scholarly journals Cardiomyocyte Protection by Hibernating Brown Bear Serum: Toward the Identification of New Protective Molecules Against Myocardial Infarction

2021 ◽  
Vol 8 ◽  
Author(s):  
Lucas Givre ◽  
Claire Crola Da Silva ◽  
Jon E. Swenson ◽  
Jon M. Arnemo ◽  
Guillemette Gauquelin-Koch ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cell Death ◽  
Reperfusion Injury ◽  
Ursus Arctos ◽  
Cell Injury ◽  
Clinical Success ◽  
Brown Bear ◽  
Optimal Dose ◽  
Positive Control ◽  
Hypoxia Reoxygenation

Ischemic heart disease remains one of the leading causes of death worldwide. Despite intensive research on the treatment of acute myocardial infarction, no effective therapy has shown clinical success. Therefore, novel therapeutic strategies are required to protect the heart from reperfusion injury. Interestingly, despite physical inactivity during hibernation, brown bears (Ursus arctos) cope with cardiovascular physiological conditions that would be detrimental to humans. We hypothesized that bear serum might contain circulating factors that could provide protection against cell injury. In this study, we sought to determine whether addition of bear serum might improve cardiomyocyte survival following hypoxia–reoxygenation. Isolated mouse cardiomyocytes underwent 45 min of hypoxia followed by reoxygenation. At the onset of reoxygenation, cells received fetal bovine serum (FBS; positive control), summer (SBS) or winter bear serum (WBS), or adult serums of other species, as indicated. After 2 h of reoxygenation, propidium iodide staining was used to evaluate cell viability by flow cytometry. Whereas, 0.5% SBS tended to decrease reperfusion injury, 0.5% WBS significantly reduced cell death, averaging 74.04 ± 7.06% vs. 79.20 ± 6.53% in the FBS group. This cardioprotective effect was lost at 0.1%, became toxic above 5%, and was specific to the bear. Our results showed that bear serum exerts a therapeutic effect with an efficacy threshold, an optimal dose, and a toxic effect on cardiomyocyte viability after hypoxia–reoxygenation. Therefore, the bear serum may be a potential source for identifying new therapeutic molecules to fight against myocardial reperfusion injury and cell death in general.

Reperfusion injury on cardiac myocytes after simulated ischemia

1996 ◽  
Vol 270 (4) ◽  
pp. H1334-H1341 ◽  
Author(s):  
T. L. Vanden Hoek ◽  
Z. Shao ◽  
C. Li ◽  
R. Zak ◽  
P. T. Schumacker ◽  
...  
Keyword(s):  
Cell Death ◽  
Reperfusion Injury ◽  
Cell Injury ◽  
Membrane Damage ◽  
Cardiac Injury ◽  
Cellular Membrane ◽  
Iodide Uptake ◽  
Membrane Injury ◽  
Simulated Ischemia ◽  
Lactate Dehydrogenase Release

The extent of cardiac injury incurred during reperfusion as opposed to that occurring during ischemia is unclear. This study tested the hypothesis that simulated ischemia followed by simulated reperfusion causes significant "reperfusion injury" in isolated chick cardiomyocytes. Cells were exposed to hypoxia, hypercarbic acidosis, hyperkalemia, and substrate deprivation for 1 h followed by 3 h of reperfusion. Irreversible cell membrane injury, measured by propidium iodide uptake, increased from 4% of cells at the end of ischemia to 73% after reperfusion; death occurred in only 17% of cells kept ischemic for 4 h. Lactate dehydrogenase release was consistent with these changes. Lengthening ischemia from 30 to 90 min increased cell injury as expected, but of the total cell death, > 90% occurred during reperfusion. "Chemical hypoxia" composed of cyanide (2.5 mM) plus 2-deoxyglucose augmented injury before reperfusion compared with simulated ischemia. Inhibition of oxygen radical generation by use of metal chelator 1,10-phenanthroline reduced cell death from 73% to 40% after reperfusion (P = 0.001). We conclude that simulated reperfusion significantly augments the cellular membrane damage elicited by simulated ischemia in isolated cardiomyocytes devoid of other factors and suggest that reactive oxygen species, perhaps from the mitochondria, participate in this injury.

scholarly journals miR-181c-5p Exacerbates Hypoxia/Reoxygenation-Induced Cardiomyocyte Apoptosis via Targeting PTPN4

