A Novel Suppressive Effect of Alcohol Dehydrogenase 5 in Neuronal Differentiation

Wu, Kaiyuan; Ren, Rui; Su, Wenting; Wen, Bo; Zhang, Yuying; Yi, Fei; Qiao, Xinhua; Yuan, Tingting; Wang, Jinhui; Liu, Linmin; Belmonte, Juan Carlos Izpisúa; Liu, Guanghui; Chen, Chang

doi:10.1074/jbc.c114.561860

Cited by 22 publications

(10 citation statements)

References 29 publications

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“…CYP2E1 induction in neuronal cells and the resultant oxidative stress cause apoptotic cell death in these cells, suggesting that CYP2E1 is one of the key players to target alcohol-mediated brain toxicity [ 70 ]. A possible physiological role of EtOH and its metabolites in the regulation of the growth, metabolism, differentiation and neuroendocrine function in mammals cannot be excluded [ 69 , 71 ].…”

Section: Resultsmentioning

confidence: 99%

Thallium stimulates ethanol production in immortalized hippocampal neurons

et al. 2017

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Lactate and ethanol (EtOH) were determined in cell culture medium (CCM) of immortalized hippocampal neurons (HN9.10e cell line) before and after incubation with Thallium (Tl). This cell line is a reliable, in vitro model of one of the most vulnerable regions of central nervous system. Cells were incubated for 48 h with three different single Tl doses: 1, 10, 100 μg/L (corresponding to 4.9, 49 and 490 nM, respectively). After 48 h, neurons were “reperfused” with fresh CCM every 24/48 h until 7 days after the treatment and the removed CCM was collected and analysed. Confocal microscopy was employed to observe morphological changes. EtOH was determined by head space—solid phase microextraction -gas chromatography -mass spectrometry (HS-SPME-GCMS), lactate by RP-HPLC with UV detection. Tl exposure had significant effects on neuronal growth rate and morphology. The damage degree was dose-dependent. In not exposed cells, EtOH concentration was 0.18 ± 0.013 mM, which represents about 5% of lactate concentration (3.4 ± 0.10 mM). After Tl exposure lactate and EtOH increased. In CCM of 100 and 10 μg/L Tl-treated cells, lactate increased 24 h after reperfusion up to 2 and 3.3 times the control value, respectively. In CCM of 10 and 100 μg/L Tl-treated cells 24 h after reperfusion, EtOH increased up to 0.3 and 0.58 mmol/L. respectively. These results are consistent with significant alterations in energy metabolism, despite the low doses of Tl employed and the relatively short incubation time.

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Section: Resultsmentioning

confidence: 99%

Thallium stimulates ethanol production in immortalized hippocampal neurons

et al. 2017

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“…12 To determine whether metformin was able to suppress formaldehyde-induced DNA damage, we used a recently discovered small-molecule inhibitor of Adh5, the C3 compound, to induce the accumulation of endogenous formaldehyde in FA cells. 32,33 After human FA-A patient-derived fibroblast cells PD259i were treated with 100 mM C3 for 48 hours, the levels of spontaneous radials and chromosomal breaks were significantly increased by twofold and threefold, respectively (P , .0001 in both cases; Figure 5E-F). Importantly, concurrent treatment with metformin significantly suppressed C3-induced radials and chromosomal breaks (P , .0001 and P , .001, respectively; Figure 5E-F), consistent with a role for metformin in detoxifying formaldehyde.…”

Section: Metformin May Act By Aldehyde Detoxificationmentioning

confidence: 99%

Metformin improves defective hematopoiesis and delays tumor formation in Fanconi anemia mice

