scholarly journals Mutant Kras as a Biomarker Plays a Favorable Role in FL118-Induced Apoptosis, Reactive Oxygen Species (ROS) Production and Modulation of Survivin, Mcl-1 and XIAP in Human Bladder Cancer

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3413
Author(s):  
Sreevidya Santha ◽  
Xiang Ling ◽  
Ieman A. M. Aljahdali ◽  
Sailee S. Rasam ◽  
Xue Wang ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Bladder Cancer ◽  
Reactive Oxygen ◽  
In Vivo Studies ◽  
Parp Cleavage ◽  
Ros Generation ◽  
Ros Production ◽  
Oxygen Species ◽  
Wild Type ◽  
Kras Mutations

Tumor heterogeneity in key gene mutations in bladder cancer (BC) is a major hurdle for the development of effective treatments. Using molecular, cellular, proteomics and animal models, we demonstrated that FL118, an innovative small molecule, is highly effective at killing T24 and UMUC3 high-grade BC cells, which have Hras and Kras mutations, respectively. In contrast, HT1376 BC cells with wild-type Ras are insensitive to FL118. This concept was further demonstrated in additional BC and colorectal cancer cells with mutant Kras versus those with wild-type Kras. FL118 strongly induced PARP cleavage (apoptosis hallmark) and inhibited survivin, XIAP and/or Mcl-1 in both T24 and UMUC3 cells, but not in the HT1376 cells. Silencing mutant Kras reduced both FL118-induced PARP cleavage and downregulation of survivin, XIAP and Mcl-1 in UMUC3 cells, suggesting mutant Kras is required for FL118 to exhibit higher anticancer efficacy. FL118 increased reactive oxygen species (ROS) production in T24 and UMUC3 cells, but not in HT1376 cells. Silencing mutant Kras in UMUC3 cells reduced FL118-mediated ROS generation. Proteomics analysis revealed that a profound and opposing Kras-relevant signaling protein is changed in UMUC3 cells and not in HT1376 cells. Consistently, in vivo studies indicated that UMUC3 tumors are highly sensitive to FL118 treatment, while HT1376 tumors are highly resistant to this agent. Silencing mutant Kras in UMUC3 cell-derived tumors decreases UMUC3 tumor sensitivity to FL118 treatment. Together, our studies revealed that mutant Kras is a favorable biomarker for FL118 targeted treatment.

scholarly journals Reactive Oxygen Species in Host Plant Are Required for an Early Defense Response against Attack of Stagonospora nodorum Berk. Necrotrophic Effectors SnTox

Plants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1586
Author(s):  
Svetlana Veselova ◽  
Tatyana Nuzhnaya ◽  
Guzel Burkhanova ◽  
Sergey Rumyantsev ◽  
Igor Maksimov
Keyword(s):  
Reactive Oxygen Species ◽  
Early Stage ◽  
Reactive Oxygen ◽  
Triticum Aestivum L ◽  
Redox Status ◽  
Stagonospora Nodorum ◽  
Ros Generation ◽  
Ros Production ◽  
Oxygen Species ◽  
Necrotrophic Effectors

Reactive oxygen species (ROS) play a central role in plant immune responses. The most important virulence factors of the Stagonospora nodorum Berk. are multiple fungal necrotrophic effectors (NEs) (SnTox) that affect the redox-status and cause necrosis and/or chlorosis in wheat lines possessing dominant susceptibility genes (Snn). However, the effect of NEs on ROS generation at the early stages of infection has not been studied. We studied the early stage of infection of various wheat genotypes with S nodorum isolates -Sn4VD, SnB, and Sn9MN, carrying a different set of NE genes. Our results indicate that all three NEs of SnToxA, SnTox1, SnTox3 significantly contributed to cause disease, and the virulence of the isolates depended on their differential expression in plants (Triticum aestivum L.). The Tsn1–SnToxA, Snn1–SnTox1and Snn3–SnTox3 interactions played an important role in inhibition ROS production at the initial stage of infection. The Snn3–SnTox3 inhibited ROS production in wheat by affecting NADPH-oxidases, peroxidases, superoxide dismutase and catalase. The Tsn1–SnToxA inhibited ROS production in wheat by affecting peroxidases and catalase. The Snn1–SnTox1 inhibited the production of ROS in wheat by mainly affecting a peroxidase. Collectively, these results show that the inverse gene-for gene interactions between effector of pathogen and product of host sensitivity gene suppress the host’s own PAMP-triggered immunity pathway, resulting in NE-triggered susceptibility (NETS). These results are fundamentally changing our understanding of the development of this economical important wheat disease.

