Upregulation of antioxidant thioredoxin by antidepressants fluoxetine and venlafaxine

Bharti, Veni; Tan, Hua; Deol, Jaspreet; Wu, Zijian; Wang, Jun-Feng

doi:10.1007/s00213-019-05350-9

Cited by 16 publications

(8 citation statements)

References 39 publications

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“…It can reduce the cysteine residues of oxidized Trx and further acts as an electron donor for ribonucleotide reduction, maintaining its antioxidant capacity [ 37 ], so that it is an important participant in antioxidant free radicals, antiapoptosis, and promoting cell growth in cells. Several reports have shown that Trx has an obvious antioxidant effect [ 38 , 39 ], and the serum content of Trx is decreased in patients with depression. As the preclinical systematic review study found, KXS, most treated for Alzheimer's Disease and Depression, has an effect on antioxidant activity by decreased ROS and MDA levels via increased GSH and SOD levels.…”

Section: Discussionmentioning

confidence: 99%

Antidepressant Mechanism of Kaixinsan and Its Active Compounds Based on Upregulation of Antioxidant Thioredoxin

Wang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Objectives. Kaixinsan (KXS), a traditional Chinese medicine formula, has been demonstrated to be effective in the treatment of depression. The present study applied a network pharmacology approach to dig out the new targets and mechanism of action of KXS and the active compounds in the treatment of depression. Methods. A network pharmacology approach based on public databases including ADME (absorption, distribution, metabolism, and excretion) evaluation, targets prediction, construction of networks, and molecule docking was used and validated the predicted new antioxidant targets and mechanisms in vitro. Based on an in vitro experiment, we verified the AKT1/Nrf2 pathway related to the thioredoxin (Trx) antioxidant mechanism. Results. The present study sorted 31 pharmacologically active components (kaempferol, ginsenoside rh2, ginsenoside rh4, stigmasterol, etc.) through the ADME algorithm from KXS. 136 potential molecular targets (AKT1, TNF, IL-1b, JUN, ESR1, NOS3, etc.) were predicted, of which there were 69 targets clearly related to depression. By compound-depression targets (C-DTs) network constructed, and protein-protein interaction networks (PPI) and KEGG pathway enrichment analyzed, we identified active compounds mediating depression-related targets to exert synergism on the predictive AKT1/Nrf2 pathway related to thioredoxin (Trx) antioxidant mechanism and other inflammation-related signaling pathways as well as neurotransmitter related signaling pathways. In the H2O2 induced SH-SY5Y cell damage model, this showed kaempferol and ginsenoside rh2 could enhance the activity of the Trx system by upregulation of AKT1 to activate Nrf2 in vitro. Conclusions. Taken together, by comprehensive systems pharmacology approach analysis, we found that KXS and its active compounds might exhibit antioxidant effects by stimulating the AKT1/Nrf2 pathway in the treatment of depression, which might shed new light on innovative therapeutic tactics for the new aspects for depression in traditional Chinese medicine in future studies.

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Section: Discussionmentioning

confidence: 99%

Antidepressant Mechanism of Kaixinsan and Its Active Compounds Based on Upregulation of Antioxidant Thioredoxin

Wang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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“…Then, we used qRT-PCR and Western blot to verify the TXNRD1 mRNA and protein expression levels, and the results showed that the TXNRD1 gene expression of K562/G01 cells in the cysteine depletion group was increased. TXNRD1 gene encodes the thioredoxin reductase 1 (TXNRD1), and the active substance of TXNRD1 is provided by cysteine [ 37 , 38 ]. Several studies have shown that the thioredoxin system is a key antioxidant system in defense against oxidative stress through its disulfide reductase activity regulating protein dithiol/disulfide balance.…”

Section: Discussionmentioning

confidence: 99%

TXNRD1: A Key Regulator Involved in the Ferroptosis of CML Cells Induced by Cysteine Depletion In Vitro

