scholarly journals Inhibition of Sphingosine-1-Phosphate Receptor 2 Prevents Thoracic Aortic Dissection and Rupture

2021 ◽  
Vol 8 ◽  
Author(s):  
Guangwei Pan ◽  
Mengyang Liao ◽  
Yong Dai ◽  
Yang Li ◽  
Xiaole Yan ◽  
...  
Keyword(s):  
Aortic Dissection ◽  
Mouse Model ◽  
Protein Expression ◽  
Inflammatory Diseases ◽  
Aortic Rupture ◽  
Elastic Fiber ◽  
Serum Levels ◽  
Specific Marker ◽  
Thoracic Aortic Dissection ◽  
Sphingosine 1 Phosphate

Background: Numerous pieces of evidence have indicated that thoracic aortic dissection (TAD) is an inflammatory disease. Sphingosine-1-phosphate receptor 2 (S1PR2) signaling is a driver in multiple inflammatory diseases. Here, we examined the S1PR2 expression in TAD lesions and explored the effect of interfering with S1PR2 on TAD formation and progression.Methods: Aorta specimens and blood samples were collected from patients with TAD and matched controls. The expression of S1PR1, S1PR2, and S1PR3 was examined. The effect of inhibiting S1PR2 on TAD was evaluated in a TAD mouse model induced by β-aminopropionitrile fumarate (BAPN) and AngII. The presence of sphingosine kinase 1 (SPHK1), S1P, and neutrophil extracellular traps (NETs) was investigated. Further, the possible association between S1PR2 signaling and NETs in TAD was analyzed.Results: In the aortic tissues of patients with TAD and a mouse model, the S1PR2 expression was significantly up-regulated. In the TAD mouse model, JTE013, a specific S1PR2 antagonist, not only blunted the TAD formation and aortic rupture, but also preserved the elastic fiber architecture, reduced the smooth muscle cells apoptosis level, and mitigated the aortic wall inflammation. Augmented tissue protein expression of SPHK1, citrullinated histone H3 (CitH3, a specific marker of NETs), and serum S1P, CitH3 were detected in TAD patients. Surgical repair normalized the serum S1P and CitH3 levels. Immunofluorescence staining revealed that S1PR2 colocalized with NETs. The protein expression levels of SPHK1 and serum S1P levels positively correlated with the protein expression and serum levels of CitH3, separately. Furthermore, JTE013 treatment reduced NETs accumulation.Conclusion: Inhibiting S1PR2 attenuates TAD formation and prevents aortic rupture. Targeting S1PR2 may provide a promising treatment strategy against TAD.

MAPK/AP-1-Targeted Anti-Inflammatory Activities of Xanthium strumarium

2016 ◽  
Vol 44 (06) ◽  
pp. 1111-1125 ◽  
Author(s):  
Muhammad Jahangir Hossen ◽  
Mi-Yeon Kim ◽  
Jae Youl Cho
Keyword(s):  
Mouse Model ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Elevated Serum ◽  
Human Monocyte ◽  
Serum Levels ◽  
Mitogen Activated Protein Kinase ◽  
Xanthium Strumarium ◽  
U937 Cells ◽  
Anti Inflammatory

Xanthium strumarium L. (Asteraceae), a traditional Chinese medicine, is prescribed to treat arthritis, bronchitis, and rhinitis. Although the plant has been used for many years, the mechanism by which it ameliorates various inflammatory diseases is not yet fully understood. To explore the anti-inflammatory mechanism of methanol extracts of X. strumarium (Xs-ME) and its therapeutic potential, we used lipopolysaccharide (LPS)-stimulated murine macrophage-like RAW264.7 cells and human monocyte-like U937 cells as well as a LPS/D-galactosamine (GalN)-induced acute hepatitis mouse model. To find the target inflammatory pathway, we used holistic immunoblotting analysis, reporter gene assays, and mRNA analysis. Xs-ME significantly suppressed the up-regulation of both the activator protein (AP)-1-mediated luciferase activity and the production of LPS-induced proinflammatory cytokines, including interleukin (IL)-1[Formula: see text], IL-6, and tumor necrosis factor (TNF)-[Formula: see text]. Moreover, Xs-ME strongly inhibited the phosphorylation of mitogen-activated protein kinase (MAPK) in LPS-stimulated RAW264.7 and U937 cells. Additionally, these results highlighted the hepatoprotective and curative effects of Xs-ME in a mouse model of LPS/D-GalN-induced acute liver injury, as assessed by elevated serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and histological damage. Therefore, our results strongly suggest that the ethnopharmacological roles of Xs-ME in hepatitis and other inflammatory diseases might result from its inhibitory activities on the inflammatory signaling of MAPK and AP-1.