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Liang Ge ◽  
Yin Cai ◽  
Fan Ying ◽  
Hao Liu ◽  
Dengwen Zhang ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Apoptosis ◽  
Cell Injury ◽  
Apoptotic Cell ◽  
Ischemia Reperfusion ◽  
Control Cell ◽  
Luciferase Reporter ◽  
Apoptosis Pathway ◽  
H9c2 Cardiomyocytes ◽  
Hypoxia Reoxygenation

Background. Activation of cell apoptosis is a major form of cell death during myocardial ischemia/reperfusion injury (I/RI). Therefore, examining ways to control cell apoptosis has important clinical significance for improving postischemic recovery. Clinical evidence demonstrated that miR-181c-5p was significantly upregulated in the early phase of myocardial infarction. However, whether or not miR-181c-5p mediates cardiac I/RI through cell apoptosis pathway is unknown. Thus, the present study is aimed at investigating the role and the possible mechanism of miR-181c-5p in apoptosis during I/R injury by using H9C2 cardiomyocytes. Methods and Results. The rat origin H9C2 cardiomyocytes were subjected to hypoxia/reoxygenation (H/R, 6 hours hypoxia followed by 6 hours reoxygenation) to induce cell injury. The results showed that H/R significantly increased the expression of miR-181c-5p but not miR-181c-3p in H9C2 cells. In line with this, in an in vivo rat cardiac I/RI model, miR-181c-5p expression was also significantly increased. The overexpression of miR-181c-5p by its agomir transfection significantly aggravated H/R-induced cell injury (increased lactate dehydrogenase level and reduced cell viability) and exacerbated H/R-induced cell apoptosis (greater cleaved caspases 3 expression, Bax/Bcl-2 and more TUNEL-positive cells). In contrast, inhibition of miR-181c-5p in vitro had the opposite effect. By using computational prediction algorithms, protein tyrosine phosphatase nonreceptor type 4 (PTPN4) was predicted as a potential target gene of miR-181c-5p and was verified by the luciferase reporter assay. The overexpression of miR-181c-5p significantly attenuated the mRNA and protein expression of PTPN4 in H9C2 cardiomyocytes. Moreover, knockdown of PTPN4 significantly aggravated H/R-induced enhancement of LDH level, cleaved caspase 3 expression, and apoptotic cell death, which mimicked the proapoptotic effects of miR-181c-5p in H9C2 cardiomyocytes. Conclusions. These findings suggested that miR-181c-5p exacerbates H/R-induced cardiomyocyte injury and apoptosis via targeting PTPN4 and that miR-181c-5p/PTPN4 signaling may yield novel strategies to combat myocardial I/R injury.

scholarly journals Hydrogen Suppresses Hypoxia/Reoxygenation-Induced Cell Death in Hippocampal Neurons Through Reducing Oxidative Stress

2015 ◽  
Vol 36 (2) ◽  
pp. 585-598 ◽  
Author(s):  
Rong Wei ◽  
Rufang Zhang ◽  
Yewei Xie ◽  
Li Shen ◽  
Fang Chen
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Hippocampal Neurons ◽  
Caspase 3 ◽  
Cell Injury ◽  
Circulatory Arrest ◽  
Hydrogen Treatment ◽  
Ros Production ◽  
Brain Aneurysm ◽  
Hypoxia Reoxygenation

Background & Aims: Deep hypothermic circulatory arrest (DHCA) is a cerebral protection technique that has been used in the operations involving the aortic arch and brain aneurysm for decades. We previous showed that DHCA treated rats developed a significant oxidative stress and apoptosis in neurons. We here intend to investigate the protective the effect of hydrogen against oxidative stress-induced cell injury and the involved mechanisms using an in vitro experimental model of hypoxia/reoxygenation (H/R) on HT-22 cells. Methods: The model of H/R was established using an airtight culture container and the anaeropack. Measurement of mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) production was used H2DCFDA and JC-1 staining. Western blot was used for the quantification of Akt, p-Akt, Bcl-2, Bax and cleaved caspase-3 proteins. The microRNA (miRNA) profile in hippocampal neurons from rat model of DHCA was determined by miRNA deep sequencing. Results: The elevation of ROS and reduction of MMP were significantly induced by the treatment with hypoxia for 18 h followed by reoxygenation for 6 h. Hydrogen treatment significantly reduced H/R-caused cell death. The levels of p-Akt (Ser 473) and Bcl-2 were significantly increased while Bax and cleaved caspase-3 were decreased by hydrogen treatment on the model of H/R. The expression of miR-200 family was significantly elevated in model of DHCA and H/R. Hydrogen administration inhibited the H/R-induced expression of miR-200 family in HT-22 cells. In addition, inhibition of miR-200 family suppressed H/R-caused cell death through reducing ROS production. Conclusions: These results suggest that H/R causes oxidative stress-induced cell death and that the hydrogen protects against H/R-induced cell death in HT22 cells, in part, due to reducing expression of miR-200 family.

