discussion:The main result of this study is the demonstration that the antidiabe
ID: 82841 • Letter: D
Question
discussion:The main result of this study is the demonstration that the antidiabetic drug metformin reduces progerin expression and alleviates pathological phenotypes of HGPS cells, thus suggesting that it may be interesting to explore its therapeutic potential in patients with progeria.
Since the discovery of the molecular mechanism leading to this syndrome, three different drugs have been repositioned in HGPS for their ability to target progerin toxicity through the inhibition of the protein prenylation process, namely, pravastatin, zoledronate and lonafarnib.6,7,8,24,25 Several alternative approaches have been described more recently that directly target progerin, either by antisense oligonucleotides that mask splicing sites of the mutated pre-mRNAs,10,11 by mTOR regulation with rapamycin,13 PDGF-BB stimulation12 or through retinoids.26 Overall, these different strategies have demonstrated that targeting progerin content does indeed improve several pathological phenotypes observed in the cells of patients. In this study, we describe another method for targeting progerin content by repurposing an antidiabetic drug that has shown a very good safety profile since its discovery some decades ago. Even if the exact molecular mechanisms leading to SRSF1 modulation by metformin remain to be explored, especially to understand how this drug acts to regulate the splicing factor expression, this report describes a way of targeting progerin content that may be used alone or in combination with other drugs that target other pathways or pathological molecular mechanisms. Our study reveals that metformin treatment results in a variable, but still significant, decrease in lamin C expression across the cell types. However, the analysis of ratio lamin A/lamin C and progerin/lamin C reveals a very similar effect of metformin across the cell types (Supplementary Figure) suggesting that this drug could act on both transcription and splicing processes.
Taking into account the suggested potential of metformin as an anti-aging drug, its effect on progerin expression may be interesting to explore. Over the past 30 years, several in vivo studies have indeed described an increased longevity under metformin treatment. Metformin supplementation (50mmol/l dose) was shown to increase the average lifespan of Caenorhabditis elegans by up to 36%.27,28 In mice, several reports have revealed that long-term metformin treatment increases the average lifespan and decreases tumor incidence.29,30,31 In humans, a recent follow-up of patients with type 2 diabetes and atherosclerosis over 20 years has observed all-cause mortality that is 24% lower under metformin treatment.32 Another retrospective study of 16,417 patients with type 2 diabetes has indicated a 31% decrease in heart failure in people treated with metformin, as compared with patients treated with other drugs.33 More recently, Bannister et al.34 revealed that among 200,000 subjects, patients with type 2 diabetes initiated with metformin exhibited longer survival than those treated with sulphonylurea and overall longer survival than nondiabetic controls. Even though the possibility that the direct effect of metformin on hyperglycemia and hyperinsulinemia contributes towards these results cannot be excluded, the precise mechanisms of this protective effect remain poorly understood. A link between aging and the appearance of progerin in cells has been repeatedly established over recent years.35,36,37 Therefore, it may be interesting to reconsider the molecular basis of the effects of metformin on aging, taking into account the results of the present study and the possibility that some of the positive outcomes of the drug treatment may arise from an overall decrease in progerin content in aging cells.
please explain this figure and this discussion
by using this link
https://www.nature.com/articles/npjamd201626?WT.feed_name=subjects_drug-discovery
Explanation / Answer
Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder that is responsible for systemic accelerated aging in children. This syndrome is orignated due to a mutation in the LMNA gene that leads to the production of a truncated and toxic form of lamin A called progerin. The balance between the A-type lamins is controlled by the RNA-binding protein SRSF1. It was hypothesized that LMNA gene inhibition may have therapeutic effects for HGPS. For this purpose, author's demonstrated that the antidiabetic drug metformin when treated for 48h with 5mmol/l decreases SRSF1 and progerin expression in mesenchymal stem cells derived from HGPS induced pluripotent stem cells (HGPS MSCs).
fig 1a. show decrease in SRSF1 messenger RNA (mRNA) in HGPS MSCs with increase in dose of metphormin.
Fig b and c result was confirmed at the protein level. Demonstrating a decrease in SRSF1 protein of up to 40% when treated with 5 mmol/l of metformin.
fig d. The SRSF1 was reported to regulate the balance between A-type lamins and their expression was measured after 48 h of metformin treatment. Graph show correlated dose-dependent decrease in lamin A and progerin expression, with a maximum effect at 5mmol/l.
Explanation for Discusion
The main result of this study suggested that the antidiabetic drug metformin reduces progerin expression by allevating pathological phenotypes of HGPS cells. Thus, to explore metformin therapeutic potential in patients with progeria has to be conducted.
According to literature, the three different drugs namely, pravastatin, zoledronate and lonafarnib have been reported for their ability to target progerin toxicity through the inhibition of the protein prenylation process in HGPS. Several other studies have suggested that targeting progerin content does indeed improve several pathological phenotypes observed in the cells of patients. In this study, author describes different method for targeting progerin content by repurposing an antidiabetic drug metformin. Molecular mechanisms leading to SRSF1 modulation by metformin remain to be explored, this study postulate a way of targeting progerin content that may be used alone or in combination with other drugs that target other pathways or pathological molecular mechanisms. Author suggested that metformin treatment results in a variable, but still significant, decrease in lamin C expression across the cell types. However, the analysis of ratio lamin A/lamin C and progerin/lamin C reveals a very similar effect of metformin across the cell types attributed that metformin drug could act on both transcription and splicing processes.
Taking into consideration the suggested potential of metformin as an anti-aging drug, its effect on progerin expression may be interesting to explore. Over the past 30 years, several studies have been conducted however, the possibility that the direct effect of metformin on hyperglycemia and hyperinsulinemia could contributes SRSF1 modulation has yet to be explored. A corelation between aging and the appearance of progerin in cells has been repeatedly established over recent years. Therefore, it may be interesting to explore the molecular basis of the effects of metformin on aging, taking into account the results of the present study demonstrated positive outcomes of the drug treatment may arise from an overall decrease in progerin content in aging cells.
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