Interplay of Oxidative Stress and Necrosis-like Cell Death in Cardiac Ischemia/Reperfusion Injury: A Focus on Necroptosis

Extensive research work has been carried out to define the exact significance and contribution of regulated necrosis-like cell death program, such as necroptosis to cardiac ischemic injury. This cell damaging process plays a critical role in the pathomechanisms of myocardial infarction (MI) and post-infarction heart failure (HF). Accordingly, it has been documented that the modulation of key molecules of the canonical signaling pathway of necroptosis, involving receptor-interacting protein kinases (RIP1 and RIP3) as well as mixed lineage kinase domain-like pseudokinase (MLKL), elicit cardioprotective effects. This is evidenced by the reduction of the MI-induced infarct size, alleviation of myocardial dysfunction, and adverse cardiac remodeling. In addition to this molecular signaling of necroptosis, the non-canonical pathway, involving Ca2+/calmodulin-dependent protein kinase II (CaMKII)-mediated regulation of mitochondrial permeability transition pore (mPTP) opening, and phosphoglycerate mutase 5 (PGAM5)–dynamin-related protein 1 (Drp-1)-induced mitochondrial fission, has recently been linked to ischemic heart injury. Since MI and HF are characterized by an imbalance between reactive oxygen species production and degradation as well as the occurrence of necroptosis in the heart, it is likely that oxidative stress (OS) may be involved in the mechanisms of this cell death program for inducing cardiac damage. In this review, therefore, several observations from different studies are presented to support this paradigm linking cardiac OS, the canonical and non-canonical pathways of necroptosis, and ischemia-induced injury. It is concluded that a multiple therapeutic approach targeting some specific changes in OS and necroptosis may be beneficial in improving the treatment of ischemic heart disease.

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Anti-IL-20 Antibody Protects against Ischemia/Reperfusion-Impaired Myocardial Function through Modulation of Oxidative Injuries, Inflammation and Cardiac Remodeling

Antioxidants ◽

10.3390/antiox10020275 ◽

2021 ◽

Vol 10 (2) ◽

pp. 275

Author(s):

Kun-Ling Tsai ◽

Wan-Ching Chou ◽

Hui-Ching Cheng ◽

Yu-Ting Huang ◽

Ming-Shi Chang ◽

...

Keyword(s):

Oxidative Stress ◽

Cardiac Remodeling ◽

Myocardial Dysfunction ◽

Ischemia Reperfusion ◽

Critical Role ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Critical Event ◽

Control Group ◽

Antibody Treatment ◽

Creatine Kinase Mb

Acute myocardial infarction (AMI) is the most critical event in the disease spectrum of coronary artery disease. To rescue cardiomyocytes in AMI, it is important to restore blood supply as soon as possible to reduce ischemia-induced injury. However, worse damage can occur during the reperfusion phase, called the reperfusion injury. Under ischemia/reperfusion (I/R) injury, elevated oxidative stress plays a critical role in regulation of apoptosis, inflammation and remodeling of myocardium. Our previous study has demonstrated that interleukin (IL)-20 is increased during hypoxia/reoxygenation stimulation and promotes apoptosis in cardiomyocytes. This study was, therefore, designed to investigate whether IL-20 antibody could reduce I/R-induced myocardial dysfunction. Results from this study revealed that IL-20 antibody treatment significantly suppressed I/R-induced nicotinamide adenine dinucleotide phosphate oxidase, oxidative stress, apoptosis, proinflammatory responses, cardiac fibrosis, and expression of cardiac remodeling markers in Sprague-Dawley rats. Plasma B-type natriuretic peptide level was also reduced by IL-20 antibody injection. IL-20 antibody treatment appeared to restore cardiac function under the I/R injury in terms of greater values of ejection fraction and fractional shortening compared to the control group. Two commonly used indicators of cardiac injury, lactate dehydrogenase and creatine kinase-MB, were also lower in the IL-20 antibody injection group. Taken together, our results suggested that IL-20 antibody holds the potential to reduce the I/R-elicited cardiac dysfunction by preventing cardiac remodeling.

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LncRNA SNHG12 Improves Cerebral Ischemic-reperfusion Injury by Activating SIRT1/FOXO3a Pathway through I nhibition of Autophagy and Oxidative Stress

Current Neurovascular Research ◽

10.2174/1567202617666200727142019 ◽

2020 ◽

Vol 17 (4) ◽

pp. 394-401

Author(s):

Yuanhua Wu ◽

Yuan Huang ◽

Jing Cai ◽

Donglan Zhang ◽

Shixi Liu ◽

...

