Citrate reduced oxidative damage in stem cells by regulating cellular redox signaling pathways and represent a potential treatment for oxidative stress-induced diseases

Abstract Background Bone marrow mesenchymal stem cells (BMSCs) have been used as important cell-based tools for clinical applications. Oxidative stress-induced apoptosis causes a low survival rate after transplantation, and the underlying mechanisms remain unknown. The endoplasmic reticulum (ER) and mitochondria are vital organelles regulated by adenosine monophosphate (AMP)-activated protein kinase (AMPK), especially during oxidative stress injury. Melatonin exerts an antioxidant effect by scavenging free radicals. Here, we aimed to explore whether cytoprotective melatonin relieves ER stress-mediated mitochondrial dysfunction through AMPK in BMSCs after oxidative stress injury. Methods Mouse BMSCs were isolated and exposed to H2O2 in the absence or presence of melatonin. Thereafter, cell damage, oxidative stress levels, mitochondrial function, AMPK activity, ER stress-related proteins, and apoptotic markers were measured. Additionally, the involvement of AMPK and ER stress in the melatonin-mediated protection of BMSCs against H2O2-induced injury was investigated using pharmacologic agonists and inhibitors. Results Melatonin improved cell survival and restored mitochondrial function. Moreover, melatonin intimately regulated the phosphorylation of AMPK and molecules associated with ER stress pathways. AMPK activation and ER stress inhibition following melatonin administration improved the mitochondrial membrane potential (MMP), reduced mitochondria-initiated oxidative damage, and ultimately suppressed apoptotic signaling pathways in BMSCs. Cotreatment with N-acetyl-l-cysteine (NAC) significantly enhanced the antioxidant effect of melatonin. Importantly, pharmacological AMPK activation/ER stress inhibition promoted melatonin-induced cytoprotection, while pharmacological AMPK inactivation/ER stress induction conferred resistance to the effect of melatonin against H2O2 insult. Conclusions Our data also reveal a new, potentially therapeutic mechanism by which melatonin protects BMSCs from oxidative stress-mediated mitochondrial apoptosis, possibly by regulating the AMPK-ER stress pathway.

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Oxidative stress, redox signaling pathways, and autophagy in cachectic muscles of male patients with advanced COPD and lung cancer

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2014.11.006 ◽

2015 ◽

Vol 79 ◽

pp. 91-108 ◽

Cited By ~ 74

Author(s):

Ester Puig-Vilanova ◽

Diego A. Rodriguez ◽

Josep Lloreta ◽

Pilar Ausin ◽

Sergio Pascual-Guardia ◽

...

Keyword(s):

Oxidative Stress ◽

Lung Cancer ◽

Signaling Pathways ◽

Redox Signaling ◽

Male Patients

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Mitochondrial Redox Signaling and Oxidative Stress in Kidney Diseases

Biomolecules ◽

10.3390/biom11081144 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1144

Author(s):

Ana Karina Aranda-Rivera ◽

Alfredo Cruz-Gregorio ◽

Omar Emiliano Aparicio-Trejo ◽

José Pedraza-Chaverri

Keyword(s):

Oxidative Stress ◽

Signaling Pathways ◽

Kidney Diseases ◽

Redox Signaling ◽

Mitochondrial Metabolism ◽

Post Translational Modifications ◽

Secondary Messengers ◽

And Oxidative Stress ◽

Cell Signaling Pathways

Mitochondria are essential organelles in physiology and kidney diseases, because they produce cellular energy required to perform their function. During mitochondrial metabolism, reactive oxygen species (ROS) are produced. ROS function as secondary messengers, inducing redox-sensitive post-translational modifications (PTM) in proteins and activating or deactivating different cell signaling pathways. However, in kidney diseases, ROS overproduction causes oxidative stress (OS), inducing mitochondrial dysfunction and altering its metabolism and dynamics. The latter processes are closely related to changes in the cell redox-sensitive signaling pathways, causing inflammation and apoptosis cell death. Although mitochondrial metabolism, ROS production, and OS have been studied in kidney diseases, the role of redox signaling pathways in mitochondria has not been addressed. This review focuses on altering the metabolism and dynamics of mitochondria through the dysregulation of redox-sensitive signaling pathways in kidney diseases.