Myocardial protection against reperfusion injury: The cGMP pathway

2009 ◽  
Vol 101 (04) ◽  
pp. 635-642 ◽  
Author(s):  
Luis Agulló ◽  
Carmem Lluisa Sartorio ◽  
Marisol Ruiz-Meana ◽  
David Garcia-Dorado
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Endothelial Cells ◽  
Cell Death ◽  
Reperfusion Injury ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Myocardial Cell ◽  
Cgmp Pathway ◽  
Cgmp Synthesis

SummaryReperfusion injury may cause myocardial cell death and limit the benefit achieved by restoration of coronary artery patency in patients with acute myocardial infarction. The mechanism includes altered Ca2+ handling with cytosolic and mitochondrial Ca2+ overload, Ca2+- and ATP-dependent hypercontraction, cytoskeletal fragility, mitochondrial permeability transition and gap junction-mediated propagation of cell death, as well as alterations in non-cardiomyocyte cells, in particular platelets and endothelial cells. cGMP modulates favorably all these mechanism, mainly through PKG-mediated actions, but cGMP synthesis is altered in reperfused cardiomyocytes and endothelial cells by mechanisms that are only partially understood. Stimulation of cGMP synthesis during initial reperfusion by means of natriuretic peptides has been found protective in different animal models and in patients. Moreover, increasing evidence indicates that cGMP is an important step in signal transduction of endogenous cardioprotection. Thus, the cGMP pathway appears as a key element in the pathophysiology of myocardial ischaemiareperfusion and as a promising therapeutic target in patients with acute myocardial infarction.

scholarly journals Myocardial Ischemia-Reperfusion and Diabetes: Lessons Learned From Bedside to Bench

2021 ◽  
Vol 8 ◽  
Author(s):  
Maya Dia ◽  
Alexandre Paccalet ◽  
Bruno Pillot ◽  
Christelle Leon ◽  
Michel Ovize ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cell Death ◽  
Animal Models ◽  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ischemia Reperfusion ◽  
Cardiac Ischemia ◽  
Diabetic Patients ◽  
Myocardial Ischemia Reperfusion ◽  
Hypoxia Reoxygenation

In front of the failure to translate from bench to bedside cardioprotective drugs against myocardial ischemia-reperfusion, research scientists are currently revising their animal models. Owing to its growing incidence nowadays, type 2 diabetes (T2D) represents one of the main risk factors of co-morbidities in myocardial infarction. However, discrepancies exist between reported animal and human studies. Our aim was here to compare the impact of diabetes on cell death after cardiac ischemia-reperfusion in a human cohort of ST-elevation myocardial infarction (STEMI) patients with a diet-induced mouse model of T2D, using a high-fat high-sucrose diet for 16 weeks (HFHSD). Interestingly, a small fraction (<14%) of patients undergoing a myocardial infarct were diabetic, but treated, and did not show a bigger infarct size when compared to non-diabetic patients. On the contrary, HFHSD mice displayed an increased infarct size after an in vivo cardiac ischemia-reperfusion, together with an increased cell death after an in vitro hypoxia-reoxygenation on isolated cardiomyocytes. To mimic the diabetic patients' medication profile, 6 weeks of oral gavage with Metformin was performed in the HFHSD mouse group. Metformin treatment of the HFHSD mice led to a similar extent of lower cell death after hypoxia-reoxygenation as in the standard diet group, compared to the HFHSD cardiomyocytes. Altogether, our data highlight that due to their potential protective effect, anti-diabetic medications should be included in pre-clinical study of cardioprotective approaches. Moreover, since diabetic patients represent only a minor fraction of the STEMI patients, diabetic animal models may not be the most suitable translatable model to humans, unlike aging that appears as a common feature of all infarcted patients.

