The protective effect of metformin on mitochondrial dysfunction and endoplasmic reticulum stress in diabetic mice brain

Docrat, Taskeen; Nagiah, Savania; Naicker, Nikita; Baijnath, Sooraj; Singh, Sima; Chuturgoon, Anil A.

doi:10.1016/j.ejphar.2020.173059

Cited by 35 publications

(18 citation statements)

References 65 publications

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“…Met was also found to restore Bip expression to control levels in the two-dose protocol, while partially restored Bip expression in the four-dose protocol, possibly due to the sustained proteasome inhibition by Cfz and therefore excessive accumulation of unfolded proteins. Our data are in agreement with the literature, as it is previously shown that Met can modulate ER stress and unfolded protein response in an AMPKα-dependent downregulation of ER stress markers such as Parkin and miR-132, in the myocardium and in other organs [42][43][44]. However, to the best of our knowledge, it is the first time that the down-regulatory effect of Met specifically on Bip is presented, indicating that Met could mitigate unfolded protein response.…”

Section: Discussionsupporting

confidence: 93%

Elucidating Carfilzomib’s Induced Cardiotoxicity in an In Vivo Model of Aging: Prophylactic Potential of Metformin

Efentakis

Psarakou

Varela

et al. 2021

IJMS

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Background: Carfilzomib is a first-line proteasome inhibitor indicated for relapsed/refractory multiple myeloma (MM), with its clinical use being hampered by cardiotoxic phenomena. We have previously established a translational model of carfilzomib cardiotoxicity in young adult mice, in which metformin emerged as a prophylactic therapy. Considering that MM is an elderly disease and that age is an independent risk factor for cardiotoxicity, herein, we sought to validate carfilzomib’s cardiotoxicity in an in vivo model of aging. Methods: Aged mice underwent the translational two- and four-dose protocols without and with metformin. Mice underwent echocardiography and were subsequently sacrificed for molecular analyses in the blood and cardiac tissue. Results: Carfilzomib decreased proteasomal activity both in PBMCs and myocardium in both protocols. Carfilzomib induced mild cardiotoxicity after two doses and more pronounced cardiomyopathy in the four-dose protocol, while metformin maintained cardiac function. Carfilzomib led to an increased Bip expression and decreased AMPKα phosphorylation, while metformin coadministration partially decreased Bip expression and induced AMPKα phosphorylation, leading to enhanced myocardial LC3B-dependent autophagy. Conclusion: Carfilzomib induced cardiotoxicity in aged mice, an effect significantly reversed by metformin. The latter possesses translational importance as it further supports the clinical use of metformin as a potent prophylactic therapy.

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Section: Discussionsupporting

confidence: 93%

Elucidating Carfilzomib’s Induced Cardiotoxicity in an In Vivo Model of Aging: Prophylactic Potential of Metformin

Efentakis

Psarakou

Varela

et al. 2021

IJMS

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“…The administration of insulin to animals with type I diabetes leads to an increase in the expression level of mitochondrial proteins and an improvement of energy metabolism (an increase in the rate of ATP synthesis) [ 56 , 57 ]. The use of antidiabetic drugs (metformin, thiazolidinediones, empagliflozin, and some others) or regular exercise recovers the expression of PGC-1α, the mtDNA/nDNA ratio and improves mitochondrial energy metabolism in diabetic animals [ 58 , 59 , 60 , 61 , 62 ]. At the same time, an increase in the expression of PGC-1α results in the restoration of both energy functions and insulin sensitivity of cells [ 62 , 63 ].…”

Section: Mechanisms Of the Diabetes-induced Mitochondrial Dysfunctmentioning

confidence: 99%

“…Synthetic and natural antidiabetic compounds exhibit a bi-directional effect on MPT pore opening. Notably, metformin has been shown to inhibit MPT pore opening in mitochondria, enhances biogenesis, and prevents cell death [ 61 , 242 , 243 ]. However, there is an evidence that metformin stimulates MPT in rat liver mitochondria [ 244 ].…”

Section: Ca 2+ Handling Mpt Pore and Diabetes mentioning

confidence: 99%

Diabetes Mellitus, Mitochondrial Dysfunction and Ca2+-Dependent Permeability Transition Pore

Belosludtsev

Belosludtseva

Dubinin

2020

IJMS

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Diabetes mellitus is one of the most common metabolic diseases in the developed world, and is associated either with the impaired secretion of insulin or with the resistance of cells to the actions of this hormone (type I and type II diabetes, respectively). In both cases, a common pathological change is an increase in blood glucose—hyperglycemia, which eventually can lead to serious damage to the organs and tissues of the organism. Mitochondria are one of the main targets of diabetes at the intracellular level. This review is dedicated to the analysis of recent data regarding the role of mitochondrial dysfunction in the development of diabetes mellitus. Specific areas of focus include the involvement of mitochondrial calcium transport systems and a pathophysiological phenomenon called the permeability transition pore in the pathogenesis of diabetes mellitus. The important contribution of these systems and their potential relevance as therapeutic targets in the pathology are discussed.

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“…[ 23 ] In addition to its antidiabetic action, metformin played a neuroprotective role in epigenomic and integrated stress responses in diabetic mice by regulating the mitochondrial function, including Sirt1 and Sirt3 enzymes. [ 24 ] Due to this dual action of metformin in cancer and diabetes, and the relationship between SIRT3 and diabetes or cancer, we decided to evaluate the effects of metformin on SIRT3, a key regulating protein in the mitochondrial activity and internal cell death pathway. HT‐29 is a human colorectal adenocarcinoma cell line with an epithelial morphology.…”

Section: Introductionmentioning

confidence: 99%

Cytotoxicity of metformin against HT29 colon cancer cells contributes to mitochondrial Sirt3 upregulation

Khodaei

Hosseini

Omidi

et al. 2020

J Biochem & Molecular Tox

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Cancer and diabetes, the two mitochondria‐related diseases, have recently been linked to silent mating‐type information regulation 2 homolog 3 (SIRT3) activity irregularities. In this study, the effect of metformin, an antidiabetic with anticancer properties, has been evaluated on mitochondrial functionality markers, cell death pathways, and SIRT3 enzyme activity in the colon cancer cell line, HT‐29, and human embryonic kidney cells (HEK 293). HT‐29 cells were treated with metformin (5, 10, 20, 40, and 80 µM) for 24, 48, and 72 h for measuring the IC50 concentration. Reactive oxygen species (ROS) production, apoptosis, mitochondrial membrane potential, SIRT3 activity, and expression were evaluated against the colon cancer cell line, HT‐29. Results indicated a higher ROS production at 6 than 12 h with metformin treatment. Metformin modified the mitochondrial membrane potential, resulting in cell death induction. Results from SIRT3 activity and expression showed that metformin increased its activity and expression in cancer cells. In conclusion, metformin in HT‐29 cells disturbed the mitochondrial activity via increased ROS levels and SIRT3 activity, and these rapid modifications may play a key role in its cytotoxic property.

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The protective effect of metformin on mitochondrial dysfunction and endoplasmic reticulum stress in diabetic mice brain

Cited by 35 publications

References 65 publications

Elucidating Carfilzomib’s Induced Cardiotoxicity in an In Vivo Model of Aging: Prophylactic Potential of Metformin

Elucidating Carfilzomib’s Induced Cardiotoxicity in an In Vivo Model of Aging: Prophylactic Potential of Metformin

Diabetes Mellitus, Mitochondrial Dysfunction and Ca2+-Dependent Permeability Transition Pore

Cytotoxicity of metformin against HT29 colon cancer cells contributes to mitochondrial Sirt3 upregulation

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