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Id Subject Object Predicate Lexical cue
T1 0-22 Sentence denotes Metformin in COVID-19:
T2 23-54 Sentence denotes A possible role beyond diabetes
T3 56-69 Sentence denotes 1 Metformin:
T4 70-108 Sentence denotes Historical re-purposing and pleiotropy
T5 109-265 Sentence denotes It is a lesser-known fact that metformin was originally introduced as an anti-influenza drug and that glucose-lowering was only one of its side effects [1].
T6 266-420 Sentence denotes The many pleiotropic effects of metformin and its widespread utility in medicine today have led scientists to call it the aspirin of the 21st century [2].
T7 421-624 Sentence denotes In the current scenario, when there is no specific agent against COVID-19, and when re-purposing of drugs is the primary weapon, we suggest that metformin be used as one of the drugs to combat the virus.
T8 626-639 Sentence denotes 2 Metformin:
T9 640-678 Sentence denotes Mechanism of action on molecular level
T10 679-781 Sentence denotes Metformin activates AMP-activated protein kinase (AMPK) in hepatocytes by causing its phosphorylation.
T11 782-896 Sentence denotes This is the main mechanism by which metformin brings about favourable effects on glucose and lipid metabolism [3].
T12 898-933 Sentence denotes 2.1 Metformin-AMPK-ACE2-SARS-CoV-2
T13 934-1096 Sentence denotes The juggernaut virus, SARS-CoV-2, that has led to the deaths of over 1.7 lakh people across the world uses angiotensin-converting enzyme 2 (ACE2) as its receptor.
T14 1097-1217 Sentence denotes It enters the human body through interaction between its spike proteins (S1) and the N-terminal region of ACE2 [4], [5].
T15 1218-1354 Sentence denotes The receptor binding domain (RBD) of the virus binds with the protease domain (PD) of the ACE2 receptor and forms an RBD-PD complex [4].
T16 1355-1477 Sentence denotes Acute Respiratory Distress Syndrome (ARDS) is one of the commonest complications developing in patients with COVID-19 [6].
T17 1478-1593 Sentence denotes There have been animal studies that have implicated ACE2 in the acute lung injury (ALI) caused due to SARS-CoV [4].
T18 1594-1702 Sentence denotes It has been hypothesized that ACE2 causes ALI by bringing about autophagy through the AMPK/mTOR pathway [7].
T19 1703-1928 Sentence denotes AMPK has been shown to increase the expression of ACE2 as well as to increase its stability by phosphorylating ACE2 Ser680 in human umbilical vein endothelial cells (HUVECs) and human embryonic kidney 293 (HEK293T) cells [8].
T20 1929-2180 Sentence denotes Since metformin works through AMPK activation, which leads to phosphorylation of ACE2 [8], we can consider that theoretically this addition of a phosphate group (PO4 −3) would bring about conformational and functional changes in the ACE2 receptor [9].
T21 2181-2311 Sentence denotes This could lead to decreased binding with SARS-CoV-2 RBD due to steric hindrance by the addition of a large sized PO4 −3 molecule.
T22 2312-2395 Sentence denotes Nonetheless, once the virus is inside, there is a downregulation of ACE2 receptors.
T23 2396-2631 Sentence denotes This in turn leads to an imbalance in the renin-angiotensin-aldosterone system (RAS) promoting the deleterious effects of its pro-inflammatory and pro-fibrotic arm, further giving rise to the lethal cardio-pulmonary complications [10].
T24 2632-2692 Sentence denotes By upregulating ACE2, the imbalance in RAS could be averted.
T25 2693-2873 Sentence denotes Hence, metformin would not only prevent the entry of SARS-CoV-2 as described above, but also prevent the detrimental sequelae by causing activation of ACE2 through AMPK-signalling.
T26 2875-2906 Sentence denotes 2.2 Metformin-mTOR-Coronavirus
T27 2907-3120 Sentence denotes The mammalian target of rapamycin (mTOR) signalling plays an important role in the pathogenesis of influenza, besides modulating antibody response for cross-protective immunity against infective influenza viruses.
T28 3121-3202 Sentence denotes Metformin activates AMPK via liver kinase B1 (LKB1), inhibiting the mTOR pathway.
T29 3203-3372 Sentence denotes It also indirectly attenuates AKT activation through phosphorylation of insulin receptor substrate 1 (IRS-1) resulting in inhibition of the mTOR signalling cascade [11].
T30 3373-3516 Sentence denotes Other biguanide molecules, buformin and phenformin have been associated with better survival outcomes in animal models of influenza [12], [13].
T31 3517-3597 Sentence denotes Further, the PI3K/AKT/mTOR pathway plays major roles in MERS‑CoV infection [14].
