Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Дек. 10, 2023

Abstract Ferroptosis, a unique modality of cell death with mechanistic and morphological differences from other modes, plays pivotal role in regulating tumorigenesis offers new opportunity for modulating anticancer drug resistance. Aberrant epigenetic modifications posttranslational (PTMs) promote resistance, cancer progression, metastasis. Accumulating studies indicate that can transcriptionally translationally determine vulnerability to ferroptosis functions as driver nervous system diseases (NSDs), cardiovascular (CVDs), liver diseases, lung kidney diseases. In this review, we first summarize the core molecular mechanisms ferroptosis. Then, roles processes, including histone PTMs, DNA methylation, noncoding RNA regulation such phosphorylation, ubiquitination, SUMOylation, acetylation, ADP-ribosylation, are concisely discussed. The PTMs genesis cancers, NSD, CVDs, well application PTM modulators therapy these then discussed detail. Elucidating mediated by will facilitate development promising combination therapeutic regimens containing or PTM-targeting agents inducers be used overcome chemotherapeutic resistance could prevent addition, highlight potential approaches chemoresistance halt

Язык: Английский

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Alzheimer’s Disease: Novel Targets and Investigational Drugs for Disease Modification

Drugs, Год журнала: 2023, Номер 83(15), С. 1387 - 1408

Опубликована: Сен. 20, 2023

Novel agents addressing non-amyloid, non-tau targets in Alzheimer's Disease (AD) comprise 70% of the AD drug development pipeline currently clinical trials. Most target processes identified Common Research Ontology (CADRO) are represented by novel Inflammation and synaptic plasticity/neuroprotection CADRO categories with largest number candidate therapies. Within these categories, there few overlapping among test agents. Additional being evaluated include apolipoprotein E $$\varepsilon$$ 4 (APOE4) effects, lipids lipoprotein receptors, neurogenesis, oxidative stress, bioenergetics metabolism, vascular factors, cell death, growth factors hormones, circadian rhythm, epigenetic regulators. We highlight current drugs tested within their mechanisms. Trials will be informative regarding which can modulated to produce a slowing decline. Possible therapeutic combinations may suggested trial outcomes. Biomarkers evolving concert new agents, biomarker outcomes offer means supporting disease modification putative treatment. Identification corresponding therapeutics an important advancing treatments for AD.

Язык: Английский

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Targeting Nrf2 signaling pathway and oxidative stress by resveratrol for Parkinson’s disease: an overview and update on new developments

Molecular Biology Reports, Год журнала: 2023, Номер 50(6), С. 5455 - 5464

Опубликована: Май 8, 2023

Язык: Английский

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Immunological dimensions of neuroinflammation and microglial activation: exploring innovative immunomodulatory approaches to mitigate neuroinflammatory progression

Frontiers in Immunology, Год журнала: 2024, Номер 14

Опубликована: Янв. 8, 2024

The increasing life expectancy has led to a higher incidence of age-related neurodegenerative conditions. Within this framework, neuroinflammation emerges as significant contributing factor. It involves the activation microglia and astrocytes, leading release pro-inflammatory cytokines chemokines infiltration peripheral leukocytes into central nervous system (CNS). These instances result in neuronal damage neurodegeneration through activated nucleotide-binding domain leucine-rich repeat containing (NLR) family pyrin protein 3 (NLRP3) nuclear factor kappa B (NF-kB) pathways decreased erythroid 2-related 2 (Nrf2) activity. Due limited effectiveness regarding inhibition neuroinflammatory targets using conventional drugs, there is challenging growth search for innovative therapies alleviating CNS diseases or even before their onset. Our results indicate that interventions focusing on Interleukin-Driven Immunomodulation, Chemokine (CXC) Receptor Signaling Expression, Cold Exposure, Fibrin-Targeted strategies significantly promise mitigate processes. approaches demonstrate potential anti-neuroinflammatory effects, addressing conditions such Multiple Sclerosis, Experimental autoimmune encephalomyelitis, Parkinson’s Disease, Alzheimer’s Disease. While findings are promising, immunomodulatory often face limitations due Immune-Related Adverse Events. Therefore, conduction randomized clinical trials matter mandatory, will pave way promising future development new medicines with specific therapeutic targets.

