353 CUMULUS CELLS RESPONSE TO HEAT SHOCK AND INSULIN-LIKE GROWTH FACTOR-I

2010 ◽  
Vol 22 (1) ◽  
pp. 333 ◽  
Author(s):  
F. F. Paula-Lopes ◽  
C. M. Mendes ◽  
P. H. B. Risolia ◽  
J. S. A. Gonçalves ◽  
W. B. Feitosa ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Membrane Potential ◽  
Heat Shock ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Annexin V ◽  
Cumulus Cells ◽  
Low Grade ◽  
Mitochondrial Membrane Depolarization ◽  
Igf I

Heat-stress induced maternal hyperthermia has been shown to compromise the series of events associated with oocyte growth and maturation reducing oocyte competence. Such events are regulated by a variety of growth factors and dynamic communication between the oocyte and its surrounding cumulus cells. The objective of the current study was to evaluate the modulatory effects of COCs quality and IGF-I on mitochondrial membrane potential (MMP) and apoptosis in cumulus cells induced by heat shock. In this study high (≥3 layers of compact cumulus cells and homogeneous cytoplasm) and low-grade COCs (<3 layers of less compact cumulus cells and irregular cytoplasm) derived from slaughterhouse ovaries were exposed to control (CTR: 39°C) or heat shock (HS: 41°C) treatments in the presence of 0 or 100 ng mL-1 IGF-I during the first 12 h of in vitro maturation (12 h-IVM). Immediately after 12 h-IVM COCs were denuded by repeated pipetting and cumulus cells evaluated for MMP (MitoProbe JC-1 assay kit. JC-1 is a cationic dye that exhibits potential-depend accumulation in the mitochondria) and apoptosis (Annexin V-FITC and propidium iodide) by flow cytometry (Guava EasyCyte Mini Flow Cytometry System, Millipore, Billerica, MA, USA). This factorial experiment was replicated 4 times using 75-100 COCs per treatment. Data were subjected to three-way analysis of variance using the General Linear Models procedure of SAS. Results are shown in Table 1. Exposure of high and low-grade COCs to HS reduced (P < 0.01) the percentage of cumulus cells carrying high MMP regardless of IGF-I. Even though HS caused cumulus cells mitochondrial membrane depolarization there was neither temperature nor COCs quality effect on cumulus cells apoptosis as indicated by the lack of phosphatidylserine (PS) translocation from the inner to the outer leaflet of the plasma membrane. On the other hand, addition of IGF-I to maturation medium reduced (P < 0.05) the percentage of cumulus cells labeled with Annexin V + PI regardless of COCs quality or temperature. There was no statistical interaction between COCs quality × IGF-I × temperature. In conclusion, exposure of COCs to HS during 12 h-IVM caused cumulus cells mitochondrial depolarization without inducing apoptosis. It is possible that a period longer than 12 h is required for most PS translocation to occur in cumulus cells. Moreover, IGF-I exerted protective effect reducing cumulus cells late apoptosis/necrosis events. Table 1.Effect of heat-shock and IGF-I on cumulus cells mitochondrial membrane potential and apoptosis. Results are least-squares means ± SEM.

Inhibition of human head and neck squamous cell cancer growth by modulation of heat shock proteins and induction of the mitochondrial apoptotic pathway with withaferin A

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e17003-e17003
Author(s):  
M. S. Cohen ◽  
B. N. Timmermann ◽  
G. O'Donnell ◽  
A. K. Samadi
Keyword(s):  
Flow Cytometry ◽  
Membrane Potential ◽  
Heat Shock ◽  
Heat Shock Proteins ◽  
Cell Viability ◽  
Mitochondrial Membrane ◽  
Annexin V ◽  
Withaferin A ◽  
Shock Proteins ◽  
Mts Assay

