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1

Tseng, G. N. "Cell swelling increases membrane conductance of canine cardiac cells: evidence for a volume-sensitive Cl channel." American Journal of Physiology-Cell Physiology 262, no. 4 (April 1, 1992): C1056—C1068. http://dx.doi.org/10.1152/ajpcell.1992.262.4.c1056.

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Cardiac cell swelling occurs under abnormal conditions. Currents through volume-sensitive channels, if present in heart, will affect the cardiac electrical activity. Single canine ventricular myocytes were voltage clamped under conditions that largely suppressed Na, K, and Ca channel currents and currents generated by electrogenic transport systems. Cell width and membrane conductance were monitored continuously. Swelling was induced by increasing the osmolarity of the pipette solution or by decreasing the osmolarity of the external solution. During cell swelling, the cell widened and membrane conductance increased. This increase in membrane conductance was sensitive to Cl channel blockers and to external Cl removal, suggesting that a major component was provided by a Cl channel. The current-voltage relationship of the swelling-induced current displayed an outward rectification, with an average zero-current voltage of -60 mV. The activation of the swelling-induced current did not seem to depend on external or internal Ca and was not sensitive to a protein kinase inhibitor (H-8). Shape-altering agents chlorpromazine decreased while dipyridamole and trinitrophenol increased the membrane conductance without osmotic perturbations, suggesting that changes in tension in the cell membrane may play a role in opening and closing of the swelling-induced channels.
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2

Whalley, D. W., P. D. Hemsworth, and H. H. Rasmussen. "Regulation of intracellular pH in cardiac muscle during cell shrinkage and swelling in anisosmolar solutions." American Journal of Physiology-Heart and Circulatory Physiology 266, no. 2 (February 1, 1994): H658—H669. http://dx.doi.org/10.1152/ajpheart.1994.266.2.h658.

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The effect on intracellular pH (pHi) of exposure to solutions of progressively increasing osmolarity from 418 to 620 mosM and to hyposmolar solutions (240 mosM) was examined in guinea pig ventricular muscle using ion-selective microelectrodes. Exposure of tissue to 418 mosM Tyrode solution (100 mM sucrose added) produced an intracellular alkalosis of approximately 0.1 U, whereas exposure to 620 mosM solution (300 mM sucrose added) caused an intracellular acidosis of approximately 0.1 U. The maximal rate of recovery of pHi from acidosis induced by an NH4Cl prepulse increased progressively as extracellular osmolarity was raised from 310 to 620 mosM. This suggests that the acidosis observed at steady state in 620 mosM solution is not due to inhibition of the Na(+)-H+ exchanger. In the presence of 10 microM ryanodine, exposure to 620 mosM solution produced a sustained intracellular alkalosis. We suggest that the decrease in pHi during exposure to 620 mosM solution is due, at least in part, to the acidifying influence of Ca2+ release from the sarcoplasmic reticulum. This decrease in pHi is expected to contribute to the negative inotrop reported in studies of cardiac contractility in markedly hyperosmolar solutions. There was no change in pHi when tissue was exposed to hyposmolar solution. However, the maximal rate of recovery of pHi from acidosis was slower in hyposmolar than in isosmolar solution, despite a concomitant decrease in the intracellular buffer capacity. This suggests that osmotic cell swelling results in inhibition of the sarcolemmal Na(+)-H+ exchanger.
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3

Kajimoto, Katsuya, Dan Shao, Hiromitsu Takagi, Gregorio Maceri, Daniela Zablocki, Hideyuki Mukai, Yoshitaka Ono, and Junichi Sadoshima. "Hypotonic swelling-induced activation of PKN1 mediates cell survival in cardiac myocytes." American Journal of Physiology-Heart and Circulatory Physiology 300, no. 1 (January 2011): H191—H200. http://dx.doi.org/10.1152/ajpheart.00232.2010.

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Hypotonic cell swelling in the myocardium is induced by pathological conditions, including ischemia-reperfusion, and affects the activities of ion transporters/channels and gene expression. However, the signaling mechanism activated by hypotonic stress (HS) is not fully understood in cardiac myocytes. A specialized protein kinase cascade, consisting of Pkc1 and MAPKs, is activated by HS in yeast. Here, we demonstrate that protein kinase N1 (PKN1), a serine/threonine protein kinase and a homolog of Pkc1, is activated by HS (67% osmolarity) within 5 min and reaches peak activity at 60 min in cardiac myocytes. Activation of PKN1 by HS was accompanied by Thr774 phosphorylation and concomitant activation of PDK1, a potential upstream regulator of PKN1. HS also activated RhoA, thereby increasing interactions between PKN1 and RhoA. PP1 (10−5 M), a selective Src family tyrosine kinase inhibitor, significantly suppressed HS-induced activation of RhoA and PKN1. Constitutively active PKN1 significantly increased the transcriptional activity of Elk1-GAL4, an effect that was inhibited by dominant negative MEK. Overexpression of PKN1 significantly increased ERK phosphorylation, whereas downregulation of PKN1 inhibited HS-induced ERK phosphorylation. Downregulation of PKN1 and inhibition of ERK by U-0126 both significantly inhibited the survival of cardiac myocytes in the presence of HS. These results suggest that a signaling cascade, consisting of Src, RhoA, PKN1, and ERK, is activated by HS, thereby promoting cardiac myocyte survival.
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4

Askenasy, N., A. Vivi, M. Tassini, and G. Navon. "Cardiac energetics, cell volumes, sodium fluxes, and membrane permeability: NMR studies of cold ischemia." American Journal of Physiology-Heart and Circulatory Physiology 269, no. 3 (September 1, 1995): H1056—H1064. http://dx.doi.org/10.1152/ajpheart.1995.269.3.h1056.

