scholarly journals Report of unexpected findings after cardiac stem cell injections in a preclinical model

2021 ◽  
Author(s):  
Mira van der Naald ◽  
Hans T van den Broek ◽  
John LM Bemelmans ◽  
Klaus Neef ◽  
Maarten H Bakker ◽  
...  
Keyword(s):  
Ischemia Reperfusion ◽  
Future Research ◽  
Preclinical Model ◽  
Cardiac Cell ◽  
Cell Retention ◽  
Cell Accumulation ◽  
A Cell ◽  
Indium 111 ◽  
Total Body ◽  
Unexpected Findings

Introduction Cardiac regenerative therapy is a proposed therapy for ischemic heart disease. So far efficacy has been low and this might partly be explained by low cardiac cell retention. In this study we aimed to investigate if cardiac cell retention improves using ureido-pyrimidinone units (UPy-gel) as a cell carrier. Methods We used an ischemia-reperfusion model. Pigs were randomized to intramyocardial injections with mesenchymal stromal cells (MSC) labelled with both Indium-111 and a fluorescent tracer in either PBS or in the UPy-gel. After 4 hours, a total body scintigraphy was performed to determine the cardiac cell retention and histology was obtained. Results In the first 4 pigs, we noticed focused areas of radio activity (hotspots) outside the heart in both the control and UPy-gel arm, and decided to interrupt the study. At histology we confirmed one hotspots to be located in a lymph node. No satisfactory explanation for these, potentially harmful, hotspots was found. Conclusion This study was interrupted due to unexpected extra-cardiac hotspots. Although we do not have a conclusive explanation for these findings, we find that sharing these results is important for future research. We recommend to use total body imaging in future retention studies to confirm of reject the occurrence of extra-cardiac cell accumulation after intramyocardial cell injection and discover the pathophysiology and its clinical implications.

The pig as a preclinical model for intestinal ischemia-reperfusion and transplantation studies

2012 ◽  
Vol 178 (2) ◽  
pp. 807-819 ◽  
Author(s):  
Thierry Yandza ◽  
Michel Tauc ◽  
Marie-Christine Saint-Paul ◽  
Mehdi Ouaissi ◽  
Jean Gugenheim ◽  
...  
Keyword(s):  
Intestinal Ischemia ◽  
Ischemia Reperfusion ◽  
Preclinical Model ◽  
Intestinal Ischemia Reperfusion

The proteasome inhibitor Bortezomib aggravates renal ischemia-reperfusion injury

2009 ◽  
Vol 297 (2) ◽  
pp. F451-F460 ◽  
Author(s):  
Julia M. Huber ◽  
Andrea Tagwerker ◽  
Dorothea Heininger ◽  
Gert Mayer ◽  
Alexander R. Rosenkranz ◽  
...  
Keyword(s):  
T Cells ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Reversible Inhibitor ◽  
Tubular Necrosis ◽  
Proinflammatory Mediators ◽  
Renal Ischemia Reperfusion Injury ◽  
A Cell

Bortezomib is a well-established treatment option for patients with multiple myeloma (MM). It is a selective and reversible inhibitor of the proteasome that is responsible for the degradation of many regulatory proteins that are involved in apoptosis, cell-cycle regulation, or transcription. Because patients with MM are prone to develop acute renal failure, we evaluated the influence of Bortezomib on renal ischemia-reperfusion injury (IRI). Mice were subjected to renal IRI by having the renal pedicles clamped for 30 min followed by reperfusion for 3, 24, and 48 h. Mice were either pretreated with 0.5 mg/kg body wt Bortezomib or vehicle intravenously 12 h before induction of IRI. Serum creatinine and tubular necrosis were significantly increased in Bortezomib compared with vehicle-treated mice. The inflammatory response was found to be significantly decreased in Bortezomib-treated mice as reflected by a decreased infiltration of CD4+ T cells and a significantly decreased Th1 cytokine expression in the kidneys. In contrast, apoptosis was significantly increased in kidneys of Bortezomib-treated mice compared with vehicle-treated controls. Increased numbers of TUNEL-positive cells/mm2 and increased mRNA expression of proapoptotic factors were detected in kidneys of Bortezomib-treated mice. Of note, p21, a cell senescence marker, was also significantly increased in kidneys of Bortezomib-treated mice. In summary, we provide evidence that Bortezomib worsens the outcome of renal IRI by leading to increased apoptosis of tubular cells despite decreased infiltrating T cells and proinflammatory mediators.