e17003 Background: Epithelial cancers, particularly lung cancer and head and neck squamous cell carcinoma (HNSCC), continue to pose formidable challenges in clinical practice. Novel chemotherapeutic agents have been developed, but even those have limited long-term benefits in the treatment of these tumors, illustrating the need to continue to improve systemic therapy for affected patients. The objective of the present study was to investigate the effect of withaferin A (WA), a plant-derived small molecule, on cancer cell growth, heat shock protein expression and induction of apoptosis in human HNSCCs. Methods: MDA1986 and JMAR HNSCC cells were used in all experiments. The effect of WA on cell viability was determined by MTS assay. Apoptosis and mitochondrial membrane potential changes were assessed by annexin V/propidium iodide and JC-1 staining respectively using standard flow cytometry methods. Effect of WA on modulation of heat shock proteins was determined by Western blot analysis. Results: Withaferin A reduces cell viability in both MDA1986 and JMAR cells with IC50 levels of 265 ± 5 nM by MTS assay, which is 5 fold higher than its reported activity in breast cancer cells. WA completely down-regulates HSP90beta, GRP94, and TRAP-1 expression at 250 nM concentration in HNSCC cells at 24 hours treatment. In addition, WA markedly increased HSP70 levels and mildly increased HSP27 levels in a dose-dependent manner at 24 hours treatment. Flow cytometry with Annexin V/PI staining shows that 5 μM WA treatment for 24 hours induced apoptosis in 63% of MDA1986 and 60% of JMAR cells. WA at 5 μM also reduced mitochondrial membrane potential by JC-1 staining with flow cytometry to less than 10% of controls in both JMAR and MDA1986 cells at 24 hours treatment. Conclusions: Withaferin A is a potent novel inhibitor of HSP90 in human HNSCCs. In addition to HSP modulation, its anticancer mechanistic effects involve apoptotic cell death through the mitochondrial pathway. This molecule shows promise for further in vivo studies to establish preclinical proof of concept as a novel anticancer therapy in this disease. No significant financial relationships to disclose.

scholarly journals Anti-Cancer Effects of Clofazimine As a Single Agent and in Combination with Cisplatin in Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5897-5897 ◽  
Author(s):  
Ipek Durusu ◽  
Hazal Hepsen Husnugil ◽  
Heval Atas ◽  
Aysenur Biber ◽  
Selin Gerekci ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Membrane Potential ◽  
Fluorescence Microscopy ◽  
Cell Line ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Caspase 3 ◽  
Annexin V ◽  
Growth Inhibitory ◽  
U266 Cell

