scholarly journals Cell signalling by reactive lipid species: new concepts and molecular mechanisms

2012 ◽  
Vol 442 (3) ◽  
pp. 453-464 ◽  
Author(s):  
Ashlee Higdon ◽  
Anne R. Diers ◽  
Joo Yeun Oh ◽  
Aimee Landar ◽  
Victor M. Darley-Usmar
Keyword(s):  
Cell Death ◽  
Redox Regulation ◽  
Molecular Mechanisms ◽  
Chemical Reactivity ◽  
Cell Signalling ◽  
Significant Proportion ◽  
Covalent Modification ◽  
Lipid Species ◽  
Electrophilic Stress ◽  
Cellular Antioxidants

The process of lipid peroxidation is widespread in biology and is mediated through both enzymatic and non-enzymatic pathways. A significant proportion of the oxidized lipid products are electrophilic in nature, the RLS (reactive lipid species), and react with cellular nucleophiles such as the amino acids cysteine, lysine and histidine. Cell signalling by electrophiles appears to be limited to the modification of cysteine residues in proteins, whereas non-specific toxic effects involve modification of other nucleophiles. RLS have been found to participate in several physiological pathways including resolution of inflammation, cell death and induction of cellular antioxidants through the modification of specific signalling proteins. The covalent modification of proteins endows some unique features to this signalling mechanism which we have termed the ‘covalent advantage’. For example, covalent modification of signalling proteins allows for the accumulation of a signal over time. The activation of cell signalling pathways by electrophiles is hierarchical and depends on a complex interaction of factors such as the intrinsic chemical reactivity of the electrophile, the intracellular domain to which it is exposed and steric factors. This introduces the concept of electrophilic signalling domains in which the production of the lipid electrophile is in close proximity to the thiol-containing signalling protein. In addition, we propose that the role of glutathione and associated enzymes is to insulate the signalling domain from uncontrolled electrophilic stress. The persistence of the signal is in turn regulated by the proteasomal pathway which may itself be subject to redox regulation by RLS. Cell death mediated by RLS is associated with bioenergetic dysfunction, and the damaged proteins are probably removed by the lysosome-autophagy pathway.

scholarly journals Therapy-Induced Tumor Cell Death: Friend or Foe of Immunotherapy?

2021 ◽  
Vol 11 ◽  
Author(s):  
Thijs A. van Schaik ◽  
Kok-Siong Chen ◽  
Khalid Shah
Keyword(s):  
Cell Death ◽  
Tumor Cell ◽  
Molecular Mechanisms ◽  
Significant Proportion ◽  
Local Environment ◽  
Signaling Cascades ◽  
Tumor Cell Death ◽  
Adequate Treatment ◽  
Immunosuppressive Tumor Microenvironment ◽  
The Impact

Combinatory treatments using surgery, radiotherapy and/or chemotherapy together with immunotherapy have shown encouraging results for specific subsets of tumors, but a significant proportion of tumors remains unsusceptible. Some of these inconsistencies are thought to be the consequence of an immunosuppressive tumor microenvironment (TME) caused by therapy-induced tumor cell death (TCD). An increased understanding of the molecular mechanisms governing TCD has provided valuable insights in specific signaling cascades activated by treatment and the subsequent effects on the TME. Depending on the treatment variables of conventional chemo-, radio- and immunotherapy and the genetic composition of the tumor cells, particular cell death pathways are activated. Consequently, TCD can either have tolerogenic or immunogenic effects on the local environment and thereby affect the post-treatment anti-tumor response of immune cells. Thus, identification of these events can provide new rationales to increase the efficacy of conventional therapies combined with immunotherapies. In this review, we sought to provide an overview of the molecular mechanisms initiated by conventional therapies and the impact of treatment-induced TCD on the TME. We also provide some perspectives on how we can circumvent tolerogenic effects by adequate treatment selection and manipulation of key signaling cascades.

