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Pubblicazioni recenti - cardiac stem
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Comparative Assessment of the Methanol Extracts of the Leaf, Stem, and Root Barks of on Lung and Breast Cancer Cell Lines.
Turk J Pharm Sci2019 Dec;16(4):375-379. doi: 10.4274/tjps.galenos.2018.19942.
Oikpefan Emmanuel Oise, Ayinde Buniyamin Adesina, Mudassir Azhar, Farooq Ahsana Dar,
Abstract
Objectives:
Mill. I.M.Johnst. is a medicinal plant widely used in ethnomedicine for the treatment of cancer and other diseases.
Materials and Methods:
The effects of methanol extracts of the leaf, stem, and root barks were evaluated on breast (MCF-7) and lung (NCI-H460) cancer cells at 1-250 ?g/mL using the SRB assay and the extracts were screened for phytochemicals using the standard method.
Results:
The stem and root extracts showed no activity at the maximum concentration, while the leaf extract at 100 ?g/mL showed remarkable cell growth inhibition against breast (-14.50±0.58) and lung cancer (+53.29±4.57) in vitro. The extracts showed the presence of saponins, terpenes, cardiac glycosides, and phenolic compounds. Partitioning of the active leaf extract further enhanced its activity as the chloroform fraction exhibited GI, LC, and total growth inhibition (TGI) of 22.5, 68.75, and 43.75 ?g/mL against breast cancer, respectively, and GI and TGI of 35.4 and 55.8 ?g/ mL against lung cancer cells, respectively. However, the aqueous fraction showed no cytotoxicity against either cell line.
Conclusion:
These results justified the ethnomedicinal uses of the plant against tumor-related ailments. Isolation of the constituents responsible for the observed activity needs to be carried out to further support this claim.
©Copyright 2019 Turk J Pharm Sci, Published by Galenos Publishing House.
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Paradoxical aortic stiffening and subsequent cardiac dysfunction in Hutchinson-Gilford progeria syndrome.
J R Soc Interface2020 May;17(166):20200066. doi: 10.1098/rsif.2020.0066.
Murtada S-I, Kawamura Y, Caulk A W, Ahmadzadeh H, Mikush N, Zimmerman K, Kavanagh D, Weiss D, Latorre M, Zhuang Z W, Shadel G S, Braddock D T, Humphrey J D,
Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare disorder with devastating sequelae resulting in early death, presently thought to stem primarily from cardiovascular events. We analyse novel longitudinal cardiovascular data from a mouse model of HGPS () using allometric scaling, biomechanical phenotyping, and advanced computational modelling and show that late-stage diastolic dysfunction, with preserved systolic function, emerges with an increase in the pulse wave velocity and an associated loss of aortic function, independent of sex. Specifically, there is a dramatic late-stage loss of smooth muscle function and cells and an excessive accumulation of proteoglycans along the aorta, which result in a loss of biomechanical function (contractility and elastic energy storage) and a marked structural stiffening despite a distinctly low intrinsic material stiffness that is consistent with the lack of functional lamin A. Importantly, the vascular function appears to arise normally from the low-stress environment of development, only to succumb progressively to pressure-related effects of the lamin A mutation and become extreme in the peri-morbid period. Because the dramatic life-threatening aortic phenotype manifests during the last third of life there may be a therapeutic window in maturity that could alleviate concerns with therapies administered during early periods of arterial development.
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Intravenously delivered mesenchymal stem cells prevent microvascular obstruction formation after myocardial ischemia/reperfusion injury.
Basic Res Cardiol2020 May;115(4):40. doi: 10.1007/s00395-020-0800-8.
Wang Junzhuo, Chen Ziwei, Dai Qing, Zhao Jinxuan, Wei Zilun, Hu Jiaxin, Sun Xuan, Xie Jun, Xu Biao,
Abstract
Microvascular obstruction (MVO) after primary percutaneous coronary intervention (pPCI) is identified as an independent risk factor for poor prognosis in patients with acute myocardial infarction (AMI). The inflammatory response induced by ischemia and reperfusion (I/R) injury is considered one of the main mechanisms of MVO. Mesenchymal stem cells (MSCs) are a unique stromal cell type that confers an immunomodulatory effect in cardiac disease. The present study aimed to investigate whether immediate intravenous delivery of MSCs could be used as a potential therapeutic method to attenuate MVO formation. A cardiac catheterization-induced porcine model of myocardial I/R injury was established, and allograft MSCs were immediately delivered intravenously. Cardiac magnetic resonance (CMR) imaging was performed on days 2 and 7 after the operation to determine the infarct area, MVO, and cardiac function. The pigs with allograft MSCs showed decreased MVO and infarct size, as well as an improved left ventricular ejection fraction (LVEF). Histological analysis revealed decreased myocyte area, fibrosis, and inflammatory cell infiltration in the peri-infarct zone of pigs with allograft MSCs. Moreover, the concentrations of interleukin-1? (IL-1?), interleukin-6 (IL-6) and C-reactive protein (CRP) in the serum were reduced in the allograft MSC group compared to the control group. Flow cytometry indicated decreased natural killer (NK) cells in the peripheral blood and ischemic heart tissue in the pigs with allograft MSCs. In summary, allograft MSCs delivered intravenously and immediately after myocardial I/R injury can attenuate MVO formation in a porcine model through a decline in the number of NK cells in the myocardium.