Liver X receptor-α and miR-130a-3p regulate expression of sphingosine 1-phosphate receptor 2 in human umbilical vein endothelial cells

2016 ◽  
Vol 310 (3) ◽  
pp. C216-C226 ◽  
Author(s):  
Aihui Fan ◽  
Qian Wang ◽  
Yongjun Yuan ◽  
Jilun Cheng ◽  
Lixian Chen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Protein Expression ◽  
Inflammatory Diseases ◽  
Umbilical Vein ◽  
Specific Inhibitor ◽  
Barrier Dysfunction ◽  
Human Umbilical Vein ◽  
Tnf Α ◽  
Sphingosine 1 Phosphate ◽  
Umbilical Vein Endothelial Cells

Recent studies have shown that activation of liver X receptors (LXRs) attenuates the development of atherosclerosis, not only by regulating lipid metabolism but also by suppressing inflammatory signaling. Sphingosine 1-phosphate receptor 2 (S1PR2), an important inflammatory gene product, plays a role in the development of various inflammatory diseases. It was proposed that S1PR2 might be regulated by LXR-α. In the present study, the effect of LXR-α on tumor necrosis factor-α (TNF-α)-induced S1PR2 expression in human umbilical vein endothelial cells (HUVECs) was investigated and the underlying mechanism was explored. The results demonstrated that TNF-α led to an increase in S1PR2 expression and triggered a downregulation of LXR-α expression in HUVECs as well. Downregulation of LXR-α with specific small interfering RNA (siRNA) remarkably enhanced the primary as well as TNF-α-induced expression of S1PR2 in HUVECs. Activation of LXR-α by agonist GW3965 inhibited both primary and TNF-α-induced S1PR2 expression. GW3965 also attenuated S1PR2-induced endothelial barrier dysfunction. The data further showed that TNF-α induced a significant decrease in miR-130a-3p expression. Overexpression of miR-130a-3p with mimic product reduced S1PR2 protein expression, and inhibition of miR-130a-3p by specific inhibitor resulted in an increase in S1PR2 protein expression. Furthermore, activation of LXRs with agonist enhanced the expression of miR-130a-3p, and knockdown of LXR-α by siRNA suppressed miR-130a-3p expression. These results suggest that LXR-α might downregulate S1PR2 expression via miR-130a-3p in quiescent HUVECs. Stimulation of TNF-α attenuates the activity of LXR-α and results in enhanced S1PR2 expression.

scholarly journals S-Nitrosylation of Plastin-3 Exacerbates Thoracic Aortic Dissection Formation via Endothelial Barrier Dysfunction

2020 ◽  
Vol 40 (1) ◽  
pp. 175-188 ◽  
Author(s):  
Lihong Pan ◽  
Zhe Lin ◽  
Xin Tang ◽  
Jiaxin Tian ◽  
Qiao Zheng ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Aortic Dissection ◽  
Aortic Rupture ◽  
Mass Spectrometry Analysis ◽  
Endothelial Barrier ◽  
Cell Junction ◽  
Ang Ii ◽  
Barrier Dysfunction ◽  
Spectrometry Analysis ◽  
Thoracic Aortic Dissection

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.

Ultrasound diagnosis of dissecting thoracic aortic aneurysms: procedure with a handheld device and a video-illustrated case

2021 ◽  
Vol 51 (1) ◽  
pp. 10-15
Author(s):  
Kenneth V Iserson ◽  
Sri Devi Jagjit ◽  
Balram Doodnauth
Keyword(s):  
Aortic Dissection ◽  
Correct Diagnosis ◽  
Signs And Symptoms ◽  
Aortic Aneurysms ◽  
Thoracic Aortic Aneurysms ◽  
Handheld Device ◽  
Thoracic Aortic Dissection ◽  
Threatening Condition ◽  
Life Threatening ◽  
Handheld Ultrasound

Acute thoracic aortic dissection is an uncommon, although not rare, life-threatening condition. With protean signs and symptoms that often suggest more common cardiac or pulmonary conditions, it can be difficult to diagnose. Ultrasound has proven useful in making the correct diagnosis. This case demonstrates that training gained using standard ultrasound machines can be easily and successfully adapted to newer handheld ultrasound devices. The examination technique using the handheld device is illustrated with photos and a video.

scholarly journals Altered DNA methylation pattern reveals epigenetic regulation of Hox genes in thoracic aortic dissection and serves as a biomarker in disease diagnosis

