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Pubblicazioni recenti - cardiac fibrosis
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The conductive function of biopolymer corrects myocardial scar conduction blockage and resynchronizes contraction to prevent heart failure.
Biomaterials2020 Aug;258():120285. doi: S0142-9612(20)30531-7.
He Sheng, Wu Jun, Li Shu-Hong, Wang Li, Sun Yu, Xie Jun, Ramnath Daniel, Weisel Richard D, Yau Terrence M, Sung Hsing-Wen, Li Ren-Ke,
Abstract
Myocardial fibrosis, resulting from ischemic injury, increases tissue resistivity in the infarct area, which impedes heart synchronous electrical propagation. The uneven conduction between myocardium and fibrotic tissue leads to dys-synchronous contraction, which progresses towards ventricular dysfunction. We synthesized a conductive poly-pyrrole-chitosan hydrogel (PPY-CHI), and investigated its capabilities in improving electrical propagation in fibrotic tissue, as well as resynchronizing cardiac contraction to preserve cardiac function. In an in vitro fibrotic scar model, conductivity increased in proportion to the amount of PPY-CHI hydrogel added. To elucidate the mechanism of interaction between myocardial ionic changes and electrical current, an equivalent circuit model was used, which showed that PPY-CHI resistance was 10 times lower, and latency time 5 times shorter, compared to controls. Using a rat myocardial infarction (MI) model, PPY-CHI was injected into fibrotic tissue 7 days post MI. There, PPY-CHI reduced tissue resistance by 30%, improved electrical conduction across the fibrotic scar by 33%, enhanced field potential amplitudes by 2 times, and resynchronized cardiac contraction. PPY-CHI hydrogel also preserved cardiac function at 3 months, and reduced susceptibility to arrhythmia by 30% post-MI. These data demonstrated that the conductive PPY-CHI hydrogel reduced fibrotic scar resistivity, and enhanced electrical conduction, to synchronize cardiac contraction.
Copyright © 2020 Elsevier Ltd. All rights reserved.
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Optical capture and defibrillation in rats with monocrotaline-induced myocardial fibrosis one year after a single intravenous injection of adeno-associated virus-channelrhodopsin-2.
Heart Rhythm2020 Aug;():. doi: S1547-5271(20)30755-4.
Li Jianyi, Wang Long, Luo Junmiao, Li Haitao, Rao Panpan, Cheng Yue, Wang Xi, Huang Congxin,
Abstract
BACKGROUND:
Optogenetics uses light to regulate cardiac rhythms and terminate malignant arrhythmias.
OBJECTIVE:
To investigate the long-term validity of optical capture properties based on virus-transfected channelrhodopsin-2 (ChR2), and evaluate the effects of optogenetic-based defibrillation in an in vivo rat model of myocardial fibrosis enhanced by monocrotaline (MCT).
METHODS:
Fifteen infant rats received jugular vein injection of adeno-associated virus (AAV). After eight weeks, five rats were randomly selected to verify the effectiveness ChR2 transfection. The remaining rats were administered MCT at eleven months. Four weeks after MCT, the availability of 473 nm blue light to capture heart rhythm in these rats was verified again. Ventricular tachycardia (VT) and ventricular fibrillation (VF) were induced by burst stimulation on the basis of enhanced myocardial fibrosis, and the termination effects of the optical manipulation were tested.
RESULTS:
Eight weeks after AAV injection, there was ChR2 expression throughout the ventricular myocardium as reflected by both fluorescence imaging and optical pacing. Four weeks after MCT, significant myocardial fibrosis was achieved. Light could still trigger the corresponding ectopic heart rhythm, the pulse width and illumination area could affect the light capture rate. VT/VF was induced successfully in one-year-observation rats and the rate of termination of VT/VF under light was much higher than that of spontaneous termination.
CONCLUSION:
Viral ChR2 transfection can play a long-term role in the rat heart, and light can successfully regulate heart rhythm and defibrillate after cardiac fibrosis.
Copyright © 2020. Published by Elsevier Inc.
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Influence of early extubation on post-operative outcomes after pediatric lung transplantation.
Pediatr Transplant2020 Aug;():e13776. doi: 10.1111/petr.13776.