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Intracellular sodium accumulation, cellular swelling, and energy deficiency are ischemia-associated processes that participate in the transition to irreversible ischemic injury. This study aims to determine the relationship among these parameters in intact rat hearts during global ischemia at 4 degrees C. High-energy phosphates were determined by 31P nuclear magnetic resonance, intracellular sodium accumulation was measured by 23Na spectroscopy with the shift reagent dysprosium triethyl tetraaminohexaacetic acid [Dy(TTHA)3(-)], and cell volumes were measured by 59Co and 1H spectroscopy with use of the extracellular marker Co(CN)3-(6). Intracellular sodium flux rates were 1.53 +/- 0.17, 0.17 +/- 0.05, and 0.30 +/- 0.06 mumol.g dry wt-1.min-1 at 0-1.5, 2-7, and 9-12 h, respectively. Sodium influx resulted in accumulation of the ion: 10% after 4 h, 16% after 10 h, and 29% after 12 h. Water followed sodium into the cells at two constant molar ratios (Na+/H2O): 3.80 +/- 0.15 x 10(-3) during the first 8 h of ischemia and 7.8 x 10(-3) at 8-12 h. Relative to initial intracellular volume, cells swelled by 38% after 8 h and 46% after 12 h; reperfusion reduced cellular swelling to 25 and 36%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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5

Dick, Gregory M., Karri K. Bradley, Burton Horowitz, Joseph R. Hume, and Kenton M. Sanders. "Functional and molecular identification of a novel chloride conductance in canine colonic smooth muscle." American Journal of Physiology-Cell Physiology 275, no. 4 (October 1, 1998): C940—C950. http://dx.doi.org/10.1152/ajpcell.1998.275.4.c940.

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Swelling-activated or volume-sensitive Cl− currents are found in numerous cell types and play a variety of roles in their function; however, molecular characterization of the channels is generally lacking. Recently, the molecular entity responsible for swelling-activated Cl−current in cardiac myocytes has been identified as ClC-3. The goal of our study was to determine whether such a channel exists in smooth muscle cells of the canine colon using both molecular biological and electrophysiological techniques and, if present, to characterize its functional and molecular properties. We hypothesized that ClC-3 is present in colonic smooth muscle and is regulated in a manner similar to the molecular entity cloned from heart. Indeed, the ClC-3 gene was expressed in colonic myocytes, as demonstrated by reverse transcriptase polymerase chain reaction performed on isolated cells. The current activated by decreasing extracellular osmolarity from 300 to 250 mosM was outwardly rectifying and dependent on the Cl− gradient. Current magnitude increased and reversed at more negative potentials when Cl− was replaced by I− or Br−. Tamoxifen ([Z]-1-[p-dimethylaminoethoxy-phenyl]-1,2-diphenyl-1-butene; 10 μM) and DIDS (100 μM) inhibited the current, whereas 25 μM niflumic acid, 10 μM nicardipine, and Ca2+ removal had no effect. Current was inhibited by 1 mM extracellular ATP in a voltage-dependent manner. Cl− current was also regulated by protein kinase C, as phorbol 12,13-dibutyrate (300 nM) decreased Cl− current magnitude, while chelerythrine chloride (30 μM) activated it under isotonic conditions. Our findings indicate that a current activated by hypotonic solution is present in colonic myocytes and is likely mediated by ClC-3. Furthermore, we suggest that the ClC-3 may be an important mechanism controlling depolarization and contraction of colonic smooth muscle under conditions that impose physical stress on the cells.
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6

Horvath, Csaba, Megan Young, Izabela Jarabicova, Lucia Kindernay, Kristina Ferenczyova, Tanya Ravingerova, Martin Lewis, M. Saadeh Suleiman, and Adriana Adameova. "Inhibition of Cardiac RIP3 Mitigates Early Reperfusion Injury and Calcium-Induced Mitochondrial Swelling without Altering Necroptotic Signalling." International Journal of Molecular Sciences 22, no. 15 (July 26, 2021): 7983. http://dx.doi.org/10.3390/ijms22157983.

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Receptor-interacting protein kinase 3 (RIP3) is a convergence point of multiple signalling pathways, including necroptosis, inflammation and oxidative stress; however, it is completely unknown whether it underlies acute myocardial ischemia/reperfusion (I/R) injury. Langendorff-perfused rat hearts subjected to 30 min ischemia followed by 10 min reperfusion exhibited compromised cardiac function which was not abrogated by pharmacological intervention of RIP3 inhibition. An immunoblotting analysis revealed that the detrimental effects of I/R were unlikely mediated by necroptotic cell death, since neither the canonical RIP3–MLKL pathway (mixed lineage kinase-like pseudokinase) nor the proposed non-canonical molecular axes involving CaMKIIδ–mPTP (calcium/calmodulin-dependent protein kinase IIδ–mitochondrial permeability transition pore), PGAM5–Drp1 (phosphoglycerate mutase 5–dynamin-related protein 1) and JNK–BNIP3 (c-Jun N-terminal kinase–BCL2-interacting protein 3) were activated. Similarly, we found no evidence of the involvement of NLRP3 inflammasome signalling (NOD-, LRR- and pyrin domain-containing protein 3) in such injury. RIP3 inhibition prevented the plasma membrane rupture and delayed mPTP opening which was associated with the modulation of xanthin oxidase (XO) and manganese superoxide dismutase (MnSOD). Taken together, this is the first study indicating that RIP3 regulates early reperfusion injury via oxidative stress- and mitochondrial activity-related effects, rather than cell loss due to necroptosis.
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7

Wang, Yuan, Shan Zhu, Hongtao Liu, Wen Wei, Yi Tu, Chuang Chen, Junlong Song, et al. "Thyroxine Alleviates Energy Failure, Prevents Myocardial Cell Apoptosis, and Protects against Doxorubicin-Induced Cardiac Injury and Cardiac Dysfunction via the LKB1/AMPK/mTOR Axis in Mice." Disease Markers 2019 (December 18, 2019): 1–10. http://dx.doi.org/10.1155/2019/7420196.

