Immunomodulatory and Antiviral Activity of Metformin and Its Potential Implications in Treating Coronavirus Disease 2019 and Lung Injury

Chen, Xianyang; Guo, Huifang; Qiu, Li; Zhang, Chengdong; Deng, Qiang; Leng, Qibin

doi:10.3389/fimmu.2020.02056

Cited by 53 publications

(45 citation statements)

References 63 publications

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“…Indeed, it has been stated that the anti-inflammatory effect of metformin is through the activation of the AMPK pathway that inhibits the mTOR signaling and NF-kB pathway with subsequent suppression of IL-6 and TNF-α with the activation of anti-inflammatory IL-10. These changes triggered by metformin are also able to attenuate the cytokine production from activated macrophage and glial cells during severe COVID-19 and AIS-induced neuroinflammation ( 35 ). Zeng et al ( 36 ) confirmed that metformin has a neuroprotective effect via the inhibition of apoptosis and oxidative stress in AIS and thus can be viewed as a promising preventive agent against ischemic-reperfusion in AIS.…”

Section: Discussionmentioning

confidence: 99%

COVID-19 and Risk of Acute Ischemic Stroke and Acute Lung Injury in Patients With Type II Diabetes Mellitus: The Anti-inflammatory Role of Metformin

et al. 2021

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Background: Coronavirus disease 19 (COVID-19) is regarded as an independent risk factor for acute ischemic stroke (AIS) due to the induction of endothelial dysfunction, coagulopathy, cytokine storm, and plaque instability.Method: In this retrospective cohort study, a total of 42 COVID-19 patients with type 2 diabetes mellitus (T2DM) who presented with AIS within 1 week of displaying COVID-19 symptoms were recruited. According to the current anti-DM pharmacotherapy, patients were divided into two groups: a Metformin group of T2DM patients with COVID-19 and AIS on metformin therapy (850 mg, 3 times daily (n = 22), and a Non-metformin group of T2DM patients with COVID-19 and AIS under another anti-DM pharmacotherapy like glibenclamide and pioglitazone (n = 20). Anthropometric, biochemical, and radiological data were evaluated.Results: Ferritin serum level was lower in metformin-treated patients compared to non-metformin treated patients (365.93 ± 17.41 vs. 475.92 ± 22.78 ng/mL, p = 0.0001). CRP, LDH, and D-dimer serum levels were also lowered in metformin-treated patients compared to non-metformin treated patients (p = 0.0001). In addition, lung CT scan scores of COVID-19 patients was 30.62 ± 10.64 for metformin and 36.31 ± 5.03 for non-metformin treated patients.Conclusion: Metformin therapy in T2DM patients was linked to a lower risk of AIS during COVID-19. Further studies are needed to observe the link between AIS in COVID-19 diabetic patients and metformin therapy.

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Section: Discussionmentioning

confidence: 99%

COVID-19 and Risk of Acute Ischemic Stroke and Acute Lung Injury in Patients With Type II Diabetes Mellitus: The Anti-inflammatory Role of Metformin

et al. 2021

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“…By increasing cellular pH, metformin subsequently interferes with the endocytic cycle to inhibit viral infection by acting on the eNHEs and/or the V-ATPase (14). Reducing production of proinflammatory cytokines by macrophages and formation of neutrophil extracellular traps (NETs) might play a role as well (43). Although current evidence supports metformin use, further studies are needed to understand its mechanistic link to mortality benefits.…”

Section: Discussionmentioning

confidence: 99%

The Association Between Hypoglycemic Agents and Clinical Outcomes of COVID-19 in Patients with Diabetes: A Systematic Review and Meta-Analysis