Labarinas Sonia, Coss-Bu Jorge A, Onyearugbulem Chinyere, Heinle Jeffery S, Mallory George B, Gazzaneo Maria C,
Abstract
Lung transplantation has become an accepted therapeutic option for a select group of children with end-stage lung disease. We evaluated the impact of early extubation in a pediatric lung transplant population and its post-operative outcomes. Single-center retrospective study. PICU within a tertiary academic pediatric hospital. Patients <22 years after pulmonary transplant between January 2011 and December 2016. A total of 74 patients underwent lung transplantation. The primary pretransplantation diagnoses included cystic fibrosis (58%), pulmonary fibrosis (9%), and surfactant dysfunction disorders (10%). Of 60 patients, 36 (60%) were extubated within 24 hours and 24 patients after 24 hours (40%). A total of seven patients (11.6%) required reintubation within 24 hours. Median length of stay for the early extubation group was shorter at 3 days ([(IQR) 2.2-4.7]) compared to 5 days (IQR, 3-7) (P = .02) in the late extubation group. Median costs were lower for the early extubation group with 13,833 US dollars (IQR, 9980-22,822) vs 23 671 US dollars (IQR, 16 673-39 267) (P = .043). Fourteen patients were in the PICU prior to their transplantation; this did not affect their early extubation success. Neither did the fact of requiring invasive or non-invasive mechanical ventilation before transplantation. Early extubation appears to be safe in a pediatric population after lung transplantation and is associated with a shorter LOS and decreased hospital costs. It may prevent known complications associated with mechanical ventilation.
© 2020 Wiley Periodicals LLC.
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Alleviation of salt-induced exacerbation of cardiac, renal, and visceral fat pathology in rats with metabolic syndrome by surgical removal of subcutaneous fat.
Nutr Diabetes2020 08;10(1):28. doi: 10.1038/s41387-020-00132-1.
Aoyama Kiyoshi, Komatsu Yuki, Yoneda Mamoru, Nakano Shiho, Ashikawa Sao, Kawai Yumeno, Cui Xixi, Ikeda Katsuhide, Nagata Kohzo,
Abstract
OBJECTIVES:
Evidence suggests that visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) should be considered as distinct types of white fat. Although VAT plays a key role in metabolic syndrome (MetS), the role of subcutaneous adipose tissue (SAT) has been unclear. DahlS.Z-Lepr/Lepr (DS/obese) rats, an animal model of MetS, develop adipocyte hypertrophy and inflammation to similar extents in SAT and VAT. We have now investigated the effects of salt loading and SAT removal on cardiac, renal, and VAT pathology in DS/obese rats.
METHODS:
DS/obese rats were subjected to surgical removal of inguinal SAT or sham surgery at 8 weeks of age. They were provided with a 0.3% NaCl solution as drinking water or water alone for 4 weeks from 9 weeks of age.
RESULTS:
Salt loading exacerbated hypertension, insulin resistance, as well as left ventricular (LV) hypertrophy, inflammation, fibrosis, and diastolic dysfunction in DS/obese rats. It also reduced both SAT and VAT mass but aggravated inflammation only in VAT. Although SAT removal did not affect LV hypertrophy in salt-loaded DS/obese rats, it attenuated hypertension, insulin resistance, and LV injury as well as restored fat mass and alleviated inflammation and the downregulation of adiponectin gene expression in VAT. In addition, whereas salt loading worsened renal injury as well as upregulated the expression of renin-angiotensin-aldosterone system-related genes in the kidney, these effects were suppressed by removal of SAT.
CONCLUSIONS:
SAT removal attenuated salt-induced exacerbation of MetS and LV and renal pathology in DS/obese rats. These beneficial effects of SAT removal are likely attributable, at least in part, to inhibition of both VAT and systemic inflammation.
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Changes in left atrial function, left ventricle remodeling, and fibrosis after septal myectomy for obstructive hypertrophic cardiomyopathy.
J Thorac Cardiovasc Surg2020 Jul;():. doi: S0022-5223(20)31551-8.
Tang Bing, Song Yunhu, Yang Qiulan, Cui Hao, Ji Keshan, Zhao Shihua, Wang Shuiyun,
Abstract
BACKGROUND:
This study aimed to investigate the impact of septal myectomy on left atrial function, left ventricle remodeling, and fibrosis in patients with obstructive hypertrophic cardiomyopathy.
METHOD:
From May 2012 to September 2016, preoperative cardiac magnetic resonance imaging of 507 adult patients who underwent septal myectomy at Fuwai Hospital was retrospectively collected. Until October 2019, 57 patients were followed up with postoperative cardiac magnetic resonance imaging at 11.9 months (interquartile range, 6.4-25.3). Preoperative and postoperative left atrium and left ventricle changes, as well as late gadolinium enhancement as a surrogate of myocardial fibrosis, were analyzed.
RESULTS:
Patients with hypertrophic cardiomyopathy requiring myectomy showed increased left atrium volume, stroke volume, left ventricular ejection fraction, and left ventricle mass, as well as decreased left ventricle end-systolic volume. Echocardiography demonstrated that myectomy decreased the left ventricle outflow tract gradient, left atrium diameter, left ventricular ejection fraction, and posterior wall thickness. Postoperative cardiac magnetic resonance imaging showed that the minimal left atrium volume (P < .001), stroke volume (P = .009), left ventricle ejection fraction (P < .001), and left ventricle mass (166.9 [interquartile range, 135.8] vs 149.3 [interquartile range, 100.5] g, P < .001) decreased, whereas the left ventricle end-systolic volume (P = .001) and left atrium ejection fraction (37.9% ± 14.6% vs 47.8% ± 14%, P < .001) increased. However, left ventricle myocardial fibrosis, as detected by late gadolinium enhancement, still progressed after myectomy in patients with obstructive hypertrophic cardiomyopathy (15.2% ± 9.6% vs 18.6% [interquartile range, 21.6], P = .009).