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Background. Previous studies have demonstrated that energy failure is closely associated with cardiac injury. Doxorubicin (DOX) is a commonly used clinical chemotherapy drug that can mediate cardiac injury through a variety of mechanisms. Thyroxine is well known to play a critical role in energy generation; thus, this study is aimed at investigating whether thyroxine can attenuate DOX-induced cardiac injury by regulating energy generation. Methods. First, the effect of DOX on adenosine diphosphate (ADP) and adenosine triphosphate (ATP) ratios in mice was assessed. In addition, thyroxine was given to mice before they were treated with DOX to investigate the effects of thyroxine on DOX-induced cardiac injury. Furthermore, to determine whether the liver kinase b1 (LKB1)/adenosine 5′-monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) axis mediated the effect of thyroxine on DOX-induced cardiac injury, thyroxine was given to DOX-treated LKB1 knockout (KO) mice. Results. DOX treatment time- and dose-dependently increased the ADP/ATP ratio. Thyroxine treatment also reduced lactate dehydrogenase (LDH) and creatine kinase myocardial band (CK-MB) levels in both serum and heart tissue and alleviated cardiac dysfunction in DOX-treated mice. Furthermore, thyroxine reversed DOX-induced reductions in LKB1 and AMPK phosphorylation; mitochondrial complex I, III, and IV activity; and mitochondrial swelling and reversed DOX-induced increases in mTOR pathway phosphorylation and myocardial cell apoptosis. These effects of thyroxine on DOX-treated mice were significantly attenuated by LKB1 KO. Conclusions. Thyroxine alleviates energy failure, reduces myocardial cell apoptosis, and protects against DOX-induced cardiac injury via the LKB1/AMPK/mTOR axis in mice. Thyroxine may be a new agent for the clinical prevention of cardiac injury in tumor patients undergoing chemotherapy with DOX.
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8

Halestrap, A. P. "Calcium, mitochondria and reperfusion injury: a pore way to die." Biochemical Society Transactions 34, no. 2 (March 20, 2006): 232–37. http://dx.doi.org/10.1042/bst0340232.

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When mitochondria are exposed to high Ca2+ concentrations, especially when accompanied by oxidative stress and adenine nucleotide depletion, they undergo massive swelling and become uncoupled. This occurs as a result of the opening of a non-specific pore in the inner mitochondrial membrane, known as the MPTP (mitochondrial permeability transition pore). If the pore remains open, cells cannot maintain their ATP levels and this will lead to cell death by necrosis. This article briefly reviews what is known of the molecular mechanism of the MPTP and its role in causing the necrotic cell death of the heart and brain that occurs during reperfusion after a long period of ischaemia. Such reperfusion injury is a major problem during cardiac surgery and in the treatment of coronary thrombosis and stroke. Prevention of MPTP opening either directly, using agents such as cyclosporin A, or indirectly by reducing oxidative stress or Ca2+ overload, provides a protective strategy against reperfusion injury. Furthermore, mice in which a component of the MPTP, CyP-D (cyclophilin D), has been knocked out are protected against heart and brain ischaemia/reperfusion. When cells experience a less severe insult, the MPTP may open transiently. The resulting mitochondrial swelling may be sufficient to cause release of cytochrome c and activation of the apoptotic pathway rather than necrosis. However, the CyP-D-knockout mice develop normally and show no protection against a range of apoptotic stimuli, suggesting that the MPTP does not play a role in most forms of apoptosis.
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9

Zohar, Ron, Baoqian Zhu, Peter Liu, Jaro Sodek, and C. A. McCulloch. "Increased cell death in osteopontin-deficient cardiac fibroblasts occurs by a caspase-3-independent pathway." American Journal of Physiology-Heart and Circulatory Physiology 287, no. 4 (October 2004): H1730—H1739. http://dx.doi.org/10.1152/ajpheart.00098.2004.

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Reperfusion-induced oxidative injury to the myocardium promotes activation and proliferation of cardiac fibroblasts and repair by scar formation. Osteopontin (OPN) is a proinflammatory cytokine that is upregulated after reperfusion. To determine whether OPN enhances fibroblast survival after exposure to oxidants, cardiac fibroblasts from wild-type (WT) or OPN-null (OPN−/−) mice were treated in vitro with H2O2to model reperfusion injury. Within 1 h, membrane permeability to propidium iodide (PI) was increased from 5 to 60% in OPN−/−cells but was increased to only 20% in WT cells. In contrast, after 1–8 h of treatment with H2O2, the percent of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-stained cells was more than twofold higher in WT than OPN−/−cells. Electron microscopy of WT cells treated with H2O2showed chromatin condensation, nuclear fragmentation, and cytoplasmic and nuclear shrinkage, which are consistent with apoptosis. In contrast, H2O2-treated OPN−/−cardiac fibroblasts exhibited cell and nuclear swelling and membrane disruption that are indicative of cell necrosis. Treatment of OPN−/−and WT cells with a cell-permeable caspase-3 inhibitor reduced the percentage of TUNEL staining by more than fourfold in WT cells but decreased staining in OPN−/−cells by ∼30%. Although the percentage of PI-permeable WT cells was reduced threefold, the percent of PI-permeable OPN−/−cells was not altered. Restoration of OPN expression in OPN−/−fibroblasts reduced the percentage of PI-permeable cells but not TUNEL staining after H2O2treatment. Thus H2O2-induced cell death in OPN-deficient cardiac fibroblasts is mediated by a caspase-3-independent, necrotic pathway. We suggest that the increased expression of OPN in the myocardium after reperfusion may promote fibrosis by protecting cardiac fibroblasts from cell death.
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10

Akhmedov, Alexander, Fabrizio Montecucco, Sarah Costantino, Daria Vdovenko, Ariane Schaub Clerigué, Daniel S. Gaul, Fabienne Burger, et al. "Cardiomyocyte-Specific JunD Overexpression Increases Infarct Size following Ischemia/Reperfusion Cardiac Injury by Downregulating Sirt3." Thrombosis and Haemostasis 120, no. 01 (December 13, 2019): 168–80. http://dx.doi.org/10.1055/s-0039-3400299.

