Nrf2-mediated neuroprotection by MANF against 6-OHDA-induced cell damage via PI3K/AKT/GSK3β pathway

Zhang, Jingxing; Tong, Weifang; Sun, Hui; Jiang, Ming; Shen, Yijue; Liu, Yigang; Gu, Heng; Guo, Jia; Fang, Jianmin; Jin, Lingjing

doi:10.1016/j.exger.2017.10.021

Cited by 46 publications

(37 citation statements)

References 37 publications

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“…Differences in cell signaling pathways between Manf +/+ and Manf 2/2 islets were studied in the presence or absence of rhMANF in vitro. Previous studies have suggested that MANF exerts its protective effect on neurons through activation of the PI3K/AKT signaling pathway (41). We found a trend for an increase in AKT (Ser473) phosphorylation in Manf +/+ islets after MANF addition ( Fig.…”

Section: Insights In Manf Mechanism Of Actionsupporting

confidence: 56%

MANF Is Required for the Postnatal Expansion and Maintenance of Pancreatic β-Cell Mass in Mice

Danilova

Belevich

et al. 2018

Diabetes

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Global lack of mesencephalic astrocyte-derived neurotropic factor (MANF) leads to progressive postnatal loss of b-cell mass and insulin-dependent diabetes in mice. Similar to Manf 2/2 mice, embryonic ablation of MANF specifically from the pancreas results in diabetes. In this study, we assessed the importance of MANF for the postnatal expansion of pancreatic b-cell mass and for adult b-cell maintenance in mice. Detailed analysis of Pdx-1Cre +/2 ::Manf fl/fl mice revealed mosaic MANF expression in postnatal pancreata and a significant correlation between the number of MANF-positive b-cells and b-cell mass in individual mice. In vitro, recombinant MANF induced b-cell proliferation in islets from aged mice and protected from hyperglycemia-induced endoplasmic reticulum (ER) stress. Consequently, excision of MANF from b-cells of adult MIP-1Cre ERT ::Manf fl/fl mice resulted in reduced b-cell mass and diabetes caused largely by b-cell ER stress and apoptosis, possibly accompanied by b-cell dedifferentiation and reduced rates of b-cell proliferation. Thus, MANF expression in adult mouse b-cells is needed for their maintenance in vivo. We also revealed a mechanistic link between ER stress and inflammatory signaling pathways leading to b-cell death in the absence of MANF. Hence, MANF might be a potential target for regenerative therapy in diabetes.

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Section: Insights In Manf Mechanism Of Actionsupporting

confidence: 56%

MANF Is Required for the Postnatal Expansion and Maintenance of Pancreatic β-Cell Mass in Mice

Danilova

Belevich

et al. 2018

Diabetes

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“…As mentioned above, NRF2 (NFE2L2) is a master regulator of the antioxidant response and controls the expression of the superoxide dismutase isoenzymes and genes involved in glutathione and thioredoxin production and utilization as well as iron detoxification and storage (31). Factors promoting the activation or stabilization of NRF2 (SQSTM1, PARK7, CDKN1A, and MANF) were enriched in the INS lo UPR hi state (38)(39)(40)(41). In addition, expression of genes encoding the inhibitor of differentiation proteins (ID1-3) showed progressive upregulation in the INS lo UPR hi state (Fig.…”

Section: Stress Response In Human B-cellsmentioning

confidence: 94%

Pseudotime Ordering of Single Human β-Cells Reveals States of Insulin Production and Unfolded Protein Response

et al. 2018

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Proinsulin is a misfolding-prone protein, making its biosynthesis in the endoplasmic reticulum (ER) a stressful event. Pancreatic β-cells overcome ER stress by activating the unfolded protein response (UPR) and reducing insulin production. This suggests that β-cells transition between periods of high insulin biosynthesis and UPR-mediated recovery from cellular stress. We now report the pseudotime ordering of single β-cells from humans without diabetes detected by large-scale RNA sequencing. We identified major states with ) low UPR and low insulin gene expression,) low UPR and high insulin gene expression, or ) high UPR and low insulin gene expression. The latter state was enriched for proliferating cells. Stressed human β-cells do not dedifferentiate and show little propensity for apoptosis. These data suggest that human β-cells transition between states with high rates of biosynthesis to fulfill the body's insulin requirements to maintain normal blood glucose levels and UPR-mediated recovery from ER stress due to high insulin production.