scholarly journals Production and scavenging of reactive oxygen species both affect reproductive success in male and female Drosophila melanogaster

2021 ◽  
Author(s):  
Biz R. Turnell ◽  
Luisa Kumpitsch ◽  
Klaus Reinhardt
Keyword(s):  
Reactive Oxygen Species ◽  
Drosophila Melanogaster ◽  
Reactive Oxygen ◽  
Cellular Aging ◽  
Ros Production ◽  
Oxygen Species ◽  
Wild Type ◽  
Ros Scavenging ◽  
Respiratory Pathway ◽  
Male And Female

AbstractSperm aging is accelerated by the buildup of reactive oxygen species (ROS), which cause oxidative damage to various cellular components. Aging can be slowed by limiting the production of mitochondrial ROS and by increasing the production of antioxidants, both of which can be generated in the sperm cell itself or in the surrounding somatic tissues of the male and female reproductive tracts. However, few studies have compared the separate contributions of ROS production and ROS scavenging to sperm aging, or to cellular aging in general. We measured reproductive fitness in two lines of Drosophila melanogaster genetically engineered to (1) produce fewer ROS via expression of alternative oxidase (AOX), an alternative respiratory pathway; or (2) scavenge fewer ROS due to a loss-of-function mutation in the antioxidant gene dj-1β. Wild-type females mated to AOX males had increased fecundity and longer fertility durations, consistent with slower aging in AOX sperm. Contrary to expectations, fitness was not reduced in wild-type females mated to dj-1β males. Fecundity and fertility duration were increased in AOX and decreased in dj-1β females, indicating that female ROS levels may affect aging rates in stored sperm and/or eggs. Finally, we found evidence that accelerated aging in dj-1β sperm may have selected for more frequent mating. Our results help to clarify the relative roles of ROS production and ROS scavenging in the male and female reproductive systems.

scholarly journals Somatic production of reactive oxygen species does not predict its production in sperm cells across Drosophila melanogaster lines

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Biz R. Turnell ◽  
Luisa Kumpitsch ◽  
Anne-Cécile Ribou ◽  
Klaus Reinhardt
Keyword(s):  
Reactive Oxygen Species ◽  
Drosophila Melanogaster ◽  
Reactive Oxygen ◽  
Future Research ◽  
Ros Production ◽  
Oxygen Species ◽  
Loss Of Function ◽  
Wild Type ◽  
Ros Scavenging ◽  
Transport Chain

Abstract Objective Sperm ageing has major evolutionary implications but has received comparatively little attention. Ageing in sperm and other cells is driven largely by oxidative damage from reactive oxygen species (ROS) generated by the mitochondria. Rates of organismal ageing differ across species and are theorized to be linked to somatic ROS levels. However, it is unknown whether sperm ageing rates are correlated with organismal ageing rates. Here, we investigate this question by comparing sperm ROS production in four lines of Drosophila melanogaster that have previously been shown to differ in somatic mitochondrial ROS production, including two commonly used wild-type lines and two lines with genetic modifications standardly used in ageing research. Results Somatic ROS production was previously shown to be lower in wild-type Oregon-R than in wild-type Dahomey flies; decreased by the expression of alternative oxidase (AOX), a protein that shortens the electron transport chain; and increased by a loss-of-function mutation in dj-1β, a gene involved in ROS scavenging. Contrary to predictions, we found no differences among these four lines in the rate of sperm ROS production. We discuss the implications of our results, the limitations of our study, and possible directions for future research.

