bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pulsed‐Wave Doppler Blood Flow Through the Pulmonary Trunk as a Valuable Method to Determine Cardiac Output Following Myocardial Infarction
Authors: Platt Mathew J , Huber Jason S , Brunt Keith R , Simpson Jeremy A 
Published: November 2023

BackgroundCardiac output (CO) is a valuable measure of cardiac function, both clinically and in small animal models of cardiac injury (e.g., myocardial infarction; MI). As the product of stroke volume and heart rate, CO can be estimated from cardiac volumes acquired from one (i.e., M‐Mode) and two (i.e., single plane ellipsoid formula) dimensional echocardiographic images of the left ventricle (LV). Critically, deformations of the LV following MI (e.g., non‐uniform composition/contractile properties) invalidate the mathematical assumptions imperative to the accurate estimation of CO. Thus, the purpose of this study was to determine if pulsed‐wave Doppler flow through the pulmonary trunk – a structure independent of the remodeling in the ischemic LV – provided an alternative, and more accurate, method to quantify forward CO following MI.MethodsVariations in CO were induced either by transverse aortic constriction (TAC) or MI. CO was calculated from classical LV‐dependent methods (M‐Mode and the single‐plane ellipsoid 2D formula), pulsed‐wave Doppler through the pulmonary trunk (pulmonary flow), and intra‐thoracic flow probe.ResultsIn healthy mice, all three echocardiography methods (M‐Mode, 2D and pulmonary flow) correlated well with flow‐probe derived CO as confirmed by Bland‐Altman analysis. In MI, only pulmonary flow demonstrated both accuracy and precision, retaining the expected positive bias and demonstrating <10mls/min range difference compared to the 20–25mls/min range for either LV‐dependent method. Pulmonary flow CO in MI also demonstrated reduced inter‐ and intra‐user variability, and both an improved internal and external agreement (correlation coefficients) when compared against either M‐Mode or 2D CO calculations.ConclusionsPulmonary flow CO calculated from pulsed‐wave Doppler through the pulmonary trunk was an improved method of estimating CO over LV‐dependent formulae following MI. There was also a significant correlation between pulmonary flow, M‐Mode and 2D measures in healthy and TAC mice, demonstrating pulmonary flow was a comparable estimation of CO in these non‐ischemic conditions. This is relevant in the continuing attempt to more accurately assess cardiac function and particularly, grade preclinical therapies for treating MI.Support or Funding InformationThis work was supported by the Canadian Institutes of Health Research grant (MOP 111159) to J.A. Simpson. J.A. Simpson is a New Investigator of the Heart and Stroke Foundation of Canada.
The p53‐specific inhibitor pifithrin‐α prevents diabetic cardiomyopathy by attenuating the early‐stage apoptosis and improving late‐stage defects in glycolysis and angiogenesis
Authors: Gu Junlian , Cai Lu 
Published: November 2023

RationalElevated expression levels of the tumor suppressor p53 have been associated with various heart diseases, including diabetic cardiomyopathy (DCM). However, its underlying mechanisms are unclear.ObjectEarly cardiac cell apoptosis, the persistent reduction in glucose uptake and utilization, and an inadequate neovascularization may play important roles in the pathogenesis of DCM. The present study observed an upregulation of p53 in the heart of streptozotocin‐induced type 1 diabetes mice compared to nondiabetic mice. The aim of this study was to determine the protective mechanism and effect of pifithrin‐α in DCM.Methods and ResultsFVB mice were treated with five daily injections of 50 mg/kg streptozotocin to induce type 1 diabetes. Both hyperglycemic and age‐matched control mice were treated with or without pifithrin‐α five times a week for 2 months and then kept without treatment until 3 and 6 months. Treatment with pifithrin‐α significantly improved the progression of diabetes‐induced cardiac remodeling and dysfunction (i.e., DCM). Mechanistically, the inhibition of p53 prevented cardiac mitochondrial cell death during early‐stage diabetes (0.5 month) as well as prevented diabetes‐induced impairment of glucose metabolism and angiogenesis by increasing hypoxia‐induced factor (HIF)‐1α protein stability and upregulating the HIF‐1α transcription of specific protective genes at the later stages (3–6 months).ConclusionsThese results demonstrate for the first time that the inhibition of p53‐mediated early‐stage apoptosis and late‐stage defective glycolysis and angiogenesis effectively prevents the development of DCM, thereby suggesting that an intervention involving P53 may be a potential approach for the prevention of DCM.
Blood Plasma Concentration and Activity of Pancreatic Lipase, Pancreatic Trypsin, MMP‐9, and Elastase in Congestive Heart Failure
Authors: Courelli Vasiliki , Courelli Asimina , Stimson Ella , Modestino Augusta , Mills Paul , Schmid‐Schoenbein Geert 
Published: November 2023

