Emerging therapeutic opportunities of novel thiol-amides, NAC-amide (AD4/NACA) and thioredoxin mimetics (TXM-Peptides) for neurodegenerative-related disorders

Atlas, Daphné

doi:10.1016/j.freeradbiomed.2021.08.239

Cited by 22 publications

(19 citation statements)

References 132 publications

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“…N -acetyl cysteine amide (AD4) is a blood–brain barrier penetrating antioxidant that reduces oxidative stress. 144 , 145 AD4 delayed disease onset and reduced the severity of the disease phenotype, marked by improved motor function at PD30. 80 The reactive oxygen species scavenger KH176 (sonlicromanol) is based on the vitamin E-derivative trolox.…”

Section: Intervention Studies In Ndufs4 Mouse Modelsmentioning

confidence: 99%

Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention

Wal

Adjobo‐Hermans

Keijer

et al. 2021

Brain

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Mitochondria are small cellular constituents that generate cellular energy (ATP) by oxidative phosphorylation (OXPHOS). Dysfunction of these organelles is linked to a heterogeneous group of multisystemic disorders, including diabetes, cancer, ageing-related pathologies and rare mitochondrial diseases (MDs). With respect to the latter, mutations in subunit-encoding genes and assembly factors of the first OXPHOS complex (CI) induce isolated CI deficiency and Leigh syndrome (LS). This syndrome is an early-onset, often fatal, encephalopathy with a variable clinical presentation and poor prognosis due to the lack of effective intervention strategies. Mutations in the nuclear DNA (nDNA)-encoded NDUFS4 gene, encoding the NADH: Ubiquinone oxidoreductase subunit S4 (NDUFS4) of CI induce “mitochondrial complex I deficiency, nuclear type 1” (MC1DN1) and LS in pediatric patients. A variety of (tissue-specific) Ndufs4 knockout mouse models were developed to study the LS pathomechanism and intervention testing. Here, we review and discuss the role of CI and NDUFS4 mutations in human MD, and review how the analysis of Ndufs4 knockout mouse models has generated new insights into the MC1ND1/LS pathomechanism and its therapeutic targeting.

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Section: Intervention Studies In Ndufs4 Mouse Modelsmentioning

confidence: 99%

Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention

Wal

Adjobo‐Hermans

Keijer

et al. 2021

Brain

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“…Thus, the clinical effect of NAC for the treatment of RA patients remains controversial. Recently, novel thiol-amides, NAC-amide (AD4/NACA), and thioredoxin mimetics (TXM-peptides) have been tested for neurodegenerative disorders [ 142 ]. The AD4 compound was effective at blocking cocaine-seeking behaviors [ 143 ].…”

Section: Natural Foods Phytochemicals and Chemical Compounds With Ant...mentioning

confidence: 99%

Rheumatoid Arthritis and Reactive Oxygen Species: A Review

Kondo

Kanai

Okada

2023

CIMB

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Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease that causes progressive joint damage and can lead to lifelong disability. Numerous studies support the hypothesis that reactive oxygen species (ROS) are associated with RA pathogenesis. Recent advances have clarified the anti-inflammatory effect of antioxidants and their roles in RA alleviation. In addition, several important signaling pathway components, such as nuclear factor kappa B, activator-protein-1, nuclear factor (erythroid-derived 2)-like 2/kelch-like associated protein, signal transducer and activator of transcription 3, and mitogen-activated protein kinases, including c-Jun N-terminal kinase, have been identified to be associated with RA. In this paper, we outline the ROS generation process and relevant oxidative markers, thereby providing evidence of the association between oxidative stress and RA pathogenesis. Furthermore, we describe various therapeutic targets in several prominent signaling pathways for improving RA disease activity and its hyper oxidative state. Finally, we reviewed natural foods, phytochemicals, chemical compounds with antioxidant properties and the association of microbiota with RA pathogenesis.

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“…Significant research focused in this direction has been pivotal in exploring new horizons with the designing of small, specific, biologically active novel thiol-amides and mimetic peptides derived from the catalytic CXXC/CXC motifs, namely CB3, CB4, CB6, CB16, NAC-amides which have clearly demonstrated their roles in restoring disrupted redox state, reducing inflammation, atherosclerotic lesions, inhibition of NF-κB, JNK-p38 MAPK pathways, upregulation of GSH levels in vivo and in vitro [ 174 , 175 , 176 ]. These compounds can reverse cellular oxidative stress in a manner analogous to the Trx dithiol-disulfide exchange reaction mechanism by crossing the blood–brain barrier or permeating through the cell membrane, thus garnering further interest in developing antioxidant therapeutics based on synthetic peptides as feasible alternatives in oxidative-stress-related disorders [ 71 , 175 , 177 , 178 ].…”

Section: Drugs and Treatments: Current Potential And Challengesmentioning

confidence: 99%

S-Denitrosylation: A Crosstalk between Glutathione and Redoxin Systems

et al. 2022

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S-nitrosylation of proteins occurs as a consequence of the derivatization of cysteine thiols with nitric oxide (NO) and is often associated with diseases and protein malfunction. Aberrant S-nitrosylation, in addition to other genetic and epigenetic factors, has gained rapid importance as a prime cause of various metabolic, respiratory, and cardiac disorders, with a major emphasis on cancer and neurodegeneration. The S-nitrosoproteome, a term used to collectively refer to the diverse and dynamic repertoire of S-nitrosylated proteins, is relatively less explored in the field of redox biochemistry, in contrast to other covalently modified versions of the same set of proteins. Advancing research is gradually unveiling the enormous clinical importance of S-nitrosylation in the etiology of diseases and is opening up new avenues of prompt diagnosis that harness this phenomenon. Ever since the discovery of the two robust and highly conserved S-nitrosoglutathione reductase and thioredoxin systems as candidate denitrosylases, years of rampant speculation centered around the identification of specific substrates and other candidate denitrosylases, subcellular localization of both substrates and denitrosylases, the position of susceptible thiols, mechanisms of S-denitrosylation under basal and stimulus-dependent conditions, impact on protein conformation and function, and extrapolating these findings towards the understanding of diseases, aging and the development of novel therapeutic strategies. However, newer insights in the ever-expanding field of redox biology reveal distinct gaps in exploring the crucial crosstalk between the redoxins/major denitrosylase systems. Clarifying the importance of the functional overlap of the glutaredoxin, glutathione, and thioredoxin systems and examining their complementary functions as denitrosylases and antioxidant enzymatic defense systems are essential prerequisites for devising a rationale that could aid in predicting the extent of cell survival under high oxidative/nitrosative stress while taking into account the existence of the alternative and compensatory regulatory mechanisms. This review thus attempts to highlight major gaps in our understanding of the robust cellular redox regulation system, which is upheld by the concerted efforts of various denitrosylases and antioxidants.

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Emerging therapeutic opportunities of novel thiol-amides, NAC-amide (AD4/NACA) and thioredoxin mimetics (TXM-Peptides) for neurodegenerative-related disorders

Cited by 22 publications

References 132 publications

Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention

Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention

Rheumatoid Arthritis and Reactive Oxygen Species: A Review

S-Denitrosylation: A Crosstalk between Glutathione and Redoxin Systems

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