CONCLUSIONS:
Septal myectomy alleviated left ventricle hypertrophy and reversed left atrium and left ventricle remodeling in patients with obstructive hypertrophic cardiomyopathy. Late gadolinium enhancement in the left ventricle increased despite myectomy in patients with obstructive hypertrophic cardiomyopathy.
Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
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Restoration of Cavernous Veno-Occlusive Function through Chronic Administration of a Jun-Amino Terminal Kinase Inhibitor and a LIM-Kinase 2 Inhibitor by Suppressing Cavernous Apoptosis and Fibrosis in a Rat Model of Cavernous Nerve Injury: A Comparison with a Phosphodiesterase Type 5 Inhibitor.
World J Mens Health2020 Jul;():. doi: 10.5534/wjmh.200085.
Cho Min Chul, Lee Junghoon, Park Juhyun, Kim Soo Woong,
Abstract
PURPOSE:
To determine if chronic administration of Jun-amino terminal kinase (JNK)-inhibitors and LIM-kinase 2 (LIMK2)-inhibitors from the immediate post-injury period in a rat model of cavernous-nerve-crush-injury could normalize cavernous-veno-occlusive-function, and to compare it with phosphodiesterase type 5 (PDE5)-inhibitors.
MATERIALS AND METHODS:
A total of 75 12-week-old male Sprague-Dawley-rats were randomized into five groups: sham-surgery (S), cavernous-nerve-crush-injury (I), cavernous-nerve-crush-injury treated with 10.0 mg/kg LIMK2-inhibitor (L) or 10.0 mg/kg JNK-inhibitor and 10.0 mg/kg LIMK2-inhibitor (J+L) or 20.0 mg/kg udenafil (P) for five-weeks. Five-weeks after surgery, dynamic-infusion-cavernosometry, histological-studies, caspase-3-activity-assay, and Western-blot were investigated.
RESULTS:
Group-I had lower papaverine-response, higher maintenance-rate and higher drop-rate, compared to Group-S. Group-L, Group-J+L and Group-P showed improvement in the three dynamic-infusion-cavernosometry parameters. The papaverine-response and drop-rate in Group-J+L and Group-P recovered to sham-control level, but those in Group-L did not. Regarding apoptosis, Group-I had decreased content of ?-smooth-muscle-actin, increased caspase-3 activity and increased cJun-phosphorylation. The cJun-phosphorylation improved only in Group-J+L. The ?-smooth-muscle-actin content and caspase-3-activity in Group-J+L and Group-P improved, but those in Group-L were not. Regarding fibrosis, Group-I had decreased smooth muscle (SM)/collagen-ratio, increased protein-expression of fibronectin, and increased Cofilin-phosphorylation. Cofilin-phosphorylation was normalized in Group-L and Group-J+L, but not in Group-P. SM/collagen-ratio and protein-expression of fibronectin in Group-L, Group-J+L and Group-P improved.
CONCLUSIONS:
Our data indicate that chronic inhibition of JNK and LIMK2 can restore cavernous-veno-occlusive-function by suppressing cavernous-apoptosis and cavernous-fibrosis, comparable to the results by PDE5-inhibitors. Chronic inhibition of JNK and LIMK2 might be a potential mechanism-specific targeted therapy for cavernous-veno-occlusive-dysfunction induced by cavernous nerve-injury.
Copyright © 2020 Korean Society for Sexual Medicine and Andrology.
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Fontan-Associated Liver Disease: Screening, Management, and Transplant Considerations.
Circulation2020 Aug;142(6):591-604. doi: 10.1161/CIRCULATIONAHA.120.045597.
Emamaullee Juliet, Zaidi Ali N, Schiano Thomas, Kahn Jeffrey, Valentino Pamela L, Hofer Ryan E, Taner Timucin, Wald Joyce W, Olthoff Kim M, Bucuvalas John, Fischer Ryan,
Abstract
Surgical innovation and multidisciplinary management have allowed children born with univentricular physiology congenital heart disease to survive into adulthood. An estimated global population of 70 000 patients have undergone the Fontan procedure and are alive today, most of whom are <25 years of age. Several unexpected consequences of the Fontan circulation include Fontan-associated liver disease. Surveillance biopsies have demonstrated that virtually 100% of these patients develop clinically silent fibrosis by adolescence. As they mature, there are increasing reports of combined heart-liver transplantation resulting from advanced liver disease, including bridging fibrosis, cirrhosis, and hepatocellular carcinoma, in this population. In the absence of a transplantation option, these young patients face a poor quality of life and overall survival. Acknowledging that there are no consensus guidelines for diagnosing and monitoring Fontan-associated liver disease or when to consider heart transplantation versus combined heart-liver transplantation in these patients, a multidisciplinary working group reviewed the literature surrounding Fontan-associated liver disease, with a specific focus on considerations for transplantation.