Recent evidence suggests that pancreatic digestive enzymes may be involved in several types of organ dysfunction. This may include heart disease, but no studies exist. We hypothesize that pancreatic trypsin, pancreatic lipase, MMP‐9, and elastase may be present in blood and cardiac muscle in patients with congestive heart failure (CHF). Pancreatic enzymes may leak out of the small intestinal lumen, enter the systemic circulation and, ultimately, cause damage of the heart muscle. Pancreatic proteases, such as trypsin, are capable of activating other proteases, such as MMP‐9. Blood was drawn from 20 patients (10 CHF and 10 non‐CHF patients) while at rest. Western Blots showed a significant increase in plasma pancreatic lipase, trypsin, and MMP‐9 levels for the CHF patients when compared to non‐CHF patients. Activity assay results showed a significant increase in plasma MMP‐2/9 activity levels in CHF compared to non‐CHF patients but no differences in trypsin and elastase activity. These pilot experiments suggest that elevated plasma trypsin, lipase, and MMP‐9 concentrations as well as plasma MMP2/9 activity are correlated with CHF, may play a role in the loss of cardiac function, and may serve as potential biomarkers for CHF.Support or Funding InformationNIH Grants: 5 R01 HL073355‐01, GM 85072
Fibrinogen alpha is the precursor protein of cardiac valve amyloidosis
Authors: Miura Katsutoshi , Katoh Hideki , Tsuchida Takashi 
Published: November 2023

Amyloid deposits are frequently found in degenerated cardiac valves of elderly patients. However, their precursor proteins have not detected to date. The aim of this study is to analyze the contents to reveal their original proteins.Materials and MethodsAmyloid fibrils (AFs) were collected from fresh cardiac valves of aortic stenosis patients. AFs were separated by saline precipitation, collagenase or pepsin digestion and water extraction. AFs were dissolved in 6 M urea and isolated by SDS‐PAGE. Main bands in the gel were analyzed by MS spectrometry.Several candidate proteins were picked up and their location on the histological sections were detected by immunohistochemistry. Fibronectins, fibrinogen alpha chains (FGA), vitronectins, lysozymes and complement 3 were stained whether they were co‐localized with amyloid.ResultsOnly FGA were revealed to be present with amyloid deposits. FGA were scattered in the valves with random orientation and some areas showed co‐localization with amyloid deposits.ConclusionFGA is the precursor protein of localized cardiac valve amyloidosis.Support or Funding InformationThis work was supported by the Japan Society for the Promotion of Science KAKENHI, Scientific Research Grant Number (c) 15K08375.
Dipeptidyl Peptidase‐4 (DPP‐4) inhibition with linagliptin reduces the induction of proinflammatory/profibrotic TRAF3IP2 in the hearts of female mice fed a Western Diet
Authors: Aroor Annayya , Kandikattu Hemanthkumar , Habibi Javad , Garro Mona , Klein Thomas , Sowers James R , Valente Anthony J , DeMarco Vincent , Bysani Chandrasekar 
Published: November 2023