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Melphalan induces cardiotoxicity through oxidative stress in cardiomyocytes derived from human induced pluripotent stem cells

Stem Cell Research & Therapy ◽

10.1186/s13287-020-01984-1 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Rui Liu ◽

Dong Li ◽

Fangxu Sun ◽

Antonio Rampoldi ◽

Joshua T. Maxwell ◽

...

Keyword(s):

Oxidative Stress ◽

Stem Cells ◽

Induced Pluripotent Stem Cells ◽

Signaling Pathways ◽

Pluripotent Stem Cells ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Late Onset ◽

Cardiac Cells ◽

Induced Pluripotent

Abstract Background Treatment-induced cardiotoxicity is a leading noncancer-related cause of acute and late onset morbidity and mortality in cancer patients on antineoplastic drugs such as melphalan—increasing clinical case reports have documented that it could induce cardiotoxicity including severe arrhythmias and heart failure. As the mechanism by which melphalan impairs cardiac cells remains poorly understood, here, we aimed to use cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) to investigate the cellular and molecular mechanisms of melphalan-induced cardiotoxicity. Methods hiPSC-CMs were generated and treated with clinically relevant doses of melphalan. To characterize melphalan-induced cardiotoxicity, cell viability and apoptosis were quantified at various treatment durations. Ca2+ transient and contractility analyses were used to examine the alterations of hiPSC-CM function. Proteomic analysis, reactive oxygen species detection, and RNA-Sequencing were conducted to investigate underlying mechanisms. Results Melphalan treatment of hiPSC-CMs induced oxidative stress, caused Ca2+ handling defects and dysfunctional contractility, altered global transcriptomic and proteomic profiles, and resulted in apoptosis and cell death. The antioxidant N-acetyl-l-cysteine attenuated these genomic, cellular, and functional alterations. In addition, several other signaling pathways including the p53 and transforming growth factor-β signaling pathways were also implicated in melphalan-induced cardiotoxicity according to the proteomic and transcriptomic analyses. Conclusions Melphalan induces cardiotoxicity through the oxidative stress pathway. This study provides a unique resource of the global transcriptomic and proteomic datasets for melphalan-induced cardiotoxicity and can potentially open up new clinical mechanism-based targets to prevent and treat melphalan-induced cardiotoxicity.

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Exosomes Derived from miR-214-Enriched Bone Marrow-Derived Mesenchymal Stem Cells Regulate Oxidative Damage in Cardiac Stem Cells by Targeting CaMKII

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/4971261 ◽

2018 ◽

Vol 2018 ◽

pp. 1-21 ◽

Cited By ~ 22

Author(s):

Yan Wang ◽

Ranzun Zhao ◽

Debin Liu ◽

Wenwen Deng ◽

Guanxue Xu ◽

...

Keyword(s):

Oxidative Stress ◽

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Oxidative Damage ◽

Bioactive Molecules ◽

Cardiac Stem Cells ◽

Stress Injury ◽

Hypoxic Conditions ◽

Oxidative Stress Injury

Cardiac stem cells (CSCs) have emerged as one of the most promising stem cells for cardiac protection. Recently, exosomes from bone marrow-derived mesenchymal stem cells (BMSCs) have been found to facilitate cell proliferation and survival by transporting various bioactive molecules, including microRNAs (miRs). In this study, we found that BMSC-derived exosomes (BMSC-exos) significantly decreased apoptosis rates and reactive oxygen species (ROS) production in CSCs after oxidative stress injury. Moreover, a stronger effect was induced by exosomes collected from BMSCs cultured under hypoxic conditions (Hypoxic-exos) than those collected from BMSCs cultured under normal conditions (Nor-exos). We also observed greater miR-214 enrichment in Hypoxic-exos than in Nor-exos. In addition, a miR-214 inhibitor or mimics added to modulate miR-214 levels in BMSC-exos revealed that exosomes from miR-214-depleted BMSCs partially reversed the effects of hypoxia-induced exosomes on oxidative damage in CSCs. These data further confirmed that miR-214 is the main effector molecule in BMSC-exos that protects CSCs from oxidative damage. miR-214 mimic and inhibitor transfection assays verified that CaMKII is a target gene of miR-214 in CSCs, with exosome-pretreated CSCs exhibiting increased miR-214 levels but decreased CaMKII levels. Therefore, the miR-214/CaMKII axis regulates oxidative stress-related injury in CSCs, such as apoptosis, calcium homeostasis disequilibrium, and excessive ROS accumulation. Collectively, these findings suggest that BMSCs release miR-214-containing exosomes to suppress oxidative stress injury in CSCs through CaMKII silencing.