Язык: Английский

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Ferroptosis regulation through Nrf2 and implications for neurodegenerative diseases

Archives of Toxicology, Год журнала: 2024, Номер 98(3), С. 579 - 615

Опубликована: Янв. 24, 2024

Abstract This article provides an overview of the background knowledge ferroptosis in nervous system, as well key role nuclear factor E2-related 2 (Nrf2) regulating ferroptosis. The takes Alzheimer's disease (AD), Parkinson's (PD), Huntington's (HD), and amyotrophic lateral sclerosis (ALS) starting point to explore close association between Nrf2 ferroptosis, which is clear significant importance for understanding mechanism neurodegenerative diseases (NDs) based on oxidative stress (OS). Accumulating evidence links pathogenesis NDs. As progresses, damage antioxidant excessive OS, altered expression levels, especially inhibition by lipid peroxidation inhibitors adaptive enhancement signaling, demonstrate potential clinical significance detecting identifying targeted therapy neuronal loss mitochondrial dysfunction. These findings provide new insights possibilities treatment prevention

Язык: Английский

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Epigallocatechin-3-gallate: A phytochemical as a promising drug candidate for the treatment of Parkinson’s disease

Frontiers in Pharmacology, Год журнала: 2022, Номер 13

Опубликована: Сен. 12, 2022

Epigallocatechin 3-gallate (EGCG), an abundant polyphenolic component derived from green tea extract, possesses versatile bioactivities that can combat many diseases. During the last decade, EGCG was shown to be effective in experimental models of Parkinson's disease (PD). Several studies have suggested it has pleiotropic neuroprotective effects, which enhanced appeal as a therapeutic strategy PD. In this review, we compiled recent updates and knowledge molecular mechanisms underlying effects We focused on apoptosis, oxidative stress, inflammation, ferroptosis, modulation dopamine production, aggregation α-synuclein. The review highlights pharmacological features its implications Taken together, accumulated data indicate is promising compound for treatment

Язык: Английский

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Carbon Monoxide Signaling: Examining Its Engagement with Various Molecular Targets in the Context of Binding Affinity, Concentration, and Biologic Response

Pharmacological Reviews, Год журнала: 2022, Номер 74(3), С. 825 - 875

Опубликована: Июнь 23, 2022

Carbon monoxide (CO) has been firmly established as an endogenous signaling molecule with a variety of pathophysiological and pharmacological functions, including immunomodulation, organ protection, circadian clock regulation, among many others. In terms its molecular mechanism(s) action, CO is known to bind large number hemoproteins at least 25 identified targets, hemoglobin, myoglobin, neuroglobin, cytochrome c oxidase, P450, soluble guanylyl cyclase, myeloperoxidase, some ion channels dissociation constant values spanning the range sub-nM high μM. Although CO's binding affinity targets extensively studied established, there pressing need incorporate such information into analysis biologic response in context dosage. Especially important understand reservoir role hemoglobin storage, transport, distribution, transfer. We critically review literature inject sense quantitative assessment our analyses various relationships affinity, concentration, target occupancy level, anticipated actions. hope that this presents picture overall landscape engagement stimulates additional research, helps move field direction examining individual all concentration available CO. believe work will help further understanding relationship functions eventual development CO-based therapeutics.

