Targeting ferroptosis as a vulnerability in cancer

Nature reviews. Cancer, Journal Year: 2022, Volume and Issue: 22(7), P. 381 - 396

Published: March 25, 2022

Language: Английский

---

Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease

Antioxidants, Journal Year: 2022, Volume and Issue: 11(12), P. 2345 - 2345

Published: Nov. 27, 2022

Organisms are continually exposed to exogenous and endogenous sources of reactive oxygen species (ROS) other oxidants that have both beneficial deleterious effects on the cell. ROS important roles in a wide range physiological processes; however, high levels associated with oxidative stress disease progression. Oxidative has been implicated nearly all major human diseases, from neurogenerative diseases neuropsychiatric disorders cardiovascular disease, diabetes, cancer. Antioxidant defence systems evolved as means protection against stress, transcription factor Nrf2 key regulator. is responsible for regulating an extensive panel antioxidant enzymes involved detoxification elimination extensively studied contexts. This review aims provide reader general overview Nrf2, including basic mechanisms activation regulation, implications various diseases.

Language: Английский

---

Nrf2/Keap1/ARE signaling: Towards specific regulation

Life Sciences, Journal Year: 2021, Volume and Issue: 291, P. 120111 - 120111

Published: Oct. 31, 2021

Language: Английский

---

A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: April 22, 2022

Targeting ferroptosis, a unique cell death modality triggered by unrestricted lipid peroxidation, in cancer therapy is hindered our incomplete understanding of ferroptosis mechanisms under specific genetic contexts. KEAP1 (kelch-like ECH associated protein 1) frequently mutated or inactivated lung cancers, and mutant cancers are refractory to most therapies, including radiotherapy. In this study, we identify suppressor 1 (FSP1, also known as AIFM2) transcriptional target nuclear factor erythroid 2-related 2 (NRF2) reveal that the ubiquinone (CoQ)-FSP1 axis mediates ferroptosis- radiation- resistance deficient cells. We further show pharmacological inhibition CoQ-FSP1 sensitizes cells patient-derived xenograft tumors radiation through inducing ferroptosis. Together, study identifies key downstream effector KEAP1-NRF2 pathway potential therapeutic for treating cancers.

Language: Английский

---

Ketone bodies: from enemy to friend and guardian angel

BMC Medicine, Journal Year: 2021, Volume and Issue: 19(1)

Published: Dec. 9, 2021

Abstract During starvation, fasting, or a diet containing little digestible carbohydrates, the circulating insulin levels are decreased. This promotes lipolysis, and breakdown of fat becomes major source energy. The hepatic energy metabolism is regulated so that under these circumstances, ketone bodies generated from β-oxidation fatty acids secreted as ancillary fuel, in addition to gluconeogenesis. Increased plasma thus indicate dietary shortage carbohydrates. Ketone not only serve fuel but also promote resistance oxidative inflammatory stress, there decrease anabolic insulin-dependent expenditure. It has been suggested beneficial non-metabolic actions on organ functions mediated by them acting ligand specific cellular targets. We propose here role different pathway initiated induction stress mitochondria during increased ketolysis. Oxidative induced body long term because it initiates an adaptive (hormetic) response characterized activation master regulators cell-protective mechanism, nuclear factor erythroid 2-related 2 (Nrf2), sirtuins, AMP-activated kinase. results resolving upregulation anti-oxidative anti-inflammatory activities, improved mitochondrial function growth, DNA repair, autophagy. In heart, enhanced ketolysis improves damage after ischemic insults cardiotoxic doxorubicin. Sodium-dependent glucose co-transporter (SGLT2) inhibitors may exert their cardioprotective action via increasing conclude synthesis use periods deficient food supply low causes latter protective which allows cells cope with lower availability. Keywords Ketogenic diet, bodies, Beta hydroxybutyrate, Insulin, Obesity, Type diabetes, Inflammation, Cardiovascular disease, SGLT2, Hormesis

Language: Английский

---

Signal amplification in the KEAP1-NRF2-ARE antioxidant response pathway

Redox Biology, Journal Year: 2022, Volume and Issue: 54, P. 102389 - 102389

Published: June 29, 2022

The KEAP1-NRF2-ARE signaling pathway plays a central role in mediating the adaptive cellular stress response to oxidative and electrophilic chemicals. This canonical has been extensively studied reviewed past two decades, but rarely was it looked at from quantitative perspective. Signal amplification, i.e., ultrasensitivity, is crucially important for robust induction of antioxidant genes appropriate levels that can adequately counteract stresses. In this review article, we examined number well-known molecular events perspective with focus on how signal amplification be achieved. We illustrated, by using series mathematical models, redox-regulated protein sequestration, stabilization, translation, nuclear trafficking, DNA promoter binding, transcriptional – which are embedded network comprising KEAP1, NRF2, sMaf, p62, BACH1 may generate highly ultrasensitive NRF2 activation gene induction. emergence degree ultrasensitivity depend strengths protein-protein protein-DNA interaction abundances. A unique, understanding will help identify sensitive targets prevention therapeutics stress-related diseases develop adverse outcome models facilitate health risk assessment

