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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 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

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

Project description:Glutathione (GSH), the most abundant nonprotein thiol functioning as an antioxidant, plays critical roles in maintaining the core functions of mesenchymal stem cells (MSCs), which are used as a cellular immunotherapy for graft-versus-host disease (GVHD). However, the role of GSH dynamics in MSCs remains elusive. Genome-wide gene expression profiling and high-throughput live-cell imaging assays revealed that CREB1 enforced the GSH-recovering capacity (GRC) of MSCs through NRF2 by directly up-regulating NRF2 target genes responsible for GSH synthesis and redox cycling. MSCs with enhanced GSH levels and GRC mediated by CREB1-NRF2 have improved self-renewal, migratory, anti-inflammatory, and T cell suppression capacities. Administration of MSCs overexpressing CREB1-NRF2 target genes alleviated GVHD in a humanized mouse model, resulting in improved survival, decreased weight loss, and reduced histopathologic damages in GVHD target organs. Collectively, these findings demonstrate the molecular and functional importance of the CREB1-NRF2 pathway in maintaining MSC GSH dynamics, determining therapeutic outcomes for GVHD treatment.

| S-EPMC7239701 | biostudies-literature

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

GDF15-GFRAL orchestrates glutathione synthesis via NRF2-elicited GCLC activation to impedes cuproptosis

Project description:GDF15-GFRAL orchestrates glutathione synthesis via NRF2-elicited GCLC activation to impedes cuproptosis

| PRJNA936846 | ENA

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

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

| PRJNA966173 | ENA

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

Nrf2 transcript alterations

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

| EGAS00001001740 | EGA

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