Inhibition of mitochondrial fission as a novel therapeutic strategy to reduce mortality upon myocardial infarction

2018 ◽  
Vol 132 (20) ◽  
pp. 2163-2167 ◽  
Author(s):  
Hannah A. Cooper ◽  
Satoru Eguchi
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Future Research ◽  
Mitochondrial Homeostasis ◽  
Acute Mi ◽  
Future Research Directions ◽  
Receive Treatment

Ischemia reperfusion (I/R) injury is a common event following myocardial infarction (MI) resulting in excessive oxidative stress, calcium overload, inflammation, and cardiomyocyte death. Mitochondrial homeostasis including their dynamics are imbalanced in cardiac I/R injury in favor of increased mitochondrial fission. Inhibition of mitochondrial fission prior to I/R injury is protective and improves cardiac function following MI. Clinically, patients with MI often receive treatment following initiation of the ischemic event. Thus, treatments with more realistic timing would have better translational value and are important to research. In a recent study published in Clinical Science, Maneechote et al. [Clin. Sci. (2018) 132, 1669–1683] examined the effect of inhibiting mitochondrial fission using the mitochondrial division inhibitor (Mdivi-1) at different time points, pre-ischemia, during-ischemia, and upon onset of reperfusion, in a rat cardiac I/R model. The findings showed the greatest cardiac function improvement with pre-ischemia treatment along with decreased mitochondrial fragmentation and increased mitochondrial function. Mdivi-1 given during ischemia and at onset of reperfusion also improved cardiac function, but to a lesser extent than pre-ischemia intervention. Maneechote et al. postulated that the LV protection by Mdivi-1 in cardiac I/R could be due to an improvement in mitochondrial dysfunction through attenuating excessive mitochondrial fission which then reduces apoptotic myocytes. Their findings provide new insights into future treatment of patients suffering acute MI which could consider targetting the excessive mitochondrial fission during cardiac ischemia or at onset of reperfusion. Here, we will further discuss the background of the study, potential molecular mechanisms of mitochondrial fission, consequences of the fission, and future research directions.

The relationship between training satisfaction, organisational citizenship behaviour, and turnover intention

2017 ◽  
Vol 4 (3) ◽  
pp. 267-290 ◽  
Author(s):  
Mumtaz Ali Memon ◽  
Rohani Sallaeh ◽  
Mohamed Noor Rosli Baharom ◽  
Shahrina Md Nordin ◽  
Hiram Ting
Keyword(s):  
Turnover Intention ◽  
Structural Equation ◽  
Oil And Gas ◽  
Positive Impact ◽  
Future Research ◽  
Content Type ◽  
Training Satisfaction ◽  
Negative Effect ◽  
Unexpected Findings

Purpose The purpose of this paper is to explore the role of training satisfaction as a predictor of organisational citizenship behaviour (OCB) and turnover intention. The study further examines the mediating role of OCB between training satisfaction and turnover intention. Design/methodology/approach Data were collected from 409 Malaysian oil and gas (O&G) sector employees. Partial least squares structural equation modelling (PLS-SEM) was used to test the hypotheses in the research model using SmartPLS 3.0. Findings This study highlights the significant positive impact of training satisfaction on OCB and the negative effect on turnover intention. Contrary to expectations, OCB proved to be neither a predictor of turnover intention nor a mediator in the model. Practical implications Although the main aim of this study was to test the theoretically driven hypotheses, the findings have a number of valuable implications for organisations. This study suggests that O&G organisations should focus on increasing employee satisfaction with training to maximise desired workplace attitudes and behaviours. Originality/value This is the first study to explore the causal links between training satisfaction, OCB and turnover intention. Although it has been observed in the past that training does not directly influence turnover intention, the present study indicates that training satisfaction significantly influences turnover intention. Further, this study unexpectedly found no direct relationship between OCB and turnover intention. Also, OCB was not a significant mediator in the present study. These unexpected findings open new avenues for future research, thus representing an important contribution of the present study.