Abstract Multiple myeloma (MM) is a malignant neoplasm of bone marrow plasma B cells with high morbidity. Clofazimine (CLF) is an FDA-approved leprostatic, anti-tuberculosis, and anti-inflammatory drug that was previously shown to have growth suppression effects on various cancer types such as hepatocellular, lung, cervix, esophageal, colon, and breast cancers as well as melanoma, neuroblastoma, and leukemia cells. The objective of this study was to evaluate the anticancer effect of CLF on U266 resistant MM cell line. The relative cell viability of a panel of hematological cell lines (Jurkat, U266, Namalwa, K562, HL60) treated with 10 µM CLF after 24 h of treatment significantly reduced the viability in all cell lines, with percentages ranging between 28% (U266) and 38% (Jurkat) (p<0.001). IC50 value of CLF was found as 9.8 ± 0.7 µM on the U266 cell line. Previous studies showed that this level of CLF does not inhibit growth of healthy cells, which supports safety of CLF. CLF had both dose (2, 5, 10 µM) and time (12, 24, and 48 h) dependent growth inhibitory effect. Combination chemotherapy is an approach to increase the effectiveness of chemotherapeutics as well as overcome drug resistance and suppresses side effects of drugs. Therefore, we evaluate the combination effect of CLF in U266 cells and showed that combination with cisplatin led to a synergistic interaction between two compounds in all tested dose regimes, resulting in a 2.5-7.1 fold marked increase in cell death. Importantly this synergism was observed in U266 cells, which have mutant p53 at A161T showing resistance to cytotoxic agents such as platinum analogs (cisplatin etc.). <>Depolarization of the mitochondrial membrane is one of the first events in apoptosis. JC-1 is a lipophilic and cationic dye that reversibly changes color from green to red as the mitochondrial membrane potential increases (depolarization). JC-1 assay used in both flow cytometry analyses and fluorescence microscopy images have shown that relative to the control, CLF treatment results in the depolarization of mitochondrial membrane 15, 20.5, 14.3 fold respectively at 12, 24, and 48 h in U266 cell line (Figure 1). The caspase family of cysteine proteases plays an important role in apoptosis. Caspase-3 is a major protease activated during the early stages of programmed cell death. 10 µM CLF was applied for 12, 24, and 48 h and anti-active caspase-3 PE stained U266 cells were analyzed by flow cytometry. Caspase-3 activity is enhanced 5.6, 24.5 and 13.6-fold relative to untreated controls at 12h, 24h and 48 h respectively. Phosphatidylserine (PS) translocation to the outer leaflet of the cellular membrane is one of the key steps in early stages of apoptosis. To support our previous findings on apoptotic effect of CLF, we employed Annexin-V assay. CLF treatment caused a significant increase in the percentage of early and late apoptotic cells at 12 h (2.1 and 1.8 fold respectively), 24 h (4.1 and 12.3 fold) and 48 h (10.1 and 11.5 fold). Fluorescence microscopy images also supported flow cytometry data (Figure 2). Collectively, all three apoptosis assay results show that CLF significantly induces apoptosis in U266 cells. Our study is the first to show apoptotic and growth inhibitory effects of CLF on a p53-mutant resistant MM cell line U266. Our results also proved that combined therapy employing CLF together with chemotherapeutics seems to be a possible future therapeutic approach for MM. Further in vivo and clinical studies are warranted to evaluate its therapeutic potential for resistant MM treatment. Figure 1 Effect of 10 µM CLF on mitochondrial membrane potential. Flow cytometry fluorescence intensity A) Dot plots B) Bar plots of cells stained with JC-1 (n=3). C) Fluorescence microscopy image of JC-1-stained untreated cells indicating healthy mitochondria (red), D) In CLF-treated cells, green color shows diffusion of JC-1 from damaged mitochondria. Figure 1. Effect of 10 µM CLF on mitochondrial membrane potential. Flow cytometry fluorescence intensity A) Dot plots B) Bar plots of cells stained with JC-1 (n=3). C) Fluorescence microscopy image of JC-1-stained untreated cells indicating healthy mitochondria (red), D) In CLF-treated cells, green color shows diffusion of JC-1 from damaged mitochondria. Figure 2 Flow cytometry analysis of Annexin V-PE/7-AAD stained U266 cells treated with 10 µM CLF. A) Representative dot plots of Annexin V-PE vs 7-AAD signals gated as live, early apoptotic and late apoptotic quadrants B) Cell population bar graphs of corresponding dot plot quadrants (n=3). C) Early apoptotic U266 cell (right) stained with Annexin V-PE (green) and a late apoptotic U266 cell (left) stained with both Annexin V-PE (green) and nuclear dye PI (red) D) Close-up micrograph (160X) of a late apoptotic U266 cell. Figure 2. Flow cytometry analysis of Annexin V-PE/7-AAD stained U266 cells treated with 10 µM CLF. A) Representative dot plots of Annexin V-PE vs 7-AAD signals gated as live, early apoptotic and late apoptotic quadrants B) Cell population bar graphs of corresponding dot plot quadrants (n=3). C) Early apoptotic U266 cell (right) stained with Annexin V-PE (green) and a late apoptotic U266 cell (left) stained with both Annexin V-PE (green) and nuclear dye PI (red) D) Close-up micrograph (160X) of a late apoptotic U266 cell. Disclosures No relevant conflicts of interest to declare.

