Metformin promotes osteogenic differentiation and protects against oxidative stress-induced damage in periodontal ligament stem cells via activation of the Akt/Nrf2 signaling pathway

Jia, Linglu; Xiong, Yixuan; Zhang, Wenjing; Ma, Xiaoni; Xu, Xin

doi:10.1016/j.yexcr.2019.111717

Cited by 53 publications

(47 citation statements)

References 56 publications

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“…During the process of HG-caused oxidative stress and angiogenic impairment, Nrf2 has been identified as a potential target of MET for promoting angiogenesis under the HG situation. Substantial previous reports have demonstrated the antioxidative activity of MET via Nrf2 and its target genes ( Yan et al., 2019 ; Jia et al., 2020 ), indicating that MET could exert its antioxidative effect, at least partially through Nrf2. In this study, we found that Nrf2 expression was suppressed by GDM/HG, and administration of MET could reversely increase the Nrf2 level and its nuclear stabilization under GDM/HG condition to enhance the angiogenic ability.…”

Section: Discussionmentioning

confidence: 92%

Metformin Ameliorates Gestational Diabetes Mellitus-Induced Endothelial Dysfunction via Downregulation of p65 and Upregulation of Nrf2

et al. 2020

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Gestational diabetes mellitus (GDM) causes oxidative stress in mothers and infants and causes vascular endothelial dysfunction, which is a key factor for maternal and fetal cardiovascular diseases in the later stage of GDM, seriously threatening the life and health of mothers and infants. Nowadays, metformin (MET) has been discovered to improve endothelial function, but studies regarding the mechanism of MET improving endothelial cell function and alleviating endothelial function under hyperglycemia are still extremely limited. We aimed to investigate whether MET exerts its protective role against hyperglycemia-induced endothelial dysfunction through p65 and Nrf2. In our studies, applying cell migration assay and tube formation assay, we observed an obvious improvement of endothelial function under MET-treated, as characterized by that MET accelerated GDM-attenuated migration and angiogenesis of HUVECs. And ELISA assay results uncovered that Nrf2 expression level was decreased in GDM placenta, HVUECs and maternal serum comparing with normal group, however activation Nrf2 largely ameliorated tube formation under hyperglycemic condition. Furthermore, MET elevated the Nrf2 expression level and the level of nuclear Nrf2 accumulation in hyperglycemic HUVECs. Besides, preliminary evidence predicted that Nrf2 expression was modulated by transcription factor p65, which was increased in GDM peripheral blood, placenta and HUVECs, and suppression of p65 could recover GDM-induced suppression of angiogenesis. In addition, we also confirmed MET restores the GDM-induced angiogenesis impairment may via downregulation of p65 and upregulation of Nrf2. Taken together, the endothelial protective effect of MET under GDM (HG) conditions could be partly attributed to its role in downregulating p65 and upregulating Nrf2.

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Section: Discussionmentioning

confidence: 92%

Metformin Ameliorates Gestational Diabetes Mellitus-Induced Endothelial Dysfunction via Downregulation of p65 and Upregulation of Nrf2

et al. 2020

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“…Since glucose induces histone O-GlcNAcylation (O-N-acetyl glucosaminylation) via the hexosamine biosynthesis pathway [46,47], the ability of metformin to impair glucose consumption by acting as an inhibitor of hexokinase-II [48,49] may globally link the cellular energy status with the regulation of the epigenome [50,51]. Additionally, there are several examples of the metabolic ability of metformin to facilitate (or impede) the transition from one cell type to another, including neuronal [52][53][54], osteogenic [55][56][57][58], adipogenic [39,59], myofibroblast and myoblast [60,61] differentiation, or monocyte-to-macrophage differentiation [62], among others. The fact that metformin targets a set of core "hub" metabolites with epigenetic properties and with emerging roles as central mediators of aging strongly supports the notion that it can regulate cell fate transitions by changing metabolite levels that allow the reorganization of specific chromatin marks [63].…”

Section: Metformin: a Metabolic Landscaper Of The Epigenomementioning

confidence: 99%

Metformin: Sentinel of the Epigenetic Landscapes That Underlie Cell Fate and Identity

