A Dual Pharmacological Strategy against COVID-19: The Therapeutic Potential of Metformin and Atorvastatin
Luis Adrián De Jesús-González, Rosa María Del Ángel, Selvin Noé Palacios-Rápalo, Carlos Daniel Cordero-Rivera, Adrián Rodríguez-Carlos, Juan Valentin Trujillo-Paez, Carlos Noe Farfan-Morales, Juan Fidel Osuna-Ramos, José Manuel Reyes-Ruiz, Bruno Rivas-Santiago, Moisés León-Juárez, Ana Cristina García-Herrera, Adriana Clara Ramos-Cortes, Erika Alejandra López-Gándara, Estefanía Martínez-Rodríguez
Microorganisms, doi:10.3390/microorganisms12020383
Metformin (MET) and atorvastatin (ATO) are promising treatments for COVID-19. This review explores the potential of MET and ATO, commonly prescribed for diabetes and dyslipidemia, respectively, as versatile medicines against SARS-CoV-2. Due to their immunomodulatory and antiviral capabilities, as well as their cost-effectiveness and ubiquitous availability, they are highly suitable options for treating the virus. MET's effect extends beyond managing blood sugar, impacting pathways that can potentially decrease the severity and fatality rates linked with COVID-19. It can partially block mitochondrial complex I and stimulate AMPK, which indicates that it can be used more widely in managing viral infections. ATO, however, impacts cholesterol metabolism, a crucial element of the viral replicative cycle, and demonstrates anti-inflammatory characteristics that could modulate intense immune reactions in individuals with COVID-19. Retrospective investigations and clinical trials show decreased hospitalizations, severity, and mortality rates in patients receiving these medications. Nevertheless, the journey from observing something to applying it in a therapeutic setting is intricate, and the inherent diversity of the data necessitates carefully executed, forwardlooking clinical trials. This review highlights the requirement for efficacious, easily obtainable, and secure COVID-19 therapeutics and identifies MET and ATO as promising treatments in this worldwide health emergency.
Conflicts of Interest: The authors declare no conflicts of interest.
References
Abdelmoneim, Eissa, Aboalela, Naoe, Matsumura et al., Metformin Enhances the Antitumor Activity of Oncolytic Herpes Simplex Virus HF10 (Canerpaturev) in a Pancreatic Cell Cancer Subcutaneous Model, Sci. Rep,
doi:10.1038/s41598-022-25065-wAkkiz, Implications of the Novel Mutations in the SARS-CoV-2 Genome for Transmission, Disease Severity, and the Vaccine Development, Front. Med,
doi:10.3389/fmed.2021.636532Al-Kuraishy, Al-Gareeb, Saad, Batiha, The Potential Therapeutic Effect of Statins in Multiple Sclerosis: Beneficial or Detrimental Effects, Inflammopharmacology,
doi:10.1007/s10787-023-01240-xBadr, Kurban, Abbas, Metformin in Dermatology: An Overview, J. Eur. Acad. Dermatol. Venereol,
doi:10.1111/jdv.12116Blankier, Mccrindle, Ito, Yeung, The Role of Atorvastatin in Regulating the Immune Response Leading to Vascular Damage in a Model of Kawasaki Disease, Clin. Exp. Immunol,
doi:10.1111/j.1365-2249.2011.04331.xBoulware, Bramante, Pullen, Buse, Odde et al., Metformin Reduced SARS-CoV-2 Viral Load in a Phase 3 Randomized Clinical Trial, Top. Antivir. Med
Bramante, Buse, Liebovitz, Nicklas, Puskarich et al., Outpatient Treatment of COVID-19 and Incidence of Post-COVID-19 Condition over 10 Months (COVID-OUT): A Multicentre, Randomised, Quadruple-Blind, Parallel-Group, Phase 3 Trial, Lancet Infect. Dis,
doi:10.1016/S1473-3099(23)00299-2Bramante, Huling, Tignanelli, Buse, Liebovitz et al., Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for COVID-19, N. Engl. J. Med,
doi:10.1056/NEJMoa2201662Bramante, Ingraham, Murray, Marmor, Hovertsen et al., Metformin and Risk of Mortality in Patients Hospitalised with COVID-19: A Retrospective Cohort Analysis, Lancet Healthy Longev,
doi:10.1016/S2666-7568(20)30033-7Bryan-Marrugo, Arellanos-Soto, Rojas-Martinez, Barrera-Saldaña, Ramos-Jimenez et al., The Anti-dengue Virus Properties of Statins May Be Associated with Alterations in the Cellular Antiviral Profile Expression, Mol. Med. Rep,
doi:10.3892/mmr.2016.5519Calza, Trapani, Bartoletti, Manfredi, Colangeli et al., Statin Therapy Decreases Serum Levels of High-Sensitivity C-Reactive Protein and Tumor Necrosis Factor-α in HIV-Infected Patients Treated with Ritonavir-Boosted Protease Inhibitors, HIV Clin. Trials,
doi:10.1310/hct1303-153Cascella, Rajnik, Aleem, Dulebohn, Di Napoli et al., Evaluation, and Treatment of Coronavirus (COVID-19)
Chaudhary, Kurundkar, Elmets, Kopelovich, Athar et al., an Antidiabetic Agent Reduces Growth of Cutaneous Squamous Cell Carcinoma by Targeting mTOR Signaling Pathway †, Photochem. Photobiol,
doi:10.1111/j.1751-1097.2012.01165.xChen, Guo, Qiu, Zhang, Deng et al., Immunomodulatory and Antiviral Activity of Metformin and Its Potential Implications in Treating Coronavirus Disease 2019 and Lung Injury, Front. Immunol,
doi:10.3389/fimmu.2020.02056Chi, Wang, Huang, Stamnes, Chen, Roles of Rho GTPases in Intracellular Transport and Cellular Transformation, Int. J. Mol. Sci,
doi:10.3390/ijms14047089Conde, Pineda, Newton, Fernandez, Hypocholesterolemic Effects of 3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG-CoA) Reductase Inhibitors in the Guinea Pig: Atorvastatin versus Simvastatin, Biochem. Pharmacol,
doi:10.1016/S0006-2952(99)00203-8Corcoran, Jacobs, Metformin, None
Cortés, Brischetto, Martinez-Campanario, Ninfali, Domínguez et al., Inflammatory Macrophages Reprogram to Immunosuppression by Reducing Mitochondrial Translation, Nat. Commun,
doi:10.1038/s41467-023-42277-4Curry, Johnson, Mollaee, Tassone, Amin et al., Metformin Clinical Trial in HPV+ and HPV-Head and Neck Squamous Cell Carcinoma: Impact on Cancer Cell Apoptosis and Immune Infiltrate, Front. Oncol,
doi:10.3389/fonc.2018.00436Davoodi, Jafarpour, Oladi, Zakariaei, Tabarestani et al., Atorvastatin Therapy in COVID-19 Adult Inpatients: A Double-Blind, Randomized Controlled Trial, Int. J. Cardiol. Heart Vasc,
doi:10.1016/j.ijcha.2021.100875Del Campo, García, Valdecasas, Gil Gómez, Rojas Alvarez-Ossorio et al., Simvastatin and Metformin Inhibit Cell Growth in Hepatitis C Virus Infected Cells via mTOR Increasing PTEN and Autophagy, PLoS ONE,
doi:10.1371/journal.pone.0191805Ding, Liang, Yao, Zhang, Liu et al., Metformin Prevents Cancer Metastasis by Inhibiting M2-like Polarization of Tumor Associated Macrophages, Oncotarget,
doi:10.18632/oncotarget.5541Duarte, Copertino, Iñiguez, Marston, Bram et al., Identifying FDA-Approved Drugs with Multimodal Properties against COVID-19 Using a Data-Driven Approach and a Lung Organoid Model of SARS-CoV-2 Entry, Mol. Med,
doi:10.1186/s10020-021-00356-6El-Mir, Nogueira, Fontaine, Avéret, Rigoulet et al., Dimethylbiguanide Inhibits Cell Respiration via an Indirect Effect Targeted on the Respiratory Chain Complex I, J. Biol. Chem,
doi:10.1074/jbc.275.1.223Episcopio, Aminov, Benjamin, Germain, Datan et al., Atorvastatin Restricts the Ability of Influenza Virus to Generate Lipid Droplets and Severely Suppresses the Replication of the Virus, FASEB J,
doi:10.1096/fj.201900428RRFarfan-Morales, Cordero-Rivera, Osuna-Ramos, Monroy-Muñoz, De Jesús-González et al., The Antiviral Effect of Metformin on Zika and Dengue Virus Infection, Sci. Rep,
doi:10.1038/s41598-021-87707-9Farfan-Morales, Cordero-Rivera, Reyes-Ruiz, Hurtado-Monzón, Osuna-Ramos et al., Anti-Flavivirus Properties of Lipid-Lowering Drugs, Front. Physiol,
doi:10.3389/fphys.2021.749770Fessler, Regulation of Adaptive Immunity in Health and Disease by Cholesterol Metabolism, Curr. Allergy Asthma Rep,
doi:10.1007/s11882-015-0548-7Fontaine, Metformin-Induced Mitochondrial Complex I Inhibition: Facts, Uncertainties, and Consequences, Front. Endocrinol,
doi:10.3389/fendo.2018.00753Frid, Sterner, Löndahl, Wiklander, Cato et al., Novel Assay of Metformin Levels in Patients with Type 2 Diabetes and Varying Levels of Renal Function: Clinical Recommendations, Diabetes Care,
doi:10.2337/dc09-1284Fullerton, Galic, Marcinko, Sikkema, Pulinilkunnil et al., Single Phosphorylation Sites in Acc1 and Acc2 Regulate Lipid Homeostasis and the Insulin-Sensitizing Effects of Metformin, Nat. Med,
doi:10.1038/nm.3372Ganesan, Crum-Cianflone, Higgins, Qin, Rehm et al., High Dose Atorvastatin Decreases Cellular Markers of Immune Activation without Affecting HIV-1 RNA Levels: Results of a Double-Blind Randomized Placebo Controlled Clinical Trial, J. Infect. Dis,
doi:10.1093/infdis/jiq115Gheblawi, Wang, Viveiros, Nguyen, Zhong et al., Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System, Circ. Res,
doi:10.1161/CIRCRESAHA.120.317015Granato, Gilardini Montani, Romeo, Santarelli, Gonnella et al., Metformin Triggers Apoptosis in PEL Cells and Alters Bortezomib-Induced Unfolded Protein Response Increasing Its Cytotoxicity and Inhibiting KSHV Lytic Cycle Activation, Cell. Signal,
doi:10.1016/j.cellsig.2017.09.020Guan, Sun, Liang, Dong, Zhang et al., Atorvastatin Attenuates Coxsackie Virus B3m-Induced Viral Myocarditis in Mice, J. Cardiovasc. Pharmacol,
