tbuckley/cabot-search huggingface dataset:
Platycodin D, a triterpene saponin from Platycodon grandiflorum, inhibits vascular endothelial growth factor-induced angiogenesis in vitro and in vivo.
Authors: Ju-Ah Son, Won-Yoon Chung, Yeong-Shik Kim, Young-Wan Ha, Kwang-Kyun Park
Journal: Cancer Research (2008)

477  Platycodin D is the major constituent of triterpene saponins in the root of Platycodon grandiflorum. Recently, it has been reported to have a number of pharmacologic activities including anti-inflammatory, anti-allergic activity and inhibition of tumor growth. Angiogenesis, the sprouting of new blood capillaries from preexisting vessels, comprises a cascade of events emanating from endothelial cell proliferation, migration, and maturation to form capillary tubes. Angiogenesis is involved in physiological processes such as embryonic development or wound healing, and also in the progression of disease including rheumatoid arthritis and cancer. Especially, it is now widely accepted that tumor growth depends on angiogenesis to provide first oxygen and nutrients to proliferating cells and then a physical route for metastasis transport. Therefore, the investigation of agents that can inhibit angiogenesis is of great clinical importance. Here, we examined the anti-angiogenicactivity of platycodin D using in vitro and in vivo assay systems. Platycodin D inhibited vascular endothelial growth factor (VEGF)-induced proliferation, DNA synthesis, chemotactic motility and tube formation in a dose-dependent manner in primary cultured human umbilical vein endothelial cells (HUVECs). To examine whether VEGF-mediated angiogenesis could be inhibited by platycodin D in vivo, we conducted the chorioallantoic membrane (CAM) assay in fertilized eggs and the Matrigel plug assay in mice. Blood vessel formation on CAM and in Matrigel with VEGF significantly was reduced by platycodin D. Oral administration of platycodin D also suppressed VEGF-mediated angiogenesis. Furthermore, to explain the signaling mechanism underlying the anti-angiogenic activity of platycodin D, we determined the alterations in VEGF, chemokines and their respective receptors that play important roles in the regulation of angiogenesis. Taken together, our results demonstrate that platycodin D possesses the potent anti-angiogenic activity. Therefore, it may be valuable to develop as a pharmaceutical drug for treatment and/or prevention of angiogenesis-dependent human diseases such as tumor.
Abstract P404: Membrane Composition Of Cardiac-derived Extracellular Vesicles Changes With Vesicle Origin And Determines Uptake
Authors: Sruti Bheri, Jessica R Hoffman, Hyun-Ji Park, Michael E Davis
Journal: Circulation Research (2021)

Introduction: Myocardial infarction (MI) is a leading cause of mortality worldwide. The potency of cell-based therapies for MI is increasingly attributed to the release of extracellular vesicles (EVs) which consist of a lipid/protein membrane and encapsulate RNA cargo. Specifically, EVs from ckit+ progenitor cells (CPCs) and mesenchymal stromal cells (MSCs) are shown to be pro-reparative, with clinical trials ongoing. Despite copious research into EV cargo, the role of donor cell type on EV membrane composition and its effects on EV uptake mechanism by recipient cells remain unclear. This is crucial for designing EV-based therapeutics as uptake mechanism dictates the functionality of the cargo. Thus, we hypothesized that (1) EV membrane composition varies by donor cell type and (2) this variation covaries with the mechanism of uptake. Methods: EVs were isolated using differential ultracentrifugation from four cardiac cell types: CPCs, MSCs, cardiac endothelial cells (CECs) and rat cardiac fibroblasts (RCFs) grown in normoxia (18% O 2 ) or hypoxia (1% O 2 ) to mimic ischemic conditions. EVs were characterized for size and concentration. EV lipid membrane profile was assessed through LC/MS/MS. Donor cell’s role on EV uptake mechanism was determined by inhibiting known uptake pathways (clathrin, dynamin, macropinocytosis and caveolae/lipid raft) with small molecules and quantifying CEC/RCF endocytosis of EVs with flow cytometry. Finally, partial least squares regression was used to determine the most important lipids involved in EV uptake mechanism. Results: EVs were successfully isolated and characterized. The EV membrane lipid profiles clustered by donor cell type. Uptake mechanism of EVs varied based on both donor and recipient cell type with dynamin mediated endocytosis being the most common. Further, the uptake mechanism was independent of normoxic/hypoxic conditioning. Finally, supervised learning methods revealed specific lipid classes (sphingolipids and glycerophospholipids) covaried with EV uptake mechanism. Conclusion: This work highlights the importance of the understudied EV membrane and its role in delivering therapeutic cargo. Active donor cell selection for efficient EV uptake will allow for more potent EV-based MI therapies.