Significance Statement

The carbon therapeutic agent significantly rely on therapeutically relevant varying affinity. This examines by quantitatively analyzing intricate for CO, state carboxyhemoglobin provide holistic approach action

Язык: Английский

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The Neuroprotective Effects and Therapeutic Potential of the Chalcone Cardamonin for Alzheimer’s Disease

Brain Sciences, Год журнала: 2023, Номер 13(1), С. 145 - 145

Опубликована: Янв. 14, 2023

Neurodegenerative diseases (ND) include a wide range of conditions that result from progressive damage to the neurons. Alzheimer's disease (AD) is one most common NDs, and neuroinflammation oxidative stress (OS) are major factors in development progression disease. Many naturally occurring phytochemical compounds exhibit antioxidant anti-inflammatory activities with potential neuroprotective effects. Several plant species, including Alpinia katsumadai conchigera, contain cardamonin (CD). CD (2',4'-dihydroxy-6'methoxychalcone) has many therapeutic properties, anticancer, anti-inflammatory, antioxidant, antiviral, antibiotic activities. potent compound can reduce OS modulate inflammatory processes play significant part developing neurodegenerative diseases. been shown variety signaling molecules involved ND, transcription (NF-kB STAT3), cytokines (TNF-α, IL-1, IL-6), enzymes (COX-2, MMP-9, ALDH1), other proteins genes (Bcl-2, XIAP, cyclin D1). Additionally, effectively modulates miRNA levels autophagy-related CD-protective mechanisms against neurodegeneration. In summary, this review provides mechanistic insights into CD's ability modify multiple stress-antioxidant system pathways, Nrf2, neuroinflammation. it points possible preventive utilization diseases, specifically AD.

Язык: Английский

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Neuroinflammation in Parkinson’s Disease: From Gene to Clinic: A Systematic Review

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(6), С. 5792 - 5792

Опубликована: Март 17, 2023

Parkinson’s disease is a neurodegenerative whose progression and clinical characteristics have close bidirectional multilevel relationship with the process of neuroinflammation. In this context, it necessary to understand mechanisms involved in neuroinflammation–PD link. This systematic search was, hereby, conducted focus on four levels where alterations associated neuroinflammation PD been described (genetic, cellular, histopathological clinical-behavioral) by consulting PubMed, Google Scholar, Scielo Redalyc engines, including studies, review articles, book chapters case studies. Initially, 585,772 articles were included, and, after applying inclusion exclusion criteria, 84 obtained that contained information about association gene, molecular, tissue neuroanatomical expression as well clinical-behavioral manifestations PD.

Язык: Английский

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Icariin prevents methylmercury-induced experimental neurotoxicity: Evidence from cerebrospinal fluid, blood plasma, brain samples, and in-silico investigations

Heliyon, Год журнала: 2024, Номер 10(1), С. e24050 - e24050

Опубликована: Янв. 1, 2024

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that causes significant neurodegeneration. Methylmercury (MeHg) neurotoxin induces axonal neurodegeneration and motor nerve degeneration by destroying oligodendrocytes, degenerating white matter, inducing apoptosis, excitotoxicity, reducing myelin basic protein (MBP). This study examines the inhibition of SIRT-1 (silence information regulator 1), Nrf-2 (nuclear factor E2-related 2), HO-1 (heme oxygenase TDP-43 (TAR-DNA-binding 43) accumulation in context ALS, as well modulation these proteins icariin (15 30 mg/kg, orally), glycoside flavonoid with neuroprotective properties. Neuroprotective activates SIRT-1, Nrf-2, HO-1, mitigating inflammation neuronal injury disorders. In-vivo in-silico testing experimental ALS models confirmed efficacy modulating cellular targets. The addition sirtinol 10 an inhibitor helps determine effectiveness icariin. In this study, we also examined neurobehavioral, neurochemical, histopathological, LFB (Luxol fast blue) markers various biological samples, including Cerebrospinal fluid (CSF), blood plasma, brain homogenates (Cerebral Cortex, Hippocampus, Striatum, mid-brain, Cerebellum). These results demonstrate administration ameliorates mechanism underlying benefits likely related to regulating signaling pathways.

Язык: Английский

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