Ferroptosis inhibitors: past, present and future

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: May 23, 2024

Ferroptosis is a non-apoptotic mode of programmed cell death characterized by iron dependence and lipid peroxidation. Since the ferroptosis was proposed, researchers have revealed mechanisms its formation continue to explore effective inhibitors in disease. Recent studies shown correlation between pathological neurodegenerative diseases, as well diseases involving tissue or organ damage. Acting on ferroptosis-related targets may provide new strategies for treatment ferroptosis-mediated diseases. This article specifically describes metabolic pathways summarizes reported action natural synthetic small molecule their efficacy The paper also treatments such gene therapy, nanotechnology, summarises challenges encountered clinical translation inhibitors. Finally, relationship other modes discussed, hopefully paving way future drug design discovery.

Language: Английский

---

Induction Mechanism of Ferroptosis, Necroptosis, and Pyroptosis: A Novel Therapeutic Target in Nervous System Diseases

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(12), P. 10127 - 10127

Published: June 14, 2023

In recent years, three emerging cell deaths, ferroptosis, necroptosis and pyroptosis, have gradually attracted everyone’s attention, they also play an important role in the occurrence development of various diseases. Ferroptosis is idiographic iron-dependent form regulated death with hallmark accumulation intracellular reactive oxygen species (ROS). Necroptosis a necrotic mediated by receptor-interacting protein kinase 1(RIPK1) 3RIPK3. Pyroptosis, known as inflammatory necrosis, programmed necrosis Gasdermin D (GSDMD). It manifested continuous swelling cells until membrane ruptures, resulting release contents activation strong response. Neurological disorders remain clinical challenge patients do not respond well to conventional treatments. Nerve can aggravate neurological This article reviews specific mechanisms these types their relationship diseases evidence for diseases; understanding pathways helpful treatment

Language: Английский

---

The function of sphingolipids in different pathogenesis of Alzheimer's disease: A comprehensive review

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 171, P. 116071 - 116071

Published: Jan. 6, 2024

Sphingolipids (SPLs) represent a highly diverse and structurally complex lipid class. The discussion of SPL metabolism-related issues is importance in understanding the neuropathological progression Alzheimer's disease (AD). AD characterized by accumulation extracellular deposits amyloid β-peptide (Aβ) intraneuronal aggregates microtubule-associated protein tau. Critical roles Aβ oligomer deposited ganglioside GM1 could be formed as "seed" from insoluble GAβ polymer initiating pathogenic process, while tau might also mediate SPLs their toxicity. interaction between ceramide α-Synuclein (α-Syn) accelerates aggregation ferroptosis exacerbates pathogenesis AD. For instance, reducing levels can mitigate α-Syn inhibit progression. Meanwhile, loss may expression APOE4 confer protection against AD, disrupts homeostasis. Moreover, heightened activation sphingomyelinase promotes signaling pathway, leading to exacerbated symptoms. Ferroptosis plays vital role pathological influencing Aβ, tau, APOE, α-Syn. Conversely, development manifestation SPLs. We are compiling emerging techniques (Derivatization IM-MS) sphingolipidomics, overcome challenges diagnosis treatment. In this review, we examined intricate neuro-mechanistic interactions α-Syn, ferroptosis, mediating onset Furthermore, our findings highlight potential targeting underexplored avenue for devising innovative therapeutic strategies

Language: Английский

---

Polycatechols inhibit ferroptosis and modulate tau liquid–liquid phase separation to mitigate Alzheimer's disease

Materials Horizons, Journal Year: 2024, Volume and Issue: 11(13), P. 3082 - 3089

Published: Jan. 1, 2024

Polycatechols modulate amyloid-associated toxicities, arrest labile iron, inhibit lipid peroxidation, and regulate tau liquid–liquid phase separation (LLPS) to mitigate the pathological nexus between ferroptosis AD.

Language: Английский

---

Potential role and therapeutic implications of glutathione peroxidase 4 in the treatment of Alzheimer’s disease

Neural Regeneration Research, Journal Year: 2024, Volume and Issue: 20(3), P. 613 - 631

Published: March 1, 2024

Alzheimer’s disease is an age-related neurodegenerative disorder with a complex and incompletely understood pathogenesis. Despite extensive research, cure for has not yet been found. Oxidative stress mediates excessive oxidative responses, its involvement in pathogenesis as primary or secondary pathological event widely accepted. As member of the selenium-containing antioxidant enzyme family, glutathione peroxidase 4 reduces esterified phospholipid hydroperoxides to maintain cellular redox homeostasis. With discovery ferroptosis, central role anti-lipid peroxidation several diseases, including disease, received widespread attention. Increasing evidence suggests that expression inhibited brain, resulting stress, inflammation, apoptosis, which are closely associated damage disease. Several therapeutic approaches, such small molecule drugs, natural plant products, non-pharmacological treatments, ameliorate cognitive function by promoting enhancing activity. Therefore, upregulation may be promising strategy treatment This review provides overview gene structure, biological functions, regulatory mechanisms 4, discussion on important events related summary advances small-molecule therapies targeting Most prior studies this subject used animal models, relevant clinical lacking. Future trials required validate effects strategies