Abstract 19967: Differential Roles of the NADPH-Oxidase 1 and 2 in Platelet Activation and Thrombosis

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Michael K Delaney ◽  
Kyungho Kim ◽  
Brian Estevez ◽  
Aleksandra Stojanovic-Terpo ◽  
Bo Shen ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Platelet Activation ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Reactive Oxygen ◽  
Ros Generation ◽  
Ros Production ◽  
Oxygen Species ◽  
General Role ◽  
Glycoprotein Vi ◽  
Activation Pathways

Objective: Reactive oxygen species (ROS) generated from activated platelets is known to regulate platelet activation. However, it remains unclear whether and how different isoforms of nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidases (NOXs) play roles in different platelet activation pathways. Here we investigated the role of NOX1 and NOX2 in different platelet activation pathways using NOX1 and NOX2 knockout mice. Approach and Results: NOX1-/- platelets showed selective defects in G protein coupled receptor (GPCR)-mediated platelet activation induced by thrombin, protease-activated receptor 4 agonist peptide (PAR4AP) and thromboxane A2 analog U46619, but was not affected in platelet activation induced by collagen-related peptide (CRP), a glycoprotein VI (GPVI) agonist. In contrast, NOX2-/- platelets showed potent inhibition of CRP-induced platelet activation, and also showed partial inhibition of thrombin-induced platelet aggregation and secretion. Consistently, production of reactive oxygen species (ROS) was inhibited in NOX1-/- platelets stimulated with thrombin, but not CRP, whereas NOX2-/- platelets showed reduced ROS generation induced by CRP or thrombin. Interestingly, laser-induced arterial thrombosis was impaired in NOX2-/- mice, and in thrombocytopenic mice transfused with NOX2-/- platelets, suggesting an important role for NOX2-dependent platelet ROS production in the laser-induced injury model of thrombosis. Conclusions: NOX1 and NOX2 play differential roles in different platelet activation pathways: NOX1 mediates GPCR-mediated ROS production and platelet activation, whereas NOX2 plays a general role in GPVI- and GPCR-induced ROS production and platelet activation in vitro , and in laser-induced thrombosis in vivo .

scholarly journals Role of Reactive Oxygen Species in Pathogenesis of Radiocontrast-Induced Nephropathy

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Antonio Pisani ◽  
Eleonora Riccio ◽  
Michele Andreucci ◽  
Teresa Faga ◽  
Michael Ashour ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Contrast Media ◽  
Reactive Oxygen ◽  
In Vivo Studies ◽  
Ros Generation ◽  
Oxygen Species ◽  
Ros Scavenging ◽  
Iodinated Contrast ◽  
Ros Formation

In vitro and in vivo studies have demonstrated enhanced hypoxia and formation of reactive oxygen species (ROS) in the kidney following the administration of iodinated contrast media, which play a relevant role in the development of contrast media-induced nephropathy. Many studies indeed support this possibility, suggesting a protective effect of ROS scavenging or reduced ROS formation with the administration of N-acetylcysteine and bicarbonate infusion, respectively. Furthermore, most risk factors, predisposing to contrast-induced nephropathy, are prone to enhanced renal parenchymal hypoxia and ROS formation. In this review, the association of renal hypoxia and ROS-mediated injury is outlined. Generated during contrast-induced renal parenchymal hypoxia, ROS may exert direct tubular and vascular endothelial injury and might further intensify renal parenchymal hypoxia by virtue of endothelial dysfunction and dysregulation of tubular transport. Preventive strategies conceivably should include inhibition of ROS generation or ROS scavenging.

scholarly journals The Characterization of TA-289, a Novel Antifungal from Fusarium sp.

