Identification of a potent Nrf2 displacement activator among aspirin-containing prodrugs

Gaisina, Irina N.; Hushpulian, Dmitry M.; Gaisin, Arsen; Kazakov, Eliot H.; Kaidery, Navneet Ammal; Ahuja, Manuj; Poloznikov, Andrey; Gazaryan, Irina G.; Thatcher, Gregory R. J.; Thomas, Bobby

doi:10.1016/j.neuint.2021.105148

Cited by 5 publications

(5 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Human hepatocellular carcinoma cell line. Human hepatocellular carcinoma HepG2 cells (ATCC HB-8065; passage [20][21][22][23][24][25], purchased from Health Protection Agency Culture Collections (ECACC, Salisbury, UK), were cultured in minimum essential Eagle medium supplemented with 10% v/v fetal bovine serum and 1% v/v L-glutamine solution (Sigma-Aldrich, St. Louis, MO, USA) at 37 °C in a humidified atmosphere containing 5% CO 2 . For passaging, the cells were treated with trypsin/EDTA (Sigma-Aldrich, St. Louis, USA) at 37 °C and then harvested.…”

Section: In Silico Studiesmentioning

confidence: 99%

“…Besides its exclusive hydrolysis of choline esters, BChE is implicated in metabolizing esters such as butyrylcholine, succinylcholine, cocaine, or aspirin. [20][21][22][23][24] Since Broomfield et al first demonstrated the BChE neuroprotective function against neurotoxic agents in 1991, it has garnered substantial attention within the scientific community. 25 Its pivotal role in neurodegenerative disorders, especially Alzheimer's disease (AD), has emerged as a focal point of research.…”

Section: Introductionmentioning

confidence: 99%

“…Besides its exclusive hydrolysis of choline esters, BChE is implicated in metabolizing esters such as butyrylcholine, succinylcholine, cocaine, or aspirin. 20–24…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Carltonine-derived compounds for targeted butyrylcholinesterase inhibition

Pidany,

Kroustkova,

Jenco

et al. 2024

RSC Med. Chem.

View full text Add to dashboard Cite

show abstract

Section: In Silico Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Carltonine-derived compounds for targeted butyrylcholinesterase inhibition

Pidany,

Kroustkova,

Jenco

et al. 2024

RSC Med. Chem.

View full text Add to dashboard Cite

show abstract

“…[23] Chemical modification of Keap1 by Nrf2 activators is not specific to Keap1 and creates an additional "chemical" stress on sensitive proteins with active thiols and selenothiols. Activation by competitive displacement of Nrf2 from Keap1 in the ubiquitin ligase complex by peptides or small molecules is not efficient, [24][25][26][27][28] so the new trend in research is to combine an alkylating motif with the Keap1 recognition [29] to warrant more specific targeting to Keap1-Nrf2 couple. However, as we discussed previously, [30] even in this scenario, numerous yet uncharacterized adapter proteins in the Keap1 family of proteins can potentially be targeted, leading to unpredicted side effects.…”

Section: Regulation Of the Nrf2 Signaling Pathwaymentioning

confidence: 99%

Emerging small molecule inhibitors of Bach1 as therapeutic agents: Rationale, recent advances, and future perspectives

Hushpulian,

Kaidery,

Dutta

et al. 2023

BioEssays

Self Cite

View full text Add to dashboard Cite

The transcription factor Nrf2 is the master regulator of cellular stress response, facilitating the expression of cytoprotective genes, including those responsible for drug detoxification, immunomodulation, and iron metabolism. FDA‐approved Nrf2 activators, Tecfidera and Skyclarys for patients with multiple sclerosis and Friedreich's ataxia, respectively, are non‐specific alkylating agents exerting side effects. Nrf2 is under feedback regulation through its target gene, transcriptional repressor Bach1. Specifically, in Parkinson's disease and other neurodegenerative diseases with Bach1 dysregulation, excessive Bach1 accumulation interferes with Nrf2 activation. Bach1 is a heme sensor protein, which, upon heme binding, is targeted for proteasomal degradation, relieving the repression of Nrf2 target genes. Ideally, a combination of Nrf2 stabilization and Bach1 inhibition is necessary to achieve the full therapeutic benefits of Nrf2 activation. Here, we discuss recent advances and future perspectives in developing small molecule inhibitors of Bach1, highlighting the significance of the Bach1/Nrf2 signaling pathway as a promising neurotherapeutic strategy.

show abstract

“…It was later discovered that acetylsalicylic acid itself is effective in disrupting prostaglandin synthesis (Willetts & Foley, 2020). There is now considerable research into finding a true aspirin prodrug, which may reduce the known gastric effects of aspirin (Gaisina et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

The use of prodrugs as drugs of abuse

Ponce

2024

WIREs Forensic Science

View full text Add to dashboard Cite

Prodrugs are an important strategy for the development and design of therapeutic drugs. They involve the addition of an easily removable group (such as an ester) to a molecule in order to chemically protect it from metabolism, hydrolysis, or interaction with tissues. In the therapeutic drug market, prodrugs may reduce adverse effects, lead to more accurate tissue delivery, increase bioavailability and duration of effects. The same strategy has, however, been used in the illicit drug market. Internationally controlled drugs such as LSD, MDMA and benzodiazepines have been detected in the market with the addition of alkyl chain that can be removed in physiological conditions. Cyclical analogues may also be used, as is the case for 1cP‐LSD and GBL (a prodrug of GHB). Adequate detection requires increased care with extraction and analytical conditions—as the parent drugs may be formed as artifacts during these processes—and an in‐depth knowledge of metabolic pathways to avoid erroneous detection and allow for adequate identification of the drug used. Legislative updates may also be necessary to ensure prodrugs can be controlled at the same level as other illicit drugs.This article is categorized under: Toxicology > New Psychoactive Substances Toxicology > Drug Analysis Toxicology > Analytical

show abstract

Identification of a potent Nrf2 displacement activator among aspirin-containing prodrugs

Cited by 5 publications

References 21 publications

Carltonine-derived compounds for targeted butyrylcholinesterase inhibition

Carltonine-derived compounds for targeted butyrylcholinesterase inhibition

Emerging small molecule inhibitors of Bach1 as therapeutic agents: Rationale, recent advances, and future perspectives

The use of prodrugs as drugs of abuse

Contact Info

Product

Resources

About