doi:10.1097/FJC.0b013e3181f6b28dHaji Aghajani, Moradi, Azhdari Tehrani, Amini, Pourheidar et al., Promising Effects of Atorvastatin on Mortality and Need for Mechanical Ventilation in Patients with Severe COVID-19; a Retrospective Cohort Study, Int. J. Clin. Pract,
doi:10.1111/ijcp.14434Hawley, Boudeau, Reid, Mustard, Udd et al., Complexes between the LKB1 Tumor Suppressor, STRAD Alpha/Beta and MO25 Alpha/Beta Are Upstream Kinases in the AMP-Activated Protein Kinase Cascade, J. Biol,
doi:10.1186/1475-4924-2-28Hawley, Pan, Mustard, Ross, Bain et al., Calmodulin-Dependent Protein Kinase Kinase-Beta Is an Alternative Upstream Kinase for AMP-Activated Protein Kinase, Cell Metab,
doi:10.1016/j.cmet.2005.05.009Hawley, Ross, Chevtzoff, Green, Evans et al., Use of Cells Expressing Gamma Subunit Variants to Identify Diverse Mechanisms of AMPK Activation, Cell Metab,
doi:10.1016/j.cmet.2010.04.001Herrera-Moro Huitron, De Jesús-González, Martínez-Castillo, Ulloa-Aguilar, Cabello-Gutierrez et al., Multifaceted Nature of Lipid Droplets in Viral Interactions and Pathogenesis, Microorganisms,
doi:10.3390/microorganisms11071851Honda, Shirasaki, Terashima, Kawaguchi, Nakamura et al., Hepatitis B Virus (HBV) Core-Related Antigen During Nucleos(t)Ide Analog Therapy Is Related to Intra-Hepatic HBV Replication and Development of Hepatocellular Carcinoma, J. Infect. Dis,
doi:10.1093/infdis/jiv572Hoppe-Seyler, Herrmann, Däschle, Kuhn, Strobel et al., Effects of Metformin on the Virus/Host Cell Crosstalk in Human Papillomavirus-Positive Cancer Cells, Int. J. Cancer,
doi:10.1002/ijc.33594Ianevski, Yao, Zusinaite, Lysvand, Oksenych et al., Active Components of Commonly Prescribed Medicines Affect Influenza A Virus-Host Cell Interaction: A Pilot Study, Viruses,
doi:10.3390/v13081537Ikeda, Abe, Yamada, Dansako, Naka et al., Different Anti-HCV Profiles of Statins and Their Potential for Combination Therapy with Interferon, Hepatology,
doi:10.1002/hep.21232Ikeda, Kato, Life Style-Related Diseases of the Digestive System: Cell Culture System for the Screening of Anti-Hepatitis C Virus (HCV) Reagents: Suppression of HCV Replication by Statins and Synergistic Action with Interferon, J. Pharmacol. Sci,
doi:10.1254/jphs.FM0070050Investigators, Atorvastatin versus Placebo in Patients with COVID-19 in Intensive Care: Randomized Controlled Trial, BMJ,
doi:10.1136/bmj-2021-068407Jiang, Liu, Metformin Inhibits Tumorigenesis in HBV-Induced Hepatocellular Carcinoma by Suppressing HULC Overexpression Caused by HBX, J. Cell Biochem,
doi:10.1002/jcb.26555Kelly, Tannahill, Murphy, O'neill, Metformin Inhibits the Production of Reactive Oxygen Species from NADH:Ubiquinone Oxidoreductase to Limit Induction of Interleukin-1β (IL-1β) and Boosts Interleukin-10 (IL-10) in Lipopolysaccharide (LPS)-Activated Macrophages *, J. Biol. Chem,
doi:10.1074/jbc.M115.662114Kouhpeikar, Khosaravizade Tabasi, Khazir, Naghipour, Mohammadi Moghadam et al., Statin Use in COVID-19 Hospitalized Patients and Outcomes: A Retrospective Study, Front. Cardiovasc. Med,
doi:10.3389/fcvm.2022.820260Kumar, Liu, Wu, Drug Repurposing against SARS-CoV-2 Receptor Binding Domain Using Ensemble-Based Virtual Screening and Molecular Dynamics Simulations, Comput. Biol. Med,
doi:10.1016/j.compbiomed.2021.104634Kumari, Lu, Li, Huang, Hsu et al., A Critical Overview of Current Progress for COVID-19: Development of Vaccines, Antiviral Drugs, and Therapeutic Antibodies, J. Biomed. Sci,
doi:10.1186/s12929-022-00852-9Li, Hilgenfeld, Whitley, De Clercq, Therapeutic Strategies for COVID-19: Progress and Lessons Learned, Nat. Rev. Drug Discov,
doi:10.1038/s41573-023-00672-yLiu, Yu, Xu, Wang, Chen et al., Metformin Induces Tolerogenicity of Dendritic Cells by Promoting Metabolic Reprogramming, Cell Mol. Life Sci,
doi:10.1007/s00018-023-04932-3Madiraju, Erion, Rahimi, Zhang, Braddock et al., Metformin Suppresses Gluconeogenesis by Inhibiting Mitochondrial Glycerophosphate Dehydrogenase, Nature,
doi:10.1038/nature13270Marcianò, Palleria, Casarella, Rania, Basile et al., Effect of Statins on Lung Cancer Molecular Pathways: A Possible Therapeutic Role, Pharmaceuticals,
doi:10.3390/ph15050589Marcucci, Romeo, Caserta, Rumio, Lefoulon, Context-Dependent Pharmacological Effects of Metformin on the Immune System, Trends Pharmacol. Sci,
doi:10.1016/j.tips.2020.01.003Masich, Thompson, Fulco, Bictegravir and Metformin Drug-Drug Interaction in People with Human Immunodeficiency Virus (HIV), Infect. Dis. Rep,
doi:10.3390/idr15030024Moreno-Corona, López-Ortega, Pérez-Martínez, Martínez-Castillo, De Jesús-González et al., Dynamics of the Microbiota and Its Relationship with Post-COVID-19 Syndrome, Int. J. Mol. Sci,
doi:10.3390/ijms241914822Mystakelis, Wilson, Laidlaw, Poole, Krishnan et al., An Open Label Randomized Controlled Trial of Atorvastatin versus Aspirin in Elite Controllers and Antiretroviral-Treated People with HIV, AIDS,
doi:10.1097/QAD.0000000000003656Nasri, Rafieian-Kopaei, Metformin: Current Knowledge, J. Res. Med. Sci
Negredo, Clotet, Puig, Pérez-Alvarez, Ruiz et al., The Effect of Atorvastatin Treatment on HIV-1-Infected Patients Interrupting Antiretroviral Therapy, AIDS,
doi:10.1097/01.aids.0000210617.90954.0eNegredo, Puigdomènech, Marfil, Puig, Pérez-Alvarez et al., Association between HIV Replication and Cholesterol in Peripheral Blood Mononuclear Cells in HIV-Infected Patients Interrupting HAART, J. Antimicrob. Chemother,
doi:10.1093/jac/dkm470Osuna-Ramos, Farfan-Morales, Cordero-Rivera, De Jesús-González, Reyes-Ruiz et al., Cholesterol-Lowering Drugs as Potential Antivirals: A Repurposing Approach against Flavivirus Infections, Viruses,
doi:10.3390/v15071465Overton, Sterrett, Westfall, Kahan, Burkholder et al., Effects of Atorvastatin and Pravastatin on Immune Activation and T-Cell Function in Antiretroviral Therapy-Suppressed HIV-1-Infected Patients, AIDS,
doi:10.1097/QAD.0000000000000475Owen, Doran, Halestrap, Evidence That Metformin Exerts Its Anti-Diabetic Effects through Inhibition of Complex 1 of the Mitochondrial Respiratory Chain, Biochem. J,
doi:10.1042/bj3480607Palacios-Rápalo, Farfan-Morales, Cordero-Rivera, De Jesús-González, Reyes-Ruiz et al., An Ivermectin-Atorvastatin Combination Impairs Nuclear Transport Inhibiting Dengue Infection in Vitro and in Vivo, iScience,
doi:10.1016/j.isci.2023.108294Pedrosa, Martins, Rizzo, Silva-Nunes, Metformin in SARS-CoV-2 Infection: A Hidden Path-From Altered Inflammation to Reduced Mortality. A Review from the Literature, J. Diabetes Complicat,
doi:10.1016/j.jdiacomp.2022.108391Pepperrell, Ellis, Wang, Hill, Barriers to Worldwide Access for Paxlovid, a New Treatment for COVID-19, Open Forum Infect. Dis,
doi:10.1093/ofid/ofac174Petakh, Griga, Mohammed, Loshak, Poliak et al., Effects of Metformin, Insulin on Hematological Parameters of COVID-19 Patients with Type 2 Diabetes, Med. Arch,
doi:10.5455/medarh.2022.76.329-332Petakh, Kamyshna, Nykyforuk, Yao, Imbery et al., Immunoregulatory Intestinal Microbiota and COVID-19 in Patients with Type Two Diabetes: A Double-Edged Sword, Viruses,
doi:10.3390/v14030477Petakh, Kamyshna, Oksenych, Kainov, Kamyshnyi, Metformin Therapy Changes Gut Microbiota Alpha-Diversity in COVID-19 Patients with Type 2 Diabetes: The Role of SARS-CoV-2 Variants and Antibiotic Treatment, Pharmaceuticals,
doi:10.3390/ph16060904Planas, Pagliuzza, Ponte, Fert, Marchand et al., LILAC Pilot Study: Effects of Metformin on mTOR Activation and HIV Reservoir Persistence during Antiretroviral Therapy, EBioMedicine,
doi:10.1016/j.ebiom.2021.103270Reis, Silva, Silva, Thabane, Milagres et al., Effect of Early Treatment with Metformin on Risk of Emergency Care and Hospitalization among Patients with COVID-19: The TOGETHER Randomized Platform Clinical Trial, Lancet Reg. Health Am,
doi:10.1016/j.lana.2021.100142Reyes-Ruiz, García-Hernández, Martínez-Mier, Osuna-Ramos, De Jesús-González et al., The Role of Aspartate Aminotransferase-to-Lymphocyte Ratio Index (ALRI) in Predicting Mortality in SARS-CoV-2 Infection, Microorganisms,
doi:10.3390/microorganisms11122894Riestenberg, Furman, Cowen, Pawlowksi, Schneider et al., Differences in Statin Utilization and Lipid Lowering by Race, Ethnicity, and HIV Status in a Real-World Cohort of Persons with Human Immunodeficiency Virus and Uninfected Persons, Am. Heart J,
doi:10.1016/j.ahj.2018.11.012Rodriguez-Nava, Trelles-Garcia, Yanez-Bello, Chung, Trelles-Garcia et al., Atorvastatin Associated with Decreased Hazard for Death in COVID-19 Patients Admitted to an ICU: A Retrospective Cohort Study, Crit. Care,
doi:10.1186/s13054-020-03154-4Roglans, Verd, Peris, Alegret, Vázquez et al., High Doses of Atorvastatin and Simvastatin Induce Key Enzymes Involved in VLDL Production, Lipids,
doi:10.1007/s11745-002-0916-0Saito, Koinuma, Kawashima, Miyato, Ohzawa et al., Metformin May Improve the Outcome of Patients with Colorectal Cancer and Type 2 Diabetes Mellitus Partly through Effects on Neutrophil Extracellular Traps, BJC Rep,
doi:10.1038/s44276-023-00022-wSchieffer, Schieffer, The Rationale for the Treatment of Long-Covid Symptoms-A Cardiologist's View, Front. Cardiovasc. Med,
doi:10.3389/fcvm.2022.992686Segatori, Garona, Caligiuri, Bizzotto, Lavignolle et al., Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2-Positive Patients, Viruses,