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Toxicological evaluation of exosomes derived from human adipose tissue-derived mesenchymal stem/stromal cells.
Regul Toxicol Pharmacol2020 May;():104686. doi: S0273-2300(20)30112-4.
Ha Dae Hyun, Kim Sun-Don, Lee Joon, Kwon Hyuck Hoon, Park Gyeong-Hun, Yang Steve Hoseong, Jung Jae Yoon, Lee Jun Ho, Park Sang Rae, Youn Jinkwon, Lee Sang Hee, Kim Ji Eun, Lim Jihye, Lee Hyun-Kul, Cho Byong Seung, Yi Yong Weon,
Abstract
Several studies report that the therapeutic mechanism of action of mesenchymal stem/stromal cells (MSCs) is mainly mediated by paracrine factors that are released from MSCs such as exosomes. Exosomes are nano-sized extracellular vesicles that are transferred to target cells for cell-to-cell communication. Although MSC-derived exosomes (MSC-exosomes) are suggested as novel cell-free therapeutics for various human diseases, evaluation studies for the safety and toxicity of MSC-exosomes are limited. The purpose of our study was to evaluate the toxicological profile, including skin sensitization, photosensitization, eye and skin irritation, and acute oral toxicity using exosomes derived from human adipose tissue-derived MSCs (ASC-exosomes) in accordance with the OECD guidelines and the principles of Good Laboratory Practice. The ASC-exosomes were classified as a potential non-sensitizer in the skin sensitization test, UN GHS no category in the eye irritation test, and as a skin non-irritant in the skin irritation test, and did not induce any toxicity in the phototoxicity test or in acute oral toxicity testing. Our findings are the first to suggest that ASC-exosomes are safe for use as a topical treatment, with no adverse effects in toxicological testing, and have potential application as a therapeutic agent, cosmetic ingredient, or for other biological uses.
Copyright © 2020. Published by Elsevier Inc.
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Model of Ischemic Heart Disease and Video-Based Comparison of Cardiomyocyte Contraction Using hiPSC-Derived Cardiomyocytes.
J Vis Exp2020 May;(159):. doi: 10.3791/61104.
Liu Yun, Liang Yin, Wang Mengxue, Wang Chen, Wei Heng, Naruse Keiji, Takahashi Ken,
Abstract
Ischemic heart disease is a significant cause of death worldwide. It has therefore been the subject of a tremendous amount of research, often with small-animal models such as rodents. However, the physiology of the human heart differs significantly from that of the rodent heart, underscoring the need for clinically relevant models to study heart disease. Here, we present a protocol to model ischemic heart disease using cardiomyocytes differentiated from human induced pluripotent stem cells (hiPS-CMs) and to quantify the damage and functional impairment of the ischemic cardiomyocytes. Exposure to 2% oxygen without glucose and serum increases the percentage of injured cells, which is indicated by staining of the nucleus with propidium iodide, and decreases cellular viability. These conditions also decrease the contractility of hiPS-CMs as confirmed by displacement vector field analysis of microscopic video images. This protocol may furthermore provide a convenient method for personalized drug screening by facilitating the use of hiPS cells from individual patients. Therefore, this model of ischemic heart disease, based on iPS-CMs of human origin, can provide a useful platform for drug screening and further research on ischemic heart disease.
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Improvement in circulating endothelial progenitor cells pool after cardiac resynchronization therapy: increasing the list of benefits.
Stem Cell Res Ther2020 May;11(1):194. doi: 10.1186/s13287-020-01713-8.
Cristóvão Gonçalo, Milner James, Sousa Pedro, Ventura Miguel, Cristóvão João, Elvas Luís, Paiva Artur, Gonçalves Lino, Ribeiro Carlos Fontes, António Natália,
Abstract
BACKGROUND:
Recent studies suggest that circulating endothelial progenitor cells (EPCs) may influence the response to cardiac resynchronization therapy (CRT). The aim of this study was to evaluate the effect of CRT on EPC levels and to assess the impact of EPCs on long-term clinical outcomes.