Molecular mechanisms of ROS production and oxidative stress in diabetes

2016 ◽  
Vol 473 (24) ◽  
pp. 4527-4550 ◽  
Author(s):  
Philip Newsholme ◽  
Vinicius Fernandes Cruzat ◽  
Kevin Noel Keane ◽  
Rodrigo Carlessi ◽  
Paulo Ivo Homem de Bittencourt
Keyword(s):  
Oxidative Stress ◽  
Insulin Secretion ◽  
Redox Regulation ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Cell Function ◽  
Cell Cycle Control ◽  
Cell Signalling ◽  
Point Of View ◽  
Ros Production

Oxidative stress and chronic inflammation are known to be associated with the development of metabolic diseases, including diabetes. Oxidative stress, an imbalance between oxidative and antioxidative systems of cells and tissues, is a result of over production of oxidative-free radicals and associated reactive oxygen species (ROS). One outcome of excessive levels of ROS is the modification of the structure and function of cellular proteins and lipids, leading to cellular dysfunction including impaired energy metabolism, altered cell signalling and cell cycle control, impaired cell transport mechanisms and overall dysfunctional biological activity, immune activation and inflammation. Nutritional stress, such as that caused by excess high-fat and/or carbohydrate diets, promotes oxidative stress as evident by increased lipid peroxidation products, protein carbonylation and decreased antioxidant status. In obesity, chronic oxidative stress and associated inflammation are the underlying factors that lead to the development of pathologies such as insulin resistance, dysregulated pathways of metabolism, diabetes and cardiovascular disease through impaired signalling and metabolism resulting in dysfunction to insulin secretion, insulin action and immune responses. However, exercise may counter excessive levels of oxidative stress and thus improve metabolic and inflammatory outcomes. In the present article, we review the cellular and molecular origins and significance of ROS production, the molecular targets and responses describing how oxidative stress affects cell function including mechanisms of insulin secretion and action, from the point of view of possible application of novel diabetic therapies based on redox regulation

Signal-regulated oxidation of proteins via MICAL

2020 ◽  
Vol 48 (2) ◽  
pp. 613-620
Author(s):  
Clara Ortegón Salas ◽  
Katharina Schneider ◽  
Christopher Horst Lillig ◽  
Manuela Gellert
Keyword(s):  
Signal Transduction ◽  
Hydrogen Peroxide ◽  
Cell Death ◽  
Redox Regulation ◽  
Signal Transduction Pathways ◽  
Cellular Functions ◽  
Intracellular Signals ◽  
Amino Acid Side Chains ◽  
Specific Receptors ◽  
Sulfur Containing

Processing of and responding to various signals is an essential cellular function that influences survival, homeostasis, development, and cell death. Extra- or intracellular signals are perceived via specific receptors and transduced in a particular signalling pathway that results in a precise response. Reversible post-translational redox modifications of cysteinyl and methionyl residues have been characterised in countless signal transduction pathways. Due to the low reactivity of most sulfur-containing amino acid side chains with hydrogen peroxide, for instance, and also to ensure specificity, redox signalling requires catalysis, just like phosphorylation signalling requires kinases and phosphatases. While reducing enzymes of both cysteinyl- and methionyl-derivates have been characterised in great detail before, the discovery and characterisation of MICAL proteins evinced the first examples of specific oxidases in signal transduction. This article provides an overview of the functions of MICAL proteins in the redox regulation of cellular functions.

Potential Therapeutic Targets of Curcumin, Most Abundant Active Compound of Turmeric Spice: Role in the Management of Various Types of Cancer

2020 ◽  
Vol 15 ◽  
Author(s):  
Saleh A. Almatroodi ◽  
Mansoor Ali Syed ◽  
Arshad Husain Rahmani
Keyword(s):  
Clinical Trials ◽  
Cancer Cells ◽  
Active Compound ◽  
Molecular Mechanisms ◽  
Human Subjects ◽  
Cell Signalling ◽  
Chemopreventive Agents ◽  
Signalling Molecules ◽  
Cancer Management ◽  
Induced Apoptosis