UJI AKTIVITAS HEPATOPROTEKTOR KOMBINASI EKSTRAK ETANOL DAUN PANDAN WANGI (Pandanus amaryllifolius roxb) DAN KAYU MANIS (Cinnamomum burmanii) TERHADAP KADAR MDA YANG DIINDUKSI PARASETAMOL

2020 ◽  
pp. 68-73
Author(s):  
Yuni Asri Mulatsih Agami ◽  
Eka Wisnu Kusuma
Keyword(s):  
Oxidative Stress ◽  
Ethanol Extract ◽  
Optimal Dose ◽  
Experimental Methods ◽  
Positive Control ◽  
Negative Control ◽  
Male Rats ◽  
Negative Group ◽  
Ic50 Value ◽  
Dose Combination

Kasus penyakit hati semakin meningkat seiring penggunaan senyawa hepatotoksin salah satunya karena penggunaan parasetamol dengan dosis berlebih. Hal tersebut dapat meningkatkan produksi radikal bebas sehingga memicu terjadinya stress oksidatif yang dapat menimbulkan kerusakan jaringan yang ditandai dengan peningkatan kadar Malondialdehyde (MDA). Stress oksidatif dapat diatasi dengan antioksidan dari berbagai tanaman. Kulit kayu manis memiliki aktivitas antioksidan dengan nilai IC50 53ppm dan daun pandan wangi 39,7%  Penelitian ini bertujuan untuk mengetahui aktivitas kombinasi ekstrak etanol daun pandan wangi dan kayu manis dalam menurunkan kadar MDA. tikus yang diinduksi parasetamol. Penelitian menggunakan metode eksperimental, dilakukan selama 9 hari dengan 30 ekor tikus jantan dibagi menjadi 6 Kelompok, yaitu: Normal diberi aquadest, Kontrol Positif diberi silimarin 100 mg/kgBB, Kontrol Negatif diberi CMC-Na 0,05%, serta 3 kelompok lainnya diberi kombinasi ekstrak daun pandan wangi:kayu manis berturut-turut dosis I (25:75), dosis II (50:50), dosis III (75:25). Semua kelompok diinduksi parasetamol 2,5 g/kgBB pada hari ke-7  setelah 30 menit perlakuan, kecuali kelompok normal. Pada hari ke 9 dilakukan pengukuran kadar MDA dengan metode TBARs menggunakan spektrofotometri. Pemberian kombinasi ekstrak etanol daun pandan wangi dan kayu manis dapat menurunkan kadar MDA dengan kombinasi dosis yang paling optimal adalah 75:25 berdasarkan statistik dengan nilai signifikan 0,000<0,05 dibandingkan dengan kelompok negatif.    Cases of liver disease have increased with the use of hepatotoxin compounds, one of which is due to the use of paracetamol with excessive doses. This can increase the production of free radicals so that it triggers oxidative stress which can cause tissue damage which is characterized by increased levels of Malondialdehyde (MDA). Oxidative stress can be overcome with antioxidants from various plants. Cinnamomum burmanii has antioxidant activity with IC50 value of 53ppm and Pandanus amarrylifolius 39.7%. This study aims to determine the combined activity of ethanol extract of Pandanus amarrylifolius and Cinnamomum burmanii  in reducing MDA levels. Paracetamol-induced rats. Research using experimental methods, conducted for 9 days with 30 male rats divided into 6 groups, namely: Normal given aquadest, Positive Control were given silimarin 100 mg / kgBB, Negative Control was given CMC-Na 0.05%, and 3 other groups were given a combination of Pandanus amarrylifolius extract: Cinnamomum burmanii dose I (25:75), dose II (50:50), dose III (75:25). All groups induced paracetamol 2.5 g / kgBB on the 7th day after 30 minutes of treatment, except the normal group. On the 9th day MDA levels were measured using the TBARs method using spectrophotometry. Giving a combination of Pandanus amarrylifolius and Cinnamomum burmanii ethanol extract can reduce MDA levels with the most optimal dose combination is 75:25 based on statistics with a significant value of 0,000<0.05 compared with the negative group.