doi:10.3390/v13102084Sharma, Abohashrh, Baig, Dong, Alam et al., Screening of Drug Databank against WT and Mutant Main Protease of SARS-CoV-2: Towards Finding Potential Compound for Repurposing against COVID-19, Saudi J. Biol. Sci,
doi:10.1016/j.sjbs.2021.02.059Shaw, Lamia, Vasquez, Koo, Bardeesy et al., The Kinase LKB1 Mediates Glucose Homeostasis in Liver and Therapeutic Effects of Metformin, Science,
doi:10.1126/science.1120781Simon, Bonilla, Yan, Chung, Butt, Atorvastatin and Fluvastatin Are Associated with Dose-Dependent Reductions in Cirrhosis and Hepatocellular Carcinoma, among Patients with Hepatitis C Virus: Results from ERCHIVES, Hepatology,
doi:10.1002/hep.28506Simões E Silva, Silveira, Ferreira, Teixeira, ACE2, Angiotensin-(1-7) and Mas Receptor Axis in Inflammation and Fibrosis, Br. J. Pharmacol,
doi:10.1111/bph.12159Sorathia, Al-Rubaye, Zal, The Effect of Statins on the Functionality of CD4+CD25+FOXP3+ Regulatory T-Cells in Acute Coronary Syndrome: A Systematic Review and Meta-Analysis of Randomised Controlled Trials in Asian Populations, Eur. Cardiol,
doi:10.15420/ecr.2019.9.2Soto-Acosta, Bautista-Carbajal, Cervantes-Salazar, Angel-Ambrocio, Del et al., DENV Up-Regulates the HMG-CoA Reductase Activity through the Impairment of AMPK Phosphorylation: A Potential Antiviral Target, PLoS Pathog,
doi:10.1371/journal.ppat.1006257Stoyanova, Jabeen, Landazuri Vinueza, Ghosh Roy, Lockshin et al., Virus Triggers Autophagy to Exploit Host Lipid Metabolism and Drive Viral Replication, Cell Commun. Signal,
doi:10.1186/s12964-022-01026-8Sum, Webster, Johnson, Catalano, Cooper et al., The Effect of Intravenous Metformin on Glucose Metabolism during Hyperglycaemia in Type 2 Diabetes, Diabet. Med,
doi:10.1111/j.1464-5491.1992.tb01716.xSun, Tian, Gao, Liu, Hou et al., Metformin Ameliorates the Development of Experimental Autoimmune Encephalomyelitis by Regulating T Helper 17 and Regulatory T Cells in Mice, J. Neuroimmunol,
doi:10.1016/j.jneuroim.2016.01.014Todorovska, Caloska-Ivanova, Dimitrova-Genadieva, Trajkovska, Popova-Jovanovska et al., Atorvastatin in Combination with Pegylated Interferon and Ribavirin Provided High Rate of Sustained Virological Response in Patients with Genotype 3 Hepatitis C Virus. Open Access Maced, J. Med. Sci,
doi:10.3889/oamjms.2019.459Tsai, Chang, Sun, Chan, Wu et al., Metformin Activates Type I Interferon Signaling against HCV via Activation of Adenosine Monophosphate-Activated Protein Kinase, Oncotarget,
doi:10.18632/oncotarget.20248Tárraga López, Celada Rodríguez, ; Cerdán, Oliver, Solera Albero et al., Análisis coste-efectividad de atorvastatina frente a simvastatina como tratamiento hipolipemiante en pacientes hipercolesterolémicos en atención primaria, Aten Primaria,
doi:10.1016/S0212-6567(01)78767-7Ventura-López, Cervantes-Luevano, Aguirre-Sánchez, Flores-Caballero, Alvarez-Delgado et al., Treatment with Metformin Glycinate Reduces SARS-CoV-2 Viral Load: An in Vitro Model and Randomized, Double-Blind, Phase IIb Clinical Trial, Biomed. Pharmacother,
doi:10.1016/j.biopha.2022.113223Visos-Varela, Zapata-Cachafeiro, Pintos-Rodríguez, Bugarín-González, González-Barcala et al., Outpatient Atorvastatin Use and Severe COVID-19 Outcomes: A Population-Based Study, J. Med. Virol,
doi:10.1002/jmv.28971Wagstaff, Sivakumaran, Heaton, Harrich, Jans, Ivermectin Is a Specific Inhibitor of Importin α/β-Mediated Nuclear Import Able to Inhibit Replication of HIV-1 and Dengue Virus, Biochem. J,
doi:10.1042/BJ20120150Wang, Wang, Yi, Baker, Casey et al., Metformin Restrains ZIKV Replication and Alleviates Virus-Induced Inflammatory Responses in Microglia, Int. Immunopharmacol,
doi:10.1016/j.intimp.2023.110512Wani, Mukherjee, Mallick, Akbar, Basu, Atorvastatin Ameliorates Viral Burden and Neural Stem/Progenitor Cell (NSPC) Death in an Experimental Model of Japanese Encephalitis, J. Biosci,
doi:10.1007/s12038-020-00052-3Xiao, Heath, Saiu, Leiper, Leone et al., Structural Basis for AMP Binding to Mammalian AMP-Activated Protein Kinase, Nature,
doi:10.1038/nature06161Xun, Zhang, Pan, Mao, Qin et al., Metformin Inhibits Hepatitis B Virus Protein Production and Replication in Human Hepatoma Cells, J. Viral. Hepat,
doi:10.1111/jvh.12187Yu, Sun, Zhao, Kang, Yan, The Effect of Metformin on the Efficacy of Antiviral Therapy in Patients with Genotype 1 Chronic Hepatitis C and Insulin Resistance, Int. J. Infect. Dis,
doi:10.1016/j.ijid.2012.02.004Zapata-Cardona, Flórez-Álvarez, Zapata-Builes, Guerra-Sandoval, Guerra-Almonacid et al., Atorvastatin Effectively Inhibits Ancestral and Two Emerging Variants of SARS-CoV-2 in Vitro, Front. Microbiol,
doi:10.3389/fmicb.2022.721103Zhang, Dong, Martin, He, Gongol et al., AMP-Activated Protein Kinase Phosphorylation of Angiotensin-Converting Enzyme 2 in Endothelium Mitigates Pulmonary Hypertension, Am. J. Respir. Crit. Care Med,
doi:10.1164/rccm.201712-2570OCZhang, Feng, Luo, Zhao, Kannan et al., Metformin Hydrochloride Significantly Inhibits Rotavirus Infection in Caco2 Cell Line, Intestinal Organoids, and Mice, Pharmaceuticals,
doi:10.3390/ph16091279Zhao, Zeng, Chen, Liu, Chen et al., Lipid Droplets Are Beneficial for Rabies Virus Replication by Facilitating Viral Budding, J. Virol,
doi:10.1128/JVI.01473-21{ 'indexed': {'date-parts': [[2024, 2, 15]], 'date-time': '2024-02-15T00:44:20Z', 'timestamp': 1707957860740},
'reference-count': 128,
'publisher': 'MDPI AG',
'issue': '2',
'license': [ { 'start': { 'date-parts': [[2024, 2, 13]],
'date-time': '2024-02-13T00:00:00Z',
'timestamp': 1707782400000},
'content-version': 'vor',
'delay-in-days': 0,
'URL': 'https://creativecommons.org/licenses/by/4.0/'}],
'funder': [ {'name': 'R.M.D.Á.', 'award': ['Pronaii 302979', 'A1-S-9005 CONAHCyT (México)']},
{'name': 'FUNDACIÓN IMSS, AC'}],
'content-domain': {'domain': [], 'crossmark-restriction': False},
'abstract': '<jats:p>Metformin (MET) and atorvastatin (ATO) are promising treatments for COVID-19. This '
'review explores the potential of MET and ATO, commonly prescribed for diabetes and '
'dyslipidemia, respectively, as versatile medicines against SARS-CoV-2. Due to their '
'immunomodulatory and antiviral capabilities, as well as their cost-effectiveness and '
'ubiquitous availability, they are highly suitable options for treating the virus. MET’s '
'effect extends beyond managing blood sugar, impacting pathways that can potentially decrease '
'the severity and fatality rates linked with COVID-19. It can partially block mitochondrial '
'complex I and stimulate AMPK, which indicates that it can be used more widely in managing '
'viral infections. ATO, however, impacts cholesterol metabolism, a crucial element of the '
'viral replicative cycle, and demonstrates anti-inflammatory characteristics that could '
'modulate intense immune reactions in individuals with COVID-19. Retrospective investigations '
'and clinical trials show decreased hospitalizations, severity, and mortality rates in '
'patients receiving these medications. Nevertheless, the journey from observing something to '
'applying it in a therapeutic setting is intricate, and the inherent diversity of the data '
'necessitates carefully executed, forward-looking clinical trials. This review highlights the '
'requirement for efficacious, easily obtainable, and secure COVID-19 therapeutics and '
'identifies MET and ATO as promising treatments in this worldwide health emergency.</jats:p>',
'DOI': '10.3390/microorganisms12020383',
'type': 'journal-article',
'created': {'date-parts': [[2024, 2, 14]], 'date-time': '2024-02-14T09:18:22Z', 'timestamp': 1707902302000},
'page': '383',
'source': 'Crossref',
'is-referenced-by-count': 0,
'title': 'A Dual Pharmacological Strategy against COVID-19: The Therapeutic Potential of Metformin and '
'Atorvastatin',
'prefix': '10.3390',
'volume': '12',
'author': [ { 'ORCID': 'http://orcid.org/0000-0003-1415-6260',
'authenticated-orcid': False,
'given': 'Luis Adrián',
'family': 'De Jesús-González',
'sequence': 'first',
'affiliation': [ { 'name': 'Unidad de Investigación Biomédica de Zacatecas, Instituto '
'Mexicano del Seguro Social, Zacatecas 98000, Mexico'},
{ 'name': 'Department of Infectomics and Molecular Pathogenesis, Center for '
'Research and Advanced Studies (CINVESTAV-IPN), Mexico City '
'07360, Mexico'}]},
{ 'ORCID': 'http://orcid.org/0000-0002-6785-2035',
'authenticated-orcid': False,
'given': 'Rosa María',
'family': 'del Ángel',
'sequence': 'additional',
'affiliation': [ { 'name': 'Department of Infectomics and Molecular Pathogenesis, Center for '
'Research and Advanced Studies (CINVESTAV-IPN), Mexico City '
'07360, Mexico'}]},
{ 'ORCID': 'http://orcid.org/0000-0002-2184-6529',
'authenticated-orcid': False,
'given': 'Selvin Noé',
'family': 'Palacios-Rápalo',
'sequence': 'additional',
'affiliation': [ { 'name': 'Department of Infectomics and Molecular Pathogenesis, Center for '
'Research and Advanced Studies (CINVESTAV-IPN), Mexico City '
'07360, Mexico'}]},
{ 'ORCID': 'http://orcid.org/0000-0002-5052-2670',
'authenticated-orcid': False,
'given': 'Carlos Daniel',
'family': 'Cordero-Rivera',
'sequence': 'additional',
'affiliation': [ { 'name': 'Department of Infectomics and Molecular Pathogenesis, Center for '