Liu

Chen

et al. 2021

Oxidative Medicine and Cellular Longevity

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Cysteine metabolism plays a critical role in cancer cell survival. Cysteine depletion was reported to inhibit tumor growth and induce pancreatic cancer cell ferroptosis. Nevertheless, the effect of cysteine depletion in chronic myeloid leukemia (CML) remains to be explored. In this work, we showed that cysteine depletion can induce K562/G01 but not K562 cell death in the form of ferroptosis. However, the glutathione (GSH)/glutathione peroxidase 4 (GPX4) pathways of the two CML cell lines were both blocked after cysteine depletion. This unexpected outcome guided us to perform RNA-Seq to screen the key genes that affect the sensitivity of CML cells to cysteine depletion. Excitingly, thioredoxin reductase 1 (TXNRD1), which related to cell redox metabolism, was significantly upregulated in K562/G01 cells after cysteine depletion. We further inferred that the upregulation is negatively feedback by the enzyme activity decrease of TXNRD1. Then, we triggered the ferroptosis by applying TXNRD1 shRNA and TXNRD1 inhibitor auranofin in K562 cells after cysteine depletion. In summary, we have reason to believe that TXNRD1 is a key regulator involved in the ferroptosis of CML cells induced by cysteine depletion in vitro. These findings highlight that cysteine depletion serves as a potential therapeutic strategy for overcoming chemotherapy resistance CML.

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“…Likewise, several lines of evidence have demonstrated that oxidative mechanisms are increased in the brains of subjects with depression and other psychiatric diagnosis [94][95][96], making it possible that astrocyte-related antioxidant mechanisms such as glutathione activity limit the extent of the damage that could be reached without those mechanisms. In fact, some long-term antidepressant treatments have been found to enhance or increase the levels of antioxidant chemical species in animal models and in successfully medicated patients [97][98][99], while antioxidant treatments themselves have been proposed to exert desirable antidepressant effects [100,101].…”

Section: Role Of Astrocytes In Neuroprotective Regulation Of the Mole...mentioning

confidence: 99%

Neuroprotective astroglial response to neural damage and its relevance to affective disorders

Miguel-Hidalgo

2023

Explor Neuroprot Ther

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Astrocytes not only support neuronal function with essential roles in synaptic neurotransmission, action potential propagation, metabolic support, or neuroplastic and developmental adaptations. They also respond to damage or dysfunction in surrounding neurons and oligodendrocytes by releasing neurotrophic factors and other molecules that increase the survival of the supported cells or contribute to mechanisms of structural and molecular restoration. The neuroprotective responsiveness of astrocytes is based on their ability to sense signals of degeneration, metabolic jeopardy, and structural damage, and on their aptitude to locally deliver specific molecules to remedy threats to the molecular and structural features of their cellular partners. To the extent that neuronal and other glial cell disturbances are known to occur in affective disorders, astrocyte responsiveness to those disturbances may help to better understand the roles astrocytes play in affective disorders. The astrocytic sensing apparatus supporting those responses involves receptors for neurotransmitters, purines, cell adhesion molecules, and growth factors. Astrocytes also share with the immune system the capacity to respond to cytokines released upon neuronal damage. In addition, in response to specific signals, astrocytes release unique factors such as clusterin or humanin that have been shown to exert potent neuroprotective effects. Astrocytes integrate the signals above to further deliver structural lipids, remove toxic metabolites, stabilize the osmotic environment, normalize neurotransmitters, provide antioxidant protection, facilitate synaptogenesis, and act as barriers to contain varied deleterious signals, some of which have been described in brain regions relevant to affective disorders and related animal models. Since various injurious signals that activate astrocytes have been implicated in different aspects of the etiopathology of affective disorders, particularly in relation to the diagnosis of depression, potentiating the corresponding astrocyte neuroprotective responses may provide additional opportunities to improve or complement available pharmacological and behavioral therapies for affective disorders.

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Upregulation of antioxidant thioredoxin by antidepressants fluoxetine and venlafaxine

Cited by 16 publications

References 39 publications

Antidepressant Mechanism of Kaixinsan and Its Active Compounds Based on Upregulation of Antioxidant Thioredoxin

Antidepressant Mechanism of Kaixinsan and Its Active Compounds Based on Upregulation of Antioxidant Thioredoxin

TXNRD1: A Key Regulator Involved in the Ferroptosis of CML Cells Induced by Cysteine Depletion In Vitro

Neuroprotective astroglial response to neural damage and its relevance to affective disorders

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