2021 ◽  
Author(s):  
◽  
Natelle C H Quek
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Cell Cycle ◽  
Cell Death ◽  
Reactive Oxygen ◽  
Chemical Diversity ◽  
Mitochondrial Morphology ◽  
Ros Production ◽  
Oxygen Species ◽  
Wild Type

<p>Natural products offer vast structural and chemical diversity highly sought after in drug discovery research. Saccharomyces cerevisiae makes an ideal model eukaryotic organism for drug mode-of-action studies owing to ease of growth, sophistication of genetic tools and overall homology to higher eukaryotes. Equisetin and a closely related novel natural product, TA-289, are cytotoxic to fermenting yeast, but seemingly less so when yeast actively respire. Cell cycle analyses by flow cytometry revealed a cell cycle block at S-G2/M phase caused by TA-289; previously described oxidative stress-inducing compounds causing cell cycle delay led to further investigation in the involvement of equisetin and TA-289 in mitochondrial-mediated generation of reactive oxygen species. Chemical genomic profiling involving genome-wide scans of yeast deletion mutant strains for TA-289 sensitivity revealed sensitization of genes involved in the mitochondria, DNA damage repair and oxidative stress responses, consistent with a possible mechanism-of-action at the mitochondrion. Flow cytometric detection of reactive oxygen species (ROS) generation caused by TA-289 suggests that the compound may induce cell death via ROS production. The generation of a mutant strain resistant to TA-289 also displayed resistance to a known oxidant, H2O2, at concentrations that were cytotoxic to wild-type cells. The resistant mutant displayed a higher basal level of ROS production compared to the wild-type parent, indicating that the resistance mutation led to an up-regulation of antioxidant capacity which provides cell survival in the presence of TA-289. Yeast mitochondrial morphology was visualized by confocal light microscopy, where it was observed that cells treated with TA-289 displayed abnormal mitochondria phenotypes, further indicating that the compound is acting primarily at the mitochondrion. Similar effects observed with equisetin treatment suggest that both compounds share the same mechanism, eliciting cell death via ROS production in the mitochondrial respiratory chain.</p>

scholarly journals Impact of CD14 on Reactive Oxygen Species Production from Human Leukocytes Primed byEscherichia coliLipopolysaccharides

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Dmitry S. Kabanov ◽  
Olga Yu. Vwedenskaya ◽  
Marina A. Fokina ◽  
Elena M. Morozova ◽  
Sergey V. Grachev ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Reactive Oxygen ◽  
Polymorphonuclear Neutrophils ◽  
Ros Generation ◽  
Ros Production ◽  
Oxygen Species ◽  
Human Pmns ◽  
Species Production ◽  
The Impact ◽  
Priming Activity

Lipopolysaccharides (LPS) from Gram-negative bacteria prime human polymorphonuclear neutrophils (PMNs) via multicomponent receptor cluster including CD14 and MD-2·TLR4 for the enhanced release of reactive oxygen species (ROS) were triggered by bacterial derived peptideN-formyl-methionyl-leucyl-phenylalanine (fMLP). In this study, we investigated the impact of CD14 on LPS-induced priming of human PMNs for fMLP-triggered ROS generation (respiratory or oxidative) burst. Monoclonal antibodies against human CD14 (mAbs) as well as isotype-matched IgG2a did not influence significantly fMLP-triggered ROS production from LPS-unprimed PMNs. Anti-CD14 mAbs (clone UCHM-1) attenuated LPS-induced priming of PMNs as it had been mirrored by fMLP-triggered decrease of ROS production. Similar priming activity of S-LPS or Re-LPS fromEscherichia colifor fMLP-triggered ROS release from PMNs was found. Obtained results suggest that glycosylphosphatidylinositol-anchored CD14 is the key player in LPS-induced PMN priming for fMLP-triggered ROS production. We believe that blockade of CD14 on the cell surface and clinical use of anti-CD14 mAbs or their Fab fragments may diminish the production of ROS and improve outcomes during cardiovascular diseases manifested by LPS-induced inflammation.

