scholarly journals Uncovering molecular mechanisms of regulated cell death in the naked mole rat

Aging ◽  
2021 ◽  
Author(s):  
Alexei Evdokimov ◽  
Alexei Popov ◽  
Elena Ryabchikova ◽  
Olga Koval ◽  
Svetlana Romanenko ◽  
...  
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Regulated Cell Death ◽  
Mole Rat ◽  
Naked Mole Rat

scholarly journals Naked mole rat cells display more efficient DNA excision repair and higher resistance to toxic impacts than mouse cells

2020 ◽  
Vol 22 ◽  
pp. 01017
Author(s):  
Alexey Evdokimov ◽  
Irina Petruseva ◽  
Aleksei Popov ◽  
Olga Koval ◽  
Olga Lavrik
Keyword(s):  
Cell Death ◽  
Mus Musculus ◽  
Excision Repair ◽  
Genotoxic Stress ◽  
Cancer Resistance ◽  
Dna Excision Repair ◽  
Cell Defense ◽  
Regulated Cell Death ◽  
Mole Rat ◽  
Naked Mole Rat

Naked mole rat is the long-lived and tumor-resistant rodent. Naked mole rat possesses multiple adaptations that may contribute to longevity and cancer-resistance. Higher activity of DNA excision repair systems and their faster recovery after genotoxic impact as compare with Mus musculus directly demonstrated in our previous investigation contribute to longevity and cancer resistance of naked mole rat. In the present study the DNA-damage-induced apoptosis in naked mole rat fibroblasts was studied using conventional methods. The ability of naked mole rat cells to undergo regulated cell death in response to genotoxic stress is another group of cell defense mechanisms. Naked mole rat skin fibroblasts were demonstrated to be much more resistant towards proapoptotic reagents methyl methanesulfonate, 5-fluorouracil and etoposide as compared with fibroblasts of Mus musculus. Naked mole rat cells have demonstrated limited apoptotic response and seem to undergo also other-type regulated cell death under severe genotoxic stress.

scholarly journals The Evolving Role of Ferroptosis in Breast Cancer: Translational Implications Present and Future

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4576
Author(s):  
Hung-Yu Lin ◽  
Hui-Wen Ho ◽  
Yen-Hsiang Chang ◽  
Chun-Jui Wei ◽  
Pei-Yi Chu
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Drug Resistant ◽  
Therapeutic Targeting ◽  
The Past ◽  
Regulated Cell Death ◽  
Common Malignancy

Breast cancer (BC) is the most common malignancy among women worldwide. The discovery of regulated cell death processes has enabled advances in the treatment of BC. In the past decade, ferroptosis, a new form of iron-dependent regulated cell death caused by excessive lipid peroxidation has been implicated in the development and therapeutic responses of BC. Intriguingly, the induction of ferroptosis acts to suppress conventional therapy-resistant cells, and to potentiate the effects of immunotherapy. As such, pharmacological or genetic modulation targeting ferroptosis holds great potential for the treatment of drug-resistant cancers. In this review, we present a critical analysis of the current understanding of the molecular mechanisms and regulatory networks involved in ferroptosis, the potential physiological functions of ferroptosis in tumor suppression, its potential in therapeutic targeting, and explore recent advances in the development of therapeutic strategies for BC.

scholarly journals Comprehensive Map of the Regulated Cell Death Signaling Network: A Powerful Analytical Tool for Studying Diseases

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 990
Author(s):  
Jean-Marie Ravel ◽  
L. Cristobal Monraz Gomez ◽  
Nicolas Sompairac ◽  
Laurence Calzone ◽  
Boris Zhivotovsky ◽  
...  
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Signaling Network ◽  
Tumor Subtypes ◽  
Navigation Data ◽  
Manual Curation ◽  
Regulated Cell Death ◽  
Powerful Analytical Tool ◽  
Cell Death Signaling ◽  
The Difference

