

Protein-based therapies are potential treatments for cancer, immunological, and cardiovascular diseases. However, effective delivery systems are needed because of their instability, immunogenicity, and so on. Crosslinked negatively charged heparin polysaccharide nanoparticle (HepNP) is proposed for protein delivery. HepNP can efficiently condense vascular endothelial growth factor (VEGF) because of the unique electronegative sulfonic acid and carboxyl domain of heparin. HepNP is then assembled with VEGF-C (Hep@VEGF-C) or VEGF-A (Hep@VEGF-A) protein for the therapy of myocardial infarction (MI) via intravenous (iv) injection. Hep@VEGF-A-mediated improvement of cardiac function by promoting angiogenesis is limited because of elevated vascular permeability, while Hep@VEGF-C effectively promotes lymphangiogenesis and reduces edema. On this basis, a graded delivery of VEGF-C (0.5-1 h post-MI) and VEGF-A (5 d post-MI) using HepNP is developed. At the dose ratio of 3:1 (Hep@VEGF-C vs Hep@VEGF-A), Hep@VEGF functional complexes substantially reduce the scar formation (≈-39%; p < 0.05) and improve cardiac function (≈+74%; p < 0.05). Such a HepNP delivery system provides a simple and effective therapeutic strategy for cardiovascular diseases by delivering functional proteins. Because of the unique binding ability of heparin with cytokines and growth factors, HepNP also has considerable application prospects in protein therapy for other serious diseases.

8.
Arch Pharm Res ; 42(12): 1092-1100, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31797253

RESUMO

Gestational diabetes mellitus (GDM) is a disease characterized by insufficient insulin secretion and glucose metabolic disorder during pregnancy. Tetramethylpyrazine has been reported to inhibit endoplasmic reticulum (ER) stress and high glucose-induced inflammation, which are closely associated with GDM. This study aimed to investigate the effects of tetramethylpyrazine on inflammatory responses, ER stress and oxidative stress of the placenta in a mouse model of GDM. Our results showed that tetramethylpyrazine treatment significantly alleviated the GDM symptoms characterized by low body weight and serum insulin levels, high blood glucose, and decreased ß-cell function in pregnant C57BL/KsJdb/+ mice. In addition, tetramethylpyrazine reduced the level of malondialdehyde, and increased the levels of superoxide dismutase, glutathione peroxidase and glutathione. Moreover, tetramethylpyrazine decreased the total serum cholesterol, serum triglyceride, and serum low-density lipoprotein levels and increased the high-density lipoprotein level. Further, tetramethylpyrazine regulated the levels of serum and placental inflammatory factors and the expression of ER stress related proteins. Taken together, the present study demonstrated that tetramethylpyrazine attenuated placental oxidative stress, inflammatory responses and ER stress in GDM mice.

9.
Can J Cardiol ; 35(12): 1851-1856, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31813511

RESUMO

BACKGROUND: The relationship between clinical outcomes and gene mutations in Chinese pediatric patients with idiopathic and heritable pulmonary arterial hypertension (PAH) is unclear. METHODS: We retrospectively studied the clinical characteristics and outcomes of pediatric patients who visited Beijing Anzhen Hospital from September 2008 to December 2018. RESULTS: Eighty-two pediatric patients were included. Forty-two gene mutations were identified in 41 patients (50%), including 25 mutations in BMPR2, 5 mutations in ACVRL1, 3 mutations each in ABCA3 and NOTCH3, 2 mutations each in KCNK3 and HTR2B, 1 mutation in ENG, and 1 mutation in EIF2AK4. The mean age at diagnosis of PAH was 86.4 ± 55.1 months. Forty-eight patients (twenty-eight mutation carriers) underwent cardiac catheterization examinations, with acute vasodilator testing performed simultaneously. Results showed that mutation carriers demonstrated a higher pulmonary vascular resistance index (P = 0.037). Patients with gene mutations responded poorly to vasodilators (P = 0.001). The 1-, 2-, and 3-year survival rates of mutation noncarriers were 95.1%, 87.8%, and 82.5% respectively; while for mutation carriers, the proportions were 86.6% (P = 0.216), 63.8% (P = 0.021), and 52.2% (P = 0.010), respectively. Cardiac index was an independent predictor of death (P = 0.005; odds ratio [OR] 2.16, 95% confidence interval [CI] 1.258-3.704), as well as RAP (P = 0.01; OR 1.26, 95% CI 1.056-1.503). CONCLUSIONS: In our cohort of Chinese pediatric patients, those with an identified gene mutation demonstrated worse clinical outcomes. Therefore, early gene screening for pediatric patients with idiopathic and heritable PAH is recommended, and more aggressive treatment for mutation carriers may be advisable.