Brown Bear (Ursus arctos) Habitat Use and Food Resources on Elmendorf Air Force Base, Alaska

2007 ◽  
Author(s):  
Sean D. Farley ◽  
Herman Griese ◽  
Rick Sinnott ◽  
Jessica Coltrane ◽  
Chris Garner ◽  
...  
Keyword(s):  
Habitat Use ◽  
Air Force ◽  
Ursus Arctos ◽  
Brown Bear ◽  
Food Resources ◽  
Air Force Base

scholarly journals Charged Particle and Conventional Radiotherapy: Current Implications as Partner for Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1468
Author(s):  
Damiënne Marcus ◽  
Relinde I. Y. Lieverse ◽  
Carmen Klein ◽  
Amir Abdollahi ◽  
Philippe Lambin ◽  
...  
Keyword(s):  
Charged Particle ◽  
Clinical Success ◽  
Immune Therapy ◽  
Locally Advanced ◽  
Optimal Dose ◽  
High Energy ◽  
Advanced Lung Cancer ◽  
Antitumor Effects ◽  
Immunological Effects ◽  
Tumor Immunogenicity

Radiotherapy (RT) has been shown to interfere with inflammatory signals and to enhance tumor immunogenicity via, e.g., immunogenic cell death, thereby potentially augmenting the therapeutic efficacy of immunotherapy. Conventional RT consists predominantly of high energy photon beams. Hypofractionated RT regimens administered, e.g., by stereotactic body radiation therapy (SBRT), are increasingly investigated in combination with cancer immunotherapy within clinical trials. Despite intensive preclinical studies, the optimal dose per fraction and dose schemes for elaboration of RT induced immunogenic potential remain inconclusive. Compared to the scenario of combined immune checkpoint inhibition (ICI) and RT, multimodal therapies utilizing other immunotherapy principles such as adoptive transfer of immune cells, vaccination strategies, targeted immune-cytokines and agonists are underrepresented in both preclinical and clinical settings. Despite the clinical success of ICI and RT combination, e.g., prolonging overall survival in locally advanced lung cancer, curative outcomes are still not achieved for most cancer entities studied. Charged particle RT (PRT) has gained interest as it may enhance tumor immunogenicity compared to conventional RT due to its unique biological and physical properties. However, whether PRT in combination with immune therapy will elicit superior antitumor effects both locally and systemically needs to be further investigated. In this review, the immunological effects of RT in the tumor microenvironment are summarized to understand their implications for immunotherapy combinations. Attention will be given to the various immunotherapeutic interventions that have been co-administered with RT so far. Furthermore, the theoretical basis and first evidences supporting a favorable immunogenicity profile of PRT will be examined.

scholarly journals Using Landscape Change Analysis and Stakeholder Perspective to Identify Driving Forces of Human–Wildlife Interactions

Land ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 146
Author(s):  
Mihai Mustățea ◽  
Ileana Pătru-Stupariu
Keyword(s):  
Landscape Change ◽  
Ursus Arctos ◽  
Driving Forces ◽  
Brown Bear ◽  
Mountain Range ◽  
Change Analysis ◽  
Local Stakeholders ◽  
Stakeholder Perspective ◽  
Forested Ecosystems ◽  
Forest Habitats

Human–wildlife interactions (HWI) were frequent in the post-socialist period in the mountain range of Central European countries where forest habitats suffered transitions into built-up areas. Such is the case of the Upper Prahova Valley from Romania. In our study, we hypothesized that the increasing number of HWI after 1990 could be a potential consequence of woodland loss. The goal of our study was to analyse the effects of landscape changes on HWI. The study consists of the next steps: (i) applying 450 questionnaires to local stakeholders (both citizens and tourists) in order to collect data regarding HWI temporal occurrences and potential triggering factors; (ii) investigating the relation between the two variables through the Canonical Correspondence Analysis (CCA); (iii) modelling the landscape spatial changes between 1990 and 2018 for identifying areas with forest loss; (iv) overlapping the distribution of both the households affected by HWI and areas with loss of forested ecosystems. The local stakeholders indicate that the problematic species are the brown bear (Ursus arctos), the wild boar (Sus scrofa), the red fox (Vulpes vulpes) and the grey wolf (Canis lupus). The number of animal–human interactions recorded an upward trend between 1990 and 2018, and the most significant driving factors were the regulation of hunting practices, the loss of habitats, and artificial feeding. The landscape change analysis reveals that between 1990 and 2018, the forest habitats were replaced by built-up areas primarily on the outskirts of settlements, these areas coinciding with frequent HWI. The results are valid for both forest ecosystems conservation in the region, wildlife management, and human infrastructures durable spatial planning.

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