Abstract 13559: Activation of PDGFRA Signaling Contributes to Filamin C-Related Arrhythmogenic Cardiomyopathy
Authors: Suet Chen, Chi Keung Lam, ying-wooi wan, Shanshan Gao, Olfat MALAK, Raffaella Lombardi, Amrut V Ambardekar, Michael R Bristow, Marta Gigli, Gianfranco sinagra, Sharon L Graw, Matthew Taylor, Joseph C Wu, Luisa Mestroni
Journal: Circulation (2021)

FLNC truncating mutations ( FLNCtv ) are prevalent causes of inherited dilated cardiomyopathy (DCM). Notably, carriers of truncating mutations in FLNC are at high risk of developing arrhythmogenic cardiomyopathy (ACM). We investigated the molecular mechanisms of mutant FLNC in the pathogenesis of arrhythmogenic DCM (a-DCM) using patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Our in vitro electrophysiological and cell-contraction studies at the single cell level demonstrated that iPSC-CMs from patients with 2 different truncating mutations in FLNC displayed reduced contractility and an arrhythmia phenotype associated with dislocation of connexin 43 (GJA1) from the cell membrane as shown by immunofluorescence. iPSC-CMs with FLNC ablation revealed a similar phenotype, suggesting loss of function as a mechanism for arrhythmogenesis in FLNC truncating mutations. Furthermore, our mechanistic studies showed that cell-cell adhesion/β-catenin/PDGFRA signaling pathways were activated in the FLNC-mutant iPSC-CMs compared to the isogenic wildtype iPSC-CMs. Co-immunoprecipitation and proteomic analysis identified β-catenin (CTNNB1) as a novel binding partner of FLNC. FLNC deficiency induced nuclear translocation of CTNNB1 and subsequently activated the platelet-derived growth factor receptor-alpha (PDGFRA) pathway. These findings were corroborated by RNA sequencing and immunoblots on human hearts with a-DCM and FLNCtv mutations. We also demonstrated that PDGFRA inhibition rescued GJA1 membrane localization, prevented nuclear localization of CTNNB1 and improved contraction and electrical function of FLNC-mutant iPSC-CMs. Taken together, our findings suggest that PDGFRA signaling is implicated in the pathogenesis of a-DCM caused by FLNC haploinsufficiency mutations and that inhibition of this pathway is a potential therapeutic strategy for preventing arrhythmias in FLNC related cardiomyopathies.
