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Glutathione dynamics determines therapeutic efficacy of mesenchymal stem cells for graft-versus-host disease through CREB1-NRF2 pathway

ABSTRACT: Glutathione dynamics determines therapeutic efficacy of mesenchymal stem cells for graft-versus-host disease through CREB1-NRF2 pathway

PROVIDER: PRJNA560907 | ENA |

REPOSITORIES: ENA

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Glutathione dynamics determines therapeutic efficacy of mesenchymal stem cells for graft-versus-host disease through CREB1-NRF2 pathway

Project description:Molecular and functional significance of CREB1-NRF2 pathway on GSH dynamics of MSCs which critically determines therapeutic outcomes for treating allogeneic conflicts, including GvHD. A simple and reliable method to real-time monitor the redox status of MSCs which precisely predict their core functions including self-renewal, migration, and immunomodulatory capacities.

2020-06-04 | GSE135998 | GEO

Glutathione dynamics determine the therapeutic efficacy of mesenchymal stem cells for graft-versus-host disease via CREB1-NRF2 pathway.

Project description: Not available

| S-EPMC7239701 | biostudies-literature

Glutathione supplementation improves fat graft survival by inhibiting ferroptosis via the SLC7A11/GPX4 axis

Project description:Background: Autologous fat grafting is hampered by unpredictable graft survival, which is potentially regulated by ferroptosis. Glutathione (GSH), a powerful antioxidant used in tissue preservation, has ferroptosis-regulating activity; however, its effects on fat grafts are unclear. This study investigated the effects and mechanisms of GSH in fat graft survival. Methods: Human lipoaspirates were transplanted subcutaneously into the backs of normal saline-treated (control) or GSH-treated nude mice. Graft survival was evaluated by magnetic resonance imaging and histology. RNA sequencing was performed to identify differentially expressed genes and enriched pathways. GSH activity was evaluated in vitro using an oxygen and glucose deprivation (OGD) model of adipose-derived stem cells. Results: Compared with control group, GSH induced better outcomes, including superior graft retention, appearance, and histological structures. RNA sequencing suggested enhanced negative regulation of ferroptosis in the GSH-treated grafts, which showed reduced lipid peroxides, better mitochondrial ultrastructure, and SLC7A11/GPX4 axis activation. In vitro, OGD-induced ferroptosis was ameliorated by GSH, which restored cell proliferation, reduced oxidative stress, and upregulated ferroptosis defense factors. Conclusions: Our study confirms that ferroptosis participates in regulating fat graft survival and that GSH exerts a protective effect by inhibiting ferroptosis. GSH-assisted lipotransfer is a promising therapeutic strategy for future clinical application.

2023-05-08 | GSE231511 | GEO

Pyridoxine induces glutathione synthesis via PKM2-mediated Nrf2 transactivation and confers neuroprotection

Project description:Pyridoxine induces glutathione synthesis via PKM2-mediated Nrf2 transactivation and confers neuroprotection

| PRJNA599135 | ENA

Effect of liver-specific deletion of Gclc, Nrf2, and Gclc-Nrf2 on the liver

Project description:The rate-limiting step in glutathione (GSH) synthesis is controlled by glutamate-cysteine ligase catalytic subunit. GSH is reported to buffer oxidative stress. In the absence of GSH, the antioxidant transcription factor Nrf2 is reported to be stabilized. The liver has the highest levels of GSH, but its impact on liver homeostasis is unclear. To investigate this, we induced a liver-specific deletion of Gclc (Gclc f/f), Nrf2 (Nrf2 f/f), or Gclc-Nrf2 (Gclc f/f Nrf2 f/f) by injecting my via tail-vein with AAV-TBG-Cre, which induces recombination specifically in hepatocytes.