Background:: Curcumin, an active compound of turmeric spice is one of the most-studies natural compounds and have been widely recognized as chemopreventive agents. Several molecular mechanisms have been proven, curcumin and its analogs play a role in cancer prevention through modulating various cell signaling pathways as well as inhibition of carcinogenesis process. Objective:: To study the potential role of curcumin in the management of various types of cancer through modulating cell signalling molecules based on available literature and recent patents. Methods:: A wide-ranging literature survey was performed based on Scopus, PubMed, PubMed central and Google scholar for the implication of curcumin in cancer management along with special emphasis on human clinical trials. Moreover, patents were searched through www.google.com/patents, www.freepatentsonline.com and www.freshpatents.com. Result:: Recent studies based on cancer cells have proven that curcumin have potential effects against cancer cells, prevent the growth of cancer and act as cancer therapeutic agents. Besides, curcumin exerted anticancer effects through inducing apoptosis, activating tumor suppressor genes, cell cycle arrest, inhibiting tumor angiogenesis, initiation, promotion and progression stages of tumor. It was established that co-treatment of curcumin and anti-cancer drugs could induce apoptosis and also play a significant role in the suppression of the invasion and metastasis of cancer cells. Conclusion:: Accumulating evidences suggest that curcumin has potentiality to inhibit cancer growth, induced apoptosis and modulate various cell signalling pathways molecules. Well-designed clinical trials of curcumin based on human subjects are still needed to establish the bioavailability, mechanism of action, efficacy and safe dose in the management of various cancers.

scholarly journals Progress in understanding the role of lncRNA in programmed cell death

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Na Jiang ◽  
Xiaoyu Zhang ◽  
Xuejun Gu ◽  
Xiaozhuang Li ◽  
Lei Shang
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Molecular Mechanisms ◽  
Membrane Receptors ◽  
Gene Expressions ◽  
Apoptosis Pathway ◽  
Stem Cell Pluripotency ◽  
Extrinsic Apoptosis ◽  
Related Proteins ◽  
Cycle Regulation

AbstractLong non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides but not translated into proteins. LncRNAs regulate gene expressions at multiple levels, such as chromatin, transcription, and post-transcription. Further, lncRNAs participate in various biological processes such as cell differentiation, cell cycle regulation, and maintenance of stem cell pluripotency. We have previously reported that lncRNAs are closely related to programmed cell death (PCD), which includes apoptosis, autophagy, necroptosis, and ferroptosis. Overexpression of lncRNA can suppress the extrinsic apoptosis pathway by downregulating of membrane receptors and protect tumor cells by inhibiting the expression of necroptosis-related proteins. Some lncRNAs can also act as competitive endogenous RNA to prevent oxidation, thereby inhibiting ferroptosis, while some are known to activate autophagy. The relationship between lncRNA and PCD has promising implications in clinical research, and reports have highlighted this relationship in various cancers such as non-small cell lung cancer and gastric cancer. This review systematically summarizes the advances in the understanding of the molecular mechanisms through which lncRNAs impact PCD.

scholarly journals Fibrillar α-synuclein induces neurotoxic astrocyte activation via RIP kinase signaling and NF-κB

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Tsui-Wen Chou ◽  
Nydia P. Chang ◽  
Medha Krishnagiri ◽  
Aisha P. Patel ◽  
Marissa Lindman ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Neuronal Cell ◽  
Dopamine Neurons ◽  
Functional Markers ◽  
Kinase Signaling ◽  
Astrocyte Activation ◽  
Transcriptional Responses

AbstractParkinson’s disease (PD) is a neurodegenerative disorder characterized by the death of midbrain dopamine neurons. The pathogenesis of PD is poorly understood, though misfolded and/or aggregated forms of the protein α-synuclein have been implicated in several neurodegenerative disease processes, including neuroinflammation and astrocyte activation. Astrocytes in the midbrain play complex roles during PD, initiating both harmful and protective processes that vary over the course of the disease. However, despite their significant regulatory roles during neurodegeneration, the cellular and molecular mechanisms that promote pathogenic astrocyte activity remain mysterious. Here, we show that α-synuclein preformed fibrils (PFFs) induce pathogenic activation of human midbrain astrocytes, marked by inflammatory transcriptional responses, downregulation of phagocytic function, and conferral of neurotoxic activity. These effects required the necroptotic kinases RIPK1 and RIPK3, but were independent of MLKL and necroptosis. Instead, both transcriptional and functional markers of astrocyte activation occurred via RIPK-dependent activation of NF-κB signaling. Our study identifies a previously unknown function for α-synuclein in promoting neurotoxic astrocyte activation, as well as new cell death-independent roles for RIP kinase signaling in the regulation of glial cell biology and neuroinflammation. Together, these findings highlight previously unappreciated molecular mechanisms of pathologic astrocyte activation and neuronal cell death with implications for Parkinsonian neurodegeneration.