'Research and Advanced Studies (CINVESTAV-IPN), Mexico City '
'07360, Mexico'}]},
{ 'ORCID': 'http://orcid.org/0000-0002-3514-5299',
'authenticated-orcid': False,
'given': 'Adrián',
'family': 'Rodríguez-Carlos',
'sequence': 'additional',
'affiliation': [ { 'name': 'Unidad de Investigación Biomédica de Zacatecas, Instituto '
'Mexicano del Seguro Social, Zacatecas 98000, Mexico'}]},
{ 'given': 'Juan Valentin',
'family': 'Trujillo-Paez',
'sequence': 'additional',
'affiliation': [ { 'name': 'Unidad de Investigación Biomédica de Zacatecas, Instituto '
'Mexicano del Seguro Social, Zacatecas 98000, Mexico'}]},
{ 'ORCID': 'http://orcid.org/0000-0002-9787-5588',
'authenticated-orcid': False,
'given': 'Carlos Noe',
'family': 'Farfan-Morales',
'sequence': 'additional',
'affiliation': [ { 'name': 'Departamento de Ciencias Naturales, Universidad Autónoma '
'Metropolitana (UAM), Unidad Cuajimalpa, Ciudad de México 05348, '
'Mexico'}]},
{ 'ORCID': 'http://orcid.org/0000-0001-8280-9812',
'authenticated-orcid': False,
'given': 'Juan Fidel',
'family': 'Osuna-Ramos',
'sequence': 'additional',
'affiliation': [ { 'name': 'Facultad de Medicina, Universidad Autónoma de Sinaloa, Culiacán '
'80019, Mexico'}]},
{ 'ORCID': 'http://orcid.org/0000-0002-2379-8591',
'authenticated-orcid': False,
'given': 'José Manuel',
'family': 'Reyes-Ruiz',
'sequence': 'additional',
'affiliation': [ { 'name': 'División de Investigación en Salud, Unidad Médica de Alta '
'Especialidad, Hospital de Especialidades No. 14, Centro Médico '
'Nacional “Adolfo Ruiz Cortines”, Instituto Mexicano del Seguro '
'Social (IMSS), Veracruz 91897, Mexico'},
{ 'name': 'Facultad de Medicina, Región Veracruz, Universidad Veracruzana '
'(UV), Veracruz 91700, Mexico'}]},
{ 'ORCID': 'http://orcid.org/0000-0002-1521-1519',
'authenticated-orcid': False,
'given': 'Bruno',
'family': 'Rivas-Santiago',
'sequence': 'additional',
'affiliation': [ { 'name': 'Unidad de Investigación Biomédica de Zacatecas, Instituto '
'Mexicano del Seguro Social, Zacatecas 98000, Mexico'}]},
{ 'ORCID': 'http://orcid.org/0000-0002-5726-5953',
'authenticated-orcid': False,
'given': 'Moisés',
'family': 'León-Juárez',
'sequence': 'additional',
'affiliation': [ { 'name': 'Laboratorio de Virología Perinatal y Diseño Molecular de '
'Antígenos y Biomarcadores, Departamento de Inmunobioquímica, '
'Instituto Nacional de Perinatología, Ciudad de México 11000, '
'Mexico'}]},
{ 'given': 'Ana Cristina',
'family': 'García-Herrera',
'sequence': 'additional',
'affiliation': [ { 'name': 'Unidad de Investigación Biomédica de Zacatecas, Instituto '
'Mexicano del Seguro Social, Zacatecas 98000, Mexico'}]},
{ 'given': 'Adriana Clara',
'family': 'Ramos-Cortes',
'sequence': 'additional',
'affiliation': [ { 'name': 'Unidad de Investigación Biomédica de Zacatecas, Instituto '
'Mexicano del Seguro Social, Zacatecas 98000, Mexico'}]},
{ 'given': 'Erika Alejandra',
'family': 'López-Gándara',
'sequence': 'additional',
'affiliation': [ { 'name': 'Unidad de Investigación Biomédica de Zacatecas, Instituto '
'Mexicano del Seguro Social, Zacatecas 98000, Mexico'}]},
{ 'given': 'Estefanía',
'family': 'Martínez-Rodríguez',
'sequence': 'additional',
'affiliation': [ { 'name': 'Unidad de Investigación Biomédica de Zacatecas, Instituto '
'Mexicano del Seguro Social, Zacatecas 98000, Mexico'}]}],
'member': '1968',
'published-online': {'date-parts': [[2024, 2, 13]]},
'reference': [ { 'key': 'ref_1',
'unstructured': 'Cascella, M., Rajnik, M., Aleem, A., Dulebohn, S.C., and Di Napoli, R. '
'(2023). StatPearls, StatPearls Publishing.'},
{ 'key': 'ref_2',
'doi-asserted-by': 'crossref',
'unstructured': 'Reyes-Ruiz, J.M., García-Hernández, O., Martínez-Mier, G., Osuna-Ramos, '
'J.F., De Jesús-González, L.A., Farfan-Morales, C.N., Palacios-Rápalo, '
'S.N., Cordero-Rivera, C.D., Ordoñez-Rodríguez, T., and Ángel, R.M.d. '
'(2023). The Role of Aspartate Aminotransferase-to-Lymphocyte Ratio Index '
'(ALRI) in Predicting Mortality in SARS-CoV-2 Infection. Microorganisms, '
'11.',
'DOI': '10.3390/microorganisms11122894'},
{ 'key': 'ref_3',
'doi-asserted-by': 'crossref',
'first-page': '449',
'DOI': '10.1038/s41573-023-00672-y',
'article-title': 'Therapeutic Strategies for COVID-19: Progress and Lessons Learned',
'volume': '22',
'author': 'Li',
'year': '2023',
'journal-title': 'Nat. Rev. Drug Discov.'},
{ 'key': 'ref_4',
'doi-asserted-by': 'crossref',
'unstructured': 'Kumari, M., Lu, R.-M., Li, M.-C., Huang, J.-L., Hsu, F.-F., Ko, S.-H., '
'Ke, F.-Y., Su, S.-C., Liang, K.-H., and Yuan, J.P.-Y. (2022). A Critical '
'Overview of Current Progress for COVID-19: Development of Vaccines, '
'Antiviral Drugs, and Therapeutic Antibodies. J. Biomed. Sci., 29.',
'DOI': '10.1186/s12929-022-00852-9'},
{ 'key': 'ref_5',
'doi-asserted-by': 'crossref',
'first-page': '636532',
'DOI': '10.3389/fmed.2021.636532',
'article-title': 'Implications of the Novel Mutations in the SARS-CoV-2 Genome for '
'Transmission, Disease Severity, and the Vaccine Development',
'volume': '8',
'author': 'Akkiz',
'year': '2021',
'journal-title': 'Front. Med.'},
{ 'key': 'ref_6',
'doi-asserted-by': 'crossref',
'first-page': '223',
'DOI': '10.1074/jbc.275.1.223',
'article-title': 'Dimethylbiguanide Inhibits Cell Respiration via an Indirect Effect '
'Targeted on the Respiratory Chain Complex I',
'volume': '275',
'author': 'Nogueira',
'year': '2000',
'journal-title': 'J. Biol. Chem.'},
{ 'key': 'ref_7',
'doi-asserted-by': 'crossref',
'first-page': '554',
'DOI': '10.1016/j.cmet.2010.04.001',
'article-title': 'Use of Cells Expressing Gamma Subunit Variants to Identify Diverse '
'Mechanisms of AMPK Activation',
'volume': '11',
'author': 'Hawley',
'year': '2010',
'journal-title': 'Cell Metab.'},
{ 'key': 'ref_8',
'doi-asserted-by': 'crossref',
'first-page': '1209',
'DOI': '10.1016/S0006-2952(99)00203-8',
'article-title': 'Hypocholesterolemic Effects of 3-Hydroxy-3-Methylglutaryl Coenzyme A '
'(HMG-CoA) Reductase Inhibitors in the Guinea Pig: Atorvastatin versus '
'Simvastatin',
'volume': '58',
'author': 'Conde',
'year': '1999',
'journal-title': 'Biochem. Pharmacol.'},
{ 'key': 'ref_9',
'doi-asserted-by': 'crossref',
'first-page': '1157',
'DOI': '10.1002/j.1875-9114.1997.tb03081.x',
'article-title': 'Atorvastatin Calcium: An Addition to HMG-CoA Reductase Inhibitors',
'volume': '17',
'author': 'Chong',
'year': '1997',
'journal-title': 'Pharmacotherapy'},
{ 'key': 'ref_10',
'first-page': '100142',
'article-title': 'Effect of Early Treatment with Metformin on Risk of Emergency Care and '
'Hospitalization among Patients with COVID-19: The TOGETHER Randomized '
'Platform Clinical Trial',
'volume': '6',
'author': 'Reis',
'year': '2022',
'journal-title': 'Lancet Reg. Health Am.'},
{ 'key': 'ref_11',
'doi-asserted-by': 'crossref',
'unstructured': 'Ventura-López, C., Cervantes-Luevano, K., Aguirre-Sánchez, J.S., '
'Flores-Caballero, J.C., Alvarez-Delgado, C., Bernaldez-Sarabia, J., '
'Sánchez-Campos, N., Lugo-Sánchez, L.A., Rodríguez-Vázquez, I.C., and '
'Sander-Padilla, J.G. (2022). Treatment with Metformin Glycinate Reduces '
'SARS-CoV-2 Viral Load: An in Vitro Model and Randomized, Double-Blind, '
'Phase IIb Clinical Trial. Biomed. Pharmacother., 152.',
'DOI': '10.1016/j.biopha.2022.113223'},
{ 'key': 'ref_12',
'doi-asserted-by': 'crossref',
'first-page': 'e34',
'DOI': '10.1016/S2666-7568(20)30033-7',
'article-title': 'Metformin and Risk of Mortality in Patients Hospitalised with COVID-19: '
'A Retrospective Cohort Analysis',
'volume': '2',
'author': 'Bramante',
'year': '2021',
'journal-title': 'Lancet Healthy Longev.'},
{ 'key': 'ref_13',
'doi-asserted-by': 'crossref',
'first-page': '599',
'DOI': '10.1056/NEJMoa2201662',
'article-title': 'Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for COVID-19',
'volume': '387',
'author': 'Bramante',
'year': '2022',
'journal-title': 'N. Engl. J. Med.'},
{ 'key': 'ref_14',
'doi-asserted-by': 'crossref',
'first-page': '1119',
'DOI': '10.1016/S1473-3099(23)00299-2',
'article-title': 'Outpatient Treatment of COVID-19 and Incidence of Post-COVID-19 '
'Condition over 10 Months (COVID-OUT): A Multicentre, Randomised, '
'Quadruple-Blind, Parallel-Group, Phase 3 Trial',
'volume': '23',
'author': 'Bramante',
'year': '2023',
'journal-title': 'Lancet Infect. Dis.'},
{ 'key': 'ref_15',
'first-page': '100875',
'article-title': 'Atorvastatin Therapy in COVID-19 Adult Inpatients: A Double-Blind, '
'Randomized Controlled Trial',
'volume': '36',
'author': 'Davoodi',
'year': '2021',
'journal-title': 'Int. J. Cardiol. Heart Vasc.'},
{ 'key': 'ref_16',
'first-page': 'e068407',
'article-title': 'Atorvastatin versus Placebo in Patients with COVID-19 in Intensive '
'Care: Randomized Controlled Trial',
'volume': '376',
'author': 'Investigators',
'year': '2022',
'journal-title': 'BMJ'},
{ 'key': 'ref_17',
'first-page': '658',
'article-title': 'Metformin: Current Knowledge',
'volume': '19',
'author': 'Nasri',
'year': '2014',
'journal-title': 'J. Res. Med. Sci.'},
{ 'key': 'ref_18',
'doi-asserted-by': 'crossref',
'first-page': '574',
'DOI': '10.1056/NEJM199602293340906',
'article-title': 'Metformin',
'volume': '334',
'author': 'Bailey',
'year': '1996',