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An Addition of U0126 Protecting Heart Grafts From Prolonged Cold Ischemia Reperfusion Injury in Heart Transplantation: A New Preservation Strategy.
Transplantation2020 Jul;():. doi: 10.1097/TP.0000000000003402.
Zheng Hao, Su Yale, Zhu Cuilin, Quan Douglas, Skaro Anton I, McAlister Vivian, Lacefield James C, Jiang Jifu, Xue Peng, Wang Yefu, Zheng Xiufen,
Abstract
BACKGROUND:
Ischemia reperfusion injury (IRI) is the major cause of primary graft dysfunction in organ transplantation. The MEK/ERK signaling pathway plays a crucial role in cell physiological and pathological processes including IRI. This study aims to investigate whether inhibition of ERK signaling with U0126 can prevent prolonged cold IRI in heart transplantation.
METHODS:
Rat cardiac cell line H9c2 cells were treated with U0126 prior to exposure to hypothermic hypoxia reoxygenation (H/R) conditions. The effect of U0126 on H9c2 cells in response to H/R stress was determined by measuring cell death, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), and ERK signaling activation. Mouse syngeneic heterotopic heart transplantation was conducted where a donor heart was preserved in the University of Wisconsin (UW) solution supplemented with U0126 for 24 hrs at 4°C prior to transplantation. Heart graft function, histopathological chances, apoptosis, and fibrosis were measured to assess IRI.
RESULTS:
Phosphorylated ERK was increased in both in vitro H/R injured H9c2 cells and in vivo heart grafts with IRI. Pretreatment with U0126 inhibited ERK phosphorylation, prevented H9c2 cells from cell death, ROS generation and MMP loss in response to H/R. Preservation of donor hearts with U0126 supplemented solution improved graft function, and reduced IRI by reductions in cell apoptosis/death, neutrophil infiltration and fibrosis of the graft.
CONCLUSIONS:
Addition of U0126 to UW solution reduces ERK signal activation and attenuates prolonged cold IRI in a heart transplantation model. ERK inhibition with U0126 may be a useful strategy to minimize IRI in organ transplantation.
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Comparison of the effects of intramyocardial and intravenous injections of human mesenchymal stem cells on cardiac regeneration after heart failure.
Iran J Basic Med Sci2020 Jul;23(7):879-885. doi: 10.22038/ijbms.2020.40886.9660.
Mokhtari Behnaz, Aboutaleb Nahid, Nazarinia Donya, Nikougoftar Mahin, Razavi Tousi Seyed Mohammad Taghi, Molazem Mohammad, Azadi Mohammad-Reza,
Abstract
Objectives:
Existing studies have demonstrated that intravenous and intramyocardial-administrated mesenchymal stem cells (MSCs) lead to tissue repair after cardiac disorders. We compared the efficiency of both administration methods.
Materials and Methods:
A rat model of isoproterenol-induced heart failure (ISO-HF) was established to compare the effects of intravenous and intramyocardial-administrated MSCs on cardiac fibrosis and function. The animals were randomly assigned into six groups: i) control or normal, ii) ISO-HF (HF) iii) ISO-HF rats treated with intramyocardial administration of culture medium (HF+IM/CM), iv) ISO-HF rats treated with intravenous administration of culture medium ( HF+IV/CM), v) ISO-HF rats treated with intravenous administration of MSCs (HF+IV/MSCs), vi) ISO-HF rats treated with intramyocardial administration of MSCs ( HF+IM/MSCs). Cultured MSCs and culture medium were administrated at 4 weeks after final injection of ISO. Heart function, identification of MSCs, osteogenic differentiation, adipogenic differentiation, cardiac fibrosis and tissue damage were evaluated by echocardiography, flow-cytometery, von Kossa, oil red O, Masson's trichrome and H & E staining, respectively.
Results:
Both intravenous and intramyocardial MSCs therapy significantly improved heart function and reduced cardiac fibrosis and tissue damage (0.05), whereas the cultured medium had no beneficial effects.
Conclusion:
In sum, our results confirm the validity of both administration methods in recovery of HF, but more future research is required.
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Exercise-induced torsades de pointes as an unusual presentation of cardiac sarcoidosis: A case report and review of literature.
World J Cardiol2020 Jun;12(6):291-302. doi: 10.4330/wjc.v12.i6.291.