Recently we reported that the cytoplasmic adapter molecule TRAF3 Interacting Protein 2 (TRAF3IP2) is a major mediator of myocardial inflammation, hypertrophy, fibrosis, and dysfunction induced by chronic activation of the renin‐angiotensin‐aldosterone system. Whether TRAF3IP2 and its downstream intermediates contribute to western diet (WD)‐induced myocardial fibrosis and dysfunction is not known. We have previously reported that the DPP‐4 inhibitor linagliptin prevents diastolic dysfunction and myocardial fibrosis in female mice fed a western diet (WD) high in fat and refined sugars. We hypothesized that WD induces myocardial overexpression of TRAF3IP2 and activation of downstream signaling intermediates, and their induction can be prevented by linagliptin. We fed 4‐week old mice a WD with or without linagliptin (83mg•kg−1diet) for 16 weeks, and evaluated diastolic function, cardiac TRAF3IP2 expression, transcription factor and p38 MAP kinase activation. WD feeding induced a two‐fold increase in TRAF3IP2 expression, with similar increases in the activation of pro‐inflammatory and pro‐fibrotic transcription factors p65 (Ser536) and c‐Jun (Ser63), and the stress‐activated kinase p38 MAPK (Thr180/Thy182). Importantly, linagliptin inhibited their activation. Our results demonstrate for the first time the induction of myocardial TRAF3IP2 protein expression and downstream proinflammatory/profibrotic signaling intermediates in a translationally relevant model of diet‐induced obesity. Therapeutic targeting of DPP‐4 with linagliptin or pharmacological inhibition of TRAF3IP2 may be a promising strategy for prevention of cardiac inflammation, dysfunction and fibrosis in females with obesity/diabetes.Support or Funding InformationThis work was supported by unrestricted funding from Boehringer Ingelheim (VGD). Additional support was provided by the National Institutes of Health [R01‐HL073101 RO1‐HL107910 to JRS], Veterans Affairs Merit System (I01‐BX002255 to BC and 0018 to JRS).
Comparison between anti‐β2 Glycoprotein I antibody and anti‐phosphatidylserine/prothrombin antibody pro‐thrombotic effects on peripheral blood monocytes and endothelial cells
Authors: Cifu' Adriana , Fabris Martina , Pistis Cinzia , Domenis Rossana , Quaglia Sara , Curcio Francesco 
Published: November 2023

BACKGROUNDAntiphospholipid Syndrome (APS) is a systemic autoimmune disease characterized by vascular thrombosis (venous or arterial) and/or adverse obstetric outcomes, accompanied by persistent and elevated levels of antiphospholipid (aPL) antibodies, namely lupus anticoagulant (LA), anticardiolipin (aCL) and anti‐β2 glycoprotein I (aβ2GpI) antibodies. However, there are several other aPL that are still not included in the diagnostic criteria, but that can be useful to better define the so‐called seronegative APS patients (negative for LA, aCL and aβ2GpI), such as anti‐phosphatidylserine/prothrombin (aPS/PT) antibodies. The aim of this study was to compare the pro‐thrombotic effects of aβ2GpI IgG and aPS/PT IgG antibodies on peripheral blood mononuclear cells (PBMC) and human umbilical vein endothelial cells (HUVEC) to support the independent role of aPS/PT in APS pathogenesis and diagnosis.METHODSPBMC isolated from blood donors (BD) and HUVEC (Life Technologies) were incubated four hours with lipopolysaccharides (LPS) alone or in combination with the IgG fraction obtained from a pool sera of BD (as control), and from a pool sera of 3 APS patients who were positive only for IgG aβ2GpI and from 3 APS patients who were positive only for IgG aPS/PT. TF mRNA up‐regulation, expressed as fold increase in respect to unstimulated cells, was measured by real‐time PCR. The experiments were done in triplicate.RESULTSCompared to treatment with LPS alone (6.4±1) or LPS plus the IgG fraction isolated from BD (6.5±1.7), PBMC stimulated either with LPS plus aβ2GpI IgG or with LPS plus aPS/PT IgG demonstrated an increased expression of TF (respectively 8.2±0.9 and 9.4±1.3; vs LPS + BD IgG p<0.05), but no difference was found between aβ2GpI and aPS/PT.Similarly, the HUVEC stimulated with LPS plus aβ2GpI or aPS/PT displayed a significant increase of TF expression (respectively 90±7 and 87±2) compared to stimulation with LPS alone (18.4±5; p=0.04) or plus the IgG fraction from BD (9.45±2.9; p=0.01).CONCLUSIONSThis is the first direct comparison between the aβ2GpI and aPS/PT pro‐thrombotic effects in vitro on monocytes and endothelial cells. Our data show that both aβ2GpI and aPS/PT antibodies were able to upregulate TF expression in monocytes and HUVEC pre‐activated with LPS. As expected, the effect was stronger in endothelial cells than in monocytes, but no difference was appreciated between aβ2GpI and aPS/PT. These results suggest that aPS/PT antibodies exert an independent role on APS‐related manifestations.
Sepsis‐Associated Elastase and Proteinase 3 Induce Endothelial Permeability
Authors: Patterson Eric K , Cepinskas Gediminas K , Inoue Ken , Fraser Douglas D 
Published: November 2023