Han

Sun

et al. 2021

Preprint

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BackgroundDuring the current Coronavirus Disease 2019 (COVID-19) pandemic, diabetic patients face disproportionately more. Anti-inflammatory effects of hypoglycemic agents have been reported, and their beneficial or harmful effects in patients with diabetes and COVID-19 remain controversial.PurposeThis study was performed to clarify this association.Data SourcesRelevant literature was searched on China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform, Chinese periodical service platform VIP Database, Sinomed (China Biology Medicine, CBM), MedRxiv, PubMed, ScienceDirect, Web of Science, Ovid Databases (LWW), Springer Link, Wiley Online Library, Oxford Academic, Nature Press Group, Cochrane Library and BMJ Evidence-Based Medicine up to November 14, 2020.Study SelectionOnly observational studies of hypoglycemic agents vs. drugs or therapy without hypoglycemic agents in adult diabetic patients with COVID-19 were included.Data ExtractionData of death and poor composite outcomes were extracted.Data SynthesisThe pooled effects were calculated using the fixed-effects or random-effects models based on heterogeneity assessment.LimitationMost studies were retrospective cohort studies with relative weak capability to verify causality.ConclusionHome use of metformin might be beneficial in decreasing mortality in diabetic patients infected with SARS-CoV-2. There is insufficient evidence to conclude that metformin and other hypoglycemic agents are associated with poor composite outcomes. More prospective studies, especially RCTs are needed.Registration-PROSPEROCRD42020221951.

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“…Finally, we tested three investigational therapies previously predicted as potentially effective in SARS-CoV-2 infection, including sirolimus (25,26), metformin (27)(28)(29), and Nhydroxycytidine (30). We found that sirolimus was highly effective in reducing viral titer in tissues from three donors, but did not significantly affect titer in two donors or Vero cells ( Figure 4D).…”

Section: Antiviral Therapy In Lung Tissue Culturementioning

confidence: 94%

In vitroinfection of human lung tissue with SARS-CoV-2: Heterogeneity in host defense and therapeutic response

Schaller

Sharma

Dupee

et al. 2021

Preprint

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Cell lines are the mainstay in understanding the biology of COVID-19 infection, but do not recapitulate many of the complexities of human infection. The use of human lung tissue is one solution for the study of such novel respiratory pathogens. We hypothesized that a cryopreserved bank of human lung tissue allows for the in vitro study of the inter-individual heterogeneity of host response to SARS-CoV-2 infection, thus providing a bridge between studies with cell lines and studies in animal models. We generated a cryobank of tissues from 16 donors, most of whom had risk factors for severe illness from COVID-19. Cryopreserved tissues preserved 90% of cell viability and contained heterogeneous populations of metabolically active epithelial, endothelial, and immune cell subsets of the human lung. Samples were readily infectible with HCoV-OC43 and SARS-CoV-2 coronavirus strains, and demonstrated comparable susceptibility to infection. In contrast, we observed a marked donor-dependent heterogeneity in the expression of IL-6, CXCL8 and IFNβ in response to SARS-CoV-2 infection. Treatment of tissues with dexamethasone and the experimental drug, N-hydroxycytidine, suppressed viral growth in all samples, whereas chloroquine and remdesivir had no detectable effect. Metformin and sirolimus, molecules with predicted antiviral activity, suppressed viral replication in tissues from a subset of donors. In summary, we developed a novel system for the in vitro study of human SARS-CoV-2 infection using primary human lung tissue from a library of donor tissues. This model may be useful for drug screening and for understanding basic mechanisms of COVID-19 pathogenesis.ImportanceThe current biological systems for the study of COVID-19 are in vitro systems that differ from the human lung in many respects, and animal hosts to which the virus is not adapted. We developed another alternative for studying pathogenesis and drug susceptibility of SARS-CoV-2 in a cryopreserved bank of human lung tissues. We consider the importance of this work to relate to the practical use of this culture system as a repeatable and scalable approach that allows for the study of an important infection in relevant tissues.The tissue bank highlights the heterogeneous response to SARS-CoV-2 infection and treatment, which allows researchers to investigate why treatments work in some donors but not others.

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Immunomodulatory and Antiviral Activity of Metformin and Its Potential Implications in Treating Coronavirus Disease 2019 and Lung Injury

Cited by 53 publications

References 63 publications

COVID-19 and Risk of Acute Ischemic Stroke and Acute Lung Injury in Patients With Type II Diabetes Mellitus: The Anti-inflammatory Role of Metformin

COVID-19 and Risk of Acute Ischemic Stroke and Acute Lung Injury in Patients With Type II Diabetes Mellitus: The Anti-inflammatory Role of Metformin

The Association Between Hypoglycemic Agents and Clinical Outcomes of COVID-19 in Patients with Diabetes: A Systematic Review and Meta-Analysis

In vitroinfection of human lung tissue with SARS-CoV-2: Heterogeneity in host defense and therapeutic response

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