POPULATION AND METHODS:
Prospective study of 50 patients submitted to CRT. Two populations of circulating EPCs were quantified previously to CRT implantation: CD34KDR and CD133KDR cells. EPC levels were reassessed 6?months after CRT. Endpoints during the long-term follow-up were all-cause mortality, heart transplantation, and hospitalization for heart failure (HF) management.
RESULTS:
The proportion of non-responders to CRT was 42% and tended to be higher in patients with an ischemic vs non-ischemic etiology (64% vs 35%, p =?0.098). Patients with ischemic cardiomyopathy (ICM) showed significantly lower CD34KDR EPC levels when compared to non-ischemic dilated cardiomyopathy patients (DCM) (0.0010?±?0.0007 vs 0.0030?±?0.0024 cells/100 leukocytes, p =?0.032). There were no significant differences in baseline EPC levels between survivors and non-survivors nor between patients who were rehospitalized for HF management during follow-up or not. At 6-month follow-up, circulating EPC levels were significantly higher than baseline levels (0.0024?±?0.0023 vs 0.0047?±?0.0041 CD34KDR cells/100 leukocytes, p =?0.010 and 0.0007?±?0.0004 vs 0.0016 vs 0.0013 CD133/KDR cells/100 leukocytes, p =?0.007).
CONCLUSIONS:
Patients with ICM showed significantly lower levels of circulating EPCs when compared to their counterparts. CRT seems to improve the pool of endogenously circulating EPCs and reduced baseline EPC levels seem not to influence long-term outcomes after CRT.
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An integrated pipeline for high-throughput screening and profiling of spheroids using simple live image analysis of frame to frame variations.
Methods2020 May;():. doi: S1046-2023(19)30300-7.
Alsehli Haneen, Mosis Fuad, Thomson Christopher, Hamrud Eva, Wiseman Erika, Gentleman Eileen, Danovi Davide,
Abstract
High throughput imaging methods can be applied to relevant cell culture models, fostering their use in research and translational applications. Improvements in microscopy, computational capabilities and data analysis have enabled high-throughput, high-content approaches from endpoint 2D microscopy images. Nonetheless, trade-offs in acquisition, computation and storage between content and throughput remain, in particular when cells and cell structures are imaged in 3D. Moreover, live 3D phase contrast microscopy images are not often amenable to analysis because of the high level of background noise. Cultures of Human induced pluripotent stem cells (hiPSC) offer unprecedented scope to profile and screen conditions affecting cell fate decisions, self-organisation and early embryonic development. However, quantifying changes in the morphology or function of cell structures derived from hiPSCs over time presents significant challenges. Here, we report a novel method based on the analysis of live phase contrast microscopy images of hiPSC spheroids. We compare self-renewing versus differentiating media conditions, which give rise to spheroids with distinct morphologies; round versus branched, respectively. These cell structures are segmented from 2D projections and analysed based on frame-to-frame variations. Importantly, a tailored convolutional neural network is trained and applied to predict culture conditions from time-frame images. We compare our results with more classic and involved endpoint 3D confocal microscopy and propose that such approaches can complement spheroid-based assays developed for the purpose of screening and profiling. This workflow can be realistically implemented in laboratories using imaging-based high-throughput methods for regenerative medicine and drug discovery.
Copyright © 2020. Published by Elsevier Inc.
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Effects of stem bark aqueous extract of Fagara tessmannii Engl (Rutaceae) on cardiovascular risks related to monosodium glutamate-induced obesity in rat: In vivo and in vitro assessments.
J Ethnopharmacol2020 May;():112972. doi: S0378-8741(19)34998-0.
Fouda Yannick Bekono, Lemba Tom Esther Ngo, Atsamo Albert Donatien, Bonabe Christian, Dimo Théophile,
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE:
Fagara tessmannii is a shrub of the African rainforests in South-West, Centre, South and East provinces in Cameroon. It is used in traditional medicine for the treatment of tumors, swellings, inflammation, gonorrhoea, schistosomiasis, antifungal, heart diseases and as anti-hypertensive.
AIM OF THE STUDY:
We investigated the potential effects of F. tessmannii on cardiovascular risk related to monosodium glutamate-induced obesity.