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The Role of Ubiquitination and Sumoylation in Diabetic Nephropathy

BioMed Research International ◽

10.1155/2014/160692 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 30

Author(s):

Chenlin Gao ◽

Wei Huang ◽

Keizo Kanasaki ◽

Yong Xu

Keyword(s):

Oxidative Stress ◽

Diabetic Nephropathy ◽

Signaling Pathways ◽

Renal Injury ◽

Treatment Strategy ◽

Microvascular Complication ◽

Epigenetic Mechanism ◽

Potential Treatment ◽

Ubiquitin Proteasome

Diabetic nephropathy (DN) is a common and characteristic microvascular complication of diabetes; the mechanisms that cause DN have not been clarified, and the epigenetic mechanism was promised in the pathology of DN. Furthermore, ubiquitination and small ubiquitin-like modifier (SUMO) were involved in the progression of DN. MG132, as a ubiquitin proteasome, could improve renal injury by regulating several signaling pathways, such as NF-κB, TGF-β, Nrf2-oxidative stress, and MAPK. In this review, we summarize how ubiquitination and sumoylation may contribute to the pathology of DN, which may be a potential treatment strategy of DN.

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Melphalan induces cardiotoxicity through oxidative stress in cardiomyocytes derived from human induced pluripotent stem cells

10.21203/rs.3.rs-45895/v2 ◽

2020 ◽

Author(s):

Rui Liu ◽

Dong Li ◽

Fangxu Sun ◽

Antonio Rampoldi ◽

Joshua Maxwell ◽

...

Keyword(s):

Oxidative Stress ◽

Stem Cells ◽

Induced Pluripotent Stem Cells ◽

Signaling Pathways ◽

Pluripotent Stem Cells ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Late Onset ◽

Cardiac Cells ◽

Induced Pluripotent

Abstract Background. Treatment-induced cardiotoxicity is a leading noncancer-related cause of acute and late onset morbidity and mortality in cancer patients on antineoplastic drugs such as melphalan—increasing clinical case reports have documented that it could induce cardiotoxicity including severe arrhythmias and heart failure. As the mechanism by which melphalan impairs cardiac cells remains poorly understood, here we aimed to use cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) to investigate the cellular and molecular mechanisms of melphalan-induced cardiotoxicity and to explore potential targeted therapeutics.Methods. hiPSC-CMs were generated and treated with clinically relevant doses of melphalan. In order to characterize melphalan-induced cardiotoxicity, cell viability and apoptosis were quantified at various treatment durations. Ca2+ transient and contractility analyses were used to examine the alterations of hiPSC-CM function. Proteomic analysis, reactive oxygen species detection, and RNA-Sequencing were conducted to investigate underlying mechanisms. Results. Melphalan treatment of hiPSC-CMs induced oxidative stress, caused Ca2+-handling defects and dysfunctional contractility, altered global transcriptomic and proteomic profiles, and resulted in apoptosis and cell death. The antioxidant N-acetyl-L-cysteine attenuated these genomic, cellular and functional alterations. In addition, several other signaling pathways including the p53 and transforming growth factor-β signaling pathways were also implicated in melphalan-induced cardiotoxicity according to the proteomic and transcriptomic analyses.Conclusions. Melphalan induces cardiotoxicity through the oxidative stress pathway. This study provides a unique resource of the global transcriptomic and proteomic datasets for melphalan-induced cardiotoxicity and can potentially open up new clinical mechanism-based targets to prevent and treat melphalan-induced cardiotoxicity.

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