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AbstractIschemia/reperfusion (I/R) injury in acute myocardial infarction activates several deleterious molecular mechanisms. The transcription factor JunD regulates pathways involved in oxidative stress as well as in cellular proliferation, differentiation, and death. The present study investigated the potential role of JunD as a modulator of myocardial injury pathways in a mouse model of cardiac I/R injury. Infarct size, systemic and local inflammation, and production of reactive oxygen species, as well as cytosolic and mitochondrial apoptotic pathways were investigated in adult males after myocardial I/R. In wild-type (WT) mice, 30 minutes after ischemia and up to 24 hours following reperfusion, cardiac JunD messenger ribonucleic acid expression was reduced while JunB increased. Cardiac-specific JunD overexpressing mice (JunDTg/0 ) displayed larger infarcts compared with WT. However, postischemic inflammatory or oxidative responses did not differ. JunD overexpression reduced Sirt3 transcription by binding to its promoter, thus leading to mitochondrial dysfunction, myocardial cell death, and increased infarct size. On the other hand, JunD silencing reduced, while Sirt3 silencing increased infarct size. In human myocardial autopsy specimens, JunD-positive areas within the infarcted left ventricle staining corresponded to undetectable Sirt3 areas in consecutive sections of the same heart. Cardiac-specific JunD overexpression increases myocardial infarct size following I/R. These effects are mediated via Sirt3 transcriptional repression, mitochondrial swelling, and increased apoptosis, suggesting that JunD is a key regulator of myocardial I/R injury. The present data set the stage for further investigation of the potential role of Sirt3 activation as a novel target for the treatment of acute myocardial infarction.
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11

Luo, Shuhua, Menglin Tang, Lei Du, Lina Gong, Jin Xu, Youwen Chen, Yabo Wang, Ke Lin, and Qi An. "A Novel Minimal Invasive Mouse Model of Extracorporeal Circulation." Mediators of Inflammation 2015 (2015): 1–9. http://dx.doi.org/10.1155/2015/412319.

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Extracorporeal circulation (ECC) is necessary for conventional cardiac surgery and life support, but it often triggers systemic inflammation that can significantly damage tissue. Studies of ECC have been limited to large animals because of the complexity of the surgical procedures involved, which has hampered detailed understanding of ECC-induced injury. Here we describe a minimally invasive mouse model of ECC that may allow more extensive mechanistic studies. The right carotid artery and external jugular vein of anesthetized adult male C57BL/6 mice were cannulated to allow blood flow through a 1/32-inch external tube. All animals(n=20)survived 30 min ECC and subsequent 60 min observation. Blood analysis after ECC showed significant increases in levels of tumor necrosis factorα, interleukin-6, and neutrophil elastase in plasma, lung, and renal tissues, as well as increases in plasma creatinine and cystatin C and decreases in the oxygenation index. Histopathology showed that ECC induced the expected lung inflammation, which included alveolar congestion, hemorrhage, neutrophil infiltration, and alveolar wall thickening; in renal tissue, ECC induced intracytoplasmic vacuolization, acute tubular necrosis, and epithelial swelling. Our results suggest that this novel, minimally invasive mouse model can recapitulate many of the clinical features of ECC-induced systemic inflammatory response and organ injury.
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12

Anderson, Peter G., Stanley B. Digerness, Jerald L. Sklar, and Paul J. Boor. "Use of the Isolated Perfused Heart for Evaluation of Cardiac Toxicity." Toxicologic Pathology 18, no. 4a (January 1990): 497–510. http://dx.doi.org/10.1177/0192623390004part_108.

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The isolated perfused rat heart model can be used to evaluate cardiotoxicity, and is especially useful in distinguishing direct vs indirect cardiac injury. Various perfusion systems can be used to characterize the pathophysiologic as well as morphologic changes induced by drugs or chemicals of interest. The isolated perfused heart was used in the studies described herein to characterize the mechanism of allylamine cardiotoxicity. Rat hearts were perfused with Krebs-Henseleit buffer containing 10 mm allylamine and a latex balloon was inserted into the left ventricle to monitor pressure. Coronary flow in hearts perfused with 10 mm allylamine was similar to control hearts at 5, 10, and 30 min, but was reduced by 1 hr (11.5 ± 0.6 ml/min/g wet heart weight vs 16.0 ± 0.7, p < 0.01). Peak left ventricular systolic pressure increased in hearts perfused with allylamine for 5 min (156 ± 8 mm Hg vs 103 ± 9, p < 0.01), but by 2 hr was decreased compared to controls (89 ± 6 vs 105 ± 5, p < 0.05). End diastolic pressure was markedly increased at 2 hr (58 ± 3 vs 4 ± 0.8, p < 0.01). Morphologically, allylamine perfused hearts exhibited significant contraction band changes as well as numerous cells with marked swelling of the sarcoplasmic reticulum. The findings in this study suggest that allylamine produces direct myocardial damage that appears to be independent of coronary flow. These studies demonstrate that the isolated perfused rat heart model can be used to evaluate mechanisms of acute cardiotoxicity.
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13

Liang, He-Shiuan, Tzu-Cheng Hsu, Pong-Jeu Lu, and Fun-In Wang. "TELETHONIN AS AN EARLY IMMUNOHISTOCHEMICAL MARKER IN LIGATION-INDUCED ISCHEMIC MYOCARDIAL INJURY." Taiwan Veterinary Journal 43, no. 04 (December 2017): 295–306. http://dx.doi.org/10.1142/s1682648517500081.