Language: Английский

---

Hyperglycemia and Oxidative Stress: An Integral, Updated and Critical Overview of Their Metabolic Interconnections

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(11), P. 9352 - 9352

Published: May 27, 2023

This review focuses on the multiple and reciprocal relationships that exist between oxidative stress, hyperglycemia diabetes related metabolic disorders. Human metabolism uses most of consumed glucose under aerobic conditions. Oxygen is needed in mitochondria to obtain energy, as well for action microsomal oxidases cytosolic pro-oxidant enzymes. relentlessly generates a certain amount reactive oxygen species (ROS). Although ROS are intracellular signals necessary some physiological processes, their accumulation leads hyperglycemia, progressive resistance insulin. A cellular versus an antioxidant equilibrium would regulate levels, but pro-inflammatory conditions feed back each other relevance interconnections tends increase those Hyperglycemia promotes collateral through protein kinase C, polyols hexosamine routes. In addition, it also facilitates spontaneous auto-oxidation formation advanced glycation end products (AGEs), which turn interact with receptors (RAGE). The mentioned processes undermine structures, finally giving place progressively greater degree stress further alterations, complications. NFκB major transcription factor involved expression mediators, while Nrf2 regulating response. FoxO equilibrium, its role controversial. summarizes key factors linking diverse routes enhanced vice versa, emphasizing desirable balance proteins.

Language: Английский

---

Hypoxia and brain aging: Neurodegeneration or neuroprotection?

Ageing Research Reviews, Journal Year: 2021, Volume and Issue: 68, P. 101343 - 101343

Published: April 16, 2021

The absolute reliance of the mammalian brain on oxygen to generate ATP renders it acutely vulnerable hypoxia, whether at high altitude or in clinical settings anemia pulmonary disease. Hypoxia is pivotal pathogeneses myriad neurological disorders, including Alzheimer's, Parkinson's and other age-related neurodegenerative diseases. Conversely, reduced environmental oxygen, e.g. sojourns residing altitudes, may impart favorable effects aging mortality. Moreover, controlled hypoxia exposure represent a treatment strategy for disorders. This review discusses evidence hypoxia's beneficial vs. detrimental impacts molecular mechanisms that mediate these divergent effects. It draws upon an extensive literature search hypoxia/altitude aging, detailed analysis all identified studies directly comparing responses young aged humans rodents. Special attention directed toward risks benefits elderly, potential therapeutic applications Finally, important questions future research are discussed.

Language: Английский

---

Heme Oxygenase-1 Signaling and Redox Homeostasis in Physiopathological Conditions

Biomolecules, Journal Year: 2021, Volume and Issue: 11(4), P. 589 - 589

Published: April 16, 2021

Heme-oxygenase is the enzyme responsible for degradation of endogenous iron protoporphyirin heme; it catalyzes reaction's rate-limiting step, resulting in release carbon monoxide (CO), ferrous ions, and biliverdin (BV), which successively reduced bilirubin (BR) by reductase. Several studies have drawn attention to controversial role HO-1, inducible isoform, pointing out its implications cancer other diseases development, but also underlining importance antioxidant activity. The contribution HO-1 redox homeostasis leads a relevant decrease cells oxidative damage, can be reconducted cytoprotective effects explicated alongside mechanisms involving genes like TIGAR (TP53-induced glycolysis apoptosis regulator), therapeutic functions heme main transformation products, especially has been shown effective on GSH levels implementation sustaining body's response stress. aim this review was collect most knowledge from literature, analyzing different perspectives try put forward hypothesis revealing yet unknown HO-1-involved pathways that could useful promote development new therapeutical strategies, lay foundation further investigation fully understand important system.

Language: Английский

---

RONS and Oxidative Stress: An Overview of Basic Concepts

Oxygen, Journal Year: 2022, Volume and Issue: 2(4), P. 437 - 478

Published: Oct. 10, 2022

Oxidative stress (OS) has greatly interested the research community in understanding damaging processes occurring cells. OS is triggered by an imbalance between reactive oxygen species (ROS) production and their elimination antioxidant system; however, ROS function as second messengers under physiological conditions. are produced from endogenous exogenous sources. Endogenous sources involve mitochondria, nicotinamide adenine dinucleotide phosphate hydrogen (NADPH), oxidases (NOXs), endoplasmic reticulum (ER), xanthine (XO), endothelial nitric oxide synthase (eNOs), others. In contrast, might be generated through ultraviolet (UV) light, ionizing radiation (IR), contaminants, heavy metals, among It can damage DNA, lipids, proteins if not controlled. To avoid oxidative damage, systems activated. present review, we focus on basic concepts of OS, highlighting nitrogen (RONS) derived internal external last elimination. Moreover, include cellular system regulation ability to decrease OS. External antioxidants also proposed alternatives ameliorate Finally, review diseases involving mechanisms.

Language: Английский

---