10.
Anal Cell Pathol (Amst) ; 2019: 3013765, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31815093

RESUMO

Inflammation plays a pivotal role in the development of pulmonary arterial hypertension (PAH). Meanwhile, serum glucocorticoid-regulated kinase-1 (SGK1) has been considered to be an important factor in the regulation of inflammation in some vascular disease. However, the role of SGK1 in hypoxia-induced inflammation and PAH is still unknown. WT and SGK1-/- mice were exposed to chronic hypoxia to induce PAH. The quantitative PCR and immunohistochemistry were used to determine the expression of SGK1. The right ventricular hypertrophy index (RVHI), RV/BW ratio, right ventricle systolic pressure (RVSP), and percentage of muscularised vessels and medical wall thickness were measured to evaluate PAH development. The infiltration of macrophages and localization of SGK1 on cells were examined by histological analysis. The effects of SGK1 on macrophage function and cytokine expression were assessed by comparing WT and SGK1-/- macrophages in vitro. SGK1 has high expression in hypoxia-induced PAH. Deficiency of SGK1 prevented the development of hypoxia-induced PAH and inhibited macrophage infiltration in the lung. In addition, SGK1 knockout inhibited the expression of proinflammatory cytokines in macrophages. SGK1-induced macrophage activation and proinflammatory response contributes to the development of PAH in hypoxia-treated mice. Thus, SGK1 might be considered a promising target for PAH treatment.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31879145

RESUMO

OBJECTIVES: Thoracic aortic dissection (TAD) has a high mortality rate. Intermittent hypoxia (IH) triggers both harmful and beneficial effects in numerous physiological systems. The effects of IH on TAD development were explored in a mouse model. METHODS: ß-Aminopropionitrile monofumarate (BAPN) was used to induce TAD in C57BL/6 mice. Three week old male mice were treated with 1 g/kg/day BAPN in drinking water for four weeks and simultaneously subjected to IH (n = 30) (21%-5% O2, 90 s/cycle, 10 h/day, IH + BAPN group) or normoxia (n = 30) (21% O2, 24 h/day, BAPN group). Human VSMCs (HUASMCs) exposed to IH (30 min, 5% O2)/re-oxygenation (30 min, 21% O2) cycles with a maximum of 60 min/cycle to detect the effect of IH on HIF-1α and LOX via HIF-1α-siRNA. RESULTS: It was found that BAPN administration significantly increased the lumen size and wall thickness of aortas compared with the normal group, but was significantly reversed by IH exposure. Additionally, IH exposure significantly increased the survival rate of BAPN induced TAD (70% vs. 40%). Furthermore, IH exposure reduced BAPN induced elastin breaks and apoptosis of vascular smooth muscle cells. IH exposure also reversed BAPN induced upregulation of inflammation and extracellular matrix (ECM) degradation. Real time polymerase chain reaction (RT-PCR) confirmed that IH inhibited inflammation and ECM degradation related genes interleukin (IL)-1ß, IL-6, cathepsin S (Cat S), and matrix metalloproteinase 9 (MMP-9), but upregulated the ECM synthesis related genes lysyl oxidase (LOX) and collagen type I alpha2 (Col1a2) compared with the BAPN group. In vitro results suggest that IH promotes the expression of LOX via HIF-1α. CONCLUSIONS: The results suggest that IH alleviates BAPN induced TAD in C57BL/6 mice.

