Is Ferroptosis a Future Direction in Exploring Cryptococcal Meningitis?

Cryptococcal meningitis (CM) is the leading cause of mortality among patients infected with human immunodeficiency virus (HIV). Although treatment strategies for CM are continually being developed, the mortality rate is still high. Therefore, we need to explore more therapeutic strategies that are aimed at hindering its pathogenic mechanism. In the field of CM, several studies have observed rapid iron accumulation and lipid peroxidation within the brain, all of which are hallmarks of ferroptosis, which is a type of programmed cell death that is characterized by iron dependence and lipid peroxidation. In recent years, many studies have confirmed the involvement of ferroptosis in many diseases, including infectious diseases such as Mycobacterium tuberculosis infection and coronavirus disease-2019 (COVID-19). Furthermore, ferroptosis is considered as immunogenic and pro-inflammatory as the ferroptotic cells release damage-associated molecular pattern molecules (DAMPs) and alarmin, both of which regulate immunity and pro-inflammatory activity. Hence, we hypothesize that there might be a relationship between this unique cell death modality and CM. Herein, we review the evidence of ferroptosis in CM and consider the hypothesis that ferroptotic cell death may be involved in the cell death of CM.

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Molecular mechanisms of cell death in neurological diseases

Cell Death and Differentiation ◽

10.1038/s41418-021-00814-y ◽

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.

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In vitro antioxidant treatment recovers proliferative responses of anergic CD4+ lymphocytes from human immunodeficiency virus-infected individuals

Blood ◽

10.1182/blood.v87.11.4746.bloodjournal87114746 ◽

1996 ◽

Vol 87 (11) ◽

pp. 4746-4753 ◽

Cited By ~ 30

Author(s):

A Cayota ◽

F Vuillier ◽

G Gonzalez ◽

G Dighiero

Keyword(s):

Human Immunodeficiency Virus ◽

Cell Death ◽

Programmed Cell Death ◽

Redox Status ◽

Therapeutic Strategies ◽

Antioxidant Treatment ◽

Immunodeficiency Virus ◽

Cd4 Lymphocytes ◽

Cellular Thiol

Oxidative stress has been proposed to be involved in the immunologic defeat observed in effector calls of the immune system as well as in lymphocyte cell death and viral replication in human immunodeficiency virus (HIV)-infected patients. Because thiol-containing antioxidants such as N-acetyl-L-cysteine have been shown to have beneficial effects on CD4+ lymphocyte survival and to inhibit programmed cell death and HIV-1 replication, they may play a role in therapeutic strategies of this disease. In this work we have studied the cellular thiol levels and the affect of in vitro antioxidant treatment of purified CD4+ lymphocytes from HIV-infected patients, and correlated these parameters to proliferative responses and programmed cell death. We show that CD4+ lymphocytes from HIV-infected patients display impaired proliferative responses and a significant decrease in cellular thiol levels, indicating a disturbed redox status. Interestingly, antioxidant treatment succeeded to restore defective proliferative responses to CD3- mediated activation in 8 of 11 patients (high antioxidant responders). In contrast to high responders, patients failing to respond to antioxidant treatment (low antioxidant responders), were characterized by an abnormal ratio of apoptotic cells, which was not affected by N- acetyl-L-cysteine and/or 2-beta-mercaptoethanol preincubation. These results demonstrate for the first time that antioxidant treatment is able to revert the impaired proliferative activity of CD4 cells from HIV-infected patients and could help designing therapeutic strategies with antioxidant drugs. However, this action is not observed in cells undergoing programmed cell death.

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Osteopontin Expression in the Brain Triggers Localized Inflammation and Cell Death When Immune Cells Are Activated by Pertussis Toxin

Mediators of Inflammation ◽

10.1155/2014/358218 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 4

Author(s):

Maria Cecilia Garibaldi Marcondes ◽

Ryan Ojakian ◽

Nikki Bortell ◽

Claudia Flynn ◽

Bruno Conti ◽

...

Keyword(s):

Cell Death ◽

Pertussis Toxin ◽

Inflammatory Cells ◽

Brain Inflammation ◽

Molecular Pattern ◽

Expression Site ◽

Pattern Characteristic ◽

Peripheral Cells ◽

The Brain

Upregulation of osteopontin (OPN) is a characteristic of central nervous system pathologies. However, the role of OPN in inflammation is still controversial, since it can both prevent cell death and induce the migration of potentially damaging inflammatory cells. To understand the role of OPN in inflammation and cell survival, we expressed OPN, utilizing an adenoviral vector, in the caudoputamen of mice deficient in OPN, using beta-galactosidase- (β-gal-) expressing vector as control. The tissue pathology and the expression of proinflammatory genes were compared in both treatments. Interestingly, inflammatory infiltrate was only found when the OPN-vector was combined with a peripheral treatment with pertussis toxin (Ptx), which activated peripheral cells to express the OPN receptor CD44v6. Relative toβ-gal, OPN increased the levels of inflammatory markers, including IL13Rα1, CXCR3, and CD40L. In Ptx-treated OPN KOs, apoptotic TUNEL+ cells surrounding the OPN expression site increased, compared toβ-gal. Together, these results show that local OPN expression combined with a peripheral inflammatory stimulus, such as Ptx, may be implicated in the development of brain inflammation and induction of cell death, by driving a molecular pattern characteristic of cytotoxicity. These are characteristics of inflammatory pathologies of the CNS in which OPN upregulation is a hallmark.