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In this study, acute myocardial injuries or necrosis were experimentally induced in calves and pigs by ligation of either the left anterior descending coronary artery or left circumflex branch for 30[Formula: see text]min without reperfusion. Various antibodies directed to structural and functional proteins of the sarcomere, as well as activated proteinases, were employed in immunohistochemistry to compare for their potentials to detect early myocardial injury. For comparison, the histological criteria (designated as “Method A”) of cardiomyocyte necrosis such as nuclear pyknosis, sarcoplasmic fragmentation, flocculation, and/or the presence of a contraction band, and inflammatory infiltration were also scored. Additional criteria (designated “Method B”) of changes in late reversible stage of cell injury such as irregular nuclear shape or hyperchromasia, sarcomplasmic hypereosinophilia with either swelling or atrophy in diameter, and perinuclear vacuolation likely of swollen organelles, were also scored. In this setting, telethonin (T-cap), cardiac troponin I (cTnI), the current gold standard, and Method B, were superior to others in detecting ligation-induced ischemic injury. Other markers were either less specific, or less sensitive, or inconclusive for the current application. In conclusion, telethonin may serve as an early immunohistochemical marker in ligation-induced ischemic myocardial injury due to a combination of biomechanical stress, hypoxia, and possibly additional factor as matrix metalloproteinase activation.
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14

Hadzimichalis, Norell M., Sunanda S. Baliga, Roseli Golfetti, Kathryn M. Jaques, Bonnie L. Firestein, and Gary F. Merrill. "Acetaminophen-mediated cardioprotection via inhibition of the mitochondrial permeability transition pore-induced apoptotic pathway." American Journal of Physiology-Heart and Circulatory Physiology 293, no. 6 (December 2007): H3348—H3355. http://dx.doi.org/10.1152/ajpheart.00947.2007.

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Our laboratory has previously reported that acetaminophen confers functional cardioprotection following cardiac insult, including ischemia/reperfusion, hypoxia/reoxygenation, and exogenous peroxynitrite administration. In the present study, we further examined the mechanism of acetaminophen-mediated cardioprotection following ischemia/reperfusion injury. Langendorff-perfused guinea pig hearts were exposed to acute treatment with acetaminophen (0.35 mM) or vehicle beginning at 15 min of a 30-min baseline stabilization period. Low-flow global myocardial ischemia was subsequently induced for 30 min followed by 60 min of reperfusion. At the completion of reperfusion, hearts were homogenized and separated into cytosolic and mitochondrial fractions. Mitochondrial swelling and mitochondrial cytochrome c release were assessed and found to be significantly and completely reduced in acetaminophen- vs. vehicle-treated hearts following reperfusion. In a separate group of hearts, ventricular myocytes were isolated and subjected to fluorescence-activated cell sorting. Acetaminophen-treated hearts showed a significant decrease in late stage apoptotic myocytes compared with vehicle-treated hearts following injury (58 ± 1 vs. 81 ± 5%, respectively). These data, together with electron micrograph analysis, suggest that acetaminophen mediates cardioprotection, in part, via inhibition of the mitochondrial permeability transition pore and subsequent apoptotic pathway.
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15

Alam, Sefa Sarwath, Ashish Kumar Mazumder, Rasheda Akhter, and Selim Md Jahangir. "Study of Sub-Acute Toxicity Profile of Fenugreek (Trigonellafaenum-Graecum) Seeds in Kidney Tissues of Albino Rat: A Randomized Control Trial." Chattagram Maa-O-Shishu Hospital Medical College Journal 18, no. 1 (July 10, 2019): 36–43. http://dx.doi.org/10.3329/cmoshmcj.v18i1.42131.

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Background : The objective of the present study was to evaluate the sub-acute toxic effects of ethanol extract of fenugreek seeds on kidney tissues of albino rats. Materials and methods: The present study was conducted on 30 albino rats divided into Group A, B, C, D and R. Group A (Control group) was treated with distilled water. Group B, Group C and Group D were treated orally with ethanol extract of fenugreek seeds at a dose of 1.25 gm/kg/day, 2.5 gm/kg/day and 5 gm/kg/day respectively for 90 consecutive days. Group R (Recovery group) was treated with seed extract of 5 gm/kg/day for 90 days followed by no treatment for next 28 days to observe any toxic effect if present in highest dose whether reversible or not. On 91st day all the animals of Group A, Group B, Group C and Group D were sacrificed and Group R was sacrificed on 119th day. Blood sample was collected from all the rats by cardiac puncture before sacrifice for measurement of biochemical and hematological parameters, and kidneys were collected for histopathological examination after sacrifice. Results: Upto 2.5 gm /kg/day dose level, all parameters of all experimental groups were statistically not significant when compared with control group. At 5 gm/kg/ day dose level the seeds extract produced statistically significant change in biochemical parameters such as serum creatinine and blood urea. In gross microscopic examination of kidney, at the highest dose level showed the sign of cell injury like cellular swelling, hemorrhage, inflammatory cells infiltration, necrosis etc. Interestingly, these biochemical and microscopic findings at the highest dose level were absent in recovery group. Conclusion: Finally, the study revealed that ethanol extract of fenugreek seeds was non toxic up to 2.5 gm/kg/day dose level and produce renal toxicity at 5 gm/kg/day dose level in sub acute toxicity test. So, if needed to use in higher therapeutic dose the toxicity profile of seeds extract must be re-evaluated. Chatt Maa Shi Hosp Med Coll J; Vol.18 (1); Jan 2019; Page 36-43
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Kennard, Andrew S., and Julie A. Theriot. "Osmolarity-independent electrical cues guide rapid response to injury in zebrafish epidermis." eLife 9 (November 23, 2020). http://dx.doi.org/10.7554/elife.62386.