MATERIALS AND METHODS:
Monosodium glutamate (MSG, 4?mg/g/day) was injected subcutaneously to newborn Wistar rats for the four consecutive first days of their life and on the 6th, 8th and 10th day after birth. After 21 weeks, obese rats were treated orally with F. tessmannii (100 or 200?mg/kg/day), orlistat (10?mg/kg/day) or telmisartan (10?mg/kg/day) for 6 weeks. Body weight, obesity, body mass index (BMI), Lee index, insulin sensitivity and glucose tolerance, blood pressure, lipid profile as a Coronary Risk Index (CRI), and reactivity of isolated thoracic aorta were evaluated.
RESULTS:
In addition to significantly decrease body weight (17.60% and 20.34%), BMI, Lee's index, retroperitoneal fat, total adiposity, and coronary risk indicators, F. tessmannii has significantly decreased insulin resistance and hyperglycemia and high blood pressure observed in MSG-obese rats. The high contractility to phenylephrine as well as the hypersensitivity to sodium nitroprusside (a nitric oxide-donor), observed in MSG aortic rings were significantly reduced by the F. tessmannii extract. Enhanced serum Na and Cl levels and decreased K observed in obese rats were also significantly reversed after F. tessmannii treatment.
CONCLUSIONS:
F. tessmannii fights against obesity and associated cardiovascular risks by modulating production and vascular responsiveness to vasoactive factors, monitoring premature aging. F. tessmannii promotes the loss of ectopic fat and other fatty tissues, the sensitivity of the peripherical tissues to insulin, the energy expenditure and the renovascular decompression and regulates ions movement which prevents hypertension.
Copyright © 2020. Published by Elsevier B.V.
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From the gut to the heart: L. plantarum and inulin administration as a novel approach to control cardiac apoptosis via 5-HT2B and TrkB receptors in diabetes.
Clin Nutr2020 May;():. doi: S0261-5614(20)30220-X.
Sefidgari-Abrasi Safa, Roshangar Leila, Karimi Pouran, Morshedi Mohammad, Rahimiyan-Heravan Marziyeh, Saghafi-Asl Maryam,
Abstract
BACKGROUND & AIMS:
Type 2 diabetes mellitus, as a metabolic disorder, can lead to diabetic cardiomyopathy, identified by cardiomyocyte apoptosis and myocardial fibrosis. Brain-derived neurotrophic factor (BDNF) and serotonin are two neurotransmitters that can control cardiomyocyte apoptosis and myocardial fibrosis through their cardiac receptors. In the present study, we investigated the impacts of L. plantarum and inulin supplementation on the inhibition of cardiac apoptosis and fibrosis by modulating intestinal, serum, and cardiac levels of serotonin and BDNF as well as their cardiac receptors.
METHODS:
Diabetes was induced by a high-fat diet and streptozotocin in male Wistar rats. Rats were divided into six groups and were supplemented with L. plantarum, inulin or their combination for 8 weeks. Finally, the rats were killed and levels of intestinal, serum, and cardiac parameters were evaluated.
RESULTS:
Concurrent administration of L. plantarum and inulin caused a significant rise in the expression of cardiac serotonin and BDNF receptors (P < 0.001) as well as a significant fall in cardiac interstitial and perivascular fibrosis (P < 0.001, both) and apoptosis (P = 0.01). Moreover, there was a strong correlation of cardiac 5-Hydroxytryptamine 2B (5-HT2B) and tropomyosin receptor kinase B (TrkB) receptors with interstitial/perivascular fibrosis and apoptosis (P < 0.001, both).
CONCLUSIONS/INTERPRETATION:
Results revealed beneficial effects of L. plantarum, inulin or their combination on intestinal, serum, and cardiac serotonin and BDNF accompanied by higher expression of their cardiac receptors and lower levels of cardiac apoptotic and fibrotic markers. It seems that L. plantarum and inulin supplementation could be considered as a novel adjunct therapy to reduce cardiac complications of type 2 diabetes mellitus.
Copyright © 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
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Suppression of p38-MAPK endows endoderm propensity to human embryonic stem cells.
Biochem Biophys Res Commun2020 May;():. doi: S0006-291X(20)30859-7.
Taei Adeleh, Samadian Azam, Ghezel-Ayagh Zahra, Mollamohammadi Sepideh, Moradi Sharif, Kiani Tahereh, Janzamin Ehsan, Farzaneh Zahra, Tahamtani Yaser, Braun Thomas, Hassani Seyedeh-Nafiseh, Baharvand Hossein,
Abstract
The ability of human embryonic stem cells (hESCs) to proliferate unlimitedly and give rise to all tissues makes these cells a promising source for cell replacement therapies. To realize the full potential of hESCs in cell therapy, it is necessary to interrogate regulatory pathways that influence hESC maintenance and commitment. Here, we reveal that pharmacological attenuation of p38 mitogen-activated protein kinase (p38-MAPK) in hESCs concomitantly augments some characteristics associated with pluripotency and the expressions of early lineage markers. Moreover, this blockage capacitates hESCs to differentiate towards an endoderm lineage at the expense of other lineages upon spontaneous hESC differentiation. Notably, hESCs pre-treated with p38-MAPK inhibitor exhibit significantly improved pancreatic progenitor directed differentiation. Together, our findings suggest a new approach to the robust endoderm differentiation of hESCs and potentially enables the facile derivation of various endoderm-derived lineages such as pancreatic cells.