Role of mutant KRAS as a biomarker in FL118-induced apoptosis, reactive oxygen species (ROS) production and inhibition of survivin, Mcl-1 and XIAP in human bladder cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15651-e15651
Author(s):  
Sreevidya Santha ◽  
Ieman Aljahdali ◽  
Sailee Suryakant Rasam ◽  
Xue Wang ◽  
Xiang Ling ◽  
...  
Keyword(s):  
Gene Expression ◽  
Reactive Oxygen Species ◽  
Bladder Cancer ◽  
Protein Gene ◽  
Parp Cleavage ◽  
Ros Production ◽  
Oxygen Species ◽  
Human Bladder Cancer ◽  
Human Bladder ◽  
Western Blots

e15651 Background: Effective treatment of bladder cancer patients has not been realized over the past two decades due to heterogeneity with key oncogenic and tumor suppressor gene mutations, which is a major hurdle for effective treatment of the disease. Methods: Cancer cell growth/viability was determined using MTT assays; protein gene expression profiles were determined by both Western blots and proteomics technologies; PARP cleavage were determined by Western blots; genetic modulation of protein gene expression was realized by shRNA silencing or forced expression of the gene; reactive oxygen species (ROS) production was measured using a ROS assay kit; and human bladder xenograft tumor growth was determined using animal models. Results: Our study indicated that FL118, an innovative small molecule, exhibits differential anticancer efficacy in high-grade bladder cancer cell lines (HT1376, T24, UMUC-3). FL118 is highly effective at inhibiting the viability of T24 and UMUC-3 bladder cancer cells, which have Hras and Kras mutations, respectively. In contrast, HT1376 with wild-type Ras exhibits insensitivity to FL118-mediated inhibition of cell viability. Consistently, FL118 strongly induced PARP cleavage (hallmark of apoptosis) and inhibited the expression of survivin, XIAP and/or Mcl-1 in both T24 and UMUC-3 cells but not in the HT1376 cells. Our studies further indicated that the constitutive AKT and ERK1/2 signaling does not play a major role in these FL118-mediated effects. Instead, mutant Kras appeared to be involved in FL118 efficacy and played a positive role in mediating FL118 effects. Silencing of mutant Kras via shRNA reduced both FL118-induced PARP cleavage and downregulation of survivin, XIAP and Mcl-1 in UMUC-3 cells, suggesting mutant Kras is required for FL118 to exhibit high efficacy. FL118 increases ROS production in T24 and UMUC-3 cells but not in HT1376 cells. Silencing of mutant Kras with shRNA in UMUC-3 cells significantly reduced FL118-mediated ROS generation. Additionally, proteomics analyses of UMUC3 and HT1376 cell protein profiles after FL118 treatment support the obtained results described above. Consistent with these in vitro results, in vivo studies indicated that UMUC3 is highly sensitive and HT1376 is highly resistant to FL118 treatment. Conclusions: Our studies suggest that mutant Kras is a favorable biomarker for FL118 targeted treatment in human bladder cancer.

Reactive Oxygen Species Are Differentially Regulated in Chronic Myeloid Leukemia Versus Philadelphia Negative Myeloproliferative Neoplasms

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4215-4215
Author(s):  
Estelle Guerin ◽  
Francis Belloc ◽  
Gabriel Etienne ◽  
Pierre Duffau ◽  
Francois-Xavier Mahon ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Bone Marrow ◽  
Peripheral Blood ◽  
Myeloproliferative Neoplasms ◽  
Reactive Oxygen ◽  
Ros Generation ◽  
Separate Analysis ◽  
Ros Production ◽  
Oxygen Species ◽  
Normal Cells