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The ability of epithelial tissues to heal after injury is essential for animal life, yet the mechanisms by which epithelial cells sense tissue damage are incompletely understood. In aquatic organisms such as zebrafish, osmotic shock following injury is believed to be an early and potent activator of a wound response. We find that, in addition to sensing osmolarity, basal skin cells in zebrafish larvae are also sensitive to changes in the particular ionic composition of their surroundings after wounding, specifically the concentration of sodium chloride in the immediate vicinity of the wound. This sodium chloride-specific wound detection mechanism is independent of cell swelling, and instead is suggestive of a mechanism by which cells sense changes in the transepithelial electrical potential generated by the transport of sodium and chloride ions across the skin. Consistent with this hypothesis, we show that electric fields directly applied within the skin are sufficient to initiate actin polarization and migration of basal cells in their native epithelial context in vivo, even overriding endogenous wound signaling. This suggests that, in order to mount a robust wound response, skin cells respond to both osmotic and electrical perturbations arising from tissue injury.
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17

Engels, Miriam, Manu Kalia, Sarah Rahmati, Laura Petersilie, Peter Kovermann, Michel J. A. M. van Putten, Christine R. Rose, Hil G. E. Meijer, Thomas Gensch, and Christoph Fahlke. "Glial Chloride Homeostasis Under Transient Ischemic Stress." Frontiers in Cellular Neuroscience 15 (September 16, 2021). http://dx.doi.org/10.3389/fncel.2021.735300.

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High water permeabilities permit rapid adjustments of glial volume upon changes in external and internal osmolarity, and pathologically altered intracellular chloride concentrations ([Cl–]int) and glial cell swelling are often assumed to represent early events in ischemia, infections, or traumatic brain injury. Experimental data for glial [Cl–]int are lacking for most brain regions, under normal as well as under pathological conditions. We measured [Cl–]int in hippocampal and neocortical astrocytes and in hippocampal radial glia-like (RGL) cells in acute murine brain slices using fluorescence lifetime imaging microscopy with the chloride-sensitive dye MQAE at room temperature. We observed substantial heterogeneity in baseline [Cl–]int, ranging from 14.0 ± 2.0 mM in neocortical astrocytes to 28.4 ± 3.0 mM in dentate gyrus astrocytes. Chloride accumulation by the Na+-K+-2Cl– cotransporter (NKCC1) and chloride outward transport (efflux) through K+-Cl– cotransporters (KCC1 and KCC3) or excitatory amino acid transporter (EAAT) anion channels control [Cl–]int to variable extent in distinct brain regions. In hippocampal astrocytes, blocking NKCC1 decreased [Cl–]int, whereas KCC or EAAT anion channel inhibition had little effect. In contrast, neocortical astrocytic or RGL [Cl–]int was very sensitive to block of chloride outward transport, but not to NKCC1 inhibition. Mathematical modeling demonstrated that higher numbers of NKCC1 and KCC transporters can account for lower [Cl–]int in neocortical than in hippocampal astrocytes. Energy depletion mimicking ischemia for up to 10 min did not result in pronounced changes in [Cl–]int in any of the tested glial cell types. However, [Cl–]int changes occurred under ischemic conditions after blocking selected anion transporters. We conclude that stimulated chloride accumulation and chloride efflux compensate for each other and prevent glial swelling under transient energy deprivation.
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18

Hellas, Julia A., and R. David Andrew. "Neuronal Swelling: A Non-osmotic Consequence of Spreading Depolarization." Neurocritical Care, September 8, 2021. http://dx.doi.org/10.1007/s12028-021-01326-w.

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AbstractAn acute reduction in plasma osmolality causes rapid uptake of water by astrocytes but not by neurons, whereas both cell types swell as a consequence of lost blood flow (ischemia). Either hypoosmolality or ischemia can displace the brain downwards, potentially causing death. However, these disorders are fundamentally different at the cellular level. Astrocytes osmotically swell or shrink because they express functional water channels (aquaporins), whereas neurons lack functional aquaporins and thus maintain their volume. Yet both neurons and astrocytes immediately swell when blood flow to the brain is compromised (cytotoxic edema) as following stroke onset, sudden cardiac arrest, or traumatic brain injury. In each situation, neuronal swelling is the direct result of spreading depolarization (SD) generated when the ATP-dependent sodium/potassium ATPase (the Na+/K+ pump) is compromised. The simple, and incorrect, textbook explanation for neuronal swelling is that increased Na+ influx passively draws Cl− into the cell, with water following by osmosis via some unknown conduit. We first review the strong evidence that mammalian neurons resist volume change during acute osmotic stress. We then contrast this with their dramatic swelling during ischemia. Counter-intuitively, recent research argues that ischemic swelling of neurons is non-osmotic, involving ion/water cotransporters as well as at least one known amino acid water pump. While incompletely understood, these mechanisms argue against the dogma that neuronal swelling involves water uptake driven by an osmotic gradient with aquaporins as the conduit. Promoting clinical recovery from neuronal cytotoxic edema evoked by spreading depolarizations requires a far better understanding of molecular water pumps and ion/water cotransporters that act to rebalance water shifts during brain ischemia.
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19

Singhanat, K., N. Apaijai, T. Jaiwongkam, S. Kerdphoo, S. C. Chattipakorn, and N. Chattipakorn. "Melatonin membrane receptor 2 activation is a key determinant for melatonin-mediated cardioprotection in cardiac ischaemia-reperfusion injury." European Heart Journal 41, Supplement_2 (November 1, 2020). http://dx.doi.org/10.1093/ehjci/ehaa946.2573.

