scholarly journals Kynurenic acid- a key metabolite protecting the heart from an ischemic damage

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
M Entin-Meer ◽  
E B Bigelman ◽  
M P C Pasmanik-Chor ◽  
B D Dassa ◽  
A G Gross ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Kynurenic Acid ◽  
Medical Center ◽  
Cardiac Cells ◽  
Cardiac Mitochondria ◽  
Joint Research ◽  
Ischemic Event ◽  
Mitochondrial Structure

Abstract Background Myocardial ischemia is a major cause of death in patients with renal dysfunction. In order to identify a key metabolite which may protect cardiac function following renal injury, we have recently performed a metabolomics profiling analysis of LV lysates and plasma samples derived from animals that underwent an acute kidney injury (AKI) 1 or 7 days earlier, versus sham-operated controls. The analysis revealed that the kynurenic acid (kynurenate, KYNA) metabolite levels are highly elevated in all tested experimental samples relative to control. Purpose We wished to analyze whether KYNA may protect cardiomyocytes' survival and cardiac function upon an ischemic event and if so, to characterize whether the protecting effect may be linked to better preservation of the cardiac mitochondria. Methods Cellular viability of H9C2 rat cardiac myoblasts grown under normoxic or anoxic conditions with or without KYNA was determined by flow cytometry following Annexin-PI staining. The mitochondrial structure of the cells was determined by live cell staining with green (FITC) and deep red (Cy5) mito-tracker dyes. The potential effect of the metabolite on cardiac function following acute MI was tested in a murine model by echocardiography followed by histological staining of the cardiac sections with Picro Sirius Red. Results KYNA given at 10 mM concentration hardly affected the viability of H9C2 grown under normoxia, however the metabolite rescued the viability of the anoxic cells by 63% and largely improved their mitochondrial structure. Moreover, KYNA diluted in the drinking water of post-MI animals (250mg/ml), highly enhanced their cardiac recovery compared to untreated-animals as determined by echocardiography and collagen staining. Conclusions 1. KYNA may represent a key metabolite absorbed by the heart following AKI. 2. KYNA can enhance cardiac cell viability following an ischemic event both in vitro and in vivo in a mechanism which is mediated, at least in part, by protection of the cardiac mitochondria. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Weizmann Institute-Tel-Aviv Sourasky Medical Center joint research grant KYNA's protection of cardiac cells

scholarly journals Mechanisms for Intracellular Calcium Regulation in Heart

1973 ◽  
Vol 62 (6) ◽  
pp. 756-772 ◽  
Author(s):  
Antonio Scarpa ◽  
Pierpaolo Graziotti
Keyword(s):  
Cardiac Cells ◽  
Heart Mitochondria ◽  
Frog Heart ◽  
Cardiac Mitochondria ◽  
Physiological Regulation ◽  
Ca Transport ◽  
Ca Uptake ◽  
Intracellular Ca

Initial velocities of energy-dependent Ca++ uptake were measured by stopped-flow and dual-wavelength techniques in mitochondria isolated from hearts of rats, guinea pigs, squirrels, pigeons, and frogs. The rate of Ca++ uptake by rat heart mitochondria was 0.05 nmol/mg/s at 5 µM Ca++ and increased sigmoidally to 8 nmol/mg/s at 200 µM Ca++. A Hill plot of the data yields a straight line with slope n of 2, indicating a cooperativity for Ca++ transport in cardiac mitochondria. Comparable rates of Ca++ uptake and sigmoidal plots were obtained with mitochondria from other mammalian hearts. On the other hand, the rates of Ca++ uptake by frog heart mitochondria were higher at any Ca++ concentrations. The half-maximal rate of Ca++ transport was observed at 30, 60, 72, 87, 92 µM Ca++ for cardiac mitochondria from frog, squirrel, pigeon, guinea pig, and rat, respectively. The sigmoidicity and the high apparent Km render mitochondrial Ca++ uptake slow below 10 µM. At these concentrations the rate of Ca++ uptake by cardiac mitochondria in vitro and the amount of mitochondria present in the heart are not consistent with the amount of Ca++ to be sequestered in vivo during heart relaxation. Therefore, it appears that, at least in mammalian hearts, the energy-linked transport of Ca++ by mitochondria is inadequate for regulating the beat-to-beat Ca++ cycle. The results obtained and the proposed cooperativity for mitochondrial Ca++ uptake are discussed in terms of physiological regulation of intracellular Ca++ homeostasis in cardiac cells.