Abstract 10961: Integrated Coronary Vascular Disease Diagnosis System Based on Two-Step Neural Network Algorithm Trained by Synthetic Model and Patient Biometric Features
Authors: Young Woo Kim, Junhong Kim, Hyeong Jun Lee, JOON SANG LEE
Journal: Circulation (2021)

Introduction: Fractional flow reserve (FFR) is the golden standard that determines whether coronary artery disease (CAD) surgery is necessary or not. Invasive FFR uses pressure wire to obtain the pressure ratio of proximal and distal lesion. However, the burden from high cost and time due to invasive process makes it difficult to perform diagnosis. To overcome these limitations, FFR can be measured non-invasive through CFD analysis based on geometry models obtained from observational equipment such as coronary computer tomography (CT). However, obtaining this FFR value consumes considerable time and computer resources in the process of vessel shape extraction and CFD. In this study, we propose a non-invasive artificial intelligence-based FFR prediction technology. Methods &amp; Results: The algorithms used in this paper were separated into two steps. The first algorithm is to compute flow features from geometric features trained by synthetic models and CFD analysis. In the second step, we trained classification algorithms and regression algorithms using the flow properties obtained from the first step and patient biometric information. Classification algorithms are used to determine whether to invasive operate, and regression algorithms are used to predict FFR values. The algorithms used are 6 machine learning and 2 neural networks. To improve the performance of the algorithms, outlier data were removed through the IQR method. Among the classification algorithms, random forest had the best accuracy of 80.1%, and in the regression algorithm, artistic neural network had the lowest mean absolute error of 0.04. Furthermore, we analyze the algorithm performance within the gray zone to prove that the algorithm can provide guidance in the case of uncertain situations. Conclusions: Algorithms learned in a two-step manner determined whether the lesion need a surgery or not and predicted the FFR value. In particular, we presented guidelines for building FFR prediction algorithms with good prediction performance.
Abstract P337: CD36 Is Required To Prime Cardiomyocytes For Proliferation
Authors: Aboubakr M Salama, Riham Abouleisa, Qinghui Ou, Ahmed Gibreil, Tamer Mohamed
Journal: Circulation Research (2021)

Many approaches have been explored to regenerate the heart muscle followingischemic injury, out of which is the induction of cardiomyocytes proliferation. Ourprevious work demonstrated that cell-cycle was successfully induced incardiomyocytes by viral expression of combination of four cell-cycle factors: cyclinB1, CDK1, cyclin D1 and CDK4; termed as 4 factors (4F). However, only 15-20 % ofthe cells expressing the four factors progress into cell-cycle, while the remainderare quiescent. A pertinent question in the field of cardiac regeneration is why allviral or in vivo transgenic approaches to induce adult cardiomyocyte proliferation,e.g., 4F, YAP, and CyclinA2, promote proliferation in only a subset ofcardiomyocytes. This general finding suggests that factors or conditions beyondcell-cycle induction influence the probability and perpetuation of cardiomyocytedivision.Here we aim to investigate why only a subpopulation of cardiomyocytes is able toprogress through cell-cycle.Temporal single cell RNA sequencing of 60 days mature hiPS-CMs 24, 48 and 72hours post infection with 4F or control virus revealed that a unique population ofcardiomyocytes in the LacZ control group [1026 cells out of 6761 cells (~15%)] thatdisappears after treatment with 4F; another unique cluster with similar cellnumbers appears 24 h after 4F transduction (Cluster 3), which suggests that theinitial population was primed to proliferate. One of the major characteristics of thisprimed subpopulation is the expression of CD36, a major fatty acids transporter incardiomyocytes, and that 4F induction of cell-cycle completely abolishes CD36expression. knocking down CD36 in hiPS-CMs for 48 hours followed by induction ofproliferation using 4F led to 50-70% reduction in proliferation capacity of thecardiomyocytes compared to the control cells. Furthermore, cardiomyocytesisolated at P7 from CD36 knockout mice showed 30-40 % reduction incardiomyocytes proliferation capacity at baseline and after 4F induction ofproliferation compared to cardiomyocytes isolated from WT controls.These findings suggest that CD36 is needed to prime the CMs to proliferate, andthis can be, at least partially, through provision of energy requirements throughβ-oxidation of fatty acids.