ON THE CHARACTERISTICS OF INNOVATIVE FIRMS IN KOREA: THE ROLE OF R&D AND INNOVATION TYPE

1999 ◽  
Vol 03 (01) ◽  
pp. 111-131 ◽  
Author(s):  
YONG-TAE PARK ◽  
CHUL-HYUN KIM ◽  
JI-HYO LEE
Keyword(s):  
Large Scale ◽  
Data Gathering ◽  
Policy Implications ◽  
Future Research ◽  
Different Types ◽  
Innovative Firms ◽  
Unexpected Findings ◽  
Innovation Type ◽  
Recent Extension

In spite of the recent extension of our knowledge on technological innovation, little inquiry has been made of the distinctive characteristics between R&D firms and non-R&D firms, as well as between product-innovative firms and process-innovative firms. To this end, the main objective of this empirical study, grounded on a large-scale innovation survey of Korean manufacturing firms, is to contrast these two types of firms. The results were mixed. Some hypotheses were confirmed while others were discordant with expectation. By and large, R&D firms and product-innovative firms seem to share a similar propensity, whereas non-R&D firms and process-innovative firms are alike in character. However, there were some unexpected findings which merit attention and are worthy of in-depth examination. Although the study is subject to limitations in terms of its research design and data gathering, the results render some important policy implications. Furthermore, comparative analyses between different types of innovations need to be addressed more extensively in future research.

scholarly journals Determining Ideal Balance Among Branched-Chain Amino Acids (BCAA) as a Proof of Concept Study in Healthy Children

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1068-1068
Author(s):  
Haneen Saleemani ◽  
Rajavel Elango ◽  
Gabriella Horvath ◽  
Sylvia Stockler
Keyword(s):  
Protein Synthesis ◽  
Future Research ◽  
Acid Oxidation ◽  
P Value ◽  
Healthy Children ◽  
Proof Of Concept ◽  
Body Protein ◽  
Wide Range ◽  
Medical Foods ◽  
Total Body

Abstract Objectives Medical foods for children with in-born errors of metabolism (propionic academia, PROP) are formulated with imbalanced mixture of the BCAA (high leucine, to minimal or no valine and isoleucine), and therefore their use is controversial. The objective of the current study was to determine an ideal BCAA ratio at which total body protein synthesis is optimized in healthy children using the indicator amino acid oxidation (IAAO) method. Methods The study design was based on the oxidation of the stable isotope L-[1–,13C] phenylalanine to ,13CO2 to compare protein synthesis among seven different BCAA ratios. Leucine intake was gradually reduced from current high doses in medical foods; isoleucine and valine were kept constant. This study was done as a proof of concept in healthy children, to allow characterization of the metabolic responses to wide range of leucine test intakes, to help design narrow BCAA ratio range to test in children with PROP. Results A total of 8 healthy children were studied, completing 42 study days. ANOVA showed significant differences in F13CO2 with different BCAA ratios; P value <0.001. A BCAA ratio of (leucine: Isoleucine: Valine = 1:0:0) was associated with the highest F13CO2 compared to other ratios (p value <0.001), indicating low total body protein synthesis. By reducing leucine intake, with BCAA ratio between (1: 0.26: 0.28 to 1:0.35:0.4) protein synthesis was optimized. Conclusions Using the IAAO method in healthy children, we tested for the first time the effect of different BCAA ratios on protein synthesis. Results from this study confirmed that the BCAA ratio of (leucine: Isoleucine: Valine = 1:0:0), which is similar to the ratio in medical foods, limited total body protein synthesis. Furthermore, a balanced BCAA ratio that optimized protein synthesis was found to be between (1: 0.26: 0.28) and (1: 0.35:0.4). Thus, we propose reformulating the BCAA mixture in medical foods, by reducing leucine content by 50%. Future research in children with PROP with our proposed BCAA ratio is necessary to confirm improved patient growth outcomes. Funding Sources Faculty of Applied Medical Sciences, Department of Clinical Nutrition, King Abdulaziz University and BC Children's Hospital Research Institute.