Ghafari Chadi, Vandergheynst Frédéric, Parent Emmanuel, Tanaka Kaoru, Carlier Stéphane,
Abstract
BACKGROUND:
Sarcoidosis is a rare multisystem disease characterized histologically by non-caseating granuloma formation in the affected organ. While cardiac sarcoidosis is found on autopsy in up to 25% of sarcoidosis cases, it is still underdiagnosed and is associated with a poor prognosis. Although the etiology of sarcoidosis remains unclear, an antigen triggered exaggerated immune response has been hypothesized. Early detection and prompt management of cardiac sarcoidosis remains pivotal.
CASE SUMMARY:
A 60-year-old female, with pulmonary sarcoidosis in remission, presented to the cardiology outpatient clinic for evaluation of weeks-long dyspnea on moderate exertion (New York Heart Association class II) that was relieved by rest. Submaximal exercise stress test showed multifocal ventricular extrasystoles, followed by a self-limiting torsades de pointes. Cardiac magnetic resonance imaging showed nondilated and normotrophic left ventricle with basoseptal and mid-septal dyskinesis. The magnetic resonance imaging-derived left ventricular ejection fraction was 45%. Delayed enhancement showed patchy transmural fibrosis of the septum and hyperenhancement of the papillary muscles, all in favor of extensive cardiac involvement of sarcoidosis. A double-chamber implantable cardiac defibrillator was implanted, and methylprednisolone (12 mg/d) and methotrexate (12.5 mg/wk) treatment was initiated. Follow-up and implantable cardiac defibrillator interrogation showed episodes of asymptomatic nonsustained ventricular tachycardia and an asymptomatic episode of nonsustained ventricular tachycardia ending by the first antitachycardia pacing run.
CONCLUSION:
Along an extensive review of the literature, this unusual case report highlights the importance of early detection of cardiac involvement of sarcoidosis, in order to avoid potential complications and increase survival.
©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
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The combination of G9a histone methyltransferase inhibitors with erythropoietin protects heart against damage from acute myocardial infarction.
Am J Transl Res2020 ;12(7):3255-3271.
Sung Pei-Hsun, Luo Chi-Wen, Chiang John Y, Yip Hon-Kan,
Abstract
BACKGROUND:
This study tested the hypothesis that combined histone methyltransferase G9a inhibitor (i.e., UNC0638) and erythropoietin (EPO) was superior to either one alone for protecting myocardium from acute myocardial infarction (AMI) damage.
METHODS AND RESULTS:
Adult-male SD rats (n=30) were equally categorized into group 1 (sham-operated control), group 2 (AMI), group 3 (AMI-EPO/1000 IU/kg, I.M./3 h after AMI), group 4 (AMI- UNC0638/5 mg/kg I.P./3 h after AMI) and group 5 [AMI-UNC0638-EPO 3 h after AMI] treatment. Animals were euthanized at day 21 after AMI induction. By day 21, left-ventricular-ejection-fraction (LVEF) was highest in group 1, lowest in group 2, significantly higher in group 5 than in groups 3 and 4, but no difference between the latter two groups (all P<0.0001). The protein expressions of inflammatory (MMP-2/MM-9), fibrotic (fibronectin/Smad3/TGF-ß), apoptotic/DNA-damaged (caspas-3/PARP/?-H2AX), cell-stress response (HIF-1?/p-Akt/p-mTOR) and autophagic (beclin-1/ratio of LC3B-II to LC3B-I) biomarkers exhibited an opposite pattern, whereas the protein expressions of endothelial integrity (CD31/vWF) and anti-oxidant (SIRT1/SIRT3) exhibited an identical pattern of LVEF among the five groups (all P<0.0001). The protein expressions (SDF-1?/VEGF/CXCR4) and cellular expressions (C-kit/CD31+//Sca-1/CD31+//KDR/CD34+) of angiogenesis biomarkers were significantly progressively increased from groups 1 to 5 (all P<0.0001). The infarction/fibrotic areas, myocyte size and number of G9a cells exhibited an opposite pattern, whereas the small-vessel density displayed an identical trend of LVEF among the groups (all P<0.0001). Flow cytometric analysis showed cellular levels of inflammation (Ly6G+/MPO+/CD11b/c+), oxidative-stress (DCFDA+) and apoptosis (early+/late+) exhibited an opposite pattern to LVEF among the groups (all P<0.0001).
CONCLUSION:
EPO-BIX01294 effectively protected myocardium against AMI-induced damage.
AJTR Copyright © 2020.
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A novel tree shrew model of pulmonary fibrosis.
Lab Invest2020 Aug;():. doi: 10.1038/s41374-020-00476-3.