Copyright © 2020 Elsevier Inc. All rights reserved.
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Human pluripotent stem cell-derived cardiac stromal cells and their applications in regenerative medicine.
Stem Cell Res2020 Apr;45():101831. doi: S1873-5061(20)30132-X.
Floy Martha E, Mateyka Taylor D, Foreman Koji L, Palecek Sean P,
Abstract
Coronary heart disease is one of the leading causes of death in the United States. Recent advances in stem cell biology have led to the development and engineering of human pluripotent stem cell (hPSC)-derived cardiac cells and tissues for application in cellular therapy and cardiotoxicity studies. Initial studies in this area have largely focused on improving differentiation efficiency and maturation states of cardiomyocytes. However, other cell types in the heart, including endothelial and stromal cells, play crucial roles in cardiac development, injury response, and cardiomyocyte function. This review discusses recent advances in differentiation of hPSCs to cardiac stromal cells, identification and classification of cardiac stromal cell types, and application of hPSC-derived cardiac stromal cells and tissues containing these cells in regenerative and drug development applications.
Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.
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Single-cell analysis of murine fibroblasts identifies neonatal to adult switching that regulates cardiomyocyte maturation.
Nat Commun2020 May;11(1):2585. doi: 10.1038/s41467-020-16204-w.
Wang Yin, Yao Fang, Wang Lipeng, Li Zheng, Ren Zongna, Li Dandan, Zhang Mingzhi, Han Leng, Wang Shi-Qiang, Zhou Bingying, Wang Li,
Abstract
Cardiac maturation lays the foundation for postnatal heart development and disease, yet little is known about the contributions of the microenvironment to cardiomyocyte maturation. By integrating single-cell RNA-sequencing data of mouse hearts at multiple postnatal stages, we construct cellular interactomes and regulatory signaling networks. Here we report switching of fibroblast subtypes from a neonatal to adult state and this drives cardiomyocyte maturation. Molecular and functional maturation of neonatal mouse cardiomyocytes and human embryonic stem cell-derived cardiomyocytes are considerably enhanced upon co-culture with corresponding adult cardiac fibroblasts. Further, single-cell analysis of in vivo and in vitro cardiomyocyte maturation trajectories identify highly conserved signaling pathways, pharmacological targeting of which substantially delays cardiomyocyte maturation in postnatal hearts, and markedly enhances cardiomyocyte proliferation and improves cardiac function in infarcted hearts. Together, we identify cardiac fibroblasts as a key constituent in the microenvironment promoting cardiomyocyte maturation, providing insights into how the manipulation of cardiomyocyte maturity may impact on disease development and regeneration.
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Pulmonary Complications After Allogeneic Hematopoietic Stem Cell Transplantation for Multiple Myeloma: A Case Report.
Transplant Proc2020 May;():. doi: S0041-1345(19)31838-X.
Szlauer-Stefa?ska Anastazja, Krawczyk-Kuli? Ma?gorzata, Kami?ska-Winciorek Gra?yna, Bobek-Billewicz Barbara, Giebel Sebastian,
Abstract
We present a case of a young patient with life-threatening pulmonary complications after allogeneic hematopoietic stem cell transplantation (HSCT). The 25-year-old woman, after HSCT for multiple myeloma, developed severe chronic graft-vs-host disease (GvHD), including bronchiolitis obliterans syndrome. During the treatment of chronic GvHD, 18 months after HSCT, she experienced sudden massive pulmonary hemorrhage with cardiac arrest. The computed tomography imaging revealed lesions suggestive of fungal etiology, with cavity adjacent to the pulmonary vessels. Disqualified from invasive treatment due to poor pulmonary performance, she was treated conservatively with broad-spectrum antibiotics and antifungals. The microbiological workup consistently revealed only Pseudomonas aeruginosa colonization. Her condition steadily improved on treatment. Over 18 months after the incident, she did not experience recurrent bleeding nor serious infection, her primary disease remains in remission, and GvHD symptoms are controlled. Allogeneic HSCT offers possibility of sustained immune-mediated disease control and sometimes even cure, but despite reduced transplant related mortality, GvHD and infections may be detrimental for transplant recipients. Our report illustrates atypical manifestation of pulmonary lesions and highlights the importance of infection control during GvHD treatment.