Platelets apoptosis in rats after global brain ischemia

2018 ◽  
pp. 27-35
Author(s):  
А.А. Соколовская ◽  
Э.Д. Вирюс ◽  
В.В. Александрин ◽  
А.С. Роткина ◽  
К.А. Никифорова ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Ischemic Stroke ◽  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Brain Ischemia ◽  
Mitochondrial Membrane ◽  
Male Rats ◽  
Global Brain Ischemia ◽  
Platelet Apoptosis ◽  
Global Brain

Цель исследования. Ишемические повреждения головного мозга, являются одной из наиболее частой причин инвалидности и смертности во всем мире. Недавно была установлена роль апоптоза тромбоцитов в патофизиологии инсульта, однако его механизмы до сих пор остаются невыясненными. Несмотря на различные экспериментальные модели, направленные на мониторинг апоптоза тромбоцитов, результаты, относительно изучения и выявления апоптоза тромбоцитов при ишемии головного мозга у крыс, весьма немногочисленны. Цель исследования - анализ апоптоза тромбоцитов с помощью метода проточной цитофлуориметрии на модели глобальной ишемии мозга у крыс. Методика. В экспериментах использовано 6 крыс-самцов Вистар в возрасте от 5 до 6 мес., разделенных на 2 группы: интактный контроль (К) и глобальная ишемия головного мозга. Модель глобальной ишемии головного мозга у крыс воспроизводилась путём билатеральной окклюзии общих сонных артерий на фоне гипотензии. Уровень системного артериального давления снижали посредством кровопотери до 40-45 мм рт. ст. Суспензию тромбоцитов крыс получали методом гельфильтрации с использованием сефарозы 2B. Для анализа экстернализации фосфатидилсерина (ФС) тромбоциты крыс инкубировали с Аннексином V-PE в связывающем буфере. Для оценки митохондриального мембранного потенциала (ММП) тромбоциты инкубировали с катионным красителем JC-1. После инкубации образцы немедленно анализировали на проточном цитофлуориметре FACSCalibur (Becton Dickinson, США). Результаты. Согласно полученным данным, экстернализация ФС на тромбоцитах крыс, перенесших инсульт, была значительно выше (53,45 ± 4,21%), чем в контрольной группе крыс (5,27 ± 2,40%). Данный эффект подтверждается выраженной деполяризацией митохондриальных мембран (DYm). После экспериментальной ишемии мозга почти 40% тромбоцитов было деполяризовано. Заключение. Использованный в работе подбор методов и маркеров обеспечивает понимание механизмов апоптоза тромбоцитов как в экспериментальных, так и в клинических условиях. Полученные данные позволяют сделать заключение, что апоптоз тромбоцитов является одним из факторов развития глобальной ишемии головного мозга у крыс. Результаты могут быть использованы для понимания механизмов, участвующих в развитии ишемического повреждения, что, в свою очередь, может быть использовано при разработке новых терапевтических стратегий. Aim. Stroke is one of the most common causes of disability and mortality worldwide. Multiple experimental models of stroke have focused on monitoring of platelet apoptosis. However, studies on and detection of platelet apoptosis in rats with ischemic stroke are very scarce. We investigated platelet apoptosis in rats with global brain ischemia using flow cytometry. Methods. Experiments were carried out on healthy, adult Wistar male rats weighing 300-350 g. The rats were divided into the following 2 groups: intact rats and rats with global brain ischemia. Global brain ischemia was induced by two-vessel (2-VO) carotid occlusion in combination with hypotension. Systemic blood pressure was reduced by 40-45 mm Hg by inducing haemorrhage. Platelets were isolated by gel filtration on Sepharose 2B. For evaluation of phosphatidylserine (PS) externalization, platelets were incubated with Annexin V-PE and analyzed on FACSCalibur (BD Biosciences). Mitochondrial membrane potential (DY) was measured during platelets apoptosis using JC-1, a mitochondrial membrane potential indicator. Platelets were analyzed by flow cytometry immediately after the incubation. Results. PS externalization on platelets was significantly greater after global brain ischemia (53.45 ± 4.21%) than in the control group (5.27 ± 2.40%). Pronounced depolarization of mitochondrial membrane potential (DYm) confirmed this finding. In the rat group with experimental brain ischemia, almost 40% (35.24 ± 5.21%) of platelets were depolarized. Conclusion. Our results provide insight into mechanisms involved in platelet apoptosis during ischemic stroke and can be used in further development of new therapeutic strategies.