Keyword(s):

Oxidative Stress ◽

Molecular Mechanisms ◽

Ischemia Reperfusion ◽

Critical Role ◽

Cell Activity ◽

Ht22 Cells ◽

Cerebral Ischemic ◽

Cerebral Ischemic Reperfusion ◽

And Oxidative Stress

Background: Ischemia/reperfusion (I/R) injury involves complex biological processes and molecular mechanisms such as autophagy. Oxidative stress plays a critical role in the pathogenesis of I/R injury. LncRNAs are the regulatory factor of cerebral I/R injury. Methods: This study constructs cerebral I/R model to investigate role of autophagy and oxidative stress in cerebral I/R injury and the underline regulatory mechanism of SIRT1/ FOXO3a pathway. In this study, lncRNA SNHG12 and FOXO3a expression was up-regulated and SIRT1 expression was down-regulated in HT22 cells of I/R model. Results: Overexpression of lncRNA SNHG12 significantly increased the cell viability and inhibited cerebral ischemicreperfusion injury induced by I/Rthrough inhibition of autophagy. In addition, the transfected p-SIRT1 significantly suppressed the release of LDH and SOD compared with cells co-transfected with SIRT1 and FOXO3a group and cells induced by I/R and transfected with p-SNHG12 group and overexpression of cells co-transfected with SIRT1 and FOXO3 further decreased the I/R induced release of ROS and MDA. Conclusion: In conclusion, lncRNA SNHG12 increased cell activity and inhibited oxidative stress through inhibition of SIRT1/FOXO3a signaling-mediated autophagy in HT22 cells of I/R model. This study might provide new potential therapeutic targets for further investigating the mechanisms in cerebral I/R injury and provide.

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Protective Effect of Osmundacetone against Neurological Cell Death Caused by Oxidative Glutamate Toxicity

Biomolecules ◽

10.3390/biom11020328 ◽

2021 ◽

Vol 11 (2) ◽

pp. 328

Author(s):

Tuy An Trinh ◽

Young Hye Seo ◽

Sungyoul Choi ◽

Jun Lee ◽

Ki Sung Kang

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Defense Mechanism ◽

Neuroprotective Effect ◽

Glutamate Release ◽

Chromatin Condensation ◽

Critical Role ◽

Glutamate Toxicity ◽

Heme Oxygenase 1 ◽

Brain Functions

Oxidative stress is one of the main causes of brain cell death in neurological disorders. The use of natural antioxidants to maintain redox homeostasis contributes to alleviating neurodegeneration. Glutamate is an excitatory neurotransmitter that plays a critical role in many brain functions. However, excessive glutamate release induces excitotoxicity and oxidative stress, leading to programmed cell death. Our study aimed to evaluate the effect of osmundacetone (OAC), isolated from Elsholtzia ciliata (Thunb.) Hylander, against glutamate-induced oxidative toxicity in HT22 hippocampal cells. The effect of OAC treatment on excess reactive oxygen species (ROS), intracellular calcium levels, chromatin condensation, apoptosis, and the expression level of oxidative stress-related proteins was evaluated. OAC showed a neuroprotective effect against glutamate toxicity at a concentration of 2 μM. By diminishing the accumulation of ROS, as well as stimulating the expression of heat shock protein 70 (HSP70) and heme oxygenase-1 (HO-1), OAC triggered the self-defense mechanism in neuronal cells. The anti-apoptotic effect of OAC was demonstrated through its inhibition of chromatin condensation, calcium accumulation, and reduction of apoptotic cells. OAC significantly suppressed the phosphorylation of mitogen-activated protein kinases (MAPKs), including c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 kinases. Thus, OAC could be a potential agent for supportive treatment of neurodegenerative diseases.

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Heme induces programmed necrosis on macrophages through autocrine TNF and ROS production

Blood ◽

10.1182/blood-2011-08-375303 ◽

2012 ◽

Vol 119 (10) ◽

pp. 2368-2375 ◽

Cited By ~ 135

Author(s):

Guilherme B. Fortes ◽

Leticia S. Alves ◽

Rosane de Oliveira ◽

Fabianno F. Dutra ◽

Danielle Rodrigues ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Critical Role ◽