The processes leading to, or avoiding cell death are widely studied, because of their frequent perturbation in various diseases. Cell death occurs in three highly interconnected steps: Initiation, signaling and execution. We used a systems biology approach to gather information about all known modes of regulated cell death (RCD). Based on the experimental data retrieved from literature by manual curation, we graphically depicted the biological processes involved in RCD in the form of a seamless comprehensive signaling network map. The molecular mechanisms of each RCD mode are represented in detail. The RCD network map is divided into 26 functional modules that can be visualized contextually in the whole seamless network, as well as in individual diagrams. The resource is freely available and accessible via several web platforms for map navigation, data integration, and analysis. The RCD network map was employed for interpreting the functional differences in cell death regulation between Alzheimer’s disease and non-small cell lung cancer based on gene expression data that allowed emphasizing the molecular mechanisms underlying the inverse comorbidity between the two pathologies. In addition, the map was used for the analysis of genomic and transcriptomic data from ovarian cancer patients that provided RCD map-based signatures of four distinct tumor subtypes and highlighted the difference in regulations of cell death molecular mechanisms.

scholarly journals Molecular Mechanisms of Ferroptosis and Its Roles in Hematologic Malignancies

2021 ◽  
Vol 11 ◽  
Author(s):  
Yan Zhao ◽  
Zineng Huang ◽  
Hongling Peng
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Hematological Malignancies ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Lipid Peroxide ◽  
Kidney Injury ◽  
Hematologic Malignancies ◽  
Regulated Cell Death ◽  
Normal Metabolism

Cell death is essential for the normal metabolism of human organisms. Ferroptosis is a unique regulated cell death (RCD) mode characterized by excess accumulation of iron-dependent lipid peroxide and reactive oxygen species (ROS) compared with other well-known programmed cell death modes. It has been currently recognized that ferroptosis plays a rather important role in the occurrence, development, and treatment of traumatic brain injury, stroke, acute kidney injury, liver damage, ischemia–reperfusion injury, tumor, etc. Of note, ferroptosis may be explained by the expression of various molecules and signaling components, among which iron, lipid, and amino acid metabolism are the key regulatory mechanisms of ferroptosis. Meanwhile, tumor cells of hematological malignancies, such as leukemia, lymphoma, and multiple myeloma (MM), are identified to be sensitive to ferroptosis. Targeting potential regulatory factors in the ferroptosis pathway may promote or inhibit the disease progression of these malignancies. In this review, a systematic summary was conducted on the key molecular mechanisms of ferroptosis and the current potential relationships of ferroptosis with leukemia, lymphoma, and MM. It is expected to provide novel potential therapeutic approaches and targets for hematological malignancies.

scholarly journals Yeast Cells Exposed to Exogenous Palmitoleic Acid Either Adapt to Stress and Survive or Commit to Regulated Liponecrosis and Die

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Karamat Mohammad ◽  
Paméla Dakik ◽  
Younes Medkour ◽  
Mélissa McAuley ◽  
Darya Mitrofanova ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Lipid Metabolism ◽  
Lipid Droplets ◽  
Palmitoleic Acid ◽  
Molecular Mechanisms ◽  
Neutral Lipids ◽  
Yeast Cells ◽  
Cellular Processes ◽  
Regulated Cell Death

A disturbed homeostasis of cellular lipids and the resulting lipotoxicity are considered to be key contributors to many human pathologies, including obesity, metabolic syndrome, type 2 diabetes, cardiovascular diseases, and cancer. The yeast Saccharomyces cerevisiae has been successfully used for uncovering molecular mechanisms through which impaired lipid metabolism causes lipotoxicity and elicits different forms of regulated cell death. Here, we discuss mechanisms of the “liponecrotic” mode of regulated cell death in S. cerevisiae. This mode of regulated cell death can be initiated in response to a brief treatment of yeast with exogenous palmitoleic acid. Such treatment prompts the incorporation of exogenously added palmitoleic acid into phospholipids and neutral lipids. This orchestrates a global remodeling of lipid metabolism and transfer in the endoplasmic reticulum, mitochondria, lipid droplets, and the plasma membrane. Certain features of such remodeling play essential roles either in committing yeast to liponecrosis or in executing this mode of regulated cell death. We also outline four processes through which yeast cells actively resist liponecrosis by adapting to the cellular stress imposed by palmitoleic acid and maintaining viability. These prosurvival cellular processes are confined in the endoplasmic reticulum, lipid droplets, peroxisomes, autophagosomes, vacuoles, and the cytosol.