scholarly journals Recapitulating Cardiac Structure and Function In Vitro from Simple to Complex Engineering

Micromachines ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 386
Author(s):  
Ana Santos ◽  
Yongjun Jang ◽  
Inwoo Son ◽  
Jongseong Kim ◽  
Yongdoo Park
Keyword(s):  
Tissue Engineering ◽  
Extracellular Matrix ◽  
Computational Modeling ◽  
Cardiac Tissue ◽  
Cardiac Development ◽  
Heart Tissue ◽  
Cardiac Tissue Engineering ◽  
Cardiac Cells

Cardiac tissue engineering aims to generate in vivo-like functional tissue for the study of cardiac development, homeostasis, and regeneration. Since the heart is composed of various types of cells and extracellular matrix with a specific microenvironment, the fabrication of cardiac tissue in vitro requires integrating technologies of cardiac cells, biomaterials, fabrication, and computational modeling to model the complexity of heart tissue. Here, we review the recent progress of engineering techniques from simple to complex for fabricating matured cardiac tissue in vitro. Advancements in cardiomyocytes, extracellular matrix, geometry, and computational modeling will be discussed based on a technology perspective and their use for preparation of functional cardiac tissue. Since the heart is a very complex system at multiscale levels, an understanding of each technique and their interactions would be highly beneficial to the development of a fully functional heart in cardiac tissue engineering.

scholarly journals Kynurenic Acid Accelerates Healing of Corneal Epithelium In Vitro and In Vivo

2021 ◽  
Vol 14 (8) ◽  
pp. 753
Author(s):  
Anna Matysik-Woźniak ◽  
Waldemar A. Turski ◽  
Monika Turska ◽  
Roman Paduch ◽  
Mirosław Łańcut ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Corneal Epithelium ◽  
Kynurenic Acid ◽  
Pharmaceutical Products ◽  
Corneal Epithelial Cell ◽  
Eye Drops ◽  
Conjunctival Epithelium ◽  
Corneal Erosion

Kynurenic acid (KYNA) is an endogenous compound with a multidirectional effect. It possesses antiapoptotic, anti-inflammatory, and antioxidative properties that may be beneficial in the treatment of corneal injuries. Moreover, KYNA has been used successfully to improve the healing outcome of skin wounds. The aim of the present study is to evaluate the effects of KYNA on corneal and conjunctival cells in vitro and the re-epithelization of corneal erosion in rabbits in vivo. Normal human corneal epithelial cell (10.014 pRSV-T) and conjunctival epithelial cell (HC0597) lines were used. Cellular metabolism, cell viability, transwell migration, and the secretion of IL-1β, IL-6, and IL-10 were determined. In rabbits, after corneal de-epithelization, eye drops containing 0.002% and 1% KYNA were applied five times a day until full recovery. KYNA decreased metabolism but did not affect the proliferation of the corneal epithelium. It decreased both the metabolism and proliferation of conjunctival epithelium. KYNA enhanced the migration of corneal but not conjunctival epithelial cells. KYNA reduced the secretion of IL-1β and IL-6 from the corneal epithelium, leaving IL-10 secretion unaffected. The release of all studied cytokines from the conjunctival epithelium exposed to KYNA was unchanged. KYNA at higher concentration accelerated the healing of the corneal epithelium. These favorable properties of KYNA suggest that KYNA containing topical pharmaceutical products can be used in the treatment of ocular surface diseases.

scholarly journals “Empowering” Cardiac Cells via Stem Cell Derived Mitochondrial Transplantation- Does Age Matter?

