TGF-β1 signaling protects retinal ganglion cells from oxidative stress via modulation of the HO-1/Nrf2 pathway

Chen, Hsin‐Yi; Ho, Yi‐Jung; Chou, Hsiu‐Chuan; Liao, En‐Chi; Tsai, Yi‐Ting; Wei, Yu‐Shan; Lin, Li‐Hsun; Lin, Ming-Tzer; Wang, Yi‐Shiuan; Ko, Mei–Lan; Chan, Hong‐Lin

doi:10.1016/j.cbi.2020.109249

Cited by 25 publications

(17 citation statements)

References 42 publications

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“…This neurobiological link could be of utmost importance since it has already been demonstrated that other multimodal drugs that counteract oxidative stress can also rescue TGF-β1 levels (Caruso et al, 2019b;Fresta et al, 2020b). In two very recent research studies it has also demonstrated the ability of TGF-β1 to protect retinal ganglion cells against oxidative stress through the modulation of the HO-1/Nrf2 pathway (Chen et al, 2020) and chondrocytes via FOXO1-autophagy axis (Kurakazu et al, 2021), strongly suggesting a key role of TGF-β1 in counteracting oxidative stress induced by Aβ.…”

Section: Discussionmentioning

confidence: 98%

Antioxidant Activity of Fluoxetine and Vortioxetine in a Non-Transgenic Animal Model of Alzheimer’s Disease

et al. 2021

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Depression is a risk factor for the development of Alzheimer’s disease (AD). A neurobiological and clinical continuum exists between AD and depression, with neuroinflammation and oxidative stress being involved in both diseases. Second-generation antidepressants, in particular selective serotonin reuptake inhibitors (SSRIs), are currently investigated as neuroprotective drugs in AD. By employing a non-transgenic AD model, obtained by intracerebroventricular (i.c.v.) injection of amyloid-β (Aβ) oligomers in 2-month-old C57BL/6 mice, we recently demonstrated that the SSRI fluoxetine (FLX) and the multimodal antidepressant vortioxetine (VTX) reversed the depressive-like phenotype and memory deficits induced by Aβ oligomers rescuing the levels of transforming growth factor-β1 (TGF-β1). Aim of our study was to test FLX and VTX for their ability to prevent oxidative stress in the hippocampus of Aβ-injected mice, a brain area strongly affected in both depression and AD. The long-term intraperitoneal (i.p.) administration of FLX (10 mg/kg) or VTX (5 and 10 mg/kg) for 24 days, starting 7 days before Aβ injection, was able to prevent the over-expression of inducible nitric oxide synthase (iNOS) and NADPH oxidase 2 (Nox2) induced by Aβ oligomers. Antidepressant pre-treatment was also able to rescue the mRNA expression of glutathione peroxidase 1 (Gpx1) antioxidant enzyme. FLX and VTX also prevented Aβ-induced neurodegeneration in mixed neuronal cultures treated with Aβ oligomers. Our data represent the first evidence that the long-term treatment with the antidepressants FLX or VTX can prevent the oxidative stress phenomena related to the cognitive deficits and depressive-like phenotype observed in a non-transgenic animal model of AD.

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Section: Discussionmentioning

confidence: 98%

Antioxidant Activity of Fluoxetine and Vortioxetine in a Non-Transgenic Animal Model of Alzheimer’s Disease

et al. 2021

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“…ALDH3A1 can oxidize various aldehydes to their corresponding acids and is involved in the detoxification of alcohol-derived acetaldehyde and metabolism of corticosteroids, biogenic amines, neurotransmitters, and lipid peroxidation. The expression of ALDH3A1 is suggested to play an important role in the stress response and the anti-oxidation pathway for the protection of RGCs, transforming growth factor-beta in the treatment of diabetic retinopathy [47,48] and corneal cells against ultra-violet damage [49]. Our local network clusters analysis also indicated that there is an interaction between Aldh3a1, Oplah, and Mgst3, which are also believed to be related to the glutathione metabolic process.…”

Section: Discussionmentioning

confidence: 60%

Differential Retinal Protein Expression in Primary and Secondary Retinal Ganglion Cell Degeneration Identified by Integrated SWATH and Target-Based Proteomics