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Metabolic Regulation of Ferroptosis in Cancer

Biology ◽

10.3390/biology10020083 ◽

2021 ◽

Vol 10 (2) ◽

pp. 83

Author(s):

Min Ji Kim ◽

Greg Jiho Yun ◽

Sung Eun Kim

Keyword(s):

Lipid Peroxidation ◽

Cell Death ◽

Lipid Metabolism ◽

Metabolic Pathways ◽

Metabolic Regulation ◽

Organ Damage ◽

Cell Death Mechanism ◽

Therapeutic Uses ◽

Unique Cell ◽

Excessive Accumulation

Ferroptosis is a unique cell death mechanism that is executed by the excessive accumulation of lipid peroxidation in cells. The relevance of ferroptosis in multiple human diseases such as neurodegeneration, organ damage, and cancer is becoming increasingly evident. As ferroptosis is deeply intertwined with metabolic pathways such as iron, cyst(e)ine, glutathione, and lipid metabolism, a better understanding of how ferroptosis is regulated by these pathways will enable the precise utilization or prevention of ferroptosis for therapeutic uses. In this review, we present an update of the mechanisms underlying diverse metabolic pathways that can regulate ferroptosis in cancer.

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Theoretical insights into the mechanism of ferroptosis suppression via inactivation of a lipid peroxide radical by liproxstatin-1

Physical Chemistry Chemical Physics ◽

10.1039/c7cp00804j ◽

2017 ◽

Vol 19 (20) ◽

pp. 13153-13159 ◽

Cited By ~ 16

Author(s):

Xiehuang Sheng ◽

Chao Shan ◽

Jianbiao Liu ◽

Jintong Yang ◽

Bin Sun ◽

...

Keyword(s):

Lipid Peroxidation ◽

Cell Death ◽

Apoptotic Cell ◽

Lipid Peroxide ◽

Membrane Lipid ◽

Peroxide Radical ◽

Membrane Lipid Peroxidation ◽

Pathological Conditions ◽

Dependent Form ◽

The Brain

Ferroptosis is a recently discovered iron-dependent form of non-apoptotic cell death caused by the accumulation of membrane lipid peroxidation products, which is involved in various pathological conditions of the brain, kidneys, liver and heart.

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Ferroptosis Mechanisms Involved in Neurodegenerative Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms21228765 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8765 ◽

Cited By ~ 1

Author(s):

Cadiele Oliana Reichert ◽

Fábio Alessandro de Freitas ◽

Juliana Sampaio-Silva ◽

Leonardo Rokita-Rosa ◽

Priscila de Lima Barros ◽

...

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Central Nervous System ◽

Cell Death ◽

Nervous System ◽

Neurodegenerative Diseases ◽

Intracellular Iron ◽

The Central Nervous System ◽

The 1960S ◽

The Brain

Ferroptosis is a type of cell death that was described less than a decade ago. It is caused by the excess of free intracellular iron that leads to lipid (hydro) peroxidation. Iron is essential as a redox metal in several physiological functions. The brain is one of the organs known to be affected by iron homeostatic balance disruption. Since the 1960s, increased concentration of iron in the central nervous system has been associated with oxidative stress, oxidation of proteins and lipids, and cell death. Here, we review the main mechanisms involved in the process of ferroptosis such as lipid peroxidation, glutathione peroxidase 4 enzyme activity, and iron metabolism. Moreover, the association of ferroptosis with the pathophysiology of some neurodegenerative diseases, namely Alzheimer’s, Parkinson’s, and Huntington’s diseases, has also been addressed.

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Ferroptosis Mechanisms Involved in Hippocampal-Related Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms22189902 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9902

Author(s):

Xintong Wang ◽

Zixu Wang ◽

Jing Cao ◽

Yulan Dong ◽

Yaoxing Chen

Keyword(s):