'journal-title': 'N. Engl. J. Med.'},
{ 'key': 'ref_19',
'doi-asserted-by': 'crossref',
'first-page': '61',
'DOI': '10.1111/j.1464-5491.1992.tb01716.x',
'article-title': 'The Effect of Intravenous Metformin on Glucose Metabolism during '
'Hyperglycaemia in Type 2 Diabetes',
'volume': '9',
'author': 'Sum',
'year': '1992',
'journal-title': 'Diabet. Med.'},
{ 'key': 'ref_20',
'doi-asserted-by': 'crossref',
'first-page': '157',
'DOI': '10.3132/dvdr.2008.027',
'article-title': 'Metformin Therapy and Clinical Uses',
'volume': '5',
'author': 'Scarpello',
'year': '2008',
'journal-title': 'Diab. Vasc. Dis. Res.'},
{ 'key': 'ref_21',
'doi-asserted-by': 'crossref',
'first-page': '541',
'DOI': '10.1056/NEJM199508313330902',
'article-title': 'Efficacy of Metformin in Patients with Non-Insulin-Dependent Diabetes '
'Mellitus',
'volume': '333',
'author': 'DeFronzo',
'year': '1995',
'journal-title': 'N. Engl. J. Med.'},
{ 'key': 'ref_22',
'doi-asserted-by': 'crossref',
'first-page': '6S28',
'DOI': '10.1016/S1262-3636(03)72785-2',
'article-title': 'Reducing Insulin Resistance with Metformin: The Evidence Today',
'volume': '29',
'author': 'Giannarelli',
'year': '2003',
'journal-title': 'Diabetes Metab.'},
{ 'key': 'ref_23',
'doi-asserted-by': 'crossref',
'first-page': '542',
'DOI': '10.1038/nature13270',
'article-title': 'Metformin Suppresses Gluconeogenesis by Inhibiting Mitochondrial '
'Glycerophosphate Dehydrogenase',
'volume': '510',
'author': 'Madiraju',
'year': '2014',
'journal-title': 'Nature'},
{ 'key': 'ref_24',
'doi-asserted-by': 'crossref',
'first-page': '77',
'DOI': '10.1210/endrev/bnaa023',
'article-title': 'Cellular and Molecular Mechanisms of Metformin Action',
'volume': '42',
'author': 'LaMoia',
'year': '2021',
'journal-title': 'Endocr. Rev.'},
{ 'key': 'ref_25',
'doi-asserted-by': 'crossref',
'first-page': '496',
'DOI': '10.1038/nature06161',
'article-title': 'Structural Basis for AMP Binding to Mammalian AMP-Activated Protein '
'Kinase',
'volume': '449',
'author': 'Xiao',
'year': '2007',
'journal-title': 'Nature'},
{ 'key': 'ref_26',
'unstructured': 'Hawley, S.A., Boudeau, J., Reid, J.L., Mustard, K.J., Udd, L., Mäkelä, '
'T.P., Alessi, D.R., and Hardie, D.G. (2003). Complexes between the LKB1 '
'Tumor Suppressor, STRAD Alpha/Beta and MO25 Alpha/Beta Are Upstream '
'Kinases in the AMP-Activated Protein Kinase Cascade. J. Biol., 2.'},
{ 'key': 'ref_27',
'doi-asserted-by': 'crossref',
'first-page': '9',
'DOI': '10.1016/j.cmet.2005.05.009',
'article-title': 'Calmodulin-Dependent Protein Kinase Kinase-Beta Is an Alternative '
'Upstream Kinase for AMP-Activated Protein Kinase',
'volume': '2',
'author': 'Hawley',
'year': '2005',
'journal-title': 'Cell Metab.'},
{ 'key': 'ref_28',
'doi-asserted-by': 'crossref',
'first-page': '1642',
'DOI': '10.1126/science.1120781',
'article-title': 'The Kinase LKB1 Mediates Glucose Homeostasis in Liver and Therapeutic '
'Effects of Metformin',
'volume': '310',
'author': 'Shaw',
'year': '2005',
'journal-title': 'Science'},
{ 'key': 'ref_29',
'doi-asserted-by': 'crossref',
'first-page': '1649',
'DOI': '10.1038/nm.3372',
'article-title': 'Single Phosphorylation Sites in Acc1 and Acc2 Regulate Lipid '
'Homeostasis and the Insulin-Sensitizing Effects of Metformin',
'volume': '19',
'author': 'Fullerton',
'year': '2013',
'journal-title': 'Nat. Med.'},
{ 'key': 'ref_30',
'doi-asserted-by': 'crossref',
'first-page': '1329',
'DOI': '10.1111/jdv.12116',
'article-title': 'Metformin in Dermatology: An Overview',
'volume': '27',
'author': 'Badr',
'year': '2013',
'journal-title': 'J. Eur. Acad. Dermatol. Venereol.'},
{ 'key': 'ref_31',
'doi-asserted-by': 'crossref',
'first-page': '1291',
'DOI': '10.2337/dc09-1284',
'article-title': 'Novel Assay of Metformin Levels in Patients with Type 2 Diabetes and '
'Varying Levels of Renal Function: Clinical Recommendations',
'volume': '33',
'author': 'Frid',
'year': '2010',
'journal-title': 'Diabetes Care'},
{ 'key': 'ref_32',
'doi-asserted-by': 'crossref',
'first-page': '1569',
'DOI': '10.1016/S0022-2275(20)41379-3',
'article-title': 'The Discovery and Development of HMG-CoA Reductase Inhibitors',
'volume': '33',
'author': 'Endo',
'year': '1992',
'journal-title': 'J. Lipid Res.'},
{ 'key': 'ref_33',
'doi-asserted-by': 'crossref',
'first-page': '425',
'DOI': '10.1038/343425a0',
'article-title': 'Regulation of the Mevalonate Pathway',
'volume': '343',
'author': 'Goldstein',
'year': '1990',
'journal-title': 'Nature'},
{ 'key': 'ref_34',
'doi-asserted-by': 'crossref',
'first-page': '445',
'DOI': '10.1007/s11745-002-0916-0',
'article-title': 'High Doses of Atorvastatin and Simvastatin Induce Key Enzymes Involved '
'in VLDL Production',
'volume': '37',
'author': 'Roglans',
'year': '2002',
'journal-title': 'Lipids'},
{ 'key': 'ref_35',
'doi-asserted-by': 'crossref',
'first-page': '819',
'DOI': '10.1517/14656566.2.5.819',
'article-title': 'Atorvastatin',
'volume': '2',
'author': 'Wierzbicki',
'year': '2001',
'journal-title': 'Expert Opin. Pharmacother.'},
{ 'key': 'ref_36',
'doi-asserted-by': 'crossref',
'first-page': '78',
'DOI': '10.1016/j.virusres.2013.03.005',
'article-title': 'Requirement of Cholesterol in the Viral Envelope for Dengue Virus '
'Infection',
'volume': '174',
'author': 'Carro',
'year': '2013',
'journal-title': 'Virus Res.'},
{ 'key': 'ref_37',
'doi-asserted-by': 'crossref',
'first-page': '597',
'DOI': '10.1111/jvh.12187',
'article-title': 'Metformin Inhibits Hepatitis B Virus Protein Production and Replication '
'in Human Hepatoma Cells',
'volume': '21',
'author': 'Xun',
'year': '2014',
'journal-title': 'J. Viral. Hepat.'},
{ 'key': 'ref_38',
'doi-asserted-by': 'crossref',
'first-page': '1137',
'DOI': '10.1002/ijc.33594',
'article-title': 'Effects of Metformin on the Virus/Host Cell Crosstalk in Human '
'Papillomavirus-Positive Cancer Cells',
'volume': '149',
'author': 'Herrmann',
'year': '2021',
'journal-title': 'Int. J. Cancer'},
{ 'key': 'ref_39',
'doi-asserted-by': 'crossref',
'unstructured': 'Zhang, R., Feng, C., Luo, D., Zhao, R., Kannan, P.R., Yin, Y., Iqbal, '
'M.Z., Hu, Y., and Kong, X. (2023). Metformin Hydrochloride Significantly '
'Inhibits Rotavirus Infection in Caco2 Cell Line, Intestinal Organoids, '
'and Mice. Pharmaceuticals, 16.',
'DOI': '10.3390/ph16091279'},
{ 'key': 'ref_40',
'doi-asserted-by': 'crossref',
'first-page': '4482',
'DOI': '10.1002/jcb.26555',
'article-title': 'Metformin Inhibits Tumorigenesis in HBV-Induced Hepatocellular '
'Carcinoma by Suppressing HULC Overexpression Caused by HBX',
'volume': '119',
'author': 'Jiang',
'year': '2018',
'journal-title': 'J. Cell Biochem.'},
{ 'key': 'ref_41',
'doi-asserted-by': 'crossref',
'first-page': '8743',
'DOI': '10.1038/s41598-021-87707-9',
'article-title': 'The Antiviral Effect of Metformin on Zika and Dengue Virus Infection',
'volume': '11',
'year': '2021',
'journal-title': 'Sci. Rep.'},
{ 'key': 'ref_42',
'doi-asserted-by': 'crossref',
'first-page': '199010',
'DOI': '10.1016/j.virusres.2022.199010',
'article-title': 'Metformin Suppresses SARS-CoV-2 in Cell Culture',
'volume': '323',
'author': 'Parthasarathy',
'year': '2022',
'journal-title': 'Virus Res.'},
{ 'key': 'ref_43',
'doi-asserted-by': 'crossref',
'first-page': '436',
'DOI': '10.3389/fonc.2018.00436',
'article-title': 'Metformin Clinical Trial in HPV+ and HPV- Head and Neck Squamous Cell '
'Carcinoma: Impact on Cancer Cell Apoptosis and Immune Infiltrate',
'volume': '8',
'author': 'Curry',
'year': '2018',
'journal-title': 'Front. Oncol.'},
{ 'key': 'ref_44',
'doi-asserted-by': 'crossref',
'first-page': '21570',
'DOI': '10.1038/s41598-022-25065-w',
'article-title': 'Metformin Enhances the Antitumor Activity of Oncolytic Herpes Simplex '
'Virus HF10 (Canerpaturev) in a Pancreatic Cell Cancer Subcutaneous '
'Model',
'volume': '12',
'author': 'Abdelmoneim',
'year': '2022',
'journal-title': 'Sci. Rep.'},
{ 'key': 'ref_45',
'doi-asserted-by': 'crossref',
'first-page': '239',
'DOI': '10.1016/j.cellsig.2017.09.020',
'article-title': 'Metformin Triggers Apoptosis in PEL Cells and Alters Bortezomib-Induced '
'Unfolded Protein Response Increasing Its Cytotoxicity and Inhibiting '
'KSHV Lytic Cycle Activation',
'volume': '40',
'author': 'Granato',
'year': '2017',
'journal-title': 'Cell. Signal.'},
{ 'key': 'ref_46',
'doi-asserted-by': 'crossref',
'first-page': '110512',
'DOI': '10.1016/j.intimp.2023.110512',
'article-title': 'Metformin Restrains ZIKV Replication and Alleviates Virus-Induced '
'Inflammatory Responses in Microglia',
'volume': '121',
'author': 'Wang',
'year': '2023',
'journal-title': 'Int. Immunopharmacol.'},
{ 'key': 'ref_47',
'doi-asserted-by': 'crossref',
'unstructured': 'del Campo, J.A., García Valdecasas, M., Gil Gómez, A., Rojas '
'Alvarez-Ossorio, M.A., Gallego, P., Ampuero Herrojo, J., Gallego Durán, '
'R., Pastor, H., Grande, L., and Padillo Ruiz, F.J. (2018). Simvastatin '
'and Metformin Inhibit Cell Growth in Hepatitis C Virus Infected Cells '
'via mTOR Increasing PTEN and Autophagy. PLoS ONE, 13.',
'DOI': '10.1371/journal.pone.0191805'},
{ 'key': 'ref_48',
'doi-asserted-by': 'crossref',
'first-page': '91928',
'DOI': '10.18632/oncotarget.20248',
'article-title': 'Metformin Activates Type I Interferon Signaling against HCV via '