Zhang

Tang

Deater

et al. 2016

Blood

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• The widely used diabetes drug metformin improves hematopoiesis and delays tumor formation in a preclinical murine model of FA.• Metformin reduces DNA damage in human FA patient-derived cells.Fanconi anemia (FA) is an inherited bone marrow failure disorder associated with a high incidence of leukemia and solid tumors. Bone marrow transplantation is currently the only curative therapy for the hematopoietic complications of this disorder. However, long-term morbidity and mortality remain very high, and new therapeutics are badly needed. Here we show that the widely used diabetes drug metformin improves hematopoiesis and delays tumor formation in Fancd2 2/2 mice. Metformin is the first compound reported to improve both of these FA phenotypes. Importantly, the beneficial effects are specific to FA mice and are not seen in the wild-type controls. In this preclinical model of FA, metformin outperformed the current standard of care, oxymetholone, by improving peripheral blood counts in Fancd2 2/2 mice significantly faster. Metformin increased the size of the hematopoietic stem cell compartment and enhanced quiescence in hematopoietic stem and progenitor cells. In tumor-prone Fancd2 2/2 Trp53 1/2 mice, metformin delayed the onset of tumors and significantly extended the tumor-free survival time. In addition, we found that metformin and the structurally related compound aminoguanidine reduced DNA damage and ameliorated spontaneous chromosome breakage and radials in human FA patient-derived cells. Our results also indicate that aldehyde detoxification might be one of the mechanisms by which metformin reduces DNA damage in FA cells. (Blood. 2016; 128(24):2774-2784

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“…ADH5 RNA has been recognized in all major human tissue types with protein expression highest in smooth muscle, liver, epididymis, kidney and testis (Giri et al, 1989). GSNOR is an important negative regulator of neuronal differentiation during development (Wu et al, 2014) and is the only known ADH enzyme present in the brain (Beisswenger et al 1985; Galter et al 2003). Conversely, GSNOR protein expression is negligible or non-existent in skeletal muscle, lymph nodes, spleen, bone marrow, cerebellum and the lateral ventricle (If and Wb, 2009).…”

Section: Adh5: Structure/localizationmentioning

confidence: 99%

“…These disease states are often the result of aberrant protein S-nitrosation caused by the dysregulation of GSNO. For instance, in developing and adult mouse brains the overexpression of GSNOR results in decreased neuronal differentiation in part due to de-S-nitrosation of histone deacetylase 2 (HDAC2) (Wu et al, 2014). Conversely, ADH5 −/− mice exhibit neuromuscular atrophy as a result of a decrease in muscle mass, while also presenting with neuropathic behavior (Montagna et al, 2014).…”

Section: Gsnor Dysregulationmentioning

confidence: 99%

The role of S-nitrosoglutathione reductase (GSNOR) in human disease and therapy

Barnett

Buxton

2017

Critical Reviews in Biochemistry and Molecular Biology

119

101

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S-nitrosoglutathione reductase (GSNOR), or ADH5, is an enzyme in the alcohol dehydrogenase (ADH) family. It is unique when compared to other ADH enzymes in that primary short-chain alcohols are not its principle substrate. GSNOR metabolizes S-nitrosoglutathione (GSNO), S-hydroxymethylglutathione (the spontaneous adduct of formaldehyde and glutathione), and some alcohols. GSNOR modulates reactive nitric oxide (•NO) availability in the cell by catalyzing the breakdown of GSNO, and indirectly regulates S-nitrosothiols (RSNOs) through GSNO-mediated protein S-nitrosation. The dysregulation of GSNOR can significantly alter cellular homeostasis, leading to disease. GSNOR plays an important regulatory role in smooth muscle relaxation, immune function, inflammation, neuronal development, and cancer progression, among many other processes. In recent years, the therapeutic inhibition of GSNOR has been investigated to treat asthma, cystic fibrosis and interstitial lung disease (ILD). The direct action of •NO on cellular pathways, as well as the important regulatory role of protein S-nitrosation, are closely tied to GSNOR regulation and define this enzyme as an important therapeutic target.

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A Novel Suppressive Effect of Alcohol Dehydrogenase 5 in Neuronal Differentiation

Cited by 22 publications

References 29 publications

Thallium stimulates ethanol production in immortalized hippocampal neurons

Thallium stimulates ethanol production in immortalized hippocampal neurons

Metformin improves defective hematopoiesis and delays tumor formation in Fanconi anemia mice

The role of S-nitrosoglutathione reductase (GSNOR) in human disease and therapy

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