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Abstract Background Cardiac ischaemia/reperfusion (I/R) injury has been an economic and health burden worldwide. Previous studies have reported the beneficial effects of melatonin when given prior to cardiac ischaemia in animals with cardiac I/R injury. However, the effects of melatonin on the hearts when it is given after ischaemia or at the onset of reperfusion, which is more relevant to the clinical setting, is not known. Moreover, the mechanisms responsible for the potential benefits of melatonin and the roles of melatonin receptors on the heart during cardiac I/R injury have not been fully investigated. Purpose We tested the hypothesis that in rats with cardiac I/R injury, melatonin exerts cardioprotective effects even when it is given after ischaemia via an activation of both melatonin receptors 1 (MT1) and 2 (MT2), leading to decreased mitochondrial dysfunction, mitochondrial dynamics imbalance, excessive mitophagy, cardiomyocyte death and finally resulting in decreased infarct size and improved left ventricular (LV) function. Methods Male Wistar rats were subjected to cardiac I/R (30 min of LAD ligation and 120 min of reperfusion). These rats were divided into 4 interventions (n=12/group) including vehicle, pretreatment with melatonin, melatonin treatment during ischaemia, or at the onset of reperfusion. Melatonin was given to the rats at the dose of 10 mg/kg via intravenous injection. In addition, either a non-specific melatonin receptor blocker (Luzindole) or specific MT2 blocker (4-PPDOT) at 1 mg/kg was given intravenously to 2 additional sets of rats (n=12/set) prior to melatonin and cardiac I/R induction. At the end of cardiac I/R, infarct size, LV function, and molecular mechanisms were determined. Furthermore, in vitro experiment was conducted in MT1 or MT2 silenced H9C2 cell with hypoxia/reoxygenation (H/R) to investigate the mechanism underlying cardioprotective effects of melatonin during cardiac I/R. Results Rats in all melatonin-treated groups had similarly reduced cardiac I/R injury as indicated by reduced infarct size (Fig. 1A), arrhythmia score. Melatonin-treated rats also had decreased mitochondrial ROS production, mitochondrial depolarization and swelling, decreased p-Drp1/Drp1 ratio (Fig. 1B) and increased Mfn1, Mfn2, and OPA1, and decreased apoptosis, leading to increased %LVEF. Luzindole and 4-PPDOT abolished these protective effects of melatonin (Fig. 1A). In in vitro study, melatonin increased %cell viability (Fig. 1C), reduced mitochondrial dynamics imbalance and cardiomyocyte apoptosis in H9C2 cells with H/R. However, these beneficial effects of melatonin were abrogated only in MT2 silenced H9C2 cell with H/R. Conclusion Melatonin exerted both preventive and treatment effects in reducing cardiac I/R injury. Its cardioprotective effects were dependent upon the activation of MT2 receptor. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Science and Technology Development Agency of Thailand
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20

Watson, Lewis J., Gladys A. Ngoh, Yanqing Zhu, Ashley L. Campbell, Yu-Ting Xuan, and Steven P. Jones. "Abstract 655: Paradoxical Reduction in Glycosylation Sensitizes the Diabetic Heart to Mitochondrial Permeability Transition." Circulation 116, suppl_16 (October 16, 2007). http://dx.doi.org/10.1161/circ.116.suppl_16.ii_121-a.

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Hexosamine biosynthesis, an accessory pathway for glucose metabolism, culminates in the formation of UDP-GlcNAc, which is the monosaccharide donor for the post-translational modification, O-linked beta-N-acetylglucosamine (O-GlcNAc). Augmented hexosamine biosynthesis has been implicated in the pathogenesis of diabetes in many peripheral tissues. Yet, glucose transporters in cardiac myocytes are predominantly insulin dependent, thereby limiting intracellular glucose availability in diabetic cardiac myocytes. Driven by such paradoxes, we hypothesized that unlike other tissues, intracellular O-GlcNAc signaling would actually be reduced in diabetic hearts. HPLC revealed a 24% reduction in UDP-GlcNAc levels in db/db diabetic (2.2 +/−0.5 nmol) compared to nondiabetic (2.9 +/−0.5 nmol) mouse hearts. Immunoblots showed a reduced expression of O-GlcNAc transferase (61 +/−14% of nondiabetic), which is the enzyme that adds the O-GlcNAc modification to proteins, and reduced O-GlcNAc levels (86 +/−8% of nondiabetic) in diabetic hearts (n = 8/group). We recently reported an interaction between O-GlcNAc signaling and mitochondrial-controlled cell death and, accordingly, evaluated the sensitivity to mitochondrial permeability transition pore (mPTP) formation here. Cardiac mitochondria from diabetic hearts were more sensitive to calcium-induced mitochondrial swelling (138 +/−15% of nondiabetic) compared with mitochondria from nondiabetics (n = 3/group). Because diabetes is multi-faceted, we distilled the system to one variable, reduced O-GlcNAc levels, by injecting additional groups of nondiabetic mice with a drug (TT04) to reduce O-GlcNAc levels, or Vehicle (n =3/group). Cardiac mitochondria from nondiabetic mice with reduced O-GlcNAc levels (TT04) were also more sensitive to calcium-induced swelling (178 +/−12% of Vehicle) than cardiac mitochondria from Vehicle treated mice, thus recapitulating one element of the diabetic phenotype and supporting the idea that reduction of O-GlcNAc levels is sufficient to sensitize cardiac mPTP formation. We conclude that the paradoxical reduction in O-GlcNAc signaling in diabetic hearts may be responsible for heightened sensitivity to cardiac injury, particularly in terms of mPTP formation.
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21

Strubbe, Jasiel O., Jason Schrad, James F. Conway, Kristin N. Parent, and Jason N. Bazil. "Abstract 17188: Cryoem Analysis in Cardiac Isolated Mitochondria Reveals New Insights for CsA and mPTP Activation." Circulation 138, Suppl_1 (November 6, 2018). http://dx.doi.org/10.1161/circ.138.suppl_1.17188.