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
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Activated Cardiac Fibroblasts Control Contraction of Human Fibrotic Cardiac Microtissues by a ?-Adrenoreceptor-Dependent Mechanism.
Cells2020 May;9(5):. doi: E1270.
B?yszczuk Przemys?aw, Zuppinger Christian, Costa Ana, Nurzynska Daria, Di Meglio Franca Di, Stellato Mara, Agarkova Irina, Smith Godfrey L, Distler Oliver, Kania Gabriela,
Abstract
Cardiac fibrosis represents a serious clinical problem. Development of novel treatment strategies is currently restricted by the lack of the relevant experimental models in a human genetic context. In this study, we fabricated self-aggregating, scaffold-free, 3D cardiac microtissues using human inducible pluripotent stem cell (iPSC)-derived cardiomyocytes and human cardiac fibroblasts. Fibrotic condition was obtained by treatment of cardiac microtissues with profibrotic cytokine transforming growth factor ?1 (TGF-?1), preactivation of foetal cardiac fibroblasts with TGF-?1, or by the use of cardiac fibroblasts obtained from heart failure patients. In our model, TGF-?1 effectively induced profibrotic changes in cardiac fibroblasts and in cardiac microtissues. Fibrotic phenotype of cardiac microtissues was inhibited by treatment with TGF-?-receptor type 1 inhibitor SD208 in a dose-dependent manner. We observed that fibrotic cardiac microtissues substantially increased the spontaneous beating rate by shortening the relaxation phase and showed a lower contraction amplitude. Instead, no changes in action potential profile were detected. Furthermore, we demonstrated that contraction of human cardiac microtissues could be modulated by direct electrical stimulation or treatment with the ?-adrenergic receptor agonist isoproterenol. However, in the absence of exogenous agonists, the ?-adrenoreceptor blocker nadolol decreased beating rate of fibrotic cardiac microtissues by prolonging relaxation time. Thus, our data suggest that in fibrosis, activated cardiac fibroblasts could promote cardiac contraction rate by a direct stimulation of ?-adrenoreceptor signalling. In conclusion, a model of fibrotic cardiac microtissues can be used as a high-throughput model for drug testing and to study cellular and molecular mechanisms of cardiac fibrosis.
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Genomic integrity of human induced pluripotent stem cells across nine studies in the NHLBI NextGen program.
Stem Cell Res2020 May;46():101803. doi: S1873-5061(20)30105-7.
Kanchan Kanika, Iyer Kruthika, Yanek Lisa R, Carcamo-Orive Ivan, Taub Margaret A, Malley Claire, Baldwin Kristin, Becker Lewis C, Broeckel Ulrich, Cheng Linzhao, Cowan Chad, D'Antonio Matteo, Frazer Kelly A, Quertermous Thomas, Mostoslavsky Gustavo, Murphy George, Rabinovitch Marlene, Rader Daniel J, Steinberg Martin H, Topol Eric, Yang Wenli, Knowles Joshua W, Jaquish Cashell E, Ruczinski Ingo, Mathias Rasika A,
Abstract
Human induced pluripotent stem cell (hiPSC) lines have previously been generated through the NHLBI sponsored NextGen program at nine individual study sites. Here, we examined the structural integrity of 506 hiPSC lines as determined by copy number variations (CNVs). We observed that 149 hiPSC lines acquired 258 CNVs relative to donor DNA. We identified six recurrent regions of CNVs on chromosomes 1, 2, 3, 16 and 20 that overlapped with cancer associated genes. Furthermore, the genes mapping to regions of acquired CNVs show an enrichment in cancer related biological processes (IL6 production) and signaling cascades (JNK cascade & NF?B cascade). The genomic region of instability on chr20 (chr20q11.2) includes transcriptomic signatures for cancer associated genes such as ID1, BCL2L1, TPX2, PDRG1 and HCK. Of these HCK shows statistically significant differential expression between carrier and non-carrier hiPSC lines. Overall, while a low level of genomic instability was observed in the NextGen generated hiPSC lines, the observation of structural instability in regions with known cancer associated genes substantiates the importance of systematic evaluation of genetic variations in hiPSCs before using them as disease/research models.
Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.
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Phenotypic and functional translation of IL33 genetics in asthma.
J Allergy Clin Immunol2020 May;():. doi: S0091-6749(20)30680-1.
