Resveratrol Prevents Impairment in Activation of Retinoic Acid Receptors and MAP Kinases in the Embryos of a Rodent Model of Diabetic Embryopathy

Singh, Chandra K.; Kumar, Ambrish; LaVoie, Holly A.; DiPette, Donald J.; Singh, Uaday

doi:10.1177/1933719112438972

Cited by 19 publications

(18 citation statements)

References 51 publications

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“…Except for the unique case of ER/ERE, the current results (Figs. 7 and 8) imply a potential RXR-dependence for the SIRT1 effect to enhance transcription, as also proposed for RAR by Singh and colleagues [44]. However, we observe herein that two RXR-heterodimerizing nuclear receptors, namely LXR (Fig.…”

Section: Discussionsupporting

confidence: 79%

SIRT1 enzymatically potentiates 1,25-dihydroxyvitamin D3 signaling via vitamin D receptor deacetylation

Sabir

Khan

et al. 2017

The Journal of Steroid Biochemistry and Molecular Biology

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The hormonal metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D), binds to the vitamin D receptor (VDR) and promotes heterodimerization of VDR with a retinoid-X-receptor (RXR) to genomically regulate diverse cellular processes. Herein, it is revealed for the first time that VDR is post-translationally acetylated, and that VDR immunoprecipitated from human embryonic kidney (HEK293) cells displays a dramatic decrease in acetylated receptor in the presence of 1,25D-ligand, sirtuin-1 (SIRT1) deacetylase, or the resveratrol activator of SIRT1. To elucidate the functional significance of VDR deacetylation, vitamin-D-responsive-element (VDRE)-based transcriptional assays were performed to determine if deacetylase overexpression affects VDR/VDRE-driven transcription. In HEK293 kidney and TE85 bone cells, co-transfection of low amounts (1–5ng) of a SIRT1-expression vector elicits a reproducible and statistically significant enhancement (1.3- to 2.6-fold) in transcription mediated by VDREs from the CYP3A4 and cyp24a1 genes, where the magnitude of response to 1,25D-ligand is 6- to 30-fold. Inhibition of SIRT1 via EX-527, or utilization of a SIRT1 loss-of-function mutant (H363Y), resulted in abrogation of SIRT1-mediated VDR potentiation. Studies with a novel, non-acetylatable VDR mutant (K413R) showed that the mutant VDR possesses enhanced responsiveness to 1,25D, in conjunction with reduced, but still significant, sensitivity to exogenous SIRT1, indicating that acetylation of lysine 413 is relevant, but that other acetylated residues in VDR contribute to modulation of its activity. We conclude that the acetylation of VDR comprises a negative feedback loop that attenuates 1,25D-VDR signaling. This regulatory loop is reversed by SIRT1-catalyzed deacetylation of VDR to amplify VDR signaling and 1,25D actions.

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Section: Discussionsupporting

confidence: 79%

SIRT1 enzymatically potentiates 1,25-dihydroxyvitamin D3 signaling via vitamin D receptor deacetylation

Sabir

Khan

et al. 2017

The Journal of Steroid Biochemistry and Molecular Biology

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“…Sirtuin activators including resveratrol and SIR1720 can decrease PGC-1α acetylation and, thus, increase PGC-1α activity and its downstream target gene52. In studies of ours and others5354, resveratrol and SIR1720 can ameliorate diabetes-induced NTDs. Future studies may test the preventive effect of PPARγ agonists on diabetic embryopathy.…”

Section: Discussionmentioning

confidence: 62%

Protein kinase C-alpha suppresses autophagy and induces neural tube defects via miR-129-2 in diabetic pregnancy

Wang

Reece

et al. 2017

Nat Commun

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Gene deletion-induced autophagy deficiency leads to neural tube defects (NTDs), similar to those in diabetic pregnancy. Here we report the key autophagy regulators modulated by diabetes in the murine developing neuroepithelium. Diabetes predominantly leads to exencephaly, induces neuroepithelial cell apoptosis and suppresses autophagy in the forebrain and midbrain of NTD embryos. Deleting the Prkca gene, which encodes PKCα, reverses diabetes-induced autophagy impairment, cellular organelle stress and apoptosis, leading to an NTD reduction. PKCα increases the expression of miR-129-2, which is a negative regulator of autophagy. miR-129-2 represses autophagy by directly targeting PGC-1α, a positive regulator for mitochondrial function, which is disturbed by maternal diabetes. PGC-1α supports neurulation by stimulating autophagy in neuroepithelial cells. These findings identify two negative autophagy regulators, PKCα and miR-129-2, which mediate the teratogenicity of hyperglycaemia leading to NTDs. We also reveal a function for PGC-1α in embryonic development through promoting autophagy and ameliorating hyperglycaemia-induced NTDs.

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“…108 Suppressed expression of RAR and RXR receptors in E12 embryo of diabetic dams was improved with resveratrol treatment. 109 MAPKs also contribute to growth, differentiation and developmental processes; their activity determines the fate of embryonic organogenesis when the embryo faces teratogenic conditions. 110 Hyperglycemia increases ROS, which modulate MAPK signaling.…”

Section: Diabetes Impairs Rho Gtpase Signaling Could Resveratrol Revmentioning

confidence: 99%

“…112 Increased phospho-ERK1/2 and decreased phospho-JNK1/2 and phospho-p38 occurs in the embryos of resveratrol-treated diabetic dams compared with those not exposed to resveratrol. 109 …”

Section: Diabetes Impairs Rho Gtpase Signaling Could Resveratrol Revmentioning

confidence: 99%

Diabetic complications in pregnancy: is resveratrol a solution?

Singh

Kumar²,

LaVoie

et al. 2013

Exp Biol Med (Maywood)

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Diabetes is a metabolic disorder that, during pregnancy, may affect fetal development. Fetal outcome depends on the type of diabetes present, the concentration of blood glucose and the extent of fetal exposure to elevated or frequently fluctuating glucose concentrations. The result of some diabetic pregnancies will be embryonic developmental abnormalities, a condition referred to as diabetic embryopathy. Tight glycemic control in type 1 diabetes during pregnancy using insulin therapy together with folic acid supplementation are partially able to prevent diabetic embryopathy; however, the protection is not complete and additional interventions are needed. Resveratrol, a polyphenol found largely in the skins of red grapes, is known to have antidiabetic action and is in clinical trials for the treatment of diabetes, insulin resistance, obesity and metabolic syndrome. Studies of resveratrol in a rodent model of diabetic embryopathy reveal that it significantly improves the embryonic outcome in terms of diminishing developmental abnormalities. Improvements in maternal and embryonic outcomes observed in rodent models may arise from resveratrol’s antioxidative potential, antidiabetic action and antidyslipidemic nature. Whether resveratrol will have similar actions in human diabetic pregnancy is unknown. Here, we review the potential therapeutic use of resveratrol in diabetes and diabetic pregnancy.

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Resveratrol Prevents Impairment in Activation of Retinoic Acid Receptors and MAP Kinases in the Embryos of a Rodent Model of Diabetic Embryopathy

Cited by 19 publications

References 51 publications

SIRT1 enzymatically potentiates 1,25-dihydroxyvitamin D3 signaling via vitamin D receptor deacetylation

SIRT1 enzymatically potentiates 1,25-dihydroxyvitamin D3 signaling via vitamin D receptor deacetylation

Protein kinase C-alpha suppresses autophagy and induces neural tube defects via miR-129-2 in diabetic pregnancy

Diabetic complications in pregnancy: is resveratrol a solution?

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