Menendez

2020

Biomolecules

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The biguanide metformin is the first drug to be tested as a gerotherapeutic in the clinical trial TAME (Targeting Aging with Metformin). The current consensus is that metformin exerts indirect pleiotropy on core metabolic hallmarks of aging, such as the insulin/insulin-like growth factor 1 and AMP-activated protein kinase/mammalian Target Of Rapamycin signaling pathways, downstream of its primary inhibitory effect on mitochondrial respiratory complex I. Alternatively, but not mutually exclusive, metformin can exert regulatory effects on components of the biologic machinery of aging itself such as chromatin-modifying enzymes. An integrative metabolo-epigenetic outlook supports a new model whereby metformin operates as a guardian of cell identity, capable of retarding cellular aging by preventing the loss of the information-theoretic nature of the epigenome. The ultimate anti-aging mechanism of metformin might involve the global preservation of the epigenome architecture, thereby ensuring cell fate commitment and phenotypic outcomes despite the challenging effects of aging noise. Metformin might therefore inspire the development of new gerotherapeutics capable of preserving the epigenome architecture for cell identity. Such gerotherapeutics should replicate the ability of metformin to halt the erosion of the epigenetic landscape, mitigate the loss of cell fate commitment, delay stochastic/environmental DNA methylation drifts, and alleviate cellular senescence. Yet, it remains a challenge to confirm if regulatory changes in higher-order genomic organizers can connect the capacity of metformin to dynamically regulate the three-dimensional nature of epigenetic landscapes with the 4th dimension, the aging time.

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“…Metformin and insulin are both classic hypoglycemic medications and there are many studies about their positive influence on bone tissue [35,36]. The results showed that the distal MBL in the metformin group was higher than that in the insulin group at the 1 and 2-year followups.…”

Section: Discussionmentioning

confidence: 96%

“…T2DM individuals could have a higher marrow fat content than nondiabetic individuals, while metformin could reduce the marrow adiposity in T2DM [48]. The low concentrations of metformin could alleviate the impact of oxidative stress on periodontal ligament stem cells (PDLSCs), facilitate the osteogenic differentiation, inhibit adipose differentiation of PDLSCs and then promote alveolar bone regeneration for the periodontitis treatment [36]. The positive effects of metformin on microangiopathy and inflammation could also be found in bone formation and mineral anabolism [49].…”

Section: Discussionmentioning

confidence: 99%

Clinical and radiographic variables related to implants with simultaneous grafts among type 2 diabetic patients treated with different hypoglycemic medications: a retrospective study

et al. 2021

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Background The influence of different hypoglycemic agents on peri-implant variables among type 2 diabetes mellitus patients is still unclear. Therefore, the aim of this study was to assess the radiographic marginal bone loss and clinical parameters around implants in patients using different hypoglycemic agents. Methods In this retrospective cohort study, the dental implant records of type 2 diabetes mellitus patients who met the inclusion criteria were collected. The patients using only single medication as follows: insulin, metformin, or glucagon-like peptide-1 (GLP-1) drugs, were grouped according to their medication. These patients received implant placement with the same initial status, and all the prosthesis restorations were cement-retained ceramic crowns. The peri-implant marginal bone levels were evaluated by periapical radiographs immediately after implant placement and at 1 and 2-year follow-up visits. The baseline characteristics were compared among groups. The peri-implant radiographic marginal bone loss and clinical parameters were preliminarily compared using the Kruskal–Wallis test, and then the covariates were controlled by covariance analysis. Bonferroni post hoc adjustment test was performed for the multiple comparisons. Results After a review of more than 7000 medical records, a total of 150 patients with 308 implants at 1-year follow-up were assessed. The peri-implant marginal bone loss in the GLP-1 drug group was significantly smaller than the insulin group and metformin group (P < 0.01). The radiographic bone loss in the metformin group was higher than the insulin group (P < 0.05). Some of these included patients were lost to follow-up. Only 74 patients with 129 implants completed the 2-year follow-up. The radiographic bone loss in the metformin group was still higher than the insulin group (P < 0.05) and GLP-1 group (P < 0.01). There was no significant difference in the BOP (+) and the mean PD among groups (P > 0.05). Conclusions The radiographic variables were not exactly the same among the patients with different hypoglycemic agents at both the 1 and 2-year follow-ups. After ensuring consistency in baseline characteristics, the positive effect of GLP-1 drugs on peri-implant bone remodeling may be no less than insulin or metformin. More studies are needed to verify the direct effect of these drugs on peri-implant bone. Clinical trial registration number ChiCTR2000034211 (retrospectively registered).

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Metformin promotes osteogenic differentiation and protects against oxidative stress-induced damage in periodontal ligament stem cells via activation of the Akt/Nrf2 signaling pathway

Cited by 53 publications

References 56 publications

Metformin Ameliorates Gestational Diabetes Mellitus-Induced Endothelial Dysfunction via Downregulation of p65 and Upregulation of Nrf2

Metformin Ameliorates Gestational Diabetes Mellitus-Induced Endothelial Dysfunction via Downregulation of p65 and Upregulation of Nrf2

Metformin: Sentinel of the Epigenetic Landscapes That Underlie Cell Fate and Identity

Clinical and radiographic variables related to implants with simultaneous grafts among type 2 diabetic patients treated with different hypoglycemic medications: a retrospective study

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