Ketelaar Maria E, Portelli Michael A, Dijk F Nicole, Shrine N, Faiz A, Vermeulen C J, Xu C J, Hankinson J, Bhaker S, Henry A P, Billington C K, Shaw D E, Johnson S R, Benest A V, Pang V, Bates D, Pogson Z E K, Fogarty A, McKeever T M, Singapuri A, Heaney L, Mansur A H, Chaudhuri R, Thomson N C, Holloway J W, Lockett G A, Howarth P H, Niven R, Simpson A, Tobin M D, Hall I P, Wain L V, Blakey J D, Brightling C E, Obeidat M, Sin D D, Nickle C, Bossé Y, Vonk J M, van den Berge M, Koppelman G H, Sayers Ian, Nawijn Martijn C,
Abstract
BACKGROUND:
Asthma is a complex disease with multiple phenotypes that may differ in disease pathobiology and treatment response. Interleukin 33 (IL33) single nucleotide polymorphisms (SNPs) have been reproducibly associated with asthma. IL33 levels are elevated in sputum, and bronchial biopsies of asthma patients. The functional consequences of IL33 asthma SNPs remain unknown.
OBJECTIVE:
We studied whether IL33 SNPs associate with asthma-related phenotypes and with IL33 expression in lung or bronchial epithelium. We investigated the effect of increased IL33 expression on human bronchial epithelial cell (HBEC) function.
METHODS:
Association between IL33 SNPs (Chr9: 5,815,786-6,657,983) and asthma phenotypes (Lifelines/DAG/GASP cohorts) and between SNPs and expression (lung tissue, bronchial brushes, HBECs) was done using regression modelling. Lentiviral overexpression was used to study IL33 effects on HBECs.
RESULTS:
161 SNPs spanning the IL33 region associated with one or more asthma phenotypes after correction for multiple testing. We report one main independent signal tagged by rs992969 associating with blood eosinophil levels, asthma and eosinophilic asthma. A second, independent signal tagged by rs4008366 presented modest association with eosinophilic asthma. Neither signal associated with FEV, FEV/FVC, atopy, and age of asthma onset. The two IL33 signals are expression quantitative loci (eQTLs) in bronchial brushes and cultured HBECs, but not in lung tissue. IL33 overexpression in vitro resulted in reduced viability and ROS-capturing of HBECs, without influencing epithelial cell count, metabolic activity or barrier function.
CONCLUSION:
We identify IL33 as an epithelial susceptibility gene for eosinophilia and asthma, provide mechanistic insight, and implicate targeting of the IL33 pathway specifically in eosinophilic asthma.
Copyright © 2020. Published by Elsevier Inc.
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The efficiency of blackberry loaded AgNPs, AuNPs and Ag@AuNPs mediated pectin in the treatment of cisplatin-induced cardiotoxicity in experimental rats.
Int J Biol Macromol2020 May;():. doi: S0141-8130(20)33267-0.
Hussein Jihan, El-Naggar Mehrez E, Fouda Moustafa M G, Morsy Osama M, Ajarem Jamaan S, Almalki Ahmed M, Allam Ahmed A, Mekawi Enas Mahmoud,
Abstract
Cisplatin (cis-Diaminedichloroplatinum) is one of the most effective chemotherapeutic because of its anti-neoplastic properties against various types of tumor. However, it has a wide variety of side effects such as hepato, gastrointestinal, neuro, nephro, and cardiotoxicity (acute and/or chronic) that highly restricted its usage. Thus, research work was planned to detect the role of gold (AuNPs), silver nanoparticles (AgNPs) and Ag@AuNPs as core-shell in enhancing the benefits of blackberry extract in treatment of cisplatin-induced cardiotoxicity. In our work, solid-state process was used in order to prepare these nanoparticles using pectin as an ecologically friendly-polymer for ions reduction and at the same time as stabilizing agent for the produced nanoparticles. This nominated method for large-scale preparation of nanoparticles is simple, efficient, and convenient. The presence of individual metallic Ag, Au and both has been proven by UV-vis spectroscopy. Transmission electron microscopy (TEM) and particle size analyzer confirmed the preparation of spherical small size with a main diameter <40?nm. The data obtained from zeta potential evaluation displayed the well stabilization for the produced nanoparticles. Transmission electron microscopy (TEM), scanning electron microscopy (SEM) and particle size analyzer have verified that the spherical small size is <40?nm in diameter. Data from zeta potential assessment revealed the good stability of the produced nanoparticles. To this end, fifty sex rats were used in this study and divided into control, cisplatin (cispt), and five treated groups. After the experimental period, lipid profile was estimated and atherogenic coefficient (AC), atherogenic index (AI), and cardiac risk ratio (CRR) were calculated. Oxidant and antioxidant parameters were also estimated. Cardiovascular disease markers were estimated by ELISA. The mean levels of cholesterol, triglycerides, malondialdehyde (MDA), advanced oxidative protein products (AOPP), and cardiovascular markers were significantly increased in cispt group compared to control; whereas these parameters were attenuated in all treated groups in particular that received blackberry (bb) loaded Ag@AuNPs. Based on these results, it can be concluded that bb, has antioxidant and antilipidemic effect that help in protecting against cardiovascular disease specially when loaded with Ag@AuNPs that enhance its properties.