'Activation of Adenosine Monophosphate-Activated Protein Kinase',
'volume': '8',
'author': 'Tsai',
'year': '2017',
'journal-title': 'Oncotarget'},
{ 'key': 'ref_49',
'doi-asserted-by': 'crossref',
'first-page': 'e20284',
'DOI': '10.1016/j.heliyon.2023.e20284',
'article-title': 'Metformin Reduces the Risk of Developing Influenza A Virus Related '
'Cardiovascular Disease',
'volume': '9',
'author': 'Lee',
'year': '2023',
'journal-title': 'Heliyon'},
{ 'key': 'ref_50',
'doi-asserted-by': 'crossref',
'unstructured': 'Planas, D., Pagliuzza, A., Ponte, R., Fert, A., Marchand, L.R., '
'Massanella, M., Gosselin, A., Mehraj, V., Dupuy, F.P., and Isnard, S. '
'(2021). LILAC Pilot Study: Effects of Metformin on mTOR Activation and '
'HIV Reservoir Persistence during Antiretroviral Therapy. EBioMedicine, '
'65.',
'DOI': '10.1016/j.ebiom.2021.103270'},
{ 'key': 'ref_51',
'doi-asserted-by': 'crossref',
'first-page': '231',
'DOI': '10.3390/idr15030024',
'article-title': 'Bictegravir and Metformin Drug-Drug Interaction in People with Human '
'Immunodeficiency Virus (HIV)',
'volume': '15',
'author': 'Masich',
'year': '2023',
'journal-title': 'Infect. Dis. Rep.'},
{ 'key': 'ref_52',
'doi-asserted-by': 'crossref',
'first-page': '749770',
'DOI': '10.3389/fphys.2021.749770',
'article-title': 'Anti-Flavivirus Properties of Lipid-Lowering Drugs',
'volume': '12',
'year': '2021',
'journal-title': 'Front. Physiol.'},
{ 'key': 'ref_53',
'doi-asserted-by': 'crossref',
'unstructured': 'Osuna-Ramos, J.F., Farfan-Morales, C.N., Cordero-Rivera, C.D., De '
'Jesús-González, L.A., Reyes-Ruiz, J.M., Hurtado-Monzón, A.M., '
'Palacios-Rápalo, S.N., Jiménez-Camacho, R., Meraz-Ríos, M.A., and Del '
'Ángel, R.M. (2023). Cholesterol-Lowering Drugs as Potential Antivirals: '
'A Repurposing Approach against Flavivirus Infections. Viruses, 15.',
'DOI': '10.3390/v15071465'},
{ 'key': 'ref_54',
'doi-asserted-by': 'crossref',
'unstructured': 'Herrera-Moro Huitron, L., De Jesús-González, L.A., Martínez-Castillo, '
'M., Ulloa-Aguilar, J.M., Cabello-Gutierrez, C., Helguera-Repetto, C., '
'Garcia-Cordero, J., and León Juárez, M. (2023). Multifaceted Nature of '
'Lipid Droplets in Viral Interactions and Pathogenesis. Microorganisms, '
'11.',
'DOI': '10.3390/microorganisms11071851'},
{ 'key': 'ref_55',
'doi-asserted-by': 'crossref',
'first-page': '607',
'DOI': '10.1042/bj3480607',
'article-title': 'Evidence That Metformin Exerts Its Anti-Diabetic Effects through '
'Inhibition of Complex 1 of the Mitochondrial Respiratory Chain',
'volume': '348',
'author': 'Owen',
'year': '2000',
'journal-title': 'Biochem. J.'},
{ 'key': 'ref_56',
'doi-asserted-by': 'crossref',
'first-page': '753',
'DOI': '10.3389/fendo.2018.00753',
'article-title': 'Metformin-Induced Mitochondrial Complex I Inhibition: Facts, '
'Uncertainties, and Consequences',
'volume': '9',
'author': 'Fontaine',
'year': '2018',
'journal-title': 'Front. Endocrinol.'},
{ 'key': 'ref_57',
'doi-asserted-by': 'crossref',
'unstructured': 'Soto-Acosta, R., Bautista-Carbajal, P., Cervantes-Salazar, M., '
'Angel-Ambrocio, A.H., and Del Angel, R.M. (2017). DENV Up-Regulates the '
'HMG-CoA Reductase Activity through the Impairment of AMPK '
'Phosphorylation: A Potential Antiviral Target. PLoS Pathog., 13.',
'DOI': '10.1371/journal.ppat.1006257'},
{ 'key': 'ref_58',
'doi-asserted-by': 'crossref',
'first-page': '1096',
'DOI': '10.1093/infdis/jiv572',
'article-title': 'Hepatitis B Virus (HBV) Core-Related Antigen During Nucleos(t)Ide '
'Analog Therapy Is Related to Intra-Hepatic HBV Replication and '
'Development of Hepatocellular Carcinoma',
'volume': '213',
'author': 'Honda',
'year': '2016',
'journal-title': 'J. Infect. Dis.'},
{ 'key': 'ref_59',
'doi-asserted-by': 'crossref',
'first-page': '3152',
'DOI': '10.1016/j.sjbs.2021.02.059',
'article-title': 'Screening of Drug Databank against WT and Mutant Main Protease of '
'SARS-CoV-2: Towards Finding Potential Compound for Repurposing against '
'COVID-19',
'volume': '28',
'author': 'Sharma',
'year': '2021',
'journal-title': 'Saudi J. Biol. Sci.'},
{ 'key': 'ref_60',
'doi-asserted-by': 'crossref',
'unstructured': 'Kumar, V., Liu, H., and Wu, C. (2021). Drug Repurposing against '
'SARS-CoV-2 Receptor Binding Domain Using Ensemble-Based Virtual '
'Screening and Molecular Dynamics Simulations. Comput. Biol. Med., 135.',
'DOI': '10.1016/j.compbiomed.2021.104634'},
{ 'key': 'ref_61',
'doi-asserted-by': 'crossref',
'first-page': '105',
'DOI': '10.1186/s10020-021-00356-6',
'article-title': 'Identifying FDA-Approved Drugs with Multimodal Properties against '
'COVID-19 Using a Data-Driven Approach and a Lung Organoid Model of '
'SARS-CoV-2 Entry',
'volume': '27',
'author': 'Duarte',
'year': '2021',
'journal-title': 'Mol. Med.'},
{ 'key': 'ref_62',
'doi-asserted-by': 'crossref',
'unstructured': 'Zapata-Cardona, M.I., Flórez-Álvarez, L., Zapata-Builes, W., '
'Guerra-Sandoval, A.L., Guerra-Almonacid, C.M., Hincapié-García, J., '
'Rugeles, M.T., and Hernandez, J.C. (2022). Atorvastatin Effectively '
'Inhibits Ancestral and Two Emerging Variants of SARS-CoV-2 in Vitro. '
'Front. Microbiol., 13.',
'DOI': '10.3389/fmicb.2022.721103'},
{ 'key': 'ref_63',
'doi-asserted-by': 'crossref',
'unstructured': 'Segatori, V.I., Garona, J., Caligiuri, L.G., Bizzotto, J., Lavignolle, '
'R., Toro, A., Sanchis, P., Spitzer, E., Krolewiecki, A., and Gueron, G. '
'(2021). Effect of Ivermectin and Atorvastatin on Nuclear Localization of '
'Importin Alpha and Drug Target Expression Profiling in Host Cells from '
'Nasopharyngeal Swabs of SARS-CoV-2-Positive Patients. Viruses, 13.',
'DOI': '10.3390/v13102084'},
{ 'key': 'ref_64',
'doi-asserted-by': 'crossref',
'first-page': '2155',
'DOI': '10.3892/mmr.2016.5519',
'article-title': 'The Anti-dengue Virus Properties of Statins May Be Associated with '
'Alterations in the Cellular Antiviral Profile Expression',
'volume': '14',
'author': 'Vidaltamayo',
'year': '2016',
'journal-title': 'Mol. Med. Rep.'},
{ 'key': 'ref_65',
'doi-asserted-by': 'crossref',
'first-page': '108294',
'DOI': '10.1016/j.isci.2023.108294',
'article-title': 'An Ivermectin—Atorvastatin Combination Impairs Nuclear Transport '
'Inhibiting Dengue Infection in Vitro and in Vivo',
'volume': '26',
'year': '2023',
'journal-title': 'iScience'},
{ 'key': 'ref_66',
'doi-asserted-by': 'crossref',
'unstructured': 'Españo, E., and Kim, J.-K. (2022). Effects of Statin Combinations on '
'Zika Virus Infection in Vero Cells. Pharmaceutics, 15.',
'DOI': '10.3390/pharmaceutics15010050'},
{ 'key': 'ref_67',
'doi-asserted-by': 'crossref',
'first-page': '114',
'DOI': '10.1186/s12964-022-01026-8',
'article-title': 'Zika Virus Triggers Autophagy to Exploit Host Lipid Metabolism and '
'Drive Viral Replication',
'volume': '21',
'author': 'Stoyanova',
'year': '2023',
'journal-title': 'Cell Commun. Signal.'},
{ 'key': 'ref_68',
'doi-asserted-by': 'crossref',
'unstructured': 'Wani, M.A., Mukherjee, S., Mallick, S., Akbar, I., and Basu, A. (2020). '
'Atorvastatin Ameliorates Viral Burden and Neural Stem/Progenitor Cell '
'(NSPC) Death in an Experimental Model of Japanese Encephalitis. J. '
'Biosci., 45.',
'DOI': '10.1007/s12038-020-00052-3'},
{ 'key': 'ref_69',
'doi-asserted-by': 'crossref',
'first-page': '145',
'DOI': '10.1254/jphs.FM0070050',
'article-title': 'Life Style-Related Diseases of the Digestive System: Cell Culture '
'System for the Screening of Anti-Hepatitis C Virus (HCV) Reagents: '
'Suppression of HCV Replication by Statins and Synergistic Action with '
'Interferon',
'volume': '105',
'author': 'Ikeda',
'year': '2007',
'journal-title': 'J. Pharmacol. Sci.'},
{ 'key': 'ref_70',
'doi-asserted-by': 'crossref',
'first-page': '117',
'DOI': '10.1002/hep.21232',
'article-title': 'Different Anti-HCV Profiles of Statins and Their Potential for '
'Combination Therapy with Interferon',
'volume': '44',
'author': 'Ikeda',
'year': '2006',
'journal-title': 'Hepatology'},
{ 'key': 'ref_71',
'doi-asserted-by': 'crossref',
'first-page': '1641',
'DOI': '10.3889/oamjms.2019.459',
'article-title': 'Atorvastatin in Combination with Pegylated Interferon and Ribavirin '
'Provided High Rate of Sustained Virological Response in Patients with '
'Genotype 3 Hepatitis C Virus',
'volume': '7',
'author': 'Todorovska',
'year': '2019',
'journal-title': 'Open Access Maced. J. Med. Sci.'},
{ 'key': 'ref_72',
'doi-asserted-by': 'crossref',
'first-page': '47',
'DOI': '10.1002/hep.28506',
'article-title': 'Atorvastatin and Fluvastatin Are Associated with Dose-Dependent '
'Reductions in Cirrhosis and Hepatocellular Carcinoma, among Patients '
'with Hepatitis C Virus: Results from ERCHIVES',
'volume': '64',
'author': 'Simon',
'year': '2016',
'journal-title': 'Hepatology'},
{ 'key': 'ref_73',
'doi-asserted-by': 'crossref',
'first-page': '540',
'DOI': '10.1097/FJC.0b013e3181f6b28d',
'article-title': 'Atorvastatin Attenuates Coxsackie Virus B3m-Induced Viral Myocarditis '
'in Mice',
'volume': '56',
'author': 'Guan',
'year': '2010',
'journal-title': 'J. Cardiovasc. Pharmacol.'},
{ 'key': 'ref_74',
'doi-asserted-by': 'crossref',
'first-page': '9516',
'DOI': '10.1096/fj.201900428RR',
'article-title': 'Atorvastatin Restricts the Ability of Influenza Virus to Generate Lipid '
