Metformin to decrease COVID-19 severity and mortality: Molecular mechanisms and therapeutic potential

Kamyshnyi, О. М.; Matskevych, V. M.; Lenchuk, Tetyana; Strilbytska, Olha; Storey, Kenneth B.; Lushchak, Oleh

doi:10.1016/j.biopha.2021.112230

Cited by 43 publications

(58 citation statements)

References 153 publications

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“…Raptor subunit in mTORC1 is found to be sensitive to rapamycin and is thus inhibited by it, while Rictor subunit of mTORC2 is rapamycin-insensitive and therefore not inhibited by rapamycin. The rapamycin-sensitive mTORC1 has a key role in protein synthesis, cell growth, and so on and the rapamycin-insensitive mTORC2 is mostly involved in cell survival and cytoskeletal organization [27].…”

Section: Sars-cov-2 and Mtor Pathwaymentioning

confidence: 99%

“…Therefore, it can be helpful in the treatment of COVID-19. Recent retrospective studies suggest metformin as an effective pharmacological treatment in COVID-19 patients based on data on SARS-CoV-2 patients with diabetes mellitus [27]. Metformin inhibits mTORC1 by AMPK phosphorylation and activation via activating liver kinase B1 (LKB1).…”

Section: Metformin Tacrolimus Sapanisertib and Pp-242: Mtor Inhibitorsmentioning

confidence: 99%

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PI3K/Akt/mTOR pathway: a potential target for anti-SARS-CoV-2 therapy

Fattahi

Khalifehzadeh-Esfahani

Mohammad-Rezaei

et al. 2022

Immunol Res

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Coronavirus disease 2019 (COVID-19) is a viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A single-stranded RNA virus from a β-Coronaviridae family causes acute clinical manifestations. Its high death rate and severe clinical symptoms have turned it into the most significant challenge worldwide. Up until now, several effective COVID-19 vaccines have been designed and marketed, but our data on specialized therapeutic drugs for the treatment of COVID-19 is still limited. In order to synthesis virus particles, SARS-CoV-2 uses host metabolic pathways such as phosphoinositide3-kinase (PI3K)/protein kinase B (PKB, also known as AKT)/mammalian target of rapamycin (mTOR). mTOR is involved in multiple biological processes. Over-activation of the mTOR pathway improves viral replication, which makes it a possible target in COVID-19 therapy. Clinical data shows the hyperactivation of the mTOR pathway in lung tissues during respiratory viral infections. However, the exact impact of mTOR pathway inhibitors on the COVID-19 severity and death rate is yet to be thoroughly investigated. There are several mTOR pathway inhibitors. Rapamycin is the most famous inhibitor of mTORC1 among all. Studies on other respiratory viruses suggest that the therapeutic inhibitors of the mTOR pathway, especially rapamycin, can be a potential approach to anti-SARS-CoV-2 therapy. Using therapeutic methods that inhibit harmful immune responses can open a new chapter in treating severe COVID-19 disease. We highlighted the potential contribution of PI3K/Akt/mTOR inhibitors in the treatment of COVID-19.

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Section: Sars-cov-2 and Mtor Pathwaymentioning

confidence: 99%

Section: Metformin Tacrolimus Sapanisertib and Pp-242: Mtor Inhibitorsmentioning

confidence: 99%

PI3K/Akt/mTOR pathway: a potential target for anti-SARS-CoV-2 therapy

Fattahi

Khalifehzadeh-Esfahani

Mohammad-Rezaei

et al. 2022

Immunol Res

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“…Akkermansia muciniphila is one of the well-known utilizers of mucin, which is decreased in patients with diabetes, obesity, and cardiovascular disease not treated with metformin. It plays a vital role in maintaining intestinal mucosa integrity, reducing the migration of pro-inflammatory LPS, and improving blood glucose levels [ 141 , 142 , 143 , 144 ]. Another clinical study of 27 healthy young adults (the participants were given metformin up to 1g twice daily) found that metformin reduced Clostridium spp.…”

Section: Immunoregulation Gut Microbiota and Covid-19mentioning

confidence: 99%

Immunoregulatory Intestinal Microbiota and COVID-19 in Patients with Type Two Diabetes: A Double-Edged Sword