Che Pulin, Wang Meimei, Larson-Casey Jennifer L, Hu Rui-Han, Cheng Yiju, El Hamdaoui Mustapha, Zhao Xue-Ke, Grytz Rafael, Brent Carter A, Ding Qiang,
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease without effective therapy. Animal models effectively reproducing IPF disease features are needed to study the underlying molecular mechanisms. Tree shrews are genetically, anatomically, and metabolically closer to humans than rodents or dogs; therefore, the tree shrew model presents a unique opportunity for translational research in lung fibrosis. Here we demonstrate that tree shrews have in vivo and in vitro fibrotic responses induced by bleomycin and pro-fibrotic mediators. Bleomycin exposure induced lung fibrosis evidenced by histological and biochemical fibrotic changes. In primary tree shrew lung fibroblasts, transforming growth factor beta-1 (TGF-?1) induced myofibroblast differentiation, increased extracellular matrix (ECM) protein production, and focal adhesion kinase (FAK) activation. Tree shrew lung fibroblasts showed enhanced migration and increased matrix invasion in response to platelet derived growth factor BB (PDGF-BB). Inhibition of FAK significantly attenuated pro-fibrotic responses in lung fibroblasts. The data demonstrate that tree shrews have in vivo and in vitro fibrotic responses similar to that observed in IPF. The data, for the first time, support that the tree shrew model of lung fibrosis is a new and promising experimental animal model for studying the pathophysiology and therapeutics of lung fibrosis.
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miR-19a/19b-loaded exosomes in combination with mesenchymal stem cell transplantation in a preclinical model of myocardial infarction.
Regen Med2020 Aug;():. doi: 10.2217/rme-2019-0136.
Wang Shuo, Li Liu, Liu Tao, Jiang Wenyan, Hu Xitian,
Abstract
We aimed to investigate the protection of exogenous miR-19a/19b with bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation on cardiac function and inhibition of fibrosis in myocardial infarction (MI). BM-MSC-derived exosomes were used to deliver miR-19a/19b (exo/miR-19a/19b) to the cultured cardiac HL-1 cells, and the apoptosis of cells were evaluated. Exo/miR-19a/19b and BM-MSCs were also transplanted to an MI mouse model. The recovery of cardiac function was assessed and the level of cardiac fibrosis was determined. Exo/miR-19a/19b and MSCs reduced the area of cardiac fibrosis in the heart tissue in the mouse MI model. Using BM-MSC-derived exosomes as a vehicle, miR-19a/19b significantly suppressed the apoptosis of cardiac HL-1 cells. The combination of Exo/miR-19a/19b and MSC transplantation significantly enhanced the recovery of cardiac function and reduced cardiac fibrosis in the MI model. Our study provides an effective regenerative intervention strategy to attenuate the damage of MI.
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IGF-1 loaded injectable microspheres for potential repair of the infarcted myocardium.
J Biomater Appl2020 Aug;():885328220948501. doi: 10.1177/0885328220948501.
Rosellini Elisabetta, Barbani Niccoletta, Frati Caterina, Madeddu Denise, Massai Diana, Morbiducci Umberto, Lazzeri Luigi, Falco Angela, Graiani Gallia, Lagrasta Costanza, Audenino Alberto, Cascone Maria Grazia, Quaini Federico,
Abstract
The use of injectable scaffolds to repair the infarcted heart is receiving great interest. Thermosensitive polymers, polymerization, cross-linking, and self-assembling peptides are the most investigated approaches to obtain injectability.Aim of the present work was the preparation and characterization of a novel bioactive scaffold, in form of injectable microspheres, for cardiac repair. Gellan/gelatin microspheres were prepared by a water-in-oil emulsion and loaded by adsorption with Insulin-like growth factor 1 to promote tissue regeneration. Obtained microspheres underwent morphological, physicochemical and biological characterization, including cell culture tests in static and dynamic conditions and tests. Morphological analysis of the microspheres showed a spherical shape, a microporous surface and an average diameter of 66?±?17µm (under dry conditions) and 123?±?24?µm (under wet conditions). Chemical Imaging analysis pointed out a homogeneous distribution of gellan, gelatin and Insulin-like growth factor-1 within the microsphere matrix. cell culture tests showed that the microspheres promoted rat cardiac progenitor cells adhesion, and cluster formation. After dynamic suspension culture within an impeller-free bioreactor, cells still adhered to microspheres, spreading their cytoplasm over microsphere surface. Intramyocardial administration of microspheres in a cryoinjury rat model attenuated chamber dilatation, myocardial damage and fibrosis and improved cell homing.Overall, the findings of this study confirm that the produced microspheres display morphological, physicochemical, functional and biological properties potentially adequate for future applications as injectable scaffold for cardiac tissue engineering.
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Tissue oxygenation in peripheral muscles and functional capacity in cystic fibrosis: A cross-sectional study.
Exp Physiol2020 Aug;():. doi: 10.1113/EP088764.