Kwong

Sze

et al. 2021

IJMS

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To investigate the retinal proteins associated with primary and secondary retinal ganglion cell (RGC) degeneration and explore their molecular pathways, SWATH label-free and target-based mass spectrometry was employed to identify the proteomes in various retinal locations in response to localized optic nerve injury. Unilateral partial optic nerve transection (pONT) was performed on adult Wistar rats and their retinas were harvested 2 weeks later. To confirm the separation of primary and secondary RGC degeneration, immunohistochemistry of RNA binding protein with multiple splicing (RBPMS) and glial fibrillary acidic protein (GFAP) was performed on retinal whole-mounts. Retinal proteomes in the temporal and nasal quadrants were evaluated with high resolution hybrid quadrupole time-of-flight mass spectrometry (QTOF-MS), and SWATH-based acquisition, and their expression was compared to the corresponding retinal quadrant in contralateral control eyes and further validated by multiple reaction monitoring mass spectrometry (MRM-MS). A total of 3641 proteins (FDR < 1%) were identified using QTOF-MS. The raw data are available via ProteomeXchange with the identifier PXD026783. Bioinformatics data analysis showed that there were 37 upregulated and 25 downregulated proteins in the temporal quadrant, whereas 20 and five proteins were upregulated and downregulated, respectively, in the nasal quadrant, respectively (n = 4, p < 0.05; fold change ≥ 1.4-fold or ≤0.7). Six proteins were regulated in both the temporal and the nasal quadrants, including CLU, GFAP, GNG5, IRF2BPL, L1CAM, and CPLX1. Linear regression analysis indicated a strong association between the data obtained by means of SWATH-MS and MRM-MS (temporal, R2 = 0.97; nasal, R2 = 0.96). Gene ontology analysis revealed statistically significant changes in the biological processes and cellular components of primary RGC degeneration. The majority of the significant changes in structural, signaling, and cell death proteins were associated with the loss of RGCs in the area of primary RGC degeneration. The combined use of SWATH-MS and MRM-MS methods detects and quantifies regional changes of retinal protein expressions after localized injury. Future investigation with this integrated approach will significantly increase the understanding of diverse processes of progressive RGC degeneration from a proteomic prospective.

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“…42,43 According to a recent study, TGF-β1 protected retinal ganglion cells from H 2 O 2 -induced oxidative stress by upregulating the activation of Nrf2/HO-1 signaling. 44 It is worthy of paying attention that B3galt2 protects against BBB injury via the TGF-β1 signaling pathway, indicating that TGF-β1 is a downstream mediator of B3galt2. 9 Moreover, after treatment with TGF-β1 siRNA, the levels of SOD and GSH were down-regulated, and the levels of NLRP3, GSDMD, and ASC were increased.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have shown that TGF‐β1 may have a protective effect on immunomodulation, anti‐apoptosis, and angiogenesis in ischemic stroke 42,43 . According to a recent study, TGF‐β1 protected retinal ganglion cells from H 2 O 2 ‐induced oxidative stress by upregulating the activation of Nrf2/HO‐1 signaling 44 . It is worthy of paying attention that B3galt2 protects against BBB injury via the TGF‐β1 signaling pathway, indicating that TGF‐β1 is a downstream mediator of B3galt2 9 .…”

Section: Discussionmentioning

confidence: 99%

Intranasal administration of β‐1, 3‐galactosyltransferase 2 confers neuroprotection against ischemic stroke by likely inhibiting oxidative stress and NLRP3 inflammasome activation

et al. 2022

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Ischemic stroke is one of the major causes of morbidity and mortality. The β‐1, 3‐galactosyltransferase 2 (B3galt2), a member of β‐1, 3‐galactosyltransferase family, is playing a vital role in the pathological process of cerebral ischemic injury, but its underlying mechanisms remain unclear. In the present study, we examined the involvement of oxidative stress and NLRP3 inflammasome activation in the neuroprotective effect of B3galt2. Cerebral ischemia/reperfusion (I/R) injury was simulated in a mouse middle cerebral artery occlusion (MCAO) model. Recombinant human B3galt2 (rh‐B3galt2) was administered intranasally 1 h post MCAO, and TGF‐β1‐siRNA was administered intracerebroventricularly 24 h before MCAO. Outcome measures included brain infarct volume, neurological function, blood‐brain barrier (BBB) permeability, neuronal apoptosis, oxidative stress, and the inflammatory response. First, we found that rh‐B3galt2 significantly alleviated brain infarct volume and BBB permeability, improved neurological function, and attenuated I/R‐induced neuron apoptosis and oxidative stress. Furthermore, rh‐B3galt2 attenuated pro‐inflammatory cytokines, NF‐κB, IL‐6, TNF‐α, and IL‐1β, and inhibited NLRP3 inflammasome activation. Finally, inhibition of TGF‐β1 by TGF‐β1‐siRNA abolished the anti‐oxidative and anti‐inflammatory effects of rh‐B3galt2 in mice after I/R. Collectively, our study demonstrated that rh‐B3galt2 exerts neuroprotective effects by regulating cerebral ischemia‐induced oxidative stress and NLRP3 inflammasome, which is mainly dependent on the heightening of the TGF‐β1 pathway. Thus, B3galt2 might be considered a new therapeutic target for ischemic stroke treatment.

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TGF-β1 signaling protects retinal ganglion cells from oxidative stress via modulation of the HO-1/Nrf2 pathway

Cited by 25 publications

References 42 publications

Antioxidant Activity of Fluoxetine and Vortioxetine in a Non-Transgenic Animal Model of Alzheimer’s Disease

Antioxidant Activity of Fluoxetine and Vortioxetine in a Non-Transgenic Animal Model of Alzheimer’s Disease

Differential Retinal Protein Expression in Primary and Secondary Retinal Ganglion Cell Degeneration Identified by Integrated SWATH and Target-Based Proteomics

Intranasal administration of β‐1, 3‐galactosyltransferase 2 confers neuroprotection against ischemic stroke by likely inhibiting oxidative stress and NLRP3 inflammasome activation

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