Rapid molecular evolution of pain insensitivity in multiple African rodents

Science ◽  
2019 ◽  
Vol 364 (6443) ◽  
pp. 852-859 ◽  
Author(s):  
Ole Eigenbrod ◽  
Karlien Y. Debus ◽  
Jane Reznick ◽  
Nigel C. Bennett ◽  
Oscar Sánchez-Carranza ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Allyl Isothiocyanate ◽  
Transient Receptor Potential Channel ◽  
Leak Channel ◽  
Voltage Gated ◽  
Mole Rat ◽  
Naked Mole Rat ◽  
Transient Receptor

Noxious substances, called algogens, cause pain and are used as defensive weapons by plants and stinging insects. We identified four previously unknown instances of algogen-insensitivity by screening eight African rodent species related to the naked mole-rat with the painful substances capsaicin, acid (hydrogen chloride, pH 3.5), and allyl isothiocyanate (AITC). Using RNA sequencing, we traced the emergence of sequence variants in transduction channels, like transient receptor potential channel TRPA1 and voltage-gated sodium channel Nav1.7, that accompany algogen insensitivity. In addition, the AITC-insensitive highveld mole-rat exhibited overexpression of the leak channel NALCN (sodium leak channel, nonselective), ablating AITC detection by nociceptors. These molecular changes likely rendered highveld mole-rats immune to the stings of the Natal droptail ant. Our study reveals how evolution can be used as a discovery tool to find molecular mechanisms that shut down pain.

scholarly journals The Molecular Mechanisms of Iron Metabolism and Its Role in Cardiac Dysfunction and Cardioprotection

2020 ◽  
Vol 21 (21) ◽  
pp. 7889 ◽  
Author(s):  
Tanya Ravingerová ◽  
Lucia Kindernay ◽  
Monika Barteková ◽  
Miroslav Ferko ◽  
Adriana Adameová ◽  
...  
Keyword(s):  
Cell Death ◽  
Iron Metabolism ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Physiological Role ◽  
Cellular Respiration ◽  
Protective Mechanisms ◽  
Alcoholic Fatty Liver ◽  
Regulated Cell Death ◽  
Wide Range

Iron is an essential mineral participating in different functions of the organism under physiological conditions. Numerous biological processes, such as oxygen and lipid metabolism, protein production, cellular respiration, and DNA synthesis, require the presence of iron, and mitochondria play an important role in the processes of iron metabolism. In addition to its physiological role, iron may be also involved in the adaptive processes of myocardial “conditioning”. On the other hand, disorders of iron metabolism are involved in the pathological mechanisms of the most common human diseases and include a wide range of them, such as type 2 diabetes, obesity, and non-alcoholic fatty liver disease, and accelerate the development of atherosclerosis. Furthermore, iron also exerts potentially deleterious effects that may be manifested under conditions of ischemia/reperfusion (I/R) injury, myocardial infarction, heart failure, coronary artery angioplasty, or heart transplantation, due to its involvement in reactive oxygen species (ROS) production. Moreover, iron has been recently described to participate in the mechanisms of iron-dependent cell death defined as “ferroptosis”. Ferroptosis is a form of regulated cell death that is distinct from apoptosis, necroptosis, and other types of cell death. Ferroptosis has been shown to be associated with I/R injury and several other cardiac diseases as a significant form of cell death in cardiomyocytes. In this review, we will discuss the role of iron in cardiovascular diseases, especially in myocardial I/R injury, and protective mechanisms stimulated by different forms of “conditioning” with a special emphasis on the novel targets for cardioprotection.