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Peiru Liu ◽  
Jing Zhang ◽  
Duo Du ◽  
Dandan Zhang ◽  
Zelin Jin ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Aortic Dissection ◽  
Epigenetic Regulation ◽  
Heart Development ◽  
Type A ◽  
Methylation Pattern ◽  
Healthy Controls ◽  
Global Methylation ◽  
Thoracic Aortic Dissection

Abstract Background Thoracic aortic dissection (TAD) is a severe disease with limited understandings in its pathogenesis. Altered DNA methylation has been revealed to be involved in many diseases etiology. Few studies have examined the role of DNA methylation in the development of TAD. This study explored alterations of the DNA methylation landscape in TAD and examined the potential role of cell-free DNA (cfDNA) methylation as a biomarker in TAD diagnosis. Results Ascending aortic tissues from TAD patients (Stanford type A; n = 6) and healthy controls (n = 6) were first examined via whole-genome bisulfite sequencing (WGBS). While no obvious global methylation shift was observed, numerous differentially methylated regions (DMRs) were identified, with associated genes enriched in the areas of vasculature and heart development. We further confirmed the methylation and expression changes in homeobox (Hox) clusters with 10 independent samples using bisulfite pyrosequencing and quantitative real-time PCR (qPCR). Among these, HOXA5, HOXB6 and HOXC6 were significantly down-regulated in TAD samples relative to controls. To evaluate cfDNA methylation pattern as a biomarker in TAD diagnosis, cfDNA from TAD patients (Stanford type A; n = 7) and healthy controls (n = 4) were examined by WGBS. A prediction model was built using DMRs identified previously from aortic tissues on methylation data from cfDNA. Both high sensitivity (86%) and specificity (75%) were achieved in patient classification (AUC = 0.96). Conclusions These findings showed an altered epigenetic regulation in TAD patients. This altered epigenetic regulation and subsequent altered expression of genes associated with vasculature and heart development, such as Hox family genes, may contribute to the loss of aortic integrity and TAD pathogenesis. Additionally, the cfDNA methylation in TAD was highly disease specific, which can be used as a non-invasive biomarker for disease prediction.

scholarly journals TMOD-18. TARGETING THE PI3K/AKT PATHWAY IN MYCN AMPLIFIED HIGH GRADE GLIOMAS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii231-ii232
Author(s):  
Katharine Halligan ◽  
Ann-Catherine Stanton ◽  
Matthew Halbert ◽  
Brian Golbourn ◽  
Stephen Mack ◽  
...  
Keyword(s):  
Stem Cells ◽  
Tumor Suppressor ◽  
Mouse Model ◽  
Protein Expression ◽  
Neural Stem Cells ◽  
Tumor Suppressor Genes ◽  
Akt Pathway ◽  
High Grade ◽  
Suppressor Genes ◽  
High Grade Gliomas

Abstract Pediatric glioblastoma (pGBM) are incurable brain tumors with overall poor prognosis and response to treatments due to molecular and epigenetic heterogeneity. In particular, the MYCN subtype of pGBM are a highly aggressive form of GBM with a dismal median survival of only 14 months. Furthermore, this subtype is enriched with loss of the tumor suppressor genes TP53 and PTEN, leading to aberrantly active PI3K-AKT signaling pathway and DNA-checkpoint abnormalities. Here, we report the generation of a novel syngeneic mouse model that recapitulates the features of the MYCN subtype of pGBM. We isolated Sox2-Cre neural stem cells from C57BL/6 mice and transduced inverted retroviral-cassettes of the murine Mycn oncogene simultaneously with shRNA targeting tumor suppressor genes p53 and Pten. Retroviral-cassettes are flanked by tandem LoxP sites arranged so that Cre recombinase expression inverts the cassettes in frame allowing for MYCN protein expression and loss of the P53/PTEN proteins. Transgene activation is accompanied with selectable cell surface markers and fluorescent tags enabling for fluorescent activated cell sorting (FACS) of the desired cell populations. Neural stem cells with MYCN protein expression and concurrent silencing of P53 and PTEN protein (NPP cells) result in significantly increased proliferation and activation of PI3K-AKT pathway as compared to control neural stem cells and have. Injection of NPP cells into the forebrain of immune competent C57BL/6 mice result in the formation of invasive high-grade gliomas with a lethal phenotype at ~50 days post injection. Using several next generation brain penetrant small molecule inhibitors of the PI3K-AKT pathway, we show inhibition of tumorigenesis in vitro. Moreover, we have identified several novel mechanisms of PI3KAKT treatment resistance and are currently identifying therapies that may overcome this resistance through RNA seq analysis. In summary, well defined genetic drivers of GBM can lead to informed mouse model generation to test promising therapies.