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Excessive Ca 2+ accumulation is the main source of cardiac tissue and cell death during myocardial ischemia-reperfusion injury (IR injury) and myocardial infarction. Calcium dysregulation and overload leads to mitochondrial dysfunction, excessive reactive oxygen species (ROS) production, catastrophic energy failure, and opening of the cyclosporine A-sensitive mitochondrial permeability transition pore (mPTP). Mitochondrial Ca 2+ accumulation also results in the formation of amorphous Ca 2+ -phosphate granules localized in the mitochondrial matrix. These amorphous electron-dense granules are main components of the mitochondrial Ca 2+ sequestration and buffering system by mechanisms not yet well understood. The two aims of the present study are to test the relationship of Ca 2+ -phosphate granule size and number in cardiac mitochondria 1) exposed to a bolus calcium sufficient to elicit permeabilization and 2) whether CsA-treated mitochondria alters granule formation and size. A time course series of CryoEM images was analyzed to follow the permeabilization process. CryoEM results showed that mitochondrial incubated for longer time-courses have increased number of small granules (40 - 110 nm), swelling, membrane rupture and induction of mPTP opening. Conversely, shorter incubation time resulted in less granules per mitochondrion yet of similar size (35 - 90 nm). CsA- treated mitochondria, on the other hand, showed bigger phosphate granules (120 - 160 nm), and both lower granules per mitochondria and mPTP opening susceptibility. These results suggest a novel mechanism for CsA in which Ca 2+ -phosphate granule sizes are enhanced while maintaining fewer per mitochondrion. This effect may explain why CsA-treated mitochondria have higher calcium tolerance, delayed Ca 2+ -dependent opening of the mPTP, and protects against reperfusion-induced myocardial necrosis.
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22

Wangko, Sunny. "RABDOMIOLISIS." JURNAL BIOMEDIK (JBM) 5, no. 3 (April 16, 2014). http://dx.doi.org/10.35790/jbm.5.3.2013.4336.

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Abstract: Literally, rhabdomyolysis is the occurence of skeletal muscle destruction, resulting in massive liberation of muscle fiber constituents (electrolytes, myoglobin, creatine kinase, and other sarcoplasmic proteins) into the extracellular fluid and the blood circulation. The etiological spectrum of rhabdomyolysis is extensive, consisting of: physical factors such as trauma and compression, ischemia of skeletal muscle tissue, strenuous physical exercise, prolonged immobilization, high-voltage electrical injury, hyperthermia; and non-physical factors such as metabolic myopathy (genetic disorders), drugs and toxins, viral and bacterial infections, electrolyte and endocrin abnormalities, connective tissue disorders; and unknown causes. Although the causes of rhabdomyolysis vary extensively, the histopathological findings usually show a loss of cell nuclei and muscular striation with the absence of inflammatory cells. The pathophysiology of rhabdomyolysis includes changes in cellular metabolism, reperfusion injury, and the compartment syndrome. The degrees of rhabdomyolysis vary from a subclinical rise of creatinine kinase to an emergency condition with multiorgan failure. Classically, the clinical findings are muscular aches and swelling, as well as dysfunction, stiffness, numbness, weakness, and tea-colored urine. The most important laboratory examinations are serum creatinine kinase, besides serum and urine myoglobin. The life-threatening complications of rhabdomyolysis are hypovolemia, arrhythmia and cardiac arrest, acute kidney injury, and DIC. Its early diagnosis and prompt management are very important to the progress of the patient as well as to the effective control of rhabdomyolysis. Medical personnel, pharmacists, sport/gym instructors, and athletes have to be aware of the signs and symptoms of this rhabdomyolysis. Keywords: rhabdomyolysis, electrolytes, myoglobin, creatine kinase Abstrak: Rabdomiolisis adalah terjadinya destruksi serat otot rangka yang berakibat terlepasnya konstituen serat otot (elektrolit, mioglobin, kreatin kinase, dan protein sarkoplasma lainnya) ke dalam cairan ekstrasel dan sirkulasi. Penyebab rabdomiolisis multifaktorial, terdiri dari: faktor fisik, antara lain trauma dan kompresi, iskemia jaringan otot, latihan fisik berat, imobilisasi berkepanjangan, paparan listrik bertegangan tinggi, hipertermia; faktor non-fisik, antara lain miopati metabolik (genetik), obat-obatan dan toksin, infeksi virus dan mikroba, gangguan elektrolit dan endokrin, kelainan jaringan ikat; dan penyebab yang tidak diketahui. Walaupun penyebab rabdomiolisis sangat bervariasi, gambaran histologik yang ditemukan umumnya berupa hilangnya inti serat otot dan corak serat, tanpa disertai adanya sel-sel radang. Patofisiologi rabdomiolisis yaitu perubahan metabolisme sel, cedera reperfusi, dan sindroma kompartemen. Derajat rabdomiolisis dapat bervariasi dari peningkatan kreatin kinase subklinis sampai yang memerlukan penanganan darurat disertai kegagalan multiorgan. Gejala klinis klasik berupa nyeri, pembengkakan dan disfungsi otot, kaku, kesemutan, kelemahan, serta urin berwarna teh. Pemeriksaan penunjang utama yaitu kreatin kinase serum, serta miogobin urin dan serum. Komplikasi yang sangat mengancam kehidupan ialah hipovolemia, aritmia dan gagal jantung, gagal ginjal akut, serta DIC. Diagnosis dini dan penanganan segera sangat berperan dalam perlangsungan rabdomiolisis dan prognosis pasien. Tenaga medis, tenaga farmasi, instruktur olah raga dan gym perlu diwaspadai terhadap gejala rabdomiolisis. Kata kunci: rabdomiolisis, elektrolit, mioglobin, kreatin kinase
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