Membrane Integrity ◽

Iron Chelation ◽

Heme Oxygenase 1 ◽

Cytotoxic Effects ◽

Interacting Protein ◽

Free Heme ◽

Necrosis Factor

Abstract Diseases that cause hemolysis or myonecrosis lead to the leakage of large amounts of heme proteins. Free heme has proinflammatory and cytotoxic effects. Heme induces TLR4-dependent production of tumor necrosis factor (TNF), whereas heme cytotoxicity has been attributed to its ability to intercalate into cell membranes and cause oxidative stress. We show that heme caused early macrophage death characterized by the loss of plasma membrane integrity and morphologic features resembling necrosis. Heme-induced cell death required TNFR1 and TLR4/MyD88-dependent TNF production. Addition of TNF to Tlr4−/− or to Myd88−/− macrophages restored heme-induced cell death. The use of necrostatin-1, a selective inhibitor of receptor-interacting protein 1 (RIP1, also known as RIPK1), or cells deficient in Rip1 or Rip3 revealed a critical role for RIP proteins in heme-induced cell death. Serum, antioxidants, iron chelation, or inhibition of c-Jun N-terminal kinase (JNK) ameliorated heme-induced oxidative burst and blocked macrophage cell death. Macrophages from heme oxygenase-1 deficient mice (Hmox1−/−) had increased oxidative stress and were more sensitive to heme. Taken together, these results revealed that heme induces macrophage necrosis through 2 synergistic mechanisms: TLR4/Myd88-dependent expression of TNF and TLR4-independent generation of ROS.

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Assessment of the Impact of Post-Thaw Stress Pathway Modulation on Cell Recovery following Cryopreservation in a Hematopoietic Progenitor Cell Model

Cells ◽

10.3390/cells11020278 ◽

2022 ◽

Vol 11 (2) ◽

pp. 278

Author(s):

John M. Baust ◽

Kristi K. Snyder ◽

Robert G. Van Buskirk ◽

John G. Baust

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Cell Survival ◽

Critical Role ◽

Hematopoietic Progenitor Cell ◽

Scale Production ◽

Cell Recovery ◽

Hematopoietic Progenitor ◽

Discovery Science ◽

The Impact

The development and use of complex cell-based products in clinical and discovery science continues to grow at an unprecedented pace. To this end, cryopreservation plays a critical role, serving as an enabling process, providing on-demand access to biological material, facilitating large scale production, storage, and distribution of living materials. Despite serving a critical role and substantial improvements over the last several decades, cryopreservation often remains a bottleneck impacting numerous areas including cell therapy, tissue engineering, and tissue banking. Studies have illustrated the impact and benefit of controlling cryopreservation-induced delayed-onset cell death (CIDOCD) through various “front end” strategies, such as specialized media, new cryoprotective agents, and molecular control during cryopreservation. While proving highly successful, a substantial level of cell death and loss of cell function remains associated with cryopreservation. Recently, we focused on developing technologies (RevitalICE™) designed to reduce the impact of CIDOCD through buffering the cell stress response during the post-thaw recovery phase in an effort to improve the recovery of previously cryopreserved samples. In this study, we investigated the impact of modulating apoptotic caspase activation, oxidative stress, unfolded protein response, and free radical damage in the initial 24 h post-thaw on overall cell survival. Human hematopoietic progenitor cells in vitro cryopreserved in both traditional extracellular-type and intracellular-type cryopreservation freeze media were utilized as a model cell system to assess impact on survival. Our findings demonstrated that through the modulation of several of these pathways, improvements in cell recovery were obtained, regardless of the freeze media and dimethyl sulfoxide concentration utilized. Specifically, through the use of oxidative stress inhibitors, an average increase of 20% in overall viability was observed. Furthermore, the results demonstrated that by using the post-thaw recovery reagent on samples cryopreserved in intracellular-type media (Unisol™), improvements in overall cell survival approaching 80% of non-frozen controls were attained. While improvements in overall survival were obtained, an assessment on the impact of specific cell subpopulations and functionality remains to be completed. While work remains, these results represent an important step forward in the development of improved cryopreservation processes for use in discovery science, and commercial and clinical settings.

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Necroptotic Cell Death Signaling and Execution Pathway: Lessons from Knockout Mice

Mediators of Inflammation ◽

10.1155/2015/128076 ◽

2015 ◽

Vol 2015 ◽

pp. 1-15 ◽

Cited By ~ 38

Author(s):

José Belizário ◽

Luiz Vieira-Cordeiro ◽

Sylvia Enns

Keyword(s):

Cell Death ◽

Knockout Mice ◽

Critical Role ◽

Stress Conditions ◽

Dna Integrity ◽

Caspase 8 ◽

Necrotic Cell Death ◽

Necrotic Cell ◽

Injury Death ◽

Regulated Necrosis

Under stress conditions, cells in living tissue die by apoptosis or necrosis depending on the activation of the key molecules within a dying cell that either transduce cell survival or death signals that actively destroy the sentenced cell. Multiple extracellular (pH, heat, oxidants, and detergents) or intracellular (DNA damage and Ca2+overload) stress conditions trigger various types of the nuclear, endoplasmic reticulum (ER), cytoplasmatic, and mitochondrion-centered signaling events that allow cells to preserve the DNA integrity, protein folding, energetic, ionic and redox homeostasis, thus escaping from injury. Along the transition from reversible to irreversible injury, death signaling is highly heterogeneous and damaged cells may engage autophagy, apoptotic, or necrotic cell death programs. Studies on multiple double- and triple- knockout mice identifiedcaspase-8,flip, andfaddgenes as key regulators of embryonic lethality and inflammation. Caspase-8 has a critical role in pro- and antinecrotic signaling pathways leading to the activation of receptor interacting protein kinase 1 (RIPK1), RIPK3, and the mixed kinase domain-like (MLKL) for a convergent execution pathway of necroptosis or regulated necrosis. Here we outline the recent discoveries into how the necrotic cell death execution pathway is engaged in many physiological and pathological outcome based on genetic analysis of knockout mice.

