Isocitrate dehydrogenase (IDH) mutation is a common genetic abnormality in human malignancies characterized by remarkable metabolic reprogramming. Our present study demonstrated that IDH1-mutated cells showed elevated levels of reactive oxygen species and higher demands on Nrf2-guided glutathione de novo synthesis. Our findings showed that triptolide, a diterpenoid epoxide from Tripterygium wilfordii, served as a potent Nrf2 inhibitor, which exhibited selective cytotoxicity to patient-derived IDH1-mutated glioma cells in vitro and in vivo. Mechanistically, triptolide compromised the expression of GCLC, GCLM, and SLC7A11, which disrupted glutathione metabolism and established synthetic lethality with reactive oxygen species derived from IDH1 mutant neomorphic activity. Our findings highlight triptolide as a valuable therapeutic approach for IDH1-mutated malignancies by targeting the Nrf2-driven glutathione synthesis pathway.

https://www.pnas.org/content/pnas/117/18/9964.full.pdf

Triptolide suppresses IDH1-mutated malignancy via Nrf2-driven glutathione metabolism

Triptolide (TP), a major active and toxic ingredient isolated from the traditional Chinese herb Tripterygium wilfordii Hook f. (TWHF). A widespread application of TP raises the question on the safety of its use in clinical settings. The metabolism of TP is mediated by hepatic cytochrome P450s, and a strong correlation exists between TP toxicity and CPY3A. Toxicity of TP and the molecular mechanisms of its toxic effects have been studied in recent years. Studies have demonstrated that TP exposure results in injury of various organs, including the liver, kidney, testes, ovary, and heart in animals and even in humans, according to clinical case reports. Moreover, on the cellular level, TP has been reported to be associated with diverse toxic effects, encompassing membrane damage, mitochondrial disruption, metabolism dysfunction, endoplasmic reticulum stress, oxidative stress, apoptosis and autophagy. This review presents an overview of the current findings related to TP toxicity with an emphasis on biological targets and the molecular mechanisms that may be involved, thus providing a systematic understanding of the mechanisms by which TP affects cells and tissues in vitro and in vivo.

Iconographies supplémentaires de l'article : Toxicity of triptolide and the molecular mechanisms involved

Background and Purpose:
Increasing evidence suggests systemic inflammation-caused skeletal muscle atrophy as a major clinical feature of cachexia Triptolide obtained from Tripterygium wilfordii Hook F possesses potent anti-inflammatory and immunosuppressive effects The present study aims to evaluate the protective effects and molecular mechanisms of triptolide on inflammation-induced skeletal muscle atrophy

Experimental Approach:
The effects of triptolide on skeletal muscle atrophy were investigated in LPS-treated C2C12 myotubes and C57BL/6 mice Protein expressions and mRNA levels were analysed by western blot and qPCR, respectively Skeletal muscle mass, volume and strength were measured by histological analysis, micro-CT and grip strength, respectively Locomotor activity was measured using the open field test

KEY RESULTS:
Triptolide (10–100 fM) up-regulated protein synthesis signals (IGF-1/p-IGF-1R/IRS-1/p-Akt/p-mTOR) and down-regulated protein degradation signal atrogin-1 in C2C12 myotubes In LPS (100 ng·ml−1)-treated C2C12 myotubes, triptolide up-regulated MyHC, IGF-1, p-IGF-1R, IRS-1 and p-Akt Triptolide also down-regulated ubiquitin-proteasome molecules (n-FoxO3a/atrogin-1/MuRF1), proteasome activity, autophagy-lysosomal molecules (LC3-II/LC3-I and Bnip3) and inflammatory mediators (NF-κB, Cox-2, NLRP3, IL-1β and TNF-α) However, AG1024, an IGF-1R inhibitor, suppressed triptolide-mediated effects on MyHC, myotube diameter, MuRF1 and p62 in LPS-treated C2C12 myotubes In LPS (1 mg·kg−1, ip)-challenged mice, triptolide (5 and 20 μg·kg−1·day−1, ip) decreased plasma TNF-α levels and it increased skeletal muscle volume, cross-sectional area of myofibers, weights of the gastrocnemius and tibialis anterior muscles, forelimb grip strength and locomotion

Conclusions and Implications:
These findings reveal that triptolide prevented LPS-induced inflammation and skeletal muscle atrophy and have implications for the discovery of novel agents for preventing muscle wasting

Triptolide prevents LPS-induced skeletal muscle atrophy via inhibiting NF-κB/TNF-α and regulating protein synthesis/degradation pathway.

The transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) triggers homeostatic responses against a plethora of environmental or endogenous deviations in redox metabolism, inflammation, proteostasis, etc. Therefore, pharmacological activation of NRF2 is a promising therapeutic strategy for several chronic diseases that are underlined by low-grade oxidative inflammation and dysregulation of redox metabolism, such as neurodegenerative, cardiovascular, and metabolic diseases. While NRF2 activation is useful in inhibiting carcinogenesis, its inhibition is needed in constituted tumors where NRF2 provides a survival advantage in the challenging tumor niche. This review describes the electrophilic and non-electrophilic NRF2 activators with clinical projection in various chronic diseases. We also analyze the status of NRF2 inhibitors, which are for the moment in a proof-of-concept stage. Advanced in silico screening and medicinal chemistry are expected to provide new or repurposing small molecules with increased potential for fostering the development of targeted NRF2 modulators. The nuclear factor erythroid 2 (NFE2)-related factor 2 (NRF2) is rapidly degraded by proteasomes under a basal condition in a Keap1-dependent manner. ROS oxidatively modifies Keap1 to release NRF2 and allow its nuclear translocation. Here it binds to the antioxidant response element to regulate gene transcription. An alternative mechanism controlling NRF2 stability is glycogen synthase kinase 3 (GSK-3)-induced phosphorylation. Indicated in blue are NRF2-activating and NRF2-inhibiting drugs.

Perspectives on the Clinical Development of NRF2-Targeting Drugs.

Alzheimer's disease (AD) is the most common form of dementia. An increasing body of evidence describes an elevated incidence of epilepsy in patients with AD, and many transgenic animal models of AD also exhibit seizures and susceptibility to epilepsy. However, the biological mechanisms that underlie the occurrence of seizure or increased susceptibility to seizures in AD is unknown. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that regulates various cellular signaling pathways, and plays a crucial role in the pathogenesis of AD. It has been suggested that GSK-3 might be a key factor that drives epileptogenesis in AD by interacting with the pathological hallmarks of AD, amyloid precursor protein (APP) and tau. Furthermore, seizures may also contribute to the progression of AD through GSK-3. In this way, GSK-3 might be involved in initiating a vicious cycle between AD and seizures. This review aims to summarise the possible role of GSK-3 in the link between AD and seizures. Understanding the role of GSK-3 in AD-associated seizures and epilepsy may help researchers develop new therapeutic approach that can manage seizure and epilepsy in AD patients as well as decelerate the progression of AD.

/pdf/unravelling-the-role-of-glycogen-synthase-kinase-3-in-1vy2fzm3wm.pdf

Jia Li

Papers

Triptolide induces oxidative damage in NRK-52E cells through facilitating Nrf2 degradation by ubiquitination via the GSK-3β/Fyn pathway.