Petakh

Kamyshna

Nykyforuk

et al. 2022

Viruses

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Coronavirus disease 2019, or COVID-19, is a major challenge facing scientists worldwide. Alongside the lungs, the system of organs comprising the GI tract is commonly targeted by COVID-19. The dysbiotic modulations in the intestine influence the disease severity, potentially due to the ability of the intestinal microbiota to modulate T lymphocyte functions, i.e., to suppress or activate T cell subpopulations. The interplay between the lungs and intestinal microbiota is named the gut–lung axis. One of the most usual comorbidities in COVID-19 patients is type 2 diabetes, which induces changes in intestinal microbiota, resulting in a pro-inflammatory immune response, and consequently, a more severe course of COVID-19. However, changes in the microbiota in this comorbid pathology remain unclear. Metformin is used as a medication to treat type 2 diabetes. The use of the type 2 diabetes drug metformin is a promising treatment for this comorbidity because, in addition to its hypoglycemic action, it can increase amount of intestinal bacteria that induce regulatory T cell response. This dual activity of metformin can reduce lung damage and improve the course of the COVID-19 disease.

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“…Thus, metformin may decrease the ACE2 binding ability of SARS-CoV-2 as well as increase the expression and stability of ACE2 through activating AMPK. Metformin can also be involved in the development of COVID-19 by inhibiting the mTOR signaling pathway [ 40 , 41 ] and altering the composition of the gut microbiota [ 42 ]. A recent study showed users of metformin had few adverse outcomes compared to nonusers [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Prognostic Factors for COVID-19 Hospitalized Patients with Preexisting Type 2 Diabetes

Ren

et al. 2022

International Journal of Endocrinology

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Background. Type 2 diabetes (T2D) as a worldwide chronic disease combined with the COVID-19 pandemic prompts the need for improving the management of hospitalized COVID-19 patients with preexisting T2D to reduce complications and the risk of death. This study aimed to identify clinical factors associated with COVID-19 outcomes specifically targeted at T2D patients and build an individualized risk prediction nomogram for risk stratification and early clinical intervention to reduce mortality. Methods. In this retrospective study, the clinical characteristics of 382 confirmed COVID-19 patients, consisting of 108 with and 274 without preexisting T2D, from January 8 to March 7, 2020, in Tianyou Hospital in Wuhan, China, were collected and analyzed. Univariate and multivariate Cox regression models were performed to identify specific clinical factors associated with mortality of COVID-19 patients with T2D. An individualized risk prediction nomogram was developed and evaluated by discrimination and calibration. Results. Nearly 15% (16/108) of hospitalized COVID-19 patients with T2D died. Twelve risk factors predictive of mortality were identified. Older age (HR = 1.076, 95% CI = 1.014–1.143, p = 0.016 ), elevated glucose level (HR = 1.153, 95% CI = 1.038–1.28, p = 0.0079 ), increased serum amyloid A (SAA) (HR = 1.007, 95% CI = 1.001–1.014, p = 0.022 ), diabetes treatment with only oral diabetes medication (HR = 0.152, 95%CI = 0.032–0.73, p = 0.0036 ), and oral medication plus insulin (HR = 0.095, 95%CI = 0.019–0.462, p = 0.019 ) were independent prognostic factors. A nomogram based on these prognostic factors was built for early prediction of 7-day, 14-day, and 21-day survival of diabetes patients. High concordance index (C-index) was achieved, and the calibration curves showed the model had good prediction ability within three weeks of COVID-19 onset. Conclusions. By incorporating specific prognostic factors, this study provided a user-friendly graphical risk prediction tool for clinicians to quickly identify high-risk T2D patients hospitalized for COVID-19.

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Metformin to decrease COVID-19 severity and mortality: Molecular mechanisms and therapeutic potential

Cited by 43 publications

References 153 publications

PI3K/Akt/mTOR pathway: a potential target for anti-SARS-CoV-2 therapy

PI3K/Akt/mTOR pathway: a potential target for anti-SARS-CoV-2 therapy

Immunoregulatory Intestinal Microbiota and COVID-19 in Patients with Type Two Diabetes: A Double-Edged Sword

Prognostic Factors for COVID-19 Hospitalized Patients with Preexisting Type 2 Diabetes

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