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“…Actually, pseudotime RNA sequencing analysis of single non-diabetic human beta cells revealed transition between states of high activity by insulin expression and low UPR, and states of low insulin expression and high expression of UPR markers, including the master regulator of antioxidant response NRF2 ( Xin et al, 2018 ). Interestingly, MANF was upregulated along with other UPR genes in this state and has previously been suggested to promote the activation of NRF2 ( Zhang et al, 2017 ; Xin et al, 2018 ). This UPR-mediated stress recovery state with low rates of insulin biosynthesis was also enriched for proliferating beta cells ( Xin et al, 2018 ).…”

Section: Er Stress and Upr Signaling In Beta Cellsmentioning

confidence: 75%

Emerging Roles for Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) in Pancreatic Beta Cells and Diabetes

Danilova

Lindahl

2018

Front. Physiol.

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Mesencephalic astrocyte-derived neurotrophic factor (MANF) was originally identified as a secreted trophic factor for dopamine neurons in vitro. It protects and restores damaged cells in rodent models of Parkinson’s disease, brain and heart ischemia, spinocerebellar ataxia and retina in vivo. However, its exact mechanism of action is not known. MANF is widely expressed in most human and mouse organs with high levels in secretory tissues. Intracellularly, MANF localizes to the endoplasmic reticulum (ER) and ER stress increases it’s expression in cells and tissues. Furthermore, increased MANF levels has been detected in the sera of young children with newly diagnosed Type 1 (T1D) diabetes and Type 2 (T2D) diabetic patients. ER stress is caused by the accumulation of misfolded and aggregated proteins in the ER. It activates a cellular defense mechanism, the unfolded protein response (UPR), a signaling cascade trying to restore ER homeostasis. However, if prolonged, unresolved ER stress leads to apoptosis. Unresolved ER stress contributes to the progressive death of pancreatic insulin-producing beta cells in both T1D and T2D. Diabetes mellitus is characterized by hyperglycemia, caused by the inability of the beta cells to maintain sufficient levels of circulating insulin. The current medications, insulin and antidiabetic drugs, alleviate diabetic symptoms but cannot reconstitute physiological insulin secretion which increases the risk of devastating vascular complications of the disease. Thus, one of the main strategies in improving current diabetes therapy is to define and validate novel approaches to protect beta cells from stress as well as activate their regeneration. Embryonic deletion of the Manf gene in mice led to gradual postnatal development of insulin-deficient diabetes caused by reduced beta cell proliferation and increased beta cell death due to increased and sustained ER stress. In vitro, recombinant MANF partly protected mouse and human beta cells from ER stress-induced beta cell death and potentiated mouse and human beta cell proliferation. Importantly, in vivo overexpression of MANF in the pancreas of T1D mice led to increased beta cell proliferation and decreased beta cell death, suggesting that MANF could be a new therapeutic candidate for beta cell protection and regeneration in diabetes.

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Nrf2-mediated neuroprotection by MANF against 6-OHDA-induced cell damage via PI3K/AKT/GSK3β pathway

Cited by 46 publications

References 37 publications

MANF Is Required for the Postnatal Expansion and Maintenance of Pancreatic β-Cell Mass in Mice

MANF Is Required for the Postnatal Expansion and Maintenance of Pancreatic β-Cell Mass in Mice

Pseudotime Ordering of Single Human β-Cells Reveals States of Insulin Production and Unfolded Protein Response

Emerging Roles for Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) in Pancreatic Beta Cells and Diabetes

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