Synthesis and Biological Evaluation of Novel Heterocyclic Imines Linked Coumarin- Thiazole Hybrids as Anticancer Agents

2019 ◽  
Vol 19 (4) ◽  
pp. 557-566 ◽  
Author(s):  
Nerella S. Goud ◽  
Mahammad S. Ghouse ◽  
Jatoth Vishnu ◽  
Jakkula Pranay ◽  
Ravi Alvala ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Membrane Potential ◽  
Fluorescence Spectroscopy ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Annexin V ◽  
Biological Evaluation ◽  
Dependent Manner ◽  
Dapi Staining ◽  
Dose Dependent

Background: Human Galectin-1, a protein of lectin family showing affinity towards β-galactosides has emerged as a critical regulator of tumor progression and metastasis, by modulating diverse biological events including homotypic cell aggregation, migration, apoptosis, angiogenesis and immune escape. Therefore, galectin-1 inhibitors might represent novel therapeutic agents for cancer. Methods: A new series of heterocyclic imines linked coumarin-thiazole hybrids (6a-6r) was synthesized and evaluated for its cytotoxic potential against a panel of six human cancer cell lines namely, lung (A549), prostate (DU-145), breast (MCF-7 & MDA-MB-231), colon (HCT-15 & HT-29) using MTT assay. Characteristic apoptotic assays like DAPI staining, cell cycle, annexin V and Mitochondrial membrane potential studies were performed for the most active compound. Furthermore, Gal-1 inhibition was confirmed by ELISA and fluorescence spectroscopy. Results: Among all, compound 6g 3-(2-(2-(pyridin-2-ylmethylene) hydrazineyl) thiazol-4-yl)-2H-chromen-2- one exhibited promising growth inhibition against HCT-15 colorectal cancer cells with an IC50 value of 1.28 ± 0.14 µM. The characteristic apoptotic morphological features like chromatin condensation, membrane blebbing and apoptotic body formation were clearly observed with compound 6g on HCT-15 cells using DAPI staining studies. Further, annexin V-FITC/PI assay confirmed effective early apoptosis induction by treatment with compound 6g. Loss of mitochondrial membrane potential and enhanced ROS generation were confirmed with JC-1 and DCFDA staining method, respectively by treatment with compound 6g, suggesting a possible mechanism for inducing apoptosis. Moreover, flow cytometric analysis revealed that compound 6g blocked G0/G1 phase of the cell cycle in a dose-dependent manner. Compound 6g effectively reduced the levels of Gal-1 protein in a dose-dependent manner. The binding constant (Ka) of 6g with Gal-1 was calculated from the intercept value which was observed as 1.9 x 107 M-1 by Fluorescence spectroscopy. Molecular docking studies showed strong interactions of compound 6g with Gal-1 protein. Conclusion: Our studies demonstrate the anticancer potential and Gal-1 inhibition of heterocyclic imines linked coumarin-thiazole hybrids.

scholarly journals Overexpression of Mitochondrial Hsp70/Hsp75 Protects Astrocytes against Ischemic Injury in vitro

2007 ◽  
Vol 28 (5) ◽  
pp. 1009-1016 ◽  
Author(s):  
Ludmila A Voloboueva ◽  
Melissa Duan ◽  
YiBing Ouyang ◽  
John F Emery ◽  
Christian Stoy ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Mitochondrial Membrane Potential ◽  
Heat Shock Protein 70 ◽  
Mitochondrial Membrane ◽  
Ischemic Injury ◽  
Glucose Deprivation ◽  
Hsp70 Family

Mitochondrial heat shock protein 70 (mtHsp70/Hsp75/Grp75/mortalin/TRAP-1/PBP74) is an essential mitochondrial chaperone and a member of the heat shock protein 70 (HSP70) family. Although many studies have shown the protective properties of overexpression of the cytosolic inducible member of the HSP70 family, Hsp72, few studies have investigated the protective potential of Hsp75 against ischemic injury. Mitochondria are one of the primary targets of ischemic injury in astrocytes. In this study, we analyzed the effects of Hsp75 overexpression on cellular levels of reactive oxygen species (ROS), mitochondrial membrane potential, ATP levels, and viability during the ischemia-like conditions of oxygen-glucose deprivation (OGD) or glucose deprivation (GD) in primary astrocytic cultures. We show that Hsp75 overexpression decreases ROS production and preserves mitochondrial membrane potential during GD, and preserves ATP levels and cell viability during OGD. These findings indicate that Hsp75 can provide protection against ischemia-like in vitro injury and suggest that it should be further studied as a potential candidate for protection against ischemic injury.

