PARP Inhibitors: An Innovative Approach to the Treatment of Inflammation and Metabolic Disorders in Sepsis

Wasyluk, Weronika; Zwolak, Agnieszka

doi:10.2147/jir.s300679

Cited by 23 publications

(24 citation statements)

References 122 publications

(159 reference statements)

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“…PARP-1 itself promotes the development of inflammatory processes by up-regulating expression of various inflammatory mediators such as tumor necrosis factor α (TNFα), inducible isoform of nitrite oxide synthase (iNOS), cyclooxygenase 2 (COX2), monocyte chemoattractant protein 1 (MCP1), interleukins 1β and 6 (IL-1β, IL-6). Here PARP-1 acts as a co-activator of transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activator proteins 1 and 2 (AP1, AP2) that regulate immune and inflammatory responses ( Figure 3 ) [ 37 , 38 , 39 , 40 ]. PARP-1 was shown to be acetylated at lysine residues (K498, K505, K508, K521, K524) by the p300/CREB-binding protein complex (CREB - cAMP-response element binding protein) and phosphorylated at Y829 by mitogen-activated protein kinases (MAPKs) in response to pro-inflammatory stimuli [ 37 , 38 ].…”

Section: Relationship Of Parp-1 With Inflammatory and Metabolic Diseasesmentioning

confidence: 99%

“…PARP-1 was shown to be acetylated at lysine residues (K498, K505, K508, K521, K524) by the p300/CREB-binding protein complex (CREB - cAMP-response element binding protein) and phosphorylated at Y829 by mitogen-activated protein kinases (MAPKs) in response to pro-inflammatory stimuli [ 37 , 38 ]. Modified in this way, PARP-1 stimulates transcription of NF-κB-dependent genes of inflammatory mediators ( Figure 3 ) [ 37 , 38 , 39 , 40 ]. Interestingly, neither the enzymatic activity of PARP-1 nor its DNA-binding activity were required for full activation of NF-kB in response to various stimuli [ 37 ].…”

Section: Relationship Of Parp-1 With Inflammatory and Metabolic Diseasesmentioning

confidence: 99%

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PARP-1-Associated Pathological Processes: Inhibition by Natural Polyphenols

Feofanov

Studitsky

2021

IJMS

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Poly (ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme involved in processes of cell cycle regulation, DNA repair, transcription, and replication. Hyperactivity of PARP-1 induced by changes in cell homeostasis promotes development of chronic pathological processes leading to cell death during various metabolic disorders, cardiovascular and neurodegenerative diseases. In contrast, tumor growth is accompanied by a moderate activation of PARP-1 that supports survival of tumor cells due to enhancement of DNA lesion repair and resistance to therapy by DNA damaging agents. That is why PARP inhibitors (PARPi) are promising agents for the therapy of tumor and metabolic diseases. A PARPi family is rapidly growing partly due to natural polyphenols discovered among plant secondary metabolites. This review describes mechanisms of PARP-1 participation in the development of various pathologies, analyzes multiple PARP-dependent pathways of cell degeneration and death, and discusses representative plant polyphenols, which can inhibit PARP-1 directly or suppress unwanted PARP-dependent cellular processes.

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Section: Relationship Of Parp-1 With Inflammatory and Metabolic Diseasesmentioning

confidence: 99%

Section: Relationship Of Parp-1 With Inflammatory and Metabolic Diseasesmentioning

confidence: 99%

PARP-1-Associated Pathological Processes: Inhibition by Natural Polyphenols

Feofanov

Studitsky

2021

IJMS

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“…Intriguingly, a more recent approach aims at harnessing these inhibitors in the treatment of non-oncological diseases, including oxidative stress, inflammatory responses, as well as neurodegenerative and cardiovascular diseases [137,174,175].…”

Section: Chemical Inhibition Of Artdsmentioning

confidence: 99%

ADP-Ribosylation Post-Translational Modification: An Overview with a Focus on RNA Biology and New Pharmacological Perspectives

et al. 2022

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Cellular functions are regulated through the gene expression program by the transcription of new messenger RNAs (mRNAs), alternative RNA splicing, and protein synthesis. To this end, the post-translational modifications (PTMs) of proteins add another layer of complexity, creating a continuously fine-tuned regulatory network. ADP-ribosylation (ADPr) is an ancient reversible modification of cellular macromolecules, regulating a multitude of key functional processes as diverse as DNA damage repair (DDR), transcriptional regulation, intracellular transport, immune and stress responses, and cell survival. Additionally, due to the emerging role of ADP-ribosylation in pathological processes, ADP-ribosyltransferases (ARTs), the enzymes involved in ADPr, are attracting growing interest as new drug targets. In this review, an overview of human ARTs and their related biological functions is provided, mainly focusing on the regulation of ADP-ribosyltransferase Diphtheria toxin-like enzymes (ARTD)-dependent RNA functions. Finally, in order to unravel novel gene functional relationships, we propose the analysis of an inventory of human gene clusters, including ARTDs, which share conserved sequences at 3′ untranslated regions (UTRs).

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“…Another suggested mechanism for the development of mitochondrial dysfunction related to oxidative and nitrative stress is the activation of poly (ADP-ribose) polymerase (PARP), an enzyme associated with numerous cellular processes, including DNA repair. Excessive activation of PARP may contribute to the formation of both inflammation and the development of metabolic disorders, by influencing the regulation of gene expression, impaired metabolism, and mechanisms leading to the production of alarmins (the role of PARP in sepsis is described in another study [ 151 ]). Although the primary location of PARP in the cell is the nucleus, it is known that their overactivation also impairs mitochondrial function [ 115 ].…”

Section: Sepsis-induced Cardiomyopathymentioning

confidence: 99%

Heart Metabolism in Sepsis-Induced Cardiomyopathy—Unusual Metabolic Dysfunction of the Heart

Wasyluk

Nowicka-Stążka

Zwolak

2021

IJERPH

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Due to the need for continuous work, the heart uses up to 8% of the total energy expenditure. Due to the relatively low adenosine triphosphate (ATP) storage capacity, the heart’s work is dependent on its production. This is possible due to the metabolic flexibility of the heart, which allows it to use numerous substrates as a source of energy. Under normal conditions, a healthy heart obtains approximately 95% of its ATP by oxidative phosphorylation in the mitochondria. The primary source of energy is fatty acid oxidation, the rest of the energy comes from the oxidation of pyruvate. A failed heart is characterised by a disturbance in these proportions, with the contribution of individual components as a source of energy depending on the aetiology and stage of heart failure. A unique form of cardiac dysfunction is sepsis-induced cardiomyopathy, characterised by a significant reduction in energy production and impairment of cardiac oxidation of both fatty acids and glucose. Metabolic disorders appear to contribute to the pathogenesis of cardiac dysfunction and therefore are a promising target for future therapies. However, as many aspects of the metabolism of the failing heart remain unexplained, this issue requires further research.

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PARP Inhibitors: An Innovative Approach to the Treatment of Inflammation and Metabolic Disorders in Sepsis

Cited by 23 publications

References 122 publications

PARP-1-Associated Pathological Processes: Inhibition by Natural Polyphenols

PARP-1-Associated Pathological Processes: Inhibition by Natural Polyphenols

ADP-Ribosylation Post-Translational Modification: An Overview with a Focus on RNA Biology and New Pharmacological Perspectives

Heart Metabolism in Sepsis-Induced Cardiomyopathy—Unusual Metabolic Dysfunction of the Heart

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