12.
J Pathol ; 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31758542

RESUMO

The immunoproteasome contains three catalytic subunits (ß1i, ß2i and ß5i) that are important modulators of immune cell homeostasis. A previous study showed a correlation between ß5i and human atherosclerotic plaque instability; however, the causative role of ß5i in atherosclerosis and the underlying mechanisms remain unknown. Here we explored this issue in apolipoprotein E (Apoe) knockout (eKO) mice with genetic deletion or pharmacological inhibition of ß5i. We found that ß5i expression was upregulated in lesional macrophages after an atherogenic diet (ATD). ß5i/Apoe double KO (dKO) mice fed on the ATD had a significant decrease in both lesion area and necrotic core area, compared with eKO controls. Moreover, dKO mice had less caspase-3+ apoptotic cell accumulation but enhanced efferocytosis of apoptotic cells and increased expression of Mer receptor tyrosine kinase (MERTK). Consistently, similar phenotypes were observed in eKO mice transplanted with dKO bone marrow or treated with ß5i-specific inhibitor PR-957. Mechanistic studies in vitro revealed that ß5i deletion reduced IκBα degradation and inhibited NF-κB activation, promoting Mertk transcription and efferocytosis, thereby attenuating apoptotic cell accumulation. In conclusion, we demonstrate that ß5i plays an important role in diet-induced atherosclerosis by altering MERTK-mediated efferocytosis. ß5i might be a potential pharmaceutical target against atherosclerosis. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

13.
Int J Mol Sci ; 20(20)2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614494

RESUMO

We investigated the effects of a fibrin-hyaluronic acid hydrogel (FBG-HA) and fibroblast growth factor 18 (FGF-18) for nucleus pulposus (NP) regeneration. Healthy bovine (n = 4) and human degenerated NP cells (n = 4) were cultured for 14 days in FBG-HA hydrogel with FGF-18 (∆51-mutant or wild-type) in the culture medium. Gene expression, DNA content, and glycosaminoglycan (GAG) synthesis were evaluated on day 7 and 14. Additionally, histology was performed. Human NP cells cultured in FBG-HA hydrogel showed an increase in collagen type II (COL2) and carbonic anhydrase XII (CA12) gene expression after 14 or 7 days of culture, respectively. GAG release into the conditioned medium increased over 14 days. Healthy bovine NP cells showed increased gene expression of ACAN from day 7 to day 14. Wild type FGF-18 up-regulated CA12 gene expression of human NP cells. Histology revealed an increase of proteoglycan deposition upon FGF-18 stimulation in bovine but not in human NP cells. The FBG-HA hydrogel had a positive modulatory effect on human degenerated NP cells. Under the tested conditions, no significant effect of FGF-18 was observed on cell proliferation or GAG synthesis in human NP cells.

14.
Diabetes Ther ; 10(6): 2265-2288, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31654346

RESUMO

INTRODUCTION: Gestational diabetes mellitus (GDM) is a gestational complication that affects maternal and child health. The placenta provides the fetus with the necessary nutrition and oxygen and takes away the metabolic waste. Patients with GDM are diagnosed and treated merely on the basis of the blood glucose level; this approach does nothing to help evaluate the status of the placenta, which is worth noting in GDM. The purpose of this research was to clarify the relation between thioredoxin-interacting protein (TXNIP) and reactive oxygen species (ROS) in the placenta of patients with GDM, which has thus far remained unclear. METHODS: The expression of TXNIP in the placentas of 10 patients with GDM and 10 healthy puerperae (control group) was investigated via immunofluorescence. The relation among TXNIP, ROS, and the function of mitochondria was explored in HTR-8/SVneo cells stimulated by high glucose (HG). RESULTS: The results showed the expression of TXNIP in the placentas of patients with GDM was higher than that in the control group, and the expression of TXNIP in HTR-8/SVneo cells treated with HG was higher than that in the control group, causing the accumulation of ROS and changes of mitochondria, promoting apoptosis and inhibition of migration. CONCLUSIONS: High expression of TXNIP caused by HG mediates the increasing ROS and the mitochondria dysfunction in GDM; this impairs the function of the placenta and is the basis for the prediction of perinatal outcome.