scholarly journals Molecular mechanisms of cell death in neurological diseases

2021 ◽  
Author(s):  
Diane Moujalled ◽  
Andreas Strasser ◽  
Jeffrey R. Liddell
Keyword(s):  
Cell Death ◽  
Neurodegenerative Diseases ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
Neurological Diseases ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Response To Therapy ◽  
Signalling Cascades ◽  
The Brain

AbstractTightly orchestrated programmed cell death (PCD) signalling events occur during normal neuronal development in a spatially and temporally restricted manner to establish the neural architecture and shaping the CNS. Abnormalities in PCD signalling cascades, such as apoptosis, necroptosis, pyroptosis, ferroptosis, and cell death associated with autophagy as well as in unprogrammed necrosis can be observed in the pathogenesis of various neurological diseases. These cell deaths can be activated in response to various forms of cellular stress (exerted by intracellular or extracellular stimuli) and inflammatory processes. Aberrant activation of PCD pathways is a common feature in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, resulting in unwanted loss of neuronal cells and function. Conversely, inactivation of PCD is thought to contribute to the development of brain cancers and to impact their response to therapy. For many neurodegenerative diseases and brain cancers current treatment strategies have only modest effect, engendering the need for investigations into the origins of these diseases. With many diseases of the brain displaying aberrations in PCD pathways, it appears that agents that can either inhibit or induce PCD may be critical components of future therapeutic strategies. The development of such therapies will have to be guided by preclinical studies in animal models that faithfully mimic the human disease. In this review, we briefly describe PCD and unprogrammed cell death processes and the roles they play in contributing to neurodegenerative diseases or tumorigenesis in the brain. We also discuss the interplay between distinct cell death signalling cascades and disease pathogenesis and describe pharmacological agents targeting key players in the cell death signalling pathways that have progressed through to clinical trials.

scholarly journals LONP1 and ClpP cooperatively regulate mitochondrial proteostasis for cancer cell survival

Oncogenesis ◽  
2021 ◽  
Vol 10 (2) ◽  
Author(s):  
Yu Geon Lee ◽  
Hui Won Kim ◽  
Yeji Nam ◽  
Kyeong Jin Shin ◽  
Yu Jin Lee ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Growth ◽  
Cell Survival ◽  
Cancer Cell ◽  
Stress Responses ◽  
Molecular Mechanisms ◽  
Tca Cycle ◽  
Mitochondrial Matrix ◽  
Mitochondrial Functions ◽  
Cancer Cell Survival

AbstractMitochondrial proteases are key components in mitochondrial stress responses that maintain proteostasis and mitochondrial integrity in harsh environmental conditions, which leads to the acquisition of aggressive phenotypes, including chemoresistance and metastasis. However, the molecular mechanisms and exact role of mitochondrial proteases in cancer remain largely unexplored. Here, we identified functional crosstalk between LONP1 and ClpP, which are two mitochondrial matrix proteases that cooperate to attenuate proteotoxic stress and protect mitochondrial functions for cancer cell survival. LONP1 and ClpP genes closely localized on chromosome 19 and were co-expressed at high levels in most human cancers. Depletion of both genes synergistically attenuated cancer cell growth and induced cell death due to impaired mitochondrial functions and increased oxidative stress. Using mitochondrial matrix proteomic analysis with an engineered peroxidase (APEX)-mediated proximity biotinylation method, we identified the specific target substrates of these proteases, which were crucial components of mitochondrial functions, including oxidative phosphorylation, the TCA cycle, and amino acid and lipid metabolism. Furthermore, we found that LONP1 and ClpP shared many substrates, including serine hydroxymethyltransferase 2 (SHMT2). Inhibition of both LONP1 and ClpP additively increased the amount of unfolded SHMT2 protein and enhanced sensitivity to SHMT2 inhibitor, resulting in significantly reduced cell growth and increased cell death under metabolic stress. Additionally, prostate cancer patients with higher LONP1 and ClpP expression exhibited poorer survival. These results suggest that interventions targeting the mitochondrial proteostasis network via LONP1 and ClpP could be potential therapeutic strategies for cancer.