Abstract Deregulation of tyrosine-kinases is a characteristic of most Myeloproliferative Neoplasms (MPN); evolution from chronic phase to acute leukemia depends on the acquisition of additional mutations. Reactive Oxygen Species (ROS), the production of which is increased by tyrosine-kinase activation, can be responsible for additional mutations. The role of ROS in generating genetic aberrations has been mainly studied in BCR-ABL-positive cell lines. Little is known of ROS metabolism in primary cells from CML or Philadelphia-negative MPN (Ph-MPN). After informed consent, cells from blood or bone marrow were obtained from patients diagnosed with CML (12 bone marrow (BM), 8 peripheral blood (PB)), or Ph-MPN (4 Polycythemia Vera, 6 Essential Thrombocythemia, 3 Primary Myelofibroses, 2 atypical CML) and from healthy donors (bone marrow donors) or patients devoid of hematological disease undergoing thoracotomy. Cells were incubated with DCFDA, a fluorogenic marker of ROS production, labelled with an anti-CD45 antibody, stimulated with either the oxidant hydrogen peroxide (H2O2) or the PKC activator Phorbol Myristate Acetate (PMA), and analysed for ROS production by flow cytometry. CD45/SSC gating allowed separate analysis of granulocytes, monocytes or lymphocytes. The basal level of ROS was not higher in CML cells as compared to normal BM or PB leukocytes. It was even significantly lower in CML lymphocytes, either from the BM (2.35 Arbitrary Units vs 8.3 AU, p=5.5 10−5) or PB (2.47 AU vs 7.4 AU, p=3.10−5) and in CML granulocytes from peripheral blood (14 AU vs 45 AU, p =10 −5), but not bone marrow. The ROS levels of Ph-MPN cells were similar or slightly higher than control cells. Upon H2O2 stimulation however, ROS production increased significantly more in CML cells as compared to normal cells (6 fold increase), whatever the cell type (granulocytes, monocytes and lymphocytes) or their origin (PB or BM). In contrast, for Ph-MPN cells, H2O2-stimulated ROS production was close to that of normal cells, with only BM lymphocytes showing ROS generation four fold higher than control BM lymphocytes. After PMA stimulation, which yielded a more modest ROS production than H2O2, CML cells behaved similarly to normal cells, whereas ROS production was four fold higher in Ph-MPN cells, whatever their type and origin. In conclusion, ROS levels at the basal stage are not higher in MPN cells, whether they are Philadelphia positive or negative, as compared to normal cells. Various kinds of stimulation induce different patterns of response, CML cells being more sensitive to oxidants whereas Ph-MPN cells respond more to the cytokine-mimicking agent PMA. These results suggest that the mechanisms of ROS generation and thus of genetic instability are different in CML and Ph-MPN.

Lung endothelial cell proliferation with decreased shear stress is mediated by reactive oxygen species

2006 ◽  
Vol 290 (1) ◽  
pp. C66-C76 ◽  
Author(s):  
Tatyana Milovanova ◽  
Shampa Chatterjee ◽  
Yefim Manevich ◽  
Irina Kotelnikova ◽  
Kris DeBolt ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Proliferation ◽  
Shear Stress ◽  
Endothelial Cell ◽  
Nadph Oxidase ◽  
Reactive Oxygen ◽  
Proliferation Index ◽  
Ros Production ◽  
Oxygen Species ◽  
Wild Type

Acute cessation of flow (ischemia) leads to depolarization of the endothelial cell (EC) membrane mediated by KATP channels and followed by production of reactive oxygen species (ROS) from NADPH oxidase. We postulated that ROS are a signal for initiating EC proliferation associated with the loss of shear stress. Flow cytometry was used to identify proliferating CD31-positive pulmonary microvascular endothelial cells (mPMVECs) from wild-type, Kir6.2−/−, and gp91 phox−/− mice. mPMVECs were labeled with PKH26 and cultured in artificial capillaries for 72 h at 5 dyn/cm2 (flow adaptation), followed by 24 h of stop flow or continued flow. ROS production during the first hour of ischemia was markedly diminished compared with wild-type mice in both types of gene-targeted mPMVECs. Cell proliferation was defined as the proliferation index (PI). After 72 h of flow, >98% of PKH26-labeled wild-type mPMVECs were at a single peak (PI 1.0) and the proportion of cells in the S+G2/M phases were at 5.8% on the basis of cell cycle analysis. With ischemia (24 h), PI increased to 2.5 and the ratio of cells in S+G2/M phases were at 35%. Catalase, diphenyleneiodonium, and cromakalim markedly inhibited ROS production and cell proliferation in flow-adapted wild-type mPMVECs. Significant effects of ischemia were not observed in Kir6.2−/− and gp91 phox−/− cells. ANG II activation of NADPH oxidase was unaffected by KATP gene deletion. Thus loss of shear stress in flow-adapted mPMVECs results in cell division associated with ROS generated by NADPH oxidase. This effect requires a functioning cell membrane KATP channel.

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