2021 ◽  
Vol 22 (4) ◽  
pp. 1824
Author(s):  
Matthias Mietsch ◽  
Rabea Hinkel
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Treatment Strategies ◽  
Cardiac Cells ◽  
Aging Effects ◽  
Beneficial Effects ◽  
Micro Rnas ◽  
New Treatment

With cardiovascular diseases affecting millions of patients, new treatment strategies are urgently needed. The use of stem cell based approaches has been investigated during the last decades and promising effects have been achieved. However, the beneficial effect of stem cells has been found to being partly due to paracrine functions by alterations of their microenvironment and so an interesting field of research, the “stem- less” approaches has emerged over the last years using or altering the microenvironment, for example, via deletion of senescent cells, application of micro RNAs or by modifying the cellular energy metabolism via targeting mitochondria. Using autologous muscle-derived mitochondria for transplantations into the affected tissues has resulted in promising reports of improvements of cardiac functions in vitro and in vivo. However, since the targeted treatment group represents mainly elderly or otherwise sick patients, it is unclear whether and to what extent autologous mitochondria would exert their beneficial effects in these cases. Stem cells might represent better sources for mitochondria and could enhance the effect of mitochondrial transplantations. Therefore in this review we aim to provide an overview on aging effects of stem cells and mitochondria which might be important for mitochondrial transplantation and to give an overview on the current state in this field together with considerations worthwhile for further investigations.

Creation of a primary breast cancer culture repository from patients with a BMI >30 kg/m2: A Mexican endeavor.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e12574-e12574
Author(s):  
Daniela Shveid Gerson ◽  
Alejandro Zentella - Dehesa ◽  
Raquel Gerson Cwilich ◽  
Benigno Rodriguez ◽  
Omar Serrano Villamayor ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Primary Breast Cancer ◽  
Medical Center ◽  
Primary Cultures ◽  
Obese Women ◽  
Cellular Analysis ◽  
Response To Chemotherapy

e12574 Background: Currently there are no primary cultures or cell lines derived from patients with breast cancer and obesity. It has been postulated that breast cancer in obese women behaves differently as it does in non-obese women, as is composed of distinct biological features, as was generated in a different metabolic environment, as well as pertains to a different prognosis and different response to chemotherapy, lower rates of overall survival and a greater probability of recurrence. By creating a primary breast cancer culture bank of breast cancer tumors from women with obesity (BMI > 30kg/m2), we will establish a cell line exclusive to obese women in Mexico, where targeted therapy may be tested and treatment may be individualized depending on the characteristics of the patient. Methods: This study recruited 32 women with breast cancer and a BMI > 30 kg/m2, matched by 6 controls with are non-obese women with breast cancer. Elegibility criteria was determined by women with breast cancer confirmed by pathology, who had not been subjected to prior treatment regarding the neoplasm. The breast cancer removing surgeries and the patients were selected from the ABC Medical Center in Mexico City and all procedures were approved by the research and ethics committee of the hospital in question. Results: Through extensive communication a cooperative protocol was established between the departments of surgery, oncology, pathology and nursing to coordinate efforts and be able to take a 2 – 5 mm sample of the breast tumor removed from the patient. To be able to distinguish cancer cells from non-cancer cells (epithelial cells, fibroblasts, adipocytes) the Hayflick limit was be utilized. Once a primary breast cancer culture was established, 12 million cells will be injected into the subscapular area of athymic, nu-nu mice to be able to monitor tumoral growth in vivo and conduct a subsequent cellular analysis, determining it still pertains to the same characteristics of the tumor from which it was obtained. Conclusions: A primary breast cancer culture repository from patients with a BMI > 30 kg/m2 was established. This is the first primary breast cancer culture for both Mexican and obese women with breast cancer, the first in vitro method of analysis of specific characteristics typical of the Mexican population. Translational research may now be conducted on these new tumoral cultures to create individualized therapy for women with the distinct, aforementioned characteristics.

Abstract 14391: Transient Cell Cycle Induction in Cardiomyocytes is a Promising Approach to Treat Ischemia Induced Heart Failure

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Riham Abouleisa ◽  
Qinghui Ou ◽  
Xian-liang Tang ◽  
Mitesh Solanki ◽  
Yiru Guo ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cardiac Function ◽  
Single Cell ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiomyocyte Proliferation ◽  
Specific Expression ◽  
Control Virus