IMMU-48. IMMUNOMODULATION WITH RESIQUIMOD REPOLARIZES THE IMMUNE MICROENVIRONMENT TO INHIBIT MEDULLOBLASTOMA PROGRESSION
Authors: Christopher Park, Coral Del Mar, Morrent Thang, Taylor Dismuke, Duhyeong Hwang, Chaemin Lim, Bhalchandra Mirlekar, Andrew Donson, Rajeev Vibhakar, Marina Sokolsky, Yuliya Pylayeva-Gupta, Timothy Gershon
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND New, non-cytotoxic treatments may improve outcomes for medulloblastoma, the most common malignant pediatric brain tumor. Sonic hedgehog (SHH) subgroup medulloblastoma, which includes subtypes with poor prognosis, can be modeled in immunocompetent, transgenic mice. These models are ideal for preclinical testing of immunotherapies. Here, we show that immune stimulation using resiquimod, a small molecule agonist of Toll-like receptor 7 and 8 (TLR 7/8), alters myeloid populations in medulloblastoma and significantly reduces tumor growth. METHOD We generated mice with medulloblastoma by interbreeding the hGFAP-Cre and SmoM2 mouse lines. The resultant hGFAP-Cre/SmoM2 (G-Smo) mice develop SHH medulloblastoma with 100% frequency. We analyzed myeloid populations and demonstrated TLR7/8 expression patterns in G-Smo tumors. We then compared survival of untreated G-Smo mice versus G-Smo mice treated with three doses of resiquimod at postnatal days 10, 12, and 14. We also assessed pharmacodynamic effects at progressive intervals after a single dose. RESULTS Approximately 10% of cells in G-Smo medulloblastomas were myeloid cells, and these cells were the only cells that expressed TLR7/8. Resiquimod slowed tumor growth and increased the survival of mice with medulloblastoma. Untreated median survival was 14.5 days (n=12), compared to resiquimod-treated median survival of 37 days (n=10; p=0.0003). All treated mice eventually demonstrated tumor progression. Immunohistochemistry for IBA1, a pan-macrophage marker, demonstrated significant increase in myeloid cells within the tumor by 24 hours after treatment (p=0.0178), however the IGF1+ fraction of myeloid cells decreased (p=0.0275). CONCLUSION Resiquimod prolongs survival in mice with SHH-driven medulloblastoma, demonstrating the potential for therapies that target myeloid cells to produce significant anti-tumor effects. Myeloid-derived IGF-1 has been shown to support tumor progression and resiquimod may act by disrupting this paracrine signaling.
Abstract 10815: C-Terminal Src Kinase Inhibits Endothelial Fibrosis and is Upregulated in Early-Stage Experimental Pulmonary Arterial Hypertension
Authors: Bradley M Wertheim, Rui-Sheng Wang, Yingyi Zhang, Andriy O Samokhin, George A Alba, Elena Arons, William M Oldham, Bradley A Maron
Journal: Circulation (2021)

Introduction: Advanced-stage pulmonary arterial hypertension (asPAH) is characterized by endothelial dysfunction and fibrotic remodeling of pulmonary arterioles that promotes irreversible right heart failure. Thus, identifying mechanisms that regulate vascular fibrosis in early PAH (esPAH) may have translational importance. Hypothesis: We hypothesized that profibrotic molecular pathways differentiate esPAH from asPAH. Methods: To test this hypothesis, male Sprague-Dawley rats were administered one dose of monocrotaline (60 mg/kg; day 0) to induce inflammatory PAH. Cardiac catheterization and pulmonary artery endothelial cell (PAEC) transcriptomic analyses were performed on days 15 and 21 for esPAH and asPAH, respectively. Results: The esPAH profile included: right ventricular-pulmonary arterial (RV-PA) uncoupling (1.13 ± 0.05 vs. 0.90 ± 0.06, RV end-systolic elastance/PA elastance, P=0.02, N=6) and increased indexed pulmonary vascular resistance (50 ± 8 vs. 213 ± 29 mmHg*min*g -1 *mL -1 , P&lt;0.001, N=6) without substantial elevation in PA systolic pressure (25 ± 1.2 vs. 33 ± 2.7 mmHg, P=0.02, N=6). Network medicine identified upregulation of c-terminal src kinase (Csk) as a mediator of PAEC fibrosis in esPAH but not asPAH in silico . Pulmonary endothelial expression of Csk protein by immunofluorescence correlated with vascular collagen by picrosirius red stain (r=+0.87, P=0.006, N=4). To validate these findings in vitro , human PAECs (HPAEC) were treated with an inflammatory stimulus of lipopolysaccaride (0.03 mg/mL) + interferon-γ (50 ng/mL) + interleukin-1β (50 ng/mL), or vehicle control (V). Compared to V-control, inflammation increased Csk protein and mRNA expression by 2.3- and 2.0-fold, respectively (P&lt;0.05, N=4). Inflammation also increased HPAEC hydroxyproline, an indicator of collagen abundance, by 3.1-fold (P=1.4x10 -4 , N=4) vs. V-treated cells. Overexpression of Csk by adenovirus transfection attenuated inflammation-mediated hydroxyproline accumulation by 84% (P=1.3x10 -5 , N=3). Conclusions: These data suggest that impaired Csk may underlie HPAEC fibrosis in esPAH, which, in turn, may have potential therapeutic implications for the prevention of fibrotic vascular remodeling and PAH progression.