Efferocytosis during myocardial infarction

2020 ◽  
Vol 168 (1) ◽  
pp. 1-6
Author(s):  
Chikashi Yoshimura ◽  
Akiomi Nagasaka ◽  
Hitoshi Kurose ◽  
Michio Nakaya
Keyword(s):  
Myocardial Infarction ◽  
Cell Death ◽  
Crucial Role ◽  
Molecular Mechanisms ◽  
Causes Of Death ◽  
Inflammatory Responses ◽  
Heart Cells ◽  
Dead Cell ◽  
Related Cell

Abstract Myocardial infarction is one of the major causes of death worldwide. Many heart cells die during myocardial infarction through various processes such as necrosis, apoptosis, necroptosis, autophagy-related cell death, pyroptosis and ferroptosis. These dead cells in infarcted hearts expose the so-called ‘eat-me’ signals, such as phosphatidylserine, on their surfaces, enhancing their removal by professional and non-professional phagocytes. Clearance of dead cells by phagocytes in the diseased hearts plays a crucial role in the pathology of myocardial infarction by inhibiting the inflammatory responses caused by the leakage of contents from dead cells. This review focuses on the rapidly growing understanding of the molecular mechanisms of dead cell phagocytosis, termed efferocytosis, during myocardial infarction, which contributes to the pathophysiology of myocardial infarction.

An Insight into the Role of Apoptosis and Autophagy in Nitric Oxide–Induced Articular Chondrocyte Cell Death

Cartilage ◽  
2020 ◽  
pp. 194760352097676
Author(s):  
Ekkapol Akaraphutiporn ◽  
Takafumi Sunaga ◽  
Eugene C. Bwalya ◽  
Wang Yanlin ◽  
Mwale Carol ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cell Death ◽  
Western Blot ◽  
Cell Apoptosis ◽  
Molecular Mechanisms ◽  
Interleukin 1 ◽  
Chondrocyte Apoptosis ◽  
Protective Mechanism ◽  
Autophagic Flux ◽  
Qpcr Analysis

Objective To investigate the role and characterize the molecular mechanisms regulating apoptosis and autophagy in nitric oxide (NO)–induced chondrocyte cell death. Design Cell apoptosis and autophagy were evaluated in chondrocytes treated with sodium nitroprusside (SNP) combined with the presence or absence of interleukin-1 beta (IL-1β) and nutrient-deprived conditions. The concentration of nitrite was determined by Griess reaction. Activation of apoptosis and autophagy were determined by immunocytochemistry, Western blot, and quantitative real-time polymerase chain reaction (qPCR) analysis. Flow cytometry and MTT assay were used to assess cell viability. Results Cotreatment of chondrocytes with SNP and IL-1β under nutrient-deprived condition potentially enhanced the effect of NO-induced cell death. Immunocytochemistry, Western blot, and qPCR analysis indicated that treatment of chondrocytes with SNP significantly reduced autophagic activity, autophagic flux, and multiple autophagy-related (Atg) genes expression. These findings were associated with an increase in ERK, Akt, and mTOR phosphorylation, whereas autophagy induction through mTOR/p70S6K inhibition by rapamycin significantly suppressed NO-induced cell apoptosis. Furthermore, the cleavage of poly(ADP-ribose) polymerase (PARP) and caspase-3 activation in response to apoptosis was weakly detected. These results corresponded with a significant increase in apoptosis-inducing factor (AIF) expression, suggesting the involvement of the caspase-independent pathway. Conclusions These results demonstrate that in chondrocyte cultures with cells induced into an osteoarthritis state, NO inhibits autophagy and induces chondrocyte apoptosis mainly, but not completely through the caspase-independent pathway. Our data suggest that autophagy is a protective mechanism in the pathogenesis of osteoarthritis and could be proposed as a therapeutic target for degenerative joint diseases.

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