15.
Fish Shellfish Immunol ; 94: 861-870, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31585246

RESUMO

The main advantage of antimicrobial peptides (AMPs) used as the effectors in the innate immunity system of invertebrates is that the high specificity is not indispensable. And they play important roles in the systemic defenses against microbial invasion. In this study, a new full-length cDNA of the crustins molecule was identified in red swamp crayfish, P. clarkii (named Pc-crustin 4). The ORF of Pc-crustin 4 contained 369 bp which encoded a protein of 122 amino acids, with a 20-amino-acid signal peptide sequence. On the base of the classification method established by Smith et al., Pc-crustin 4 belonged to Type Ⅰ crustin molecule. The Pc-crustin 4 transcripts were expressed in hemocytes at relatively high level, and relatively low level in hepatopancreas, gills, and intestine in normal crayfish. After respectively challenged with S. aureus or E. ictaluri, the expression levels of Pc-crustin 4 showed up-regulation trends at different degrees in the hemocytes, hepatopancreas, gills, and intestine tissues. Besides, the results of liquid antibacterial assay showed that rPc-crustin 4 inhibited obviously the growth of S. aureus and E. ictaluri. The results of bacteria binding assay showed that rPc-crustin 4 could bind strongly to S. aureus and E. ictaluri. Finally, RNAi assay was performed to study the immunity roles of Pc-crustin 4 in crayfish in vivo. Taken together, Pc-crustin 4 is an important immunity effector molecule, which plays crucial roles in defending against bacterial infection in crayfish.

16.
J Clin Transl Hepatol ; 7(3): 221-225, 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31608213

RESUMO

Background and Aims: Genotype (GT) 1 remains the predominant hepatitis c virus (HCV) GT in Chinese patients. Over 80% of those Chinese patients harbor the interferon-sensitive CC allele of IFNL4rs12979860, which is favorable for interferon-based treatment regimens. This phase III clinical trial aimed to evaluate the efficacy and safety of the ritonavir-boosted danoprevir plus pegylated-interferon α-2a and ribavirin regimen for 12 weeks in treatment-naïve mainland Chinese patients infected with HCV GT1 without cirrhosis. Methods: One hundred and forty-one treatment-naïve, non-cirrhotic HCV GT1 Chinese patients (age ≥18 years) were enrolled for this single-arm, multicenter, phase III MANASA study (NCT03020082). Patients received a combination of ritonavir-boosted danoprevir (100 mg/100 mg) twice a day plus subcutaneous injection of weekly pegylated-interferon α-2a (180 µg) and oral ribavirin (1000/1200 mg/day body weight <75/≥75 kg) for 12 weeks. The primary end-point was sustained virologic response rate at 12 weeks after the end of treatment. The secondary end-points were safety outcomes, tolerability, virologic response over time and relapse rate. Results: All enrolled patients were HCV GT1-infected, and most among them (97.9%, 123/141) had the HCV GT1b subtype. Single-nucleotide polymorphism test showed that the majority of patients were of the IFNL4 rs12979860 CC genotype (87.2%, 123/141). Overall, 140 patients completed the 12-week treatment, and 97.1% (136/140) patients achieved sustained virologic response at 12 weeks (per protocol population group, 95% confidence interval: 92.9-99.2%). Only drug-related serious adverse event occurred. Most of the adverse events were grade 1 and grade 2 alanine aminotransferase elevation or liver dysfunction. One patient discontinued treatment because of severe head injury in a car accident. Conclusions: The triple regimen of ritonavir-boosted danoprevir plus pegylated-interferon α-2a and ribavirin produced a sustained virologic response rate of 97.1% after 12 weeks treatment in noncirrhotic HCV GT1-infected Chinese patients, and was safe and well tolerated. Trial Registration Clinical-Trials.gov Identifier: NCT03020082.

17.
Sci Rep ; 9(1): 14083, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575993

RESUMO

Low-density lipoprotein cholesterol (LDL-C) has been associated with the occurrence of abdominal aortic aneurysm. However, whether LDL-C elevation associated with aneurysms in large vessel vasculitis is unknown. The aim of this study is to investigate the clinical and laboratory features of Takayasu arteritis (TAK) and explore the risk factors that associated with aneurysm in these patients. This retrospective study compared the clinical manifestations, laboratory parameters, and imaging results of 103 TAK patients with or without aneurysms and analyzed the risk factors of aneurysm formation. 20.4% of TAK patients were found to have aneurysms. The LDL-C levels was higher in the aneurysm group than in the non-aneurysm group (2.9 ± 0.9 mmol/l vs. 2.4 ± 0.9 mmol/l, p = 0.032). Elevated serum LDL-C levels increased the risk of aneurysm by 5.8-fold (p = 0.021, odds ratio [OR] = 5.767, 95% confidence interval [CI]: 1.302-25.543), and the cutoff value of level of serum LDL-C was 3.08 mmol/l. The risk of aneurysm was 4.2-fold higher in patients with disease duration >5 years (p = 0.042, OR = 4.237, 95% CI: 1.055-17.023), and 2.9-fold higher when an elevated erythrocyte sedimentation rate was present (p = 0.077, OR = 2.851, 95% CI: 0.891-9.115). In this study, elevated LDL-C levels increased the risk of developing aneurysms in patients with TAK.