Coelho Cristiane Cenachi, Aquino Evanirso da Silva, Diniz Ana Luiza Reis, Santos Mariana da Silva, Oliveira Lídia Cunha, Poeiras Priscila Trindade Caetano, Pereira Danielle Aparecida Gomes,
Abstract
NEW FINDINGS:
What is the central question of this study? How do peripheral muscle tissue oxygenation and physical conditioning levels of children and adolescents with cystic fibrosis compare to demographically matched controls? What is the main finding and is its importance? Children and adolescents with cystic fibrosis consumed more oxygen, more quickly and exhibited slower recovery, demonstrating that there may have been deficiencies in oxygen supply related to both oxygen uptake and transport.
ABSTRACT:
Cystic fibrosis affects skeletal muscle performance and functional capacity. However, it is currently unclear how peripheral muscle behavior is affected, especially in children and adolescents. To examine this, we compared tissue oxygenation of children and adolescents with cystic fibrosis against healthy volunteers. We also evaluated the functional capacity of participants via the modified shuttle test (MST) and assessed for associations between performance and near-infrared spectroscopy (NIRS). A total of 124 participants enrolled. Participants were divided into either the cystic fibrosis group (CFG) or the healthy group (HG). Statistical comparisons between groups were evaluated with Mann-Whitney U tests and associations with functional capacity were evaluated using Spearman's correlation coefficient. CFG volunteers scored lower on the MST compared to the HG. They walked shorter distances (p = 0.001) with less efficiency because they performed the tests with a less efficient walking economy (p = 0.001) and a greater deoxyhemoglobin concentration (p = 0.001). Further, they experienced less tissue oxygen saturation (p = 0.037) faster than the HG. As a result, they presented lower respiratory (p = 0.001) and lower heart (p = 0.001) rate values at the end of the MST, with a longer post-test heart rate recovery time (p = 0.005). There was a significant association between deoxygenation time and functional capacity. The CFG consumed more oxygen, more quickly, with a slower recovery, reflecting impairments in the dynamics of muscle oxygen extraction. The results suggest differences in functional capacity and hemodynamic recovery in children and adolescents with cystic fibrosis. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
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Noncoding RNAs in peritoneal fibrosis: Background, Mechanism, and Therapeutic Approach.
Biomed Pharmacother2020 Jul;129():110385. doi: S0753-3322(20)30578-3.
Guo Yanhong, Wang Liuwei, Gou Rong, Tang Lin, Liu Peipei,
Abstract
Peritoneal fibrosis (PF) is the main reason for patients to withdraw from peritoneal dialysis, while the mechanism underlying PF remains unclear. Increasing evidence has demonstrated the regulatory roles of different classes of noncoding RNAs (ncRNAs) in PF. MicroRNAs (miRNAs), which belong to a distinct class of ncRNAs, play crucial roles in the post-transcriptional regulation of gene expression. Studies have suggested that miRNAs play important roles in the pathogenesis of PF and have the potential to be used as diagnostic markers and therapeutic targets for PF in the future. Long noncoding RNAs (lncRNAs) have raised much attention in the recent years, which are involved in the pathophysiological processes of many diseases, including tumors, heart diseases and so on. Recently, some researchers have begun to notice the roles of lncRNAs in PF, and found that lncRNAs play certain roles in the pathogenesis of PF. Circular RNAs (circRNAs) have been proven to be participated in the pathogenesis of many diseases, including tumor metastasis, organ fibrosis and so on. However, studies on the correlation of circRNAs and PF are rather poor compared with miRNAs and lncRNAs. In this review, we will focus on the findings of ncRNAs in peritoneal dialysis therapy and discuss the rising interests in ncRNAs as diagnostic and therapeutic targets of PF.
Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.
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Disruption of endothelial cell intraflagellar transport protein 88 exacerbates doxorubicin-induced cardiotoxicity.
Life Sci2020 Aug;():118216. doi: S0024-3205(20)30968-1.
Luu Vincent Z, Luu Albert Z, Chowdhury Biswajit, Elbardisy Omar, Pan Yi, Al-Omran Mohammed, Quan Adrian, Teoh Hwee, Hess David A, Verma Subodh,
Abstract
AIMS:
Doxorubicin (DOX) is a potent anticancer drug with severe dose-dependent cardiotoxicity. To address this issue, previous research has primarily focused on DOX-induced toxicity on cardiomyocyte. However, research has refocused on the endothelium as a therapeutic target due to the emerging role of endothelial cells in support of cardiomyocyte survival and function.
MAIN METHODS:
We investigated a novel role of endothelial cell primary cilia in the prevention of DOX-mediated cardiotoxicity. Mice lacking endothelial cell primary cilia, via the deletion of endothelial cell-specific intraflagellar protein 88 (IFT88) expression, were administered DOX (20?mg/kg i.p.), and assessed for survival, cardiac function, cardiac structure changes, and indices of cardiomyocyte injury.