scholarly journals A cell penetrating heme oxygenase protein protects heart graft against ischemia/reperfusion injury

Gene Therapy ◽  
2008 ◽  
Vol 16 (3) ◽  
pp. 320-328 ◽  
Author(s):  
J Ma ◽  
C K Lau ◽  
A Obed ◽  
A Dada ◽  
A Doenecke ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Heme Oxygenase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Heart Graft ◽  
Cell Penetrating ◽  
A Cell

Regulation of stress-associated scaffold proteins JIP1 and JIP3 on the c-Jun NH2-terminal kinase in ischemia–reperfusion

2010 ◽  
Vol 88 (11) ◽  
pp. 1084-1092 ◽  
Author(s):  
Bing Xu ◽  
Yaling Zhou ◽  
Karmin O ◽  
Patrick C. Choy ◽  
Grant N. Pierce ◽  
...  
Keyword(s):  
Protein Expression ◽  
Cell Model ◽  
Ischemia Reperfusion ◽  
Scaffold Proteins ◽  
Signaling Cascade ◽  
Interacting Proteins ◽  
H9c2 Cells ◽  
Signaling Specificity ◽  
Sirna Treatment ◽  
A Cell

Ischemia–reperfusion (IR)-induced cell apoptosis involves the activation of c-Jun NH2-terminal kinase (JNK). The activation of JNK requires the presence of scaffold proteins called JNK-interacting proteins (JIP), which bind several members of a signaling cascade for proper signaling specificity. In this study, the expression of scaffold proteins JIP1 and JIP3 and their roles in the regulation of JNK activity were investigated in simulated IR in a cell model (H9c2). JIP1 protein expression was significantly decreased, whereas JIP3 protein expression was increased in IR H9c2 cells. Adenovirus-induced overexpression of JIP1 reduced IR-induced JNK activity and apoptosis. Conversely, overexpression of JIP3 increased JNK activity and apoptosis following IR. Depletion of endogenous JIP1 by siRNA treatment increased the IR-induced JNK activity, whereas siRNA-mediated depletion of endogenous JIP3 inhibited JNK activity. These results suggest that JIP1 and JIP3 play important roles in the activation of JNK during simulated IR challenge in H9c2 cells.

scholarly journals Improved post-stroke spontaneous recovery by astrocytic extracellular vesicles

2021 ◽  
Author(s):  
Yessica Heras-Romero ◽  
Axayacatl Morales-Guadarrama ◽  
Ricardo Santana-Martínez ◽  
Isaac Ponce ◽  
Ruth Rincón-Heredia ◽  
...  
Keyword(s):  
Corpus Callosum ◽  
Extracellular Vesicles ◽  
Spontaneous Recovery ◽  
Ischemia Reperfusion ◽  
Multiphoton Microscopy ◽  
Preclinical Model ◽  
Post Stroke ◽  
Compound Action Potentials ◽  
Cellular Mediators ◽  
Compound Action

Spontaneous recovery after a stroke accounts for a major part of the neurological recovery in patients. However limited, the spontaneous recovery is mechanistically driven by axonal restorative processes for which several molecular cues have been previously described. We report the acceleration of spontaneous recovery in a preclinical model of ischemia/reperfusion in rats via a single intracerebroventricular administration of extracellular vesicles released from primary cortical astrocytes. We used MRI, confocal and multiphoton microscopy to correlate the structural remodeling of the corpus callosum and striatocortical circuits with neurological performance over 21 days. We also evaluated the functionality of the corpus callosum by repetitive recordings of compound action potentials to show that the recovery facilitated by astrocytic extracellular vesicles was both anatomical and functional. Our data provide compelling evidence that astrocytes can hasten the basal recovery that naturally occurs post-stroke through the release of cellular mediators contained in extracellular vesicles.

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