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Activation of BNIP3-mediated mitophagy protects against renal ischemia–reperfusion injury

Cell Death and Disease ◽

10.1038/s41419-019-1899-0 ◽

2019 ◽

Vol 10 (9) ◽

Cited By ~ 22

Author(s):

Chengyuan Tang ◽

Hailong Han ◽

Zhiwen Liu ◽

Yuxue Liu ◽

Lijun Yin ◽

...

Keyword(s):

Cell Death ◽

Ischemia Reperfusion Injury ◽

Tissue Injury ◽

Ischemia Reperfusion ◽

Critical Role ◽

Glucose Deprivation ◽

Renal Ischemia ◽

Renal Tubules ◽

Renal Tubular Cells

Abstract Acute kidney injury (AKI) is a syndrome of abrupt loss of renal functions. The underlying pathological mechanisms of AKI remain largely unknown. BCL2-interacting protein 3 (BNIP3) has dual functions of regulating cell death and mitophagy, but its pathophysiological role in AKI remains unclear. Here, we demonstrated an increase of BNIP3 expression in cultured renal proximal tubular epithelial cells following oxygen-glucose deprivation-reperfusion (OGD-R) and in renal tubules after renal ischemia–reperfusion (IR)-induced injury in mice. Functionally, silencing Bnip3 by specific short hairpin RNAs in cultured renal tubular cells reduced OGD-R-induced mitophagy, and potentiated OGD-R-induced cell death. In vivo, Bnip3 knockout worsened renal IR injury, as manifested by more severe renal dysfunction and tissue injury. We further showed that Bnip3 knockout reduced mitophagy, which resulted in the accumulation of damaged mitochondria, increased production of reactive oxygen species, and enhanced cell death and inflammatory response in kidneys following renal IR. Taken together, these findings suggest that BNIP3-mediated mitophagy has a critical role in mitochondrial quality control and tubular cell survival during AKI.

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Effect of alpha-ketoglutarate and N-acetyl cysteine on cyanide-induced oxidative stress mediated cell death in PC12 cells

Toxicology and Industrial Health ◽

10.1177/0748233710365695 ◽

2010 ◽

Vol 26 (5) ◽

pp. 297-308 ◽

Cited By ~ 13

Author(s):

RM Satpute ◽

J. Hariharakrishnan ◽

R. Bhattacharya

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Pc12 Cells ◽

Caspase 3 ◽

Critical Role ◽

Total Antioxidant Status ◽

Protective Effects ◽

Simultaneous Treatment ◽

Acetyl Cysteine

Cyanide is a mitochondrial poison, which is ubiquitously present in the environment. Cyanide-induced oxidative stress is known to play a key role in mediating the neurotoxicity and cell death in rat pheochromocytoma (PC12) cells. PC12 cells are widely used as a model for neurotoxicity assays in vitro. In the present study, we investigated the protective effects of alpha-ketoglutarate (A-KG), a potential cyanide antidote, and N-acetyl cysteine (NAC), an antioxidant against toxicity of cyanide in PC12 cells. Cells were treated with various concentrations (0.625—1.25 mM) of potassium cyanide (KCN) for 4 hours, in the presence or absence of simultaneous treatment of A-KG (0.5 mM) and NAC (0.25 mM). Cyanide caused marked decrease in the levels of cellular antioxidants like superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR). Lipid peroxidation indicated by elevated levels of malondialdehyde (MDA) was found to be accompanied by decreased levels of reduced glutathione (GSH) and total antioxidant status (TAS) of the cells. Cyanide-treated cells showed notable increase in caspase-3 activity and induction of apoptotic type of cell death after 24 hours. A-KG and NAC alone were very effective in restoring the levels of GSH and TAS, but together they significantly resolved the effects of cyanide on antioxidant enzymes, MDA levels, and caspase-3 activity. The present study reveals that combination of A-KG and NAC has critical role in abbrogating the oxidative stress-mediated toxicity of cyanide in PC12 cells. The results suggest potential role of A-KG and NAC in cyanide antagonism.

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