KEY FINDINGS:
Compared to wild-type littermates, DOX-treatment resulted in reduced survival and measurements of cardiac function (ejection fraction and fractional shortening) in EC-IFT88 mice. Cardiomyocyte vacuolization, cardiac fibrosis, and serum CK-MB levels were increased in DOX-treated animals compared to SAL-treated controls. However, these parameters were not significantly different when comparing WT and EC-IFT88 mice after DOX treatment.
SIGNIFICANCE:
The loss of endothelial cell primary cilia accelerated DOX-mediated mortality and reduced cardiac function, suggesting pathways downstream of ciliary-mediated signal transduction as potential targets to promote EC support of cardiomyocyte function during DOX treatment.
Copyright © 2020. Published by Elsevier Inc.
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Impact of aerobic training with and without whole-body vibration training on metabolic features and quality of life in non-alcoholic fatty liver disease patients.
Ann Endocrinol (Paris)2020 Aug;():. doi: S0003-4266(20)31049-0.
Sald?ran Tülay Çevik, Mutluay Fatma Karantay, Ya?c? ?lker, Y?lmaz Yusuf,
Abstract
The present study examined the effectiveness of including exercises with whole-body vibration (WBV) to aerobic training in terms of metabolic features and quality of life. Patients with non-alcoholic fatty liver disease confirmed on imaging underwent an 8-week individualized exercise program randomized between aerobic training with and without WBV. Training was performed at 60-80% heart-rate workload for 155?min/week. The WBV amplitude was 2-4?mm and the training frequency was 30?Hz, for 15?min. Assessments were carried out on surrogate scores of steatosis and fibrosis including transient elastography (FibroScan), metabolic features (biochemical analysis) and quality of life (SF-36). Insulin resistance was markedly reduced (-2.36; 95%CI: -4.96 to -0.24; P: 0.049) in aerobic training with WBV. The decrease in serum aspartate transaminase was significantly greater in aerobic training without WBV (-14.81; 95%CI: -23.36 to -6.25; P: 0.029). There were no significant differences between groups for the other metabolic features (P?0.05). All quality-of-life well-being domains improved in both groups (P?0.05). Given this reduction in insulin resistance, WBV can usefully be added to aerobic training. However, WBV did not provide further benefits in improving metabolic properties or quality of life.
Copyright © 2020 Elsevier Masson SAS. All rights reserved.
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Azithromycin and tezacaftor/ivacaftor is associated with first-degree heart block in an adult with cystic fibrosis.
J Cyst Fibros2020 Aug;():. doi: S1569-1993(20)30808-0.
Song Yang, Palacios Alexandra Coronel, Thiagalingam Aravinda, Middleton Peter G,
Abstract
The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene is expressed in the heart, but this is not known to cause myocardial dysfunction or abnormalities in the ECG in people with CF. CFTR modulators such as tezacaftor/ivacaftor improve lung function and overall health in people with CF. Minor adverse events have been reported in the early clinical trials, but no consistent changes in the ECGs have been reported. This case highlights an unusual side effect of first degree heart block that occurred after more than 8 months of azithromycin and tezacaftor/ivacaftor in combination. Drug withdrawal and reintroduction confirmed that neither drug alone, but only the combination, caused this change. As tezacaftor/ivacaftor is also present in elexacaftor/tezacaftor/ivacaftor, care may be needed to exclude this delayed interaction with azithromycin.
Copyright © 2020. Published by Elsevier B.V.
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Diversified Synthetic Pathway of 1, 4-Dihydropyridines: A Class of Pharmacologically Important Molecules.
Mini Rev Med Chem2020 Aug;():. doi: 10.2174/1389557520666200807130215.
Khot Shubham, Auti Pratibha B, Khedkar Samrat A,
Abstract
The current review discusses the different synthetic pathways for one of the most important and interesting heterocyclic ring systems 1,4-dihydropyridine. This cyclic system depicts diverse pharmacological action at several receptors, channels, and enzymes. Dihydropyridine moiety plays an important role in several calcium-channel blockers. Moreover, it has been exploited for the treatment of a variety of cardiovascular diseases due to its potential antihypertensive, anti-angina, vasodilator, and cardiac depressant activities. Furthermore, it also shows antibacterial, anticancer, antileishmanial, anticoagulant, anticonvulsant, anti-tubercular, antioxidant, antiulcer, and neuroprotective properties. Several reports have demonstrated dihydropyridine derivatives as a potentiator of cystic fibrosis transmembrane conductance regulator protein, potent antimalarial agent and HIV-1 protease inhibitor. Herein, we have briefly reviewed different novel chemistry and synthesis of 1,4-dihydropyridine.
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