18.
Cardiovasc Res ; 2019 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-31605122

RESUMO

AIMS: Genetic contribution to coronary artery disease (CAD) remains largely unillustrated. Although transcriptomic profiles have identified dozens of genes that are differentially expressed in normal and atherosclerotic vessels, whether those genes are genetically associated with CAD remains to be determined. Here, we combined genetic association studies, transcriptome profiles and in vitro and in vivo functional experiments to identify novel susceptibility genes for CAD. METHODS AND RESULTS: Through an integrative analysis of transcriptome profiles with genome-wide association studies for CAD, we obtained 18 candidate genes and selected one representative SNP for each gene for multi-centered validations. We identified an intragenic SNP, rs1056515 in RGS5 gene (OR = 1.17, 95%CI =1.10-1.24, P = 3.72 × 10-8) associated with CAD at genome-wide significance. Rare genetic variants in linkage disequilibrium with rs1056515 were identified in CAD patients leading to a decreased expression of RGS5. The decreased expression was also observed in atherosclerotic vessels and endothelial cells treated by various cardiovascular risk factors. Through siRNA knockdown and adenoviral overexpression, we further showed that RGS5 regulated endothelial inflammation, vascular remodeling, as well as canonical NF-κB signaling activation. Moreover, CXCL12, a specific downstream target of the noncanonical NF-κB pathway, was strongly affected by RGS5. However, the p100 processing, a well-documented marker for noncanonical NF-κB pathway activation, was not altered, suggesting an existence of a novel mechanism by which RGS5 regulates CXCL12. CONCLUSIONS: We identified RGS5 as a novel susceptibility gene for CAD and showed that the decreased expression of RGS5 impaired endothelial cell function and functionally contributed to atherosclerosis through a variety of molecular mechanisms. How RGS5 regulates the expression of CXCL12 needs further studies. TRANSLATIONAL PERSPECTIVE: Current knowledge of the genetic contribution to CAD and mechanism underlying CAD associated loci identified in GWAS are both limited. Our study identifies a common variant rs1056515 as a genetic marker for CAD and rare variants in LD with rs1056515 leading to decreased expression of RGS5, which contributes to atherosclerosis by impairing endothelial cell function. Our study provides novel means for (i) Identification of patients at risk of CAD, (ii) Understanding the basis for disease pathogenesis, and (iii) development of new therapeutic strategies for the treatment of the disease.

19.
Cancer Gene Ther ; 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31543512

RESUMO

The present study discusses the expression and effect of the SOX17 gene in endometrioid adenocarcinoma. MTT assay is performed to determine the growth inhibition ratio of the DNA methyltransferase inhibitor 5-AZA for endometrial carcinoma cells, and the real-time fluorescence quantification PCR (qRT-PCR) was used to detect the mRNA expression of SOX17, ß-catenin, and CyclinD1 in endometrial carcinoma tissues before and after using 5-AZA to treat the endometrial carcinoma cell line. There were 30 cases on endometrioid adenocarcinoma tissues and 10 cases on normal endometrial tissues. The results revealed that the expression of SOX17 in endometrioid adenocarcinoma tissues was downregulated (P < 0.05), the expression of ß-catenin and CyclinD1 was upregulated (P < 0.05), and the expression of SOX17, CyclinD1, and ß-catenin was negatively correlated (r = -0.353, P > 0.05; R = -0.463, P < 0.05). The higher the histological grade and FIGO staging were, the lower the expression level of SOX17 was (P < 0.05). After HEC1A cells were treated by 5-AZA, the cell growth inhibition was most obvious (IC50 = 12.033) at 72 h, as determined by MTT assay. After cell treatment by 5-AZA, the genetic expression of SOX17 significantly increased, when compared with that before treatment (P < 0.05), while the genetic expression of ß-catenin and CyclinD1 significantly declined (P < 0.05). These results indicate that the expression level of SOX17 in endometrioid adenocarcinoma declined, and the upregulated expression level of SOX17 in cells inhibited the growth of tumor cells.

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