The Inhibitor of Cyclin-Dependent Kinase4a (INK4a) Signaling Pathway Induces Aging in Human Skeletal Muscle Myoblasts and Decreases the Mitochondrial Membrane Potential

2019 ◽  
Vol 9 (9) ◽  
pp. 1192-1198
Author(s):  
Dong Yan ◽  
Xiang Liao ◽  
Li-Xia Zhao ◽  
Chang-Hong Xiao
Keyword(s):  
Skeletal Muscle ◽  
Flow Cytometry ◽  
Membrane Potential ◽  
Signaling Pathway ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Human Skeletal Muscle ◽  
Lentiviral Vector ◽  
Accelerated Aging ◽  
Senescence Phenotype

The effect of the inhibitor of cyclin-dependent kinase4a (INK4a) signaling pathway on myoblastic aging was studied in this paper. Human skeletal muscle myoblasts were transfected with a recombinant lentiviral vector, pLVX-p16INK4a, encoding the p16INK4a gene, and RT-qPCR and western blotting were used to identify p16INK4a gene transcription and protein expression. The degree of cell senescence was assessed using Senescence-associated β-galactosidase staining. flow cytometry and JC-1 staining was used to analyze the mitochondrial membrane potential (MMP). The senescence phenotype was observed in myoblasts transfected with p16INK4a, the MMP was significantly decrease in p16INK4a-transfected myoblasts, while the MMP was decreased only slightly in control cells. Upregulation of the INK4a signaling pathway directly induced aging in human skeletal muscle myoblasts. Moreover, INK4a signaling pathway activated the mitochondrial pro-aging pathway by reducing the MMP, which indirectly accelerated aging in myoblasts.

GATA-4 protects against hypoxia-induced cardiomyocyte injury: effects on mitochondrial membrane potential

2014 ◽  
Vol 92 (8) ◽  
pp. 669-678 ◽  
Author(s):  
Hong-Xia Li ◽  
Ya-Feng Zhou ◽  
Xin Zhao ◽  
Bin Jiang ◽  
Xiang-Jun Yang
Keyword(s):  
Bone Marrow ◽  
Membrane Potential ◽  
Growth Factor ◽  
Mitochondrial Membrane Potential ◽  
Neutralizing Antibodies ◽  
Mitochondrial Membrane ◽  
Annexin V ◽  
Neonatal Rat ◽  
Low Oxygen ◽  
Cell Protection

Our previous studies have suggested that GATA-4 increases the differentiation of bone-marrow-derived mesenchymal stem cells (MSCs) into cardiac phenotypes. This study further investigated whether GATA-4 enhances MSC-mediated cardioprotection following hypoxia. MSCs were harvested from rat bone marrow and transduced with GATA-4 (MSCGATA-4). To mimic ischemic injury, cultured cardiomyocytes (CMs) isolated from neonatal rat ventricles were exposed to hypoxia or were pretreated with concentrated conditioned medium (CdM) from MSCGATA-4 or transduced control MSC (MSCNull) for 16 h before exposure to hypoxic culture conditions (low glucose and low oxygen). Myocyte damage was estimated by annexin-V-PE and TUNEL technique and by lactate dehydrogenase (LDH) release. Cell survival was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium (MTT) uptake. Mitochondrial membrane potential was determined using confocal microscopy. ELISA studies indicated that insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF) were significantly increased in MSCGATA-4 compared with MSCNull. Hypoxia-induced apoptosis/cell death was significantly reduced when CMs were co-cultured with MSCGATA-4 in a dual-chamber system. Cell protection mediated by MSCGATA-4 was mimicked by treating CMs with CdM from MSCGATA-4 and abrogated with IGF-1- and VEGF-neutralizing antibodies. MSCGATA-4 protects CMs under hypoxic conditions. The release of IGF-1 and VEGF from MSCGATA-4 is likely to be responsible for protection of CMs.

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