scholarly journals FRI0322 INSULIN RESISTANCE IN NON-DIABETES PATIENTS WITH SPONDYLOARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 752.2-753
Author(s):  
J. C. Quevedo-Abeledo ◽  
F. Genre ◽  
J. Rueda-Gotor ◽  
A. Corrales ◽  
V. Hernández-Hernández ◽  
...  
Keyword(s):  
Cell Function ◽  
Inflammatory Diseases ◽  
Univariate Analysis ◽  
Serum Levels ◽  
Β Cell ◽  
Related Factors ◽  
C Peptide ◽  
Related Data ◽  
Β Cell Function ◽  
Beta Coefficient

Background:Insulin resistance (IR) is a state in which a given concentration of insulin is associated with a subnormal glucose response. IR constitutes a major underlying abnormality driving cardiovascular disease in the general population and has been linked to inflammatory diseases. In this sense, several reports have confirmed that inflammation worsens IR and impairs pancreatic β-cell function in inflammatory diseases such as rheumatoid arthritis and systemic lupus erythematosus.Objectives:In this study we aimed to determine the prevalence of IR in patients with spondyloarthritis (SpA) compared to controls, and whether IR can be explained by disease-related features in SpA patients.Methods:Study of 577 subjects, 306 patients diagnosed with SpA according to ASAS criteria and 271 controls. Insulin and C-peptide serum levels, IR and β-cell function (%B) indexes by homeostatic model assessment (HOMA2), and lipid profiles were assessed in patients and controls. A multivariate regression analysis was performed to evaluate the differences in IR indexes between patients and controls and to determine how IR is associated with disease-related characteristics.Results:SpA patients showed higher serum levels of insulin (8.7 [4.8-15.9] vs. 8.0 [5.7-11.2] uU/ml, p=0.001) and C peptide (1.4 [0.7-2.5] vs. 1.2 [0.7-1.7] ng/ml, p=0.000) than controls in the univariate analysis. Similarly, HOMA2-B% and IR were all significantly higher in SpA patients. These differences were still evident when the comparisons were made after the multivariate analysis had been adjusted for traditional IR-related factors (sex, age, BMI, hypertension, dyslipidemia, smoking and, cholesterol), glucocorticoids intake, insulin and C-peptide. Moreover, HOMA2-B% and HOMA2-IR scores, both calculated with insulin or C-peptide, yielded statistically higher significant values in SpA patients than controls.Classic IR-related factors (age, BMI, waist circumference, hypertension, obesity, dyslipidemia, atherogenic index, and triglycerides), as well as CRP serum levels, were all related, to a greater or lesser degree, with IR and β-cell function. Regarding disease-related data, ASDAS-CRP, BASFI and BASMI scores were positively associated with IR; and BASMI and BASDAI scores were positively related to HOMA2-%B-C peptide. Moreover, the use of NSAID and prednisone were, respectively, positive and negatively related to β-cell function. However, only some of the associations of the univariate analysis were maintained after adjusting for confounders. In this sense, disease duration (beta coefficient 2 [95% CI 1-3], p=0.001) and positivity for HLA-B27 (beta coefficient 30 [95% CI 12-49], p=0.002) were associated with higher β-cell functionality after the multivariate analysis.Conclusion:Patients with SpA have an increased IR compared to controls. SpA disease-related data like disease duration and HLA-B27 are independently associated with β-cell dysfunction.Disclosure of Interests:Juan Carlos Quevedo-Abeledo Speakers bureau: Abbvie, Fernanda Genre: None declared, Javier Rueda-Gotor: None declared, Alfonso Corrales Speakers bureau: Abbvie, Vanessa Hernández-Hernández Speakers bureau: Pfizer, Abbvie, MSD, Natalia Fañanas-Rodríguez: None declared, Bernardo Lavín-Gómez: None declared, delgado frias esmeralda Speakers bureau: Pfizer, Abbvie, MSD, Antonia de Vera-González: None declared, Alejandra Delgado-González: None declared, Laura de Armas-Rillo: None declared, Maria Teresa García-Unzueta: None declared, Miguel A González-Gay Grant/research support from: Pfizer, Abbvie, MSD, Speakers bureau: Pfizer, Abbvie, MSD, Iván Ferraz-Amaro Grant/research support from: Pfizer, Abbvie, Speakers bureau: Pfizer, Abbvie, MSD.

Sign in / Sign up

Export Citation Format

Share Document