T32 3598-3705 Sentence denotes Since metformin inhibits the same pathway, it would be interesting to decipher its role against SARS-CoV-2.
T33 3707-3778 Sentence denotes 2.3 Protein-protein interaction map and network-based drug repurposing
T34 3779-3939 Sentence denotes A study was attempted to narrow the existing molecular-level knowledge gap of SARS-CoV-2 by mapping the interactions between SARS-CoV-2 and human proteins [15].
T35 3940-4066 Sentence denotes With the help of affinity purification mass spectrometry (AP-MS), 332 protein–protein interactions (PPIs) could be identified.
T36 4067-4232 Sentence denotes Further, 66 druggable human proteins/factors targeted by 69 medicines which were either FDA-approved or in clinical trials or pre-clinical molecules were recognized.
T37 4233-4413 Sentence denotes To our interest, it was found that human proteins regulated by the mTORC1 signalling pathway, specifically LARP1 and FKBP7, interact with important viral proteins, N and Orf8 [15].
T38 4414-4581 Sentence denotes Since metformin inhibits mTOR signalling, it could act as an indirect modulator of the protein–protein complex, thus preventing the viral replication and pathogenesis.
T39 4583-4606 Sentence denotes 2.4 Viral replication:
T40 4607-4637 Sentence denotes Lessons learnt from Zika virus
T41 4638-4723 Sentence denotes Zika virus (ZIKV), a single-stranded RNA virus, is a mosquito transmitted flavivirus.
T42 4724-4880 Sentence denotes A study using HUVECs and human retinal vascular endothelial cells (HRvECs) showed that AMPK restricts the replication of ZIKV in the endothelial cells [16].
T43 4881-5056 Sentence denotes Activation of AMPK with the help of two well-known AMPK activators, metformin and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) led to attenuation of ZIKV replication.
T44 5057-5251 Sentence denotes Activated AMPK further potentiated the expression of certain genes with known antiviral properties such as IFNs, OAS2, ISG15, and MX1 while inhibiting inflammatory mediators like TNF-α and CCL5.
T45 5252-5326 Sentence denotes It would be useful to explore whether the same is observed for SARS-CoV-2.
T46 5327-5486 Sentence denotes A recent study has reported that inhibition of glycolysis by non-toxic concentration of 2-DG completely attenuated SARS-CoV-2 replication in Caco-2 cells [17].
T47 5487-5573 Sentence denotes All of these indicate towards a possible frontline role of metformin against COVID-19.
T48 5575-5613 Sentence denotes 2.5 Insulin resistance and SARS-CoV-2
T49 5614-5788 Sentence denotes A few case reports from China and Italy, along with a Chinese meta-analysis, have shown diabetes to be an important risk factor for severe disease requiring ventilation [18].
T50 5789-6029 Sentence denotes Further, a study had shown a direct metabolic link between SARS-CoV and diabetes, postulating that the virus enters the pancreatic islets which express ACE2, leading to acute β-cell damage and transient Type 2 diabetes mellitus (T2DM) [19].
T51 6030-6219 Sentence denotes Evidence from an animal study points toward increased ACE2 activity in pancreas of persons with diabetes besides its elevated expression in other tissues such as lung, liver and heart [20].
T52 6220-6330 Sentence denotes Hence, optimal control of T2DM, for both chronic and transient cases, might help in the treatment of COVID-19.
T53 6331-6676 Sentence denotes Although recent discussions point out that oral hypoglycaemic agents such as Sodium-Glucose-Transporter-2 inhibitors (SGLT-2i), Glucagon-Like-Peptide-1 Receptor Agonists (GLP-1RAs), Pioglitazone and even Insulin might actually be harmful for COVID-19 individuals with diabetes [21], [22], limited evidence is available on metformin for the same.
T54 6677-6943 Sentence denotes Considering its pleiotropic effects and a possible role in combating hepatitis C virus (HCV), hepatitis B virus (HBV) and human immunodeficiency virus (HIV) through increasing insulin sensitivity [23], metformin can be a real game-changer for treating this pandemic.
T55 6945-6952 Sentence denotes Funding
T56 6953-7021 Sentence denotes No funding has been received for the preparation of this manuscript.
T57 7023-7033 Sentence denotes Authorship
T58 7034-7404 Sentence denotes All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this article, take responsibility for the integrity of the work as a whole and that it will not be published elsewhere in the same form, in English or in any other language, including electronically, and have given their approval for this version to be published.
T59 7406-7430 Sentence denotes Authorship contributions
T60 7431-7481 Sentence denotes SS, AR and BS co-wrote and revised the manuscript.
T61 7483-7516 Sentence denotes Declaration of Competing Interest
T62 7517-7687 Sentence denotes The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.