Sepsis is a systemic inflammatory response to known or suspected infection, and associated with microvascular dysfunction and capillary leak. The cause of capillary leak may be due to substances released by activated polymorphonuclear neutrophils (PMNs) that adhere to microvascular endothelial cells. Following binding, PMN often degranulate releasing azurophilic enzymes (e.g. elastase (HLE) and proteinase 3 (PR3)) at the endothelial surface and into plasma. We hypothesized that the actions of these enzymes, particularly HLE and PR3 contribute to the loss of endothelial integrity.Patients with severe sepsis (sepsis with evidence of at least one organ dysfunctioning), were recruited on admission to the intensive care unit. Patient samples were paired with age and sex‐matched controls. The mean age was 54 ± 12 and 52 ± 11 years for sepsis and controls respectively while both groups had 6/15 males. Septic patient pathogens were determined to be 4 gram positive, 7 gram negative, 1 fungal and 3 culture negative. We employed ELISAs to determine plasma HLE and PR3 concentrations and in vitro assays using human umbilical vein endothelial cells (HUVEC) treated with HLE or PR3. HUVEC monolayer resistance and Texas Red‐Dextran flow‐through were used to determine the enzyme's effect on monolayer integrity.The sepsis plasma concentrations were significantly higher (p < 0.0001) compared to healthy volunteers in both HLE (224 ± 66.0 vs 13.9 ± 0.899 ng/mL) and PR3 (52.2 ± 7.63 vs 8.02 ± 2.18 ng/mL). For in vitro assays, we employed concentrations of HLE and PR3 higher than the plasma measurements in order to more closely mimic conditions at the site of degranulation. Treatment with 1, 2 or 5 μg/mL of either enzyme significantly decreased HUVEC monolayer resistance over the course of 90 minutes compared to control. Further, 1 hour of HLE or PR3 treatment significantly increased HUVEC permeability to Texas Red‐Dextran compared to controls.The loss of endothelial integrity secondary to azurophilic enzyme release by adhered PMNs could result in microvascular dysfunction and capillary leak. Endothelial injury could also exacerbate further PMN recruitment. We conclude that neutrophil degranulation, as evidenced by increased plasma concentrations, can lead to increased endothelial permeability through a mechanism which in part involves the actions of HLE and PR3.Support or Funding InformationFunded by the Lawson Health Research Institute Internal Research Fund.
Activation of AXL Receptor via Gas6 induces Preeclampsia in Rats
Authors: Dunaway Todd M , Lewis Joshua B , Hirschi Kelsey M , Mejia Camilo A , Mejia Juan F , Hall Parker D , Reynolds Paul R , Arroyo Juan A 
Published: November 2023

Preeclampsia (PE) is a complicated obstetric complication characterized by increased blood pressure and decreased trophoblast invasion. The growth arrest‐specific 6 (Gas6) protein is known to induce dynamic cellular responses and is elevated in PE. This discovery suggests a mechanistic role for the Gas6 signaling pathway during PE progression. Gas6 binds to the AXL tyrosine kinase receptor and AXL‐mediated signaling is implicated in proliferation and migratory mechanisms in several tissues. Our objective was to determine the role of Gas6 and AXL signaling in the development of PE in the rat.We utilized Gas6 to induce preeclamptic conditions in pregnant rats. Briefly, pregnant rats were divided into 3 groups that received daily ip injections of PBS, Gas6, or Gas6 + R428 (an AXL inhibitor). Treatment was done from embryonic day 7.5 (E7.5) to E18.5, at which time they were euthanized and tissues were harvested for histological and molecular characterization. Fetal and placental weights were recorded. Blood pressure, proteinuria and cell invasion was determined. We additionally characterized inflammatory conditions in the maternal lung due to links between respiratory sufficiency, placentation, and fetal health. Bronchoalveolar lavage fluid (BALF) was procured from maternal lungs for the assessment of inflammatory cells and cytokine secretion. Western blot was performed to determine AXL protein expression. We observed: increased proteinuria and elevated blood pressure in Gas6 treated animals, but each were inhibited by R428; placental and fetal weights revealed no significant changes among groups; immunohistochemical analysis revealed decreased trophoblast invasion in animals treated with Gas6. BALF revealed elevated cell diapedesis in Gas6 animals, which was absent in animals given R428. Quantitative RT‐PCR and immunoblotting revealed increased expression of RAGE (a pattern recognition receptor implicated in inflammation), AXL, and pro‐inflammatory cytokines TNF‐α and IL‐1β. We conclude that Gas6 signaling is capable of inducing PE and that inhibition of AXL receptor prevents disease progression in pregnant rats. These data suggest roles for Gas6/AXL in the development of PE and offer possible treatment avenues that could help in alleviating PE symptoms.
Revealing Age‐Associated Genetic Alterations in Mouse Oocytes by Single‐Cell Exome Sequencing
Authors: Lee Tin‐Lap , Qian Yan , Liao Jinyue , Zeng Xi , Tsui Kwok‐Wing Stephen , Li Tin‐Chiu , Chan Wai‐Yee 
Published: November 2023