Lipid Peroxidation ◽

Central Nervous System ◽

Cell Death ◽

Nervous System ◽

Glutathione Metabolism ◽

Intracellular Iron ◽

System Disease ◽

And Function ◽

The Brain

Ferroptosis is a newly recognized type of cell death that is different from traditional forms of cell death, such as apoptosis, autophagy, and necrosis. It is caused by the accumulation of intracellular iron, promoting lipid peroxidation and leading to cell death. Iron is essential as a redox metal in several physiological functions. The brain is one of the organs known to be affected by iron homeostatic balance disruption. An increased concentration of iron in the central nervous system has been associated with oxidative stress, lipid peroxidation of proteins, and cell death. The hippocampus is an important brain region for learning, memory, and emotional responses, and is also a sensitive part of the brain to the dysfunctional homeostasis of transition metals. Damage of hippocampal structure and function are intimately involved in the pathogenic mechanisms underlying neurodegenerative diseases. Currently, ferroptosis is playing an increasingly important role in treatment areas of central nervous system diseases. Thus, we provide an overview of ferroptosis regulatory mechanisms, such as lipid metabolism, glutathione metabolism, and iron metabolism in this review. We also highlight the role of ferroptosis in hippocampal-related diseases and investigate a theoretical basis for further research on the role of ferroptosis in nervous system disease treatment.

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Biological response of the organism to the introduction of metal nanocomposites

Russian Journal of Occupational Health and Industrial Ecology ◽

10.31089/1026-9428-2019-59-9-761-762 ◽

2020 ◽

pp. 761-762

Author(s):

L. M. Sosedova ◽

V. S. Rukavishnikov ◽

E. A. Titov

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Biological Response ◽

Brain Cell ◽

Metal Nanocomposites ◽

The Brain

The results of a study on rats toxicity of nanoparticles of metals bismuth, gadolinium and silver encapsulated in a natural biopolymer matrix arabinogalactan are presented. When intake of nanocomposite of silver revealed the readiness of the brain cell to apoptosis. The effect of bismuth and gadolinium nanocomposites did not cause an increase in the process of programmed cell death.

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Role of Flavonoids in Neurodegenerative Disorders with Special Emphasis on Tangeritin

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527318666190916141934 ◽

2019 ◽

Vol 18 (8) ◽

pp. 581-597 ◽

Cited By ~ 1

Author(s):

Ambreen Fatima ◽

Yasir Hasan Siddique

Keyword(s):

Medicinal Plants ◽

Mechanism Of Action ◽

Neurodegenerative Disorders ◽

Treatment Strategies ◽

Dietary Supplementation ◽

Plant Polyphenols ◽

Promising Candidate ◽

Naturally Occurring ◽

The Brain

Flavonoids are naturally occurring plant polyphenols found universally in all fruits, vegetables and medicinal plants. They have emerged as a promising candidate in the formulation of treatment strategies for various neurodegenerative disorders. The use of flavonoid rich plant extracts and food in dietary supplementation have shown favourable outcomes. The present review describes the types, properties and metabolism of flavonoids. Neuroprotective role of various flavonoids and the possible mechanism of action in the brain against the neurodegeneration have been described in detail with special emphasis on the tangeritin.

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Transient Receptor Potential C 1/4/5 Is a Determinant of MTI-101 Induced Calcium Influx and Cell Death in Multiple Myeloma

Cells ◽

10.3390/cells10061490 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1490

Author(s):

Osama M. Elzamzamy ◽

Brandon E. Johnson ◽

Wei-Chih Chen ◽

Gangqing Hu ◽

Reinhold Penner ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Death ◽

Transient Receptor Potential ◽

Cyclic Peptide ◽

Calcium Influx ◽

Acquired Resistance ◽

Treatment Strategies ◽

Prognostic Indicators ◽

Causative Role

Multiple myeloma (MM) is a currently incurable hematologic cancer. Patients that initially respond to therapeutic intervention eventually relapse with drug resistant disease. Thus, novel treatment strategies are critically needed to improve patient outcomes. Our group has developed a novel cyclic peptide referred to as MTI-101 for the treatment of MM. We previously reported that acquired resistance to HYD-1, the linear form of MTI-101, correlated with the repression of genes involved in store operated Ca2+ entry (SOCE): PLCβ, SERCA, ITPR3, and TRPC1 expression. In this study, we sought to determine the role of TRPC1 heteromers in mediating MTI-101 induced cationic flux. Our data indicate that, consistent with the activation of TRPC heteromers, MTI-101 treatment induced Ca2+ and Na+ influx. However, replacing extracellular Na+ with NMDG did not reduce MTI-101-induced cell death. In contrast, decreasing extracellular Ca2+ reduced both MTI-101-induced Ca2+ influx as well as cell death. The causative role of TRPC heteromers was established by suppressing STIM1, TRPC1, TRPC4, or TRPC5 function both pharmacologically and by siRNA, resulting in a reduction in MTI-101-induced Ca2+ influx. Mechanistically, MTI-101 treatment induces trafficking of TRPC1 to the membrane and co-immunoprecipitation studies indicate that MTI-101 treatment induces a TRPC1-STIM1 complex. Moreover, treatment with calpeptin inhibited MTI-101-induced Ca2+ influx and cell death, indicating a role of calpain in the mechanism of MTI-101-induced cytotoxicity. Finally, components of the SOCE pathway were found to be poor prognostic indicators among MM patients, suggesting that this pathway is attractive for the treatment of MM.

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