'Droplets and Severely Suppresses the Replication of the Virus',
'volume': '33',
'author': 'Episcopio',
'year': '2019',
'journal-title': 'FASEB J.'},
{ 'key': 'ref_75',
'doi-asserted-by': 'crossref',
'unstructured': 'Ianevski, A., Yao, R., Zusinaite, E., Lysvand, H., Oksenych, V., Tenson, '
'T., Bjørås, M., and Kainov, D. (2021). Active Components of Commonly '
'Prescribed Medicines Affect Influenza A Virus-Host Cell Interaction: A '
'Pilot Study. Viruses, 13.',
'DOI': '10.20944/preprints202107.0246.v1'},
{ 'key': 'ref_76',
'doi-asserted-by': 'crossref',
'first-page': 'e0147321',
'DOI': '10.1128/JVI.01473-21',
'article-title': 'Lipid Droplets Are Beneficial for Rabies Virus Replication by '
'Facilitating Viral Budding',
'volume': '96',
'author': 'Zhao',
'year': '2022',
'journal-title': 'J. Virol.'},
{ 'key': 'ref_77',
'doi-asserted-by': 'crossref',
'first-page': '1827',
'DOI': '10.1097/QAD.0000000000003656',
'article-title': 'An Open Label Randomized Controlled Trial of Atorvastatin versus '
'Aspirin in Elite Controllers and Antiretroviral-Treated People with HIV',
'volume': '37',
'author': 'Mystakelis',
'year': '2023',
'journal-title': 'AIDS'},
{ 'key': 'ref_78',
'doi-asserted-by': 'crossref',
'first-page': '2627',
'DOI': '10.1097/QAD.0000000000000475',
'article-title': 'Effects of Atorvastatin and Pravastatin on Immune Activation and T-Cell '
'Function in Antiretroviral Therapy-Suppressed HIV-1-Infected Patients',
'volume': '28',
'author': 'Overton',
'year': '2014',
'journal-title': 'AIDS'},
{ 'key': 'ref_79',
'doi-asserted-by': 'crossref',
'first-page': '756',
'DOI': '10.1093/infdis/jiq115',
'article-title': 'High Dose Atorvastatin Decreases Cellular Markers of Immune Activation '
'without Affecting HIV-1 RNA Levels: Results of a Double-Blind '
'Randomized Placebo Controlled Clinical Trial',
'volume': '203',
'author': 'Ganesan',
'year': '2011',
'journal-title': 'J. Infect. Dis.'},
{ 'key': 'ref_80',
'doi-asserted-by': 'crossref',
'first-page': '619',
'DOI': '10.1097/01.aids.0000210617.90954.0e',
'article-title': 'The Effect of Atorvastatin Treatment on HIV-1-Infected Patients '
'Interrupting Antiretroviral Therapy',
'volume': '20',
'author': 'Negredo',
'year': '2006',
'journal-title': 'AIDS'},
{ 'key': 'ref_81',
'doi-asserted-by': 'crossref',
'first-page': '79',
'DOI': '10.1016/j.ahj.2018.11.012',
'article-title': 'Differences in Statin Utilization and Lipid Lowering by Race, '
'Ethnicity, and HIV Status in a Real-World Cohort of Persons with Human '
'Immunodeficiency Virus and Uninfected Persons',
'volume': '209',
'author': 'Riestenberg',
'year': '2019',
'journal-title': 'Am. Heart J.'},
{ 'key': 'ref_82',
'doi-asserted-by': 'crossref',
'first-page': '400',
'DOI': '10.1093/jac/dkm470',
'article-title': 'Association between HIV Replication and Cholesterol in Peripheral Blood '
'Mononuclear Cells in HIV-Infected Patients Interrupting HAART',
'volume': '61',
'author': 'Negredo',
'year': '2008',
'journal-title': 'J. Antimicrob. Chemother.'},
{ 'key': 'ref_83',
'doi-asserted-by': 'crossref',
'first-page': '153',
'DOI': '10.1310/hct1303-153',
'article-title': 'Statin Therapy Decreases Serum Levels of High-Sensitivity C-Reactive '
'Protein and Tumor Necrosis Factor-α in HIV-Infected Patients Treated '
'with Ritonavir-Boosted Protease Inhibitors',
'volume': '13',
'author': 'Calza',
'year': '2012',
'journal-title': 'HIV Clin. Trials'},
{ 'key': 'ref_84',
'doi-asserted-by': 'crossref',
'first-page': '509',
'DOI': '10.1164/rccm.201712-2570OC',
'article-title': 'AMP-Activated Protein Kinase Phosphorylation of Angiotensin-Converting '
'Enzyme 2 in Endothelium Mitigates Pulmonary Hypertension',
'volume': '198',
'author': 'Zhang',
'year': '2018',
'journal-title': 'Am. J. Respir. Crit. Care Med.'},
{ 'key': 'ref_85',
'doi-asserted-by': 'crossref',
'first-page': '477',
'DOI': '10.1111/bph.12159',
'article-title': 'ACE2, Angiotensin-(1-7) and Mas Receptor Axis in Inflammation and '
'Fibrosis',
'volume': '169',
'author': 'Silveira',
'year': '2013',
'journal-title': 'Br. J. Pharmacol.'},
{ 'key': 'ref_86',
'doi-asserted-by': 'crossref',
'first-page': '1456',
'DOI': '10.1161/CIRCRESAHA.120.317015',
'article-title': 'Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of '
'the Renin-Angiotensin System',
'volume': '126',
'author': 'Gheblawi',
'year': '2020',
'journal-title': 'Circ. Res.'},
{ 'key': 'ref_87',
'doi-asserted-by': 'crossref',
'first-page': '1',
'DOI': '10.1016/j.apsb.2020.10.006',
'article-title': 'Angiotensin-Converting Enzyme 2 (ACE2): SARS-CoV-2 Receptor and RAS '
'Modulator',
'volume': '11',
'author': 'Bian',
'year': '2021',
'journal-title': 'Acta Pharm. Sin. B'},
{ 'key': 'ref_88',
'doi-asserted-by': 'crossref',
'first-page': '7089',
'DOI': '10.3390/ijms14047089',
'article-title': 'Roles of Rho GTPases in Intracellular Transport and Cellular '
'Transformation',
'volume': '14',
'author': 'Chi',
'year': '2013',
'journal-title': 'Int. J. Mol. Sci.'},
{ 'key': 'ref_89',
'doi-asserted-by': 'crossref',
'unstructured': 'Marcianò, G., Palleria, C., Casarella, A., Rania, V., Basile, E., '
'Catarisano, L., Vocca, C., Bianco, L., Pelaia, C., and Cione, E. (2022). '
'Effect of Statins on Lung Cancer Molecular Pathways: A Possible '
'Therapeutic Role. Pharmaceuticals, 15.',
'DOI': '10.3390/ph15050589'},
{ 'key': 'ref_90',
'doi-asserted-by': 'crossref',
'first-page': '851',
'DOI': '10.1042/BJ20120150',
'article-title': 'Ivermectin Is a Specific Inhibitor of Importin α/β-Mediated Nuclear '
'Import Able to Inhibit Replication of HIV-1 and Dengue Virus',
'volume': '443',
'author': 'Wagstaff',
'year': '2012',
'journal-title': 'Biochem. J.'},
{ 'key': 'ref_91',
'doi-asserted-by': 'crossref',
'first-page': 'e233',
'DOI': '10.1016/S2666-5247(21)00114-2',
'article-title': 'Combining Immunomodulators and Antivirals for COVID-19',
'volume': '2',
'author': 'Chen',
'year': '2021',
'journal-title': 'Lancet Microbe'},
{ 'key': 'ref_92',
'doi-asserted-by': 'crossref',
'first-page': '2056',
'DOI': '10.3389/fimmu.2020.02056',
'article-title': 'Immunomodulatory and Antiviral Activity of Metformin and Its Potential '
'Implications in Treating Coronavirus Disease 2019 and Lung Injury',
'volume': '11',
'author': 'Chen',
'year': '2020',
'journal-title': 'Front. Immunol.'},
{ 'key': 'ref_93',
'doi-asserted-by': 'crossref',
'first-page': '953',
'DOI': '10.1016/j.cmet.2014.09.018',
'article-title': 'Metformin: From Mechanisms of Action to Therapies',
'volume': '20',
'author': 'Foretz',
'year': '2014',
'journal-title': 'Cell Metab.'},
{ 'key': 'ref_94',
'doi-asserted-by': 'crossref',
'first-page': '1149',
'DOI': '10.1111/j.1751-1097.2012.01165.x',
'article-title': 'Metformin, an Antidiabetic Agent Reduces Growth of Cutaneous Squamous '
'Cell Carcinoma by Targeting mTOR Signaling Pathway†',
'volume': '88',
'author': 'Chaudhary',
'year': '2012',
'journal-title': 'Photochem. Photobiol.'},
{ 'key': 'ref_95',
'doi-asserted-by': 'crossref',
'first-page': '162',
'DOI': '10.1016/j.tips.2020.01.003',
'article-title': 'Context-Dependent Pharmacological Effects of Metformin on the Immune '
'System',
'volume': '41',
'author': 'Marcucci',
'year': '2020',
'journal-title': 'Trends Pharmacol. Sci.'},
{ 'key': 'ref_96',
'doi-asserted-by': 'crossref',
'first-page': '497',
'DOI': '10.1016/S0140-6736(20)30183-5',
'article-title': 'Clinical Features of Patients Infected with 2019 Novel Coronavirus in '
'Wuhan, China',
'volume': '395',
'author': 'Huang',
'year': '2020',
'journal-title': 'Lancet'},
{ 'key': 'ref_97',
'first-page': '463',
'article-title': 'M1 and M2 Macrophages: Oracles of Health and Disease',
'volume': '32',
'author': 'Mills',
'year': '2012',
'journal-title': 'CRI'},
{ 'key': 'ref_98',
'doi-asserted-by': 'crossref',
'first-page': '20348',
'DOI': '10.1074/jbc.M115.662114',
'article-title': 'Metformin Inhibits the Production of Reactive Oxygen Species from '
'NADH:Ubiquinone Oxidoreductase to Limit Induction of Interleukin-1β '
'(IL-1β) and Boosts Interleukin-10 (IL-10) in Lipopolysaccharide '
'(LPS)-Activated Macrophages *',
'volume': '290',
'author': 'Kelly',
'year': '2015',
'journal-title': 'J. Biol. Chem.'},
{ 'key': 'ref_99',
'doi-asserted-by': 'crossref',
'first-page': '36441',
'DOI': '10.18632/oncotarget.5541',
'article-title': 'Metformin Prevents Cancer Metastasis by Inhibiting M2-like Polarization '
'of Tumor Associated Macrophages',
'volume': '6',
'author': 'Ding',
'year': '2015',
'journal-title': 'Oncotarget'},
{ 'key': 'ref_100',
'doi-asserted-by': 'crossref',
'first-page': '20',
'DOI': '10.1038/s44276-023-00022-w',
'article-title': 'Metformin May Improve the Outcome of Patients with Colorectal Cancer '
'and Type 2 Diabetes Mellitus Partly through Effects on Neutrophil '
'Extracellular Traps',
'volume': '1',
'author': 'Saito',
'year': '2023',
'journal-title': 'BJC Rep.'},
{ 'key': 'ref_101',
'doi-asserted-by': 'crossref',
'first-page': '169',
'DOI': '10.1186/s12985-023-02116-w',
'article-title': 'Neutrophils in COVID-19: Recent Insights and Advances',
'volume': '20',
'author': 'Li',
'year': '2023',
'journal-title': 'Virol. J.'},
{ 'key': 'ref_102',
'doi-asserted-by': 'crossref',
'first-page': '58',