Abstract 11582: Prognostic Implications of Anatomical Aortic Valve Area in Patients with Bicuspid Aortic Stenosis by Three-Dimensional Transesophageal Echocardiography
Authors: Mika Maeda, Omori Taku, Shunsuke Kagawa, Goki Uno, Takahiro Shiota
Journal: Circulation (2021)

Background: Three-dimensional (3D) transesophageal echocardiography (TEE) provides high-resolution images of aortic valve area (AVA) in patients with bicuspid aortic stenosis (AS). However, the correlation with pressure gradient compared with conventional echocardiographic indices and prognostic implications of 3D TEE derived valve area (AVA 3DTEE ) has not been evaluated. Therefore, we assessed the disease severity and the prognostic value of AVA 3DTEE in patients with bicuspid AS. Methods: We retrospectively analyzed 105 patients with at least mild bicuspid AS (peak aortic velocity &gt;2.5m/sec) and LVEF ≥50% (mean transaortic pressure gradient 46±17 mm Hg) underwent transthoracic echocardiography, two-dimensional (2D) and 3D TEE between 2012 and 2019. AVA was measured using (i) the continuity equation (CE) obtained with transthoracic echocardiography, (ii) planimetric 2D TEE, and (iii) volumetric 3D TEE. Cardiac events were defined as surgical or transcatheter aortic valve replacement and/or aortic replacement, heart failure admission, or cardiac death. Results: AVA 3DTEE was larger than AVA CE (mean difference 0.21±0.03, P &lt;0.001), and smaller than AVA 2DTEE (mean difference 0.11±0.02, P &lt;0.001). AVA 3DTEE had an excellent correlation with mean transaortic pressure gradient (r=0.91, P &lt;0.001), whereas AVA 2DTEE and AVA CE showed lower correlations (r=0.81 and r=0.59, both P &lt;0.001). AVA 3DTEE significantly reduced the proportion of inconsistent AS grading, compared with AVA CE (6% versus 17%, P &lt;0.001). During a follow-up period (median, 853 days; range 513 to 1287 days), 101 surgical or transcatheter aortic valve replacement and/or aortic replacement, 6 heart failure admission, or 1 cardiac death occurred. AVA 3DTEE ≤1cm 2 was an independent predictor of cardiac events (adjusted hazard ratio (HR) 2.40, (1.41 to 4.09), P =0.001) and AVA 3DTEE of 1 cm 2 was the optimal cutoff value for predicting cardiovascular events with sensitivity of 71% and specificity of 100%. Conclusions: AVA measured by 3D TEE has a good correlation with mean transaortic pressure gradient and improved the hitherto inconsistent AS grading. AVA 3DTEE ≤1cm 2 is an important predictor for cardiac events of patients with bicuspid AS.
