Targeting liver stage malaria with metformin

Vera, Iset Medina; Ruivo, Margarida T. Grilo; Rocha, Leonardo F. Lemos; Marques, Sofia; Bhatia, Sangeeta N.; Mota, Maria M.; Mâncio-Silva, Liliana

doi:10.1172/jci.insight.127441

Cited by 34 publications

(19 citation statements)

References 72 publications

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“…The importance of host glucose metabolic status is in agreement with previous findings where Plasmodium parasites modulate the host energy sensor, AMP-activated protein kinase (AMPK) to presumably modulate glucose metabolism during liver stage development (Ruivo et al, 2016). Furthermore, the antidiabetic drug metformin effectively reduces the size of Pf liver schizonts (Vera et al, 2019). Metformin promotes binding of hGK to GKRP, resulting in a nuclear localization reminiscence of a Z1/2 phenotype (Guigas et al, 2006), shown to result in smaller schizonts in this study.…”

Section: Discussionsupporting

confidence: 92%

Zonal human hepatocytes are differentially permissive to Plasmodium falciparum malaria parasites

et al. 2021

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Plasmodium falciparum (Pf) is a major cause of human malaria and is transmitted by infected Anopheles mosquitoes. The initial asymptomatic infection is characterized by parasite invasion of hepatocytes, followed by massive replication generating schizonts with blood-infective merozoites. Hepatocytes can be categorized by their zonal location and metabolic functions within a liver lobule. To understand specific host conditions that affect infectivity, we studied Pf parasite liver stage development in relation to the metabolic heterogeneity of fresh human hepatocytes. We found selective preference of different Pf strains for a minority of hepatocytes, which are characterized by the particular presence of glutamine synthetase (hGS). Schizont growth is significantly enhanced by hGS uptake early in development, showcasing a novel import system. In conclusion, Pf development is strongly determined by the differential metabolic status in hepatocyte subtypes. These findings underscore the importance of detailed understanding of hepatocyte host-Pf interactions and may delineate novel pathways for intervention strategies.

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Section: Discussionsupporting

confidence: 92%

Zonal human hepatocytes are differentially permissive to Plasmodium falciparum malaria parasites

et al. 2021

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“…Metformin, a biguanide antidiabetic drug that primarily targets the liver, was shown to inhibit hepatic infection in vivo in the P. berghei mouse model, where it decreased both parasite numbers and intra-hepatic parasite development. The latter effect was also observed in vitro employing a model of infection of primary human hepatocytes by the human malaria parasite, P. falciparum [ 114 ]. Despite its demonstrated activity against hepatic infection, metformin only modestly impacted asexual erythrocytic stages, as shown in vivo in two rodent models of infection, P. berghei and P.yoelii , and in vitro, using P. falciparum [ 114 , 115 ].…”

Section: Targeting the Liver Stage Of Plasmodium mentioning

confidence: 91%

Repurposing Drugs to Fight Hepatic Malaria Parasites

2020

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Malaria remains one of the most prevalent infectious diseases worldwide, primarily affecting some of the most vulnerable populations around the globe. Despite achievements in the treatment of this devastating disease, there is still an urgent need for the discovery of new drugs that tackle infection by Plasmodium parasites. However, de novo drug development is a costly and time-consuming process. An alternative strategy is to evaluate the anti-plasmodial activity of compounds that are already approved for other purposes, an approach known as drug repurposing. Here, we will review efforts to assess the anti-plasmodial activity of existing drugs, with an emphasis on the obligatory and clinically silent liver stage of infection. We will also review the current knowledge on the classes of compounds that might be therapeutically relevant against Plasmodium in the context of other communicable diseases that are prevalent in regions where malaria is endemic. Repositioning existing compounds may constitute a faster solution to the current gap of prophylactic and therapeutic drugs that act on Plasmodium parasites, overall contributing to the global effort of malaria eradication.

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“…at day −2, −1, 0 of infection - Reduce airway glucose and bacterial load (without change in blood glucose) [ 150 ] P. aeruginosa In vivo, C. elegans , mouse - P. aeruginosa PA14 infection With exposure 1–100 mM metformin initiated with infection - Dose-dependent increase resistance to P. aeruginosa PA14 infection - Increase levels of active PMK-1 - p38/PMK-1-mediated innate immunity conserved from worms to mammals [ 151 ] S. aureus In vitro H441 epithelial cells With exposure 1 mM 18-h prior to infection - Increase transepithelial resistance - reduce glucose-dependent bacterial growth [ 152 ] S. aureus In vitro, human Airway epithelial cells With exposure 0, 0.03, 0.3, or 1 mM metformin 18 h prior to inoculation - Reduced paracellular flux across murine tracheas. [ 153 ] S. aureus In vivo, mouse Wild-type, C57BL/6 or db/db, Prophylactic 40 mg/kg metformin 2 days prior to infection - Modify glucose flux across the airway epithelium - Limit hyperglycemia-induced bacterial growth [ 153 ] Trypanosoma cruzi In vivo, mouse CD-1 mice on high fat diet (HFD) Prophylactic 50 mg/kg metformin by gavage (± HFD) 20 days prior to infection - Reduce mortality from 20% on HFD to 3% on HFD + metformin [ 82 ] Parasitic infection Malaria P. berghei In vitro Huh7 cells Treatment 0.04–1.25 mM metformin - Reduce of total parasite load (dose-dependent) [ 154 ] Malaria P. berghei In vivo, mouse C57BL/6 Prophylactic 500 mg/kg/day metformin, 7 days prior to infection - Reduce total burden of P. berghei liver infection and lessened disease severity [ 155 ] Malaria ...…”

Section: A Brief History Of Metformin and Agingmentioning

confidence: 99%

A geroscience perspective on immune resilience and infectious diseases: a potential case for metformin

et al. 2020

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We are in the midst of the global pandemic. Though acute respiratory coronavirus (SARS-COV2) that leads to COVID-19 infects people of all ages, severe symptoms and mortality occur disproportionately in older adults. Geroscience interventions that target biological aging could decrease risk across multiple age-related diseases and improve outcomes in response to infectious disease. This offers hope for a new hostdirected therapeutic approach that could (i) improve outcomes following exposure or shorten treatment regimens; (ii) reduce the chronic pathology associated with the infectious disease and subsequent comorbidity, frailty, and disability; and (iii) promote development of immunological memory that protects against relapse or improves response to vaccination. We review the possibility of this approach by examining available evidence in metformin: a generic drug with a proven safety record that will be used in a large-scale multicenter clinical trial. Though rigorous translational research and clinical trials are needed to test this empirically, metformin may improve host immune defenses and confer protection against long-term health consequences of infectious disease, age-related chronic diseases, and geriatric syndromes.

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Targeting liver stage malaria with metformin

Cited by 34 publications

References 72 publications

Zonal human hepatocytes are differentially permissive to Plasmodium falciparum malaria parasites

Zonal human hepatocytes are differentially permissive to Plasmodium falciparum malaria parasites

Repurposing Drugs to Fight Hepatic Malaria Parasites

A geroscience perspective on immune resilience and infectious diseases: a potential case for metformin

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