Rationale: The regenerative capacity of the heart to repair itself after myocardial infarction (MI)is limited. Our previous study showed that ectopic introduction of Cdk1/CyclinB1 andCdk4/CyclinD1 complexes (4F) promotes cardiomyocyte proliferation in vitro and in vivo andimproves cardiac function after MI. However, its clinical application is limited due to the concernsfor tumorigenic potential in other organs. Objectives: To first, identify on a single cell transcriptomic basis the necessary reprogrammingsteps that cardiomyocytes need to undertake to progress through the proliferation processfollowing 4F overexpression, and then, to determine the pre-clinical efficacy of transient andcardiomyocyte specific expression of 4F in improving cardiac function after MI in small and largeanimals. Methods and Results: Temporal bulk and single cell RNAseq of mature hiPS-CMs treated with4F or LacZ control for 24, 48, or 72 h revealed full cell cycle reprogramming in 15% of thecardiomyocyte population which was associated with sarcomere disassembly and metabolicreprogramming. Transient overexpression of 4F specifically in cardiomyocytes was achievedusing non-integrating lentivirus (NIL) driven by TNNT2 (TNNT2-4F-NIL). One week after inductionof ischemia-reperfusion injury in rats or pigs, TNNT2-4F-NIL or control virus was injectedintramyocardially. Compared with controls, rats or pigs treated with TNNT2-4F-NIL showed a 20-30% significant improvement in ejection fraction and scar size four weeks after treatment, asassessed by echocardiography and histological analysis. Quantification of cardiomyocyteproliferation in pigs using a novel cytokinesis reporter showed that ~10% of the cardiomyocyteswithin the injection site were labelled as daughter cells following injection with TNNT2-4F-NILcompared with ~0.5% background labelling in control groups. Conclusions: We provide the first understanding of the process of forced cardiomyocyteproliferation and advanced the clinical applicability of this approach through minimization ofoncogenic potential of the cell cycle factors using a novel transient and cardiomyocyte-specificviral construct.

In Vivo and In Vitro Models to Test the Hypothesis of Particle-Induced Effects on Cardiac Function and Arrhythmias

2006 ◽  
Vol 6 (1) ◽  
pp. 69-78 ◽  
Author(s):  
Loren E. Wold ◽  
Boris Z. Simkhovich ◽  
Michael T. Kleinman ◽  
Margaret A. Nordlie ◽  
Joan S. Dow ◽  
...  
Keyword(s):  
Cardiac Function ◽  
In Vitro Models

scholarly journals Paeoniflorin and Hydroxysafflor Yellow A in Xuebijing Injection Attenuate Sepsis-Induced Cardiac Dysfunction and Inhibit Proinflammatory Cytokine Production

2021 ◽  
Vol 11 ◽  
Author(s):  
Xin-Tong Wang ◽  
Zhen Peng ◽  
Ying-Ying An ◽  
Ting Shang ◽  
Guangxu Xiao ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Cardiac Tissue ◽  
Myocardial Dysfunction ◽  
Cecal Ligation ◽  
Hydroxysafflor Yellow A ◽  
Sepsis Management ◽  
Xuebijing Injection

Sepsis-induced myocardial dysfunction is a major contributor to the poor outcomes of septic shock. As an add-on with conventional sepsis management for over 15 years, the effect of Xuebijing injection (XBJ) on the sepsis-induced myocardial dysfunction was not well understood. The material basis of Xuebijing injection (XBJ) in managing infections and infection-related complications remains to be defined. A murine cecal ligation and puncture (CLP) model and cardiomyocytes in vitro culture were adopted to study the influence of XBJ on infection-induced cardiac dysfunction. XBJ significantly improved the survival of septic-mice and rescued cardiac dysfunction in vivo. RNA-seq revealed XBJ attenuated the expression of proinflammatory cytokines and related signalings in the heart which was further confirmed on the mRNA and protein levels. Xuebijing also protected cardiomyocytes from LPS-induced mitochondrial calcium ion overload and reduced the LPS-induced ROS production in cardiomyocytes. The therapeutic effect of XBJ was mediated by the combination of paeoniflorin and hydroxysafflor yellow A (HSYA) (C0127-2). C0127-2 improved the survival of septic mice, protected their cardiac function and cardiomyocytes while balancing gene expression in cytokine-storm-related signalings, such as TNF-α and NF-κB. In summary, Paeoniflorin and HSYA are key active compounds in XBJ for managing sepsis, protecting cardiac function, and controlling inflammation in the cardiac tissue partially by limiting the production of IL-6, IL-1β, and CXCL2.

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