2024-05-29 | GSE263119 | GEO

Pyridoxine induces glutathione synthesis via PKM2-mediated Nrf2 transactivation and confers neuroprotection

Project description:Oxidative stress is a major pathogenic mechanism in Parkinson’s disease (PD). As an important cellular antioxidant, glutathione (GSH) balances the production and incorporation of free radicals to protect neurons from oxidative damage. Unfortunately, the GSH level is greatly decreased in the brains of PD patients. Hence, clarifying the molecular mechanism of GSH deficiency may help deepen our knowledge of PD pathogenesis. Here we report that the astrocytic dopamine D2 receptor (DRD2) regulates GSH synthesis via PKM2-mediated Nrf2 transactivation. Besides, we find that pyridoxine can dimerize PKM2 to promote GSH biosynthesis. Further experiments show that pyridoxine supplementation increases the resistance of nigral dopaminergic neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in wild-type mice as well as in astrocytic Drd2 conditional knockout mice. Given that dopamine agonist treatment in PD is limited by their intolerable side effects and diminished effectiveness over time, we anticipate dimerizing PKM2 to be a new strategy for PD treatment.

2020-02-04 | GSE143164 | GEO

Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion

Project description:Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion

| PRJNA559171 | ENA

Nrf2 transcript alterations

Project description:WGS and RNA-seq data for Nrf2 study

| EGAS00001001740 | EGA

Depletion of Nrf2 in pancreatic cancer cells shifts arginine metabolism into the phosphocreatine energy system

Project description:Depletion of Nrf2 leads to an increase in cellular ROS, reduced glutathione and thiols, and profound reprogramming of metabolism. Unbiased transcriptome analyses show that key enzymes of glycolysis, pentose phosphate pathway, and glutathione cycle are significantly downregulated, while enzymes of arginine and medium-chain fatty acids metabolism are upregulated. Besides glutamine, pancreatic cancer cells deficient of Nrf2 axis become highly dependent on arginine, which is channelled into the synthesis of phosphocreatine and polyamines. Key enzymes of the creatine pathway, gatm and ckb, are more expressed and more active in Nrf2(-/-) than in WT cells. This metabolism shift creates an energy buffer that enables pancreatic cancer cells to handle increased energy demand. Metabolomic analysis showed that 12% of the creatine pool is phosphorylated in Nrf2(-/-) cells, while the level drops to < 0.1% in WT cells. The inhibition of the creatine pathway with cyclocreatine in Nrf2(-/-) cells, reduces by 43% the ATP level and by 70% invasion rate in matrigel. Furthermore, we found that combination therapies that can target simultaneously the creatine pathway and the KRAS G12D-Nrf2 axis produce a stronger anticancer effect than monotherapies. Taken together, our data provide the basis for the rationale design of new combination therapies against pancreatic cancer. The KRAS G12D-Nrf2 axis controls redox homeostasis and metabolism in PDAC cells. Suppression of KRAS G12D-Nrf2 decreases glycolysis, PPP and glutathione cycle and promotes a metabolic shift of arginine into the synthesis of phosphocreatine

2023-12-12 | GSE217965 | GEO

RNAi-mediated ablation of Nrf2 in PyMT-1099 LT, Py2T LT and MT∆Ecad mesenchymal breast cancer cells

Project description:Background: Epithelial-mesenchymal transition (EMT) has been implicated in metastasis, drug resistance, survival under stress and also conferring stem cell-like traits to cancer cells. We have aimed at exploring the crosstalk between ROS and an EMT induced by TGFb in breast cancer cells. Methods: We observed that cells exposed to TGFb displayed a decrease of ROS levels. Furthermore, we identified an activation of the Nrf2 transcription factor, master regulator of the antioxidant response in TGFb-induced mesenchymal cells. In order to know the effect of Nrf2 ablation in epithelial and mesenchymal cells, RNAi-mediated ablation for Nrf2 was performed. Results: RNAi-mediated ablation of Nrf2 led to mesenchymal cancer cell death due to ferroptosis, an iron- and oxidative stress-dependent cell death. Moreover, analysis revealed that several glutathione pathway genes were specifically regulated by Nrf2, suggesting a role of glutathione-related pathways in mesenchymal cell survival. Conclusion: In this study we report the criticial role of the Nrf2-mediated glutathione metabolism in the protection of metastatic breast cancer cells from ferroptosis. Therapeutic targeting of antioxidant pathways may thus be beneficial for patients with metastatic disease.

2022-10-15 | GSE187478 | GEO

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