'DOI': '10.1016/j.jneuroim.2016.01.014',
'article-title': 'Metformin Ameliorates the Development of Experimental Autoimmune '
'Encephalomyelitis by Regulating T Helper 17 and Regulatory T Cells in '
'Mice',
'volume': '292',
'author': 'Sun',
'year': '2016',
'journal-title': 'J. Neuroimmunol.'},
{ 'key': 'ref_103',
'doi-asserted-by': 'crossref',
'first-page': '283',
'DOI': '10.1007/s00018-023-04932-3',
'article-title': 'Metformin Induces Tolerogenicity of Dendritic Cells by Promoting '
'Metabolic Reprogramming',
'volume': '80',
'author': 'Liu',
'year': '2023',
'journal-title': 'Cell Mol. Life Sci.'},
{ 'key': 'ref_104',
'doi-asserted-by': 'crossref',
'first-page': '7471',
'DOI': '10.1038/s41467-023-42277-4',
'article-title': 'Inflammatory Macrophages Reprogram to Immunosuppression by Reducing '
'Mitochondrial Translation',
'volume': '14',
'author': 'Brischetto',
'year': '2023',
'journal-title': 'Nat. Commun.'},
{ 'key': 'ref_105',
'doi-asserted-by': 'crossref',
'first-page': '338',
'DOI': '10.1046/j.1365-2796.2002.00966.x',
'article-title': 'Effects of Simvastatin and Atorvastatin on Inflammation Markers in '
'Plasma',
'volume': '251',
'author': 'Wiklund',
'year': '2002',
'journal-title': 'J. Intern. Med.'},
{ 'key': 'ref_106',
'doi-asserted-by': 'crossref',
'first-page': '1671',
'DOI': '10.1007/s10787-023-01240-x',
'article-title': 'The Potential Therapeutic Effect of Statins in Multiple Sclerosis: '
'Beneficial or Detrimental Effects',
'volume': '31',
'author': 'Saad',
'year': '2023',
'journal-title': 'Inflammopharmacology'},
{ 'key': 'ref_107',
'doi-asserted-by': 'crossref',
'first-page': '193',
'DOI': '10.1111/j.1365-2249.2011.04331.x',
'article-title': 'The Role of Atorvastatin in Regulating the Immune Response Leading to '
'Vascular Damage in a Model of Kawasaki Disease',
'volume': '164',
'author': 'Blankier',
'year': '2011',
'journal-title': 'Clin. Exp. Immunol.'},
{ 'key': 'ref_108',
'doi-asserted-by': 'crossref',
'first-page': '123',
'DOI': '10.15420/ecr.2019.9.2',
'article-title': 'The Effect of Statins on the Functionality of CD4+CD25+FOXP3+ '
'Regulatory T-Cells in Acute Coronary Syndrome: A Systematic Review and '
'Meta-Analysis of Randomised Controlled Trials in Asian Populations',
'volume': '14',
'author': 'Sorathia',
'year': '2019',
'journal-title': 'Eur. Cardiol.'},
{ 'key': 'ref_109',
'doi-asserted-by': 'crossref',
'first-page': '48',
'DOI': '10.1007/s11882-015-0548-7',
'article-title': 'Regulation of Adaptive Immunity in Health and Disease by Cholesterol '
'Metabolism',
'volume': '15',
'author': 'Fessler',
'year': '2015',
'journal-title': 'Curr. Allergy Asthma Rep.'},
{ 'key': 'ref_110',
'doi-asserted-by': 'crossref',
'first-page': '317',
'DOI': '10.3390/immuno2020021',
'article-title': 'The Immunomodulatory Effects of Statins on Macrophages',
'volume': '2',
'author': 'Sheridan',
'year': '2022',
'journal-title': 'Immuno'},
{ 'key': 'ref_111',
'doi-asserted-by': 'crossref',
'first-page': '108391',
'DOI': '10.1016/j.jdiacomp.2022.108391',
'article-title': 'Metformin in SARS-CoV-2 Infection: A Hidden Path—From Altered '
'Inflammation to Reduced Mortality. A Review from the Literature',
'volume': '37',
'author': 'Pedrosa',
'year': '2023',
'journal-title': 'J. Diabetes Complicat.'},
{ 'key': 'ref_112',
'doi-asserted-by': 'crossref',
'first-page': '423',
'DOI': '10.1016/j.diabet.2020.07.006',
'article-title': 'Metformin and COVID-19: From Cellular Mechanisms to Reduced Mortality',
'volume': '46',
'author': 'Scheen',
'year': '2020',
'journal-title': 'Diabetes Metab.'},
{ 'key': 'ref_113',
'doi-asserted-by': 'crossref',
'first-page': '329',
'DOI': '10.5455/medarh.2022.76.329-332',
'article-title': 'Effects of Metformin, Insulin on Hematological Parameters of COVID-19 '
'Patients with Type 2 Diabetes',
'volume': '76',
'author': 'Petakh',
'year': '2022',
'journal-title': 'Med. Arch.'},
{ 'key': 'ref_114',
'doi-asserted-by': 'crossref',
'unstructured': 'Moreno-Corona, N.C., López-Ortega, O., Pérez-Martínez, C.A., '
'Martínez-Castillo, M., De Jesús-González, L.A., León-Reyes, G., and '
'León-Juárez, M. (2023). Dynamics of the Microbiota and Its Relationship '
'with Post-COVID-19 Syndrome. Int. J. Mol. Sci., 24.',
'DOI': '10.3390/ijms241914822'},
{ 'key': 'ref_115',
'doi-asserted-by': 'crossref',
'unstructured': 'Petakh, P., Kamyshna, I., Nykyforuk, A., Yao, R., Imbery, J.F., '
'Oksenych, V., Korda, M., and Kamyshnyi, A. (2022). Immunoregulatory '
'Intestinal Microbiota and COVID-19 in Patients with Type Two Diabetes: A '
'Double-Edged Sword. Viruses, 14.',
'DOI': '10.3390/v14030477'},
{ 'key': 'ref_116',
'doi-asserted-by': 'crossref',
'unstructured': 'Petakh, P., Kamyshna, I., Oksenych, V., Kainov, D., and Kamyshnyi, A. '
'(2023). Metformin Therapy Changes Gut Microbiota Alpha-Diversity in '
'COVID-19 Patients with Type 2 Diabetes: The Role of SARS-CoV-2 Variants '
'and Antibiotic Treatment. Pharmaceuticals, 16.',
'DOI': '10.20944/preprints202304.1127.v1'},
{ 'key': 'ref_117',
'doi-asserted-by': 'crossref',
'first-page': '429',
'DOI': '10.1186/s13054-020-03154-4',
'article-title': 'Atorvastatin Associated with Decreased Hazard for Death in COVID-19 '
'Patients Admitted to an ICU: A Retrospective Cohort Study',
'volume': '24',
'author': 'Chung',
'year': '2020',
'journal-title': 'Crit. Care'},
{ 'key': 'ref_118',
'doi-asserted-by': 'crossref',
'first-page': '820260',
'DOI': '10.3389/fcvm.2022.820260',
'article-title': 'Statin Use in COVID-19 Hospitalized Patients and Outcomes: A '
'Retrospective Study',
'volume': '9',
'author': 'Kouhpeikar',
'year': '2022',
'journal-title': 'Front. Cardiovasc. Med.'},
{ 'key': 'ref_119',
'first-page': 'e14434',
'article-title': 'Promising Effects of Atorvastatin on Mortality and Need for Mechanical '
'Ventilation in Patients with Severe COVID-19; a Retrospective Cohort '
'Study',
'volume': '75',
'author': 'Moradi',
'year': '2021',
'journal-title': 'Int. J. Clin. Pract.'},
{ 'key': 'ref_120',
'doi-asserted-by': 'crossref',
'first-page': '992686',
'DOI': '10.3389/fcvm.2022.992686',
'article-title': 'The Rationale for the Treatment of Long-Covid Symptoms—A Cardiologist’s '
'View',
'volume': '9',
'author': 'Schieffer',
'year': '2022',
'journal-title': 'Front. Cardiovasc. Med.'},
{ 'key': 'ref_121',
'doi-asserted-by': 'crossref',
'first-page': 'e28971',
'DOI': '10.1002/jmv.28971',
'article-title': 'Outpatient Atorvastatin Use and Severe COVID-19 Outcomes: A '
'Population-Based Study',
'volume': '95',
'author': 'Herdeiro',
'year': '2023',
'journal-title': 'J. Med. Virol.'},
{ 'key': 'ref_122',
'first-page': '70',
'article-title': 'Metformin Reduced SARS-CoV-2 Viral Load in a Phase 3 Randomized '
'Clinical Trial',
'volume': '31',
'author': 'Boulware',
'year': '2023',
'journal-title': 'Top. Antivir. Med.'},
{ 'key': 'ref_123',
'doi-asserted-by': 'crossref',
'first-page': 'e436',
'DOI': '10.1016/j.ijid.2012.02.004',
'article-title': 'The Effect of Metformin on the Efficacy of Antiviral Therapy in '
'Patients with Genotype 1 Chronic Hepatitis C and Insulin Resistance',
'volume': '16',
'author': 'Yu',
'year': '2012',
'journal-title': 'Int. J. Infect. Dis.'},
{ 'key': 'ref_124',
'doi-asserted-by': 'crossref',
'first-page': '191',
'DOI': '10.3389/fendo.2020.00191',
'article-title': 'Metformin and Its Benefits for Various Diseases',
'volume': '11',
'author': 'Lv',
'year': '2020',
'journal-title': 'Front. Endocrinol.'},
{ 'key': 'ref_125',
'doi-asserted-by': 'crossref',
'first-page': '18',
'DOI': '10.1016/S0212-6567(01)78767-7',
'article-title': 'Análisis coste-efectividad de atorvastatina frente a simvastatina como '
'tratamiento hipolipemiante en pacientes hipercolesterolémicos en '
'atención primaria',
'volume': '27',
'year': '2001',
'journal-title': 'Aten Primaria'},
{ 'key': 'ref_126',
'doi-asserted-by': 'crossref',
'first-page': 'ofac174',
'DOI': '10.1093/ofid/ofac174',
'article-title': 'Barriers to Worldwide Access for Paxlovid, a New Treatment for COVID-19',
'volume': '9',
'author': 'Pepperrell',
'year': '2022',
'journal-title': 'Open Forum Infect. Dis.'},
{ 'key': 'ref_127',
'unstructured': 'Corcoran, C., and Jacobs, T.F. (2023). StatPearls, StatPearls '
'Publishing.'},
{ 'key': 'ref_128',
'unstructured': '(2023, June 13). DOF—Diario Oficial de La Federación. Available online: '
'https://www.dof.gob.mx/nota_detalle.php?codigo=5588819&fecha=10/03/2020#gsc.tab=0.'}],
'container-title': 'Microorganisms',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://www.mdpi.com/2076-2607/12/2/383/pdf',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2024, 2, 14]],
'date-time': '2024-02-14T10:14:34Z',
'timestamp': 1707905674000},
'score': 1,
'resource': {'primary': {'URL': 'https://www.mdpi.com/2076-2607/12/2/383'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2024, 2, 13]]},
'references-count': 128,
'journal-issue': {'issue': '2', 'published-online': {'date-parts': [[2024, 2]]}},
'alternative-id': ['microorganisms12020383'],
'URL': 'http://dx.doi.org/10.3390/microorganisms12020383',
'relation': {},
'ISSN': ['2076-2607'],
'subject': ['Virology', 'Microbiology (medical)', 'Microbiology'],
'container-title-short': 'Microorganisms',
'published': {'date-parts': [[2024, 2, 13]]}}