Abstract 10604: Rs11091046-a Increases the Expression of Angiotensin Ii Receptor 2 Gene by Mir-208a
Authors: Liqun Zhao
Journal: Circulation (2021)

Introduction: Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. The mechanism of AF still remains unknown. In case - control study, we found that rs11091046 located in 3' - UTR of angiotensin II receptor 2 (AGTR2) gene was related to non - familial AF in Chinese Han population. It is necessary to figure out the mechanism of rs11091046 in non - familial AF. Methods: We predicted cohesion change between rs11091046 and miR-208a by RNAhybrid software and confirmed the prediction of cohesion change between rs11091046 and miR-208a by double luciferase reporter system. We detected the expression of AGTR2 gene in right atrium of patients with AF and subjects with sinus rhythm by quantitative real-time PCR. Results: RNAhybrid software showed that the cohesion between 3' - UTR of AGTR2 gene and seed region of miR - 208a was reduced because of the polymorphism of rs11091046 (wide type C mfe: -16.4kcal/mol, mutant type A mfe: -13.7kcal/mol). We also observed that the luciferase activity of transfected cells with miR - 208a and wild - type rs11091046 - C was significantly decreased by 59% while it was relatively enhanced by 22% with miR - 208a and mutant - type rs11091046 - A (Figure 1 up panel). The mRNA level of AGTR2 gene in right atrium of patients with AF was significantly increased compared with subjects with sinus rhythm. The mRNA level of AGTR2 gene in cardiomyocyte transfected by miR - 208a mimic was higher than cardiomyocyte transfected by miR - 208a (Figure 1 down panel). Conclusion: The polymorphism of rs11091046 in AGTR2 gene reduced the cohesion between 3 '- UTR of AGTR2 gene and seed region of miR - 208a, which increased the expression level of AGTR2 gene leading to occurrence of AF. Figure 1 Up panel The relative luciferase activity of transfected cells with wild - type rs11091046 - C and mutant - type rs11091046 - A (BK389: pmirGLO - rs11091046 - C, BK390: pmirGLO - rs11091046 - A). ** P &lt; 0.01. Down panel The mRNA level of AGTR2 gene in cardiomyocyte transfected by miR - 208a mimic and miR - 208a. * P &lt; 0.05.
Protective association of Klotho rs495392 gene polymorphism against hepatic steatosis in non-alcoholic fatty liver disease patients
Authors: Wen-Yue Liu, Xiaofang Zhang, Gang Li, Liang-Jie Tang, Pei-Wu Zhu, Rafael S. Rios, Kenneth I. Zheng, Hong-Lei Ma, Xiao-Dong Wang, Qiuwei Pan, Robert J. de Knegt, Luca Valenti, Mohsen Ghanbari, Ming-Hua Zheng
Journal: Clinical and Molecular Hepatology (2021)

Non-alcoholic fatty liver disease (NAFLD) is closely associated with metabolic dysfunction. Among the multiple factors, genetic variation acts as important modifiers. Klotho, an enzyme encoded by the klotho (KL) gene in human, has been implicated in the pathogenesis of metabolic dysfunctions. However, the impact of variants in KL on NAFLD risk remains poorly understood. The aim of this study was to investigate the impact of KL rs495392 C>A polymorphism on the histological severity of NAFLD. We evaluated the impact of the KL rs495392 polymorphism on liver histology in 531 Chinese with NAFLD and replicated that in the population-based Rotterdam Study cohort. The interactions between the rs495392, vitamin D, and patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 polymorphism were also analyzed. Carriage of the rs495392 A allele had a protective effect on steatosis severity (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.42-0.89; P=0.010) in Chinese patients. After adjustment for potential confounders, the A allele remained significant with a protective effect (OR, 0.66; 95% CI, 0.45-0.98; P=0.040). The effect on hepatic steatosis was confirmed in the Rotterdam Study cohort. Additional analysis showed the association between serum vitamin D levels and NAFLD specifically in rs495392 A allele carriers, but not in non-carriers. Moreover, we found that the rs495392 A allele attenuated the detrimental impact of PNPLA3 rs738409 G allele on the risk of severe hepatic steatosis. The KL rs495392 polymorphism has a protective effect against hepatic steatosis in patients with NAFLD.