scholarly journals Targeting Ferroptosis for Lung Diseases: Exploring Novel Strategies in Ferroptosis-Associated Mechanisms

2021 ◽  
Vol 2021 ◽  
pp. 1-21
Author(s):  
Tian-Liang Ma ◽  
Yong Zhou ◽  
Ci Wang ◽  
Lu Wang ◽  
Jing-Xian Chen ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Membrane ◽  
Lung Diseases ◽  
Molecular Mechanisms ◽  
Membrane Rupture ◽  
Promising Strategy ◽  
Regulated Cell Death ◽  
Regulated Necrosis ◽  
Organelle Membrane ◽  
Long Chain

Ferroptosis is an iron-dependent regulated necrosis characterized by the peroxidation damage of lipid molecular containing unsaturated fatty acid long chain on the cell membrane or organelle membrane after cellular deactivation restitution system, resulting in the cell membrane rupture. Ferroptosis is biochemically and morphologically distinct and disparate from other forms of regulated cell death. Recently, mounting studies have investigated the mechanism of ferroptosis, and numerous proteins play vital roles in regulating ferroptosis. With detailed studies, emerging evidence indicates that ferroptosis is found in multiple lung diseases, demonstrating that ferroptosis appears to be particularly important for lung diseases. The mounting interest in ferroptosis drugs specifically targeting the ferroptosis mechanism holds substantial therapeutic promise in lung diseases. The present review emphatically summarizes the functions and integrated molecular mechanisms of ferroptosis in various lung diseases, proposing that multiangle regulation of ferroptosis might be a promising strategy for the clinical treatment of lung diseases.

scholarly journals Naked mole-rat brain neurons are resistant to acid-induced cell death

2018 ◽  
Author(s):  
Zoé Husson ◽  
Ewan St John Smith
Keyword(s):  
Central Nervous System ◽  
Cell Death ◽  
Nervous System ◽  
Ion Channels ◽  
Hippocampal Neurons ◽  
Contributing Factors ◽  
Voltage Gated ◽  
Mole Rat ◽  
Naked Mole Rat ◽  
Brain Ph

AbstractRegulation of brain pH is a critical homeostatic process and changes in brain pH modulate various ion channels and receptors and thus neuronal excitability. Tissue acidosis, resulting from hypoxia or hypercapnia, can activate various proteins and ion channels, among which acid-sensing ion channels (ASICs) a family of primarily Na+permeable ion channels, which alongside classical excitotoxicity causes neuronal death. Naked mole-rats (NMRs,Heterocephalus glaber) are long-lived, fossorial, eusocial rodents that display remarkable behavioral/cellular hypoxia and hypercapnia resistance. In the central nervous system, ASIC subunit expression is similar between mouse and NMR with the exception of much lower expression of ASIC4 throughout the NMR brain. However, ASIC function and neuronal sensitivity to sustained acidosis has not been examined in the NMR brain. Here, we show with whole-cell patch-clamp electrophysiology of cultured NMR and mouse cortical and hippocampal neurons that NMR neurons have smaller voltage-gated Na+channel currents and more hyperpolarized resting membrane potentials. We further demonstrate that acid-mediated currents in NMR neurons are of smaller magnitude than in mouse, and that all currents in both species are fully blocked by the ASIC antagonist benzamil. We further demonstrate that NMR neurons show greater resistance to acid-induced cell death than mouse neurons. In summary, NMR neurons show significant cellular resistance to acidotoxicity compared to mouse neurons, contributing factors likely to be smaller ASIC-mediated currents and reduced NaV activity.AbbreviationsASIC, acid-sensing ion channel; CNS, central nervous system; DRG, dorsal root ganglion; NaV, voltage-gated Na+channel; NMR, naked mole-rat; TTX, tetrodotoxin

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