Copyright © 2018. Published by Elsevier B.V.
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Successful healthcare delivery using ambulatory hospitals-past, present and future.
Am J Med -
Exercise training reverses cardiac aging phenotypes associated with heart failure with preserved ejection fraction in male mice.
Aging Cell2020 May;():e13159. doi: 10.1111/acel.13159.
Roh Jason D, Houstis Nicholas, Yu Andy, Chang Bliss, Yeri Ashish, Li Haobo, Hobson Ryan, Lerchenmüller Carolin, Vujic Ana, Chaudhari Vinita, Damilano Federico, Platt Colin, Zlotoff Daniel, Lee Richard T, Shah Ravi, Jerosch-Herold Michael, Rosenzweig Anthony,
Abstract
Heart failure with preserved ejection fraction (HFpEF) is the most common type of HF in older adults. Although no pharmacological therapy has yet improved survival in HFpEF, exercise training (ExT) has emerged as the most effective intervention to improving functional outcomes in this age-related disease. The molecular mechanisms by which ExT induces its beneficial effects in HFpEF, however, remain largely unknown. Given the strong association between aging and HFpEF, we hypothesized that ExT might reverse cardiac aging phenotypes that contribute to HFpEF pathophysiology and additionally provide a platform for novel mechanistic and therapeutic discovery. Here, we show that aged (24-30 months) C57BL/6 male mice recapitulate many of the hallmark features of HFpEF, including preserved left ventricular ejection fraction, subclinical systolic dysfunction, diastolic dysfunction, impaired cardiac reserves, exercise intolerance, and pathologic cardiac hypertrophy. Similar to older humans, ExT in old mice improved exercise capacity, diastolic function, and contractile reserves, while reducing pulmonary congestion. Interestingly, RNAseq of explanted hearts showed that ExT did not significantly modulate biological pathways targeted by conventional HF medications. However, it reversed multiple age-related pathways, including the global downregulation of cell cycle pathways seen in aged hearts, which was associated with increased capillary density, but no effects on cardiac mass or fibrosis. Taken together, these data demonstrate that the aged C57BL/6 male mouse is a valuable model for studying the role of aging biology in HFpEF pathophysiology, and provide a molecular framework for how ExT potentially reverses cardiac aging phenotypes in HFpEF.
© 2020 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.
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Amniotic membrane mesenchymal stem cells labeled by iron oxide nanoparticles exert cardioprotective effects against isoproterenol (ISO)-induced myocardial damage by targeting inflammatory MAPK/NF-?B pathway.
Drug Deliv Transl Res2020 May;():. doi: 10.1007/s13346-020-00788-3.
Naseroleslami Maryam, Aboutaleb Nahid, Mokhtari Behnaz,
Abstract
The aim of the present study is to investigate the protective effects of human amniotic membrane-derived mesenchymal stem cells (hAMSCs) labeled by superparamagnetic iron oxide nanoparticles (SPIONs) against isoproterenol (ISO)-induced myocardial injury in the presence and absence of a magnetic field. ISO was injected subcutaneously for 4 consecutive days to induce myocardial injury in male Wistar rats. The hAMSCs were incubated with 100 ?g/ml SPIONs and injected to rats in magnet-dependent and magnet-independent groups via the tail vein. The size and shape of nanoparticles were determined by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Prussian blue staining was used to determine cell uptake of nanoparticles. Myocardial fibrosis, heart function, characterization of hAMSCs, and histopathological changes were determined using Masson's trichrome, echocardiography, flow cytometry, and H&E staining, respectively. Enzyme-linked immunosorbent assay (ELISA) was used to the expression pro-inflammatory cytokines. Immunohistochemistry assay was used to determine the expression of nuclear factor-?B (NF-?B) and the Ras/mitogen-activated protein kinase (MAPK). SPION-labeled MSCs in the presence of magnetic field significantly improved cardiac function and reduced fibrosis and tissue damage by suppressing inflammation in a NF-?B/MAPK-dependent mechanism (p
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