Language: Английский

---

Autophagy–lysosomal-associated neuronal death in neurodegenerative disease

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 148(1)

Published: Sept. 11, 2024

Language: Английский

---

Electrochemical Immunosensors Developed for Amyloid-Beta and Tau Proteins, Leading Biomarkers of Alzheimer’s Disease

Biosensors, Journal Year: 2023, Volume and Issue: 13(7), P. 742 - 742

Published: July 17, 2023

Alzheimer's disease (AD) is the most common neurological and a serious cause of dementia, which constitutes threat to human health. The clinical evidence has found that extracellular amyloid-beta peptides (Aβ), phosphorylated tau (p-tau), intracellular proteins, are derived from amyloid precursor protein (APP), leading biomarkers for accurate early diagnosis AD due their central role in pathology, correlation with progression, diagnostic value, implications therapeutic interventions. Their detection monitoring contribute significantly understanding advancing care. Available techniques, including magnetic resonance imaging (MRI) positron emission tomography (PET), mainly used validate diagnosis. However, these methods expensive, yield results difficult interpret, have side effects such as headaches, nausea, vomiting. Therefore, researchers focused on developing cost-effective, portable, point-of-care alternative devices detect specific cerebrospinal fluid (CSF) other biofluids. In this review, we summarized recent progress electrochemical immunosensors detecting (Aβ p-tau protein) subtypes (AβO, Aβ(1-40), Aβ(1-42), t-tau, cleaved-tau (c-tau), p-tau181, p-tau231, p-tau381, p-tau441). We also evaluated key characteristics performance developed immunosensing platforms, signal interfaces, nanomaterials or amplifiers, biofunctionalization methods, even primary sensing performances (i.e., sensitivity, linear range, limit (LOD), application).

Language: Английский

---

A critical appraisal of ferroptosis in Alzheimer’s and Parkinson’s disease: new insights into emerging mechanisms and therapeutic targets

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: July 8, 2024

Neurodegenerative diseases represent a pressing global health challenge, and the identification of novel mechanisms underlying their pathogenesis is utmost importance. Ferroptosis, non-apoptotic form regulated cell death characterized by iron-dependent lipid peroxidation, has emerged as pivotal player in neurodegenerative diseases. This review delves into discovery ferroptosis, critical players involved, intricate role neurodegeneration, with an emphasis on Alzheimer’s Parkinson’s We critically appraise unsolved mechanistic links involved initiation propagation such signaling cascade resulting de-repression lipoxygenase translation played mitochondrial voltage-dependent anionic channels iron homeostasis. Particular attention given to dual heme oxygenase which may be linked non-specific activity P450 reductase endoplasmic reticulum. Despite limited knowledge ferroptosis progression Nrf2/Bach1 target genes have crucial defenders anti-ferroptotic pathways. The activation Nrf2 inhibition Bach1 can counteract present promising avenue for future therapeutic interventions targeting

Language: Английский

---

A New Perspective in the Treatment of Ischemic Stroke: Ferroptosis

Neurochemical Research, Journal Year: 2024, Volume and Issue: 49(4), P. 815 - 833

Published: Jan. 3, 2024

Language: Английский

---

Drug Development for Alzheimer’s and Parkinson’s Disease: Where Do We Go Now?

Pharmaceutics, Journal Year: 2024, Volume and Issue: 16(6), P. 708 - 708

Published: May 24, 2024

Neurodegenerative diseases (NDs) are a set of progressive, chronic, and incurable characterized by the gradual loss neurons, culminating in decline cognitive and/or motor functions. Alzheimer’s disease (AD) Parkinson’s (PD) most common NDs represent an enormous burden both terms human suffering economic cost. The available therapies for AD PD only provide symptomatic palliative relief limited period unable to modify diseases’ progression. Over last decades, research efforts have been focused on developing new pharmacological treatments these NDs. However, date, no breakthrough treatment has discovered. Hence, development disease-modifying drugs able halt or reverse progression remains unmet clinical need. This review summarizes major hallmarks treatment. It also sheds light potential directions that can be pursued develop new, treat PD, describing as representative examples some advances drug candidates targeting oxidative stress adenosine A2A receptors.

Language: Английский

---