Advanced maternal age refers to women giving birth at the age of over 35. It has established that the condition links to inferior fertilization rate and higher genetic risks in the offspring. Despite external factors like hormones and follicular cells have been reported to associate with maternal aging, the genetic contribution remains largely elusive.Due to the limitation of experimental technologies and the limited amount of sample materials, oocyte per se is seldom studied previously, especially in the field of genetic alterations. In this study, we aimed to identify natural and accelerated aging‐related genetic alterations, including single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) in mouse oocyte through novel single‐cell based whole exome sequencing. Four groups of female mice consisted of a young group (6‐weeks‐old), a natural aging group (36‐weeks‐old), an accelerated aging group (treated by 4‐Vinycyclohexene diepoxide, VCD) and a vehicle group (treated by sesame oil) were mated with an adult male. The DNA samples derived from maternal oocyte and blood, and those from offspring and male mice were collected, followed by whole exome sequencing and bioinformatics analyses. De novo DNA variations (DVs) were identified in both natural and accelerated aging groups. Genes associated with aging‐related diseases (Ttn, Macf1) were identified. We also detected de novo germline variations (DNGVs) that may contribute to implantation and embryonic development. Finally, we identified an aberrant CNV region associated natural aging oocytes, where it contained genes involved in cell apoptosis, aging diseases and reproduction.Taken together, our study highlighted the key genetic targets associated with oocyte aging. The data allows dissecting the aging mechanisms that contribute to subfertility in women with advanced maternal age.
An Integrated Study of Gene Expression Profile Uncovers Similarity between Embryogenesis, Bone Development, Wound Healing, and Prostate Cancer
Authors: Rayburn Tyeler S , Mukherjee Angana , Byrd William A , Jones Jacqueline 
Published: November 2023

Embryogenesis, bone development, wound healing and cancer are intersecting processes that share common metabolic processes, growth factors and transcription factors. While solid tumors are controllable, bone metastases remain a death sentence, which is due to the complex area of the bone. Interestingly, studies have shown that 100% of prostate cancer deaths involve bone metastases. Although the role of transcription factors in embryogenesis, bone development, wound healing, and prostate cancer are studied separately, the overlapping of factors or genes across the processes remains unexplored. This study aims to develop an approach for identifying the overlapping gene signatures and analyzing their expression and correlation with embryogenesis, bone development, wound healing, and prostate cancer. We extracted data for the 4 processes from Gene Expression Omnibus (GEO); accession numbers: GSE18290 (n=9), GSE51812 (n=12), GSE24742 (n=12) and GSE3325 (n=19). Twenty overlapping genes were randomly identified and statistical analysis performed to compare the gene expressions across all the processes. Most genes in a cluster analysis exhibited common expression patterns in all the processes. Interestingly, a PCA analysis revealed a clear positive correlation between prostate cancer and bone development. Furthermore RUNX2, FGFR1, TWIST1, FOXP1, FOXA1, NKFB1, ELF1, PDGFA, IL6, JAG1, JAG2, and PDGFA were significantly up‐regulated in prostate cancer. Thus, we concluded that the transcription factors that play a role in the fundamental processes of early bone development, embryogenesis, and wound healing also play a critical role in prostate cancer bone metastases. We have identified, using a novel gene expression profiling together with a meta‐analysis validation approach, a set of overlapping gene signatures in embryogenesis, bone development, wound healing and prostate cancer, which can be used as prognostic markers for prostate cancer bone metastasis.Support or Funding InformationThis work was supported by the Department of Environmental and Biological Sciences, Troy University.