PPAR Ligands Induce Antiviral Effects Targeting Perturbed Lipid Metabolism during SARS-CoV-2, HCV, and HCMV Infection

Fantacuzzi, Marialuigia; Amoroso, Rosa; Ammazzalorso, Alessandra

doi:10.3390/biology11010114

Cited by 21 publications

(25 citation statements)

References 95 publications

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“…Stimulation of PPARγ by natural or synthetic agonists may modulate the cytokine storm typical of viral infection by preventing cytokine overproduction and the inflammatory cascade ( 6 ) ( 27 ). Several natural PPARγ ligands have been proposed to treat COVID-19 ( 8 ). Due to its ability to reduce inflammatory parameters, the PPARγ agonist pioglitazone has also been proposed as an effective treatment for COVID-19 patients with diabetes, hypertension, and cardiovascular comorbidities ( 28 ).…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that respiratory virus, such as a respiratory syncytial virus (RSV), alter PPARγ expression ( 6 , 7 ). In addition, PPARγ ligands are proposed as anti-SARS-CoV-2 drugs based on their anti-inflammatory, antioxidant and immunomodulatory properties ( 8 , 9 ). Several PPARγ agonists have been documented to attenuate inflammation and alleviate influenza infection in mouse studies.…”

Section: Introductionmentioning

confidence: 99%

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Influenza virus causes lung immunopathology through down-regulating PPARγ activity in macrophages

et al. 2022

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Fatal influenza (flu) virus infection often activates excessive inflammatory signals, leading to multi-organ failure and death, also referred to as cytokine storm. PPARγ (Peroxisome proliferator-activated receptor gamma) agonists are well-known candidates for cytokine storm modulation. The present study identified that influenza infection reduced PPARγ expression and decreased PPARγ transcription activity in human alveolar macrophages (AMs) from different donors. Treatment with PPARγ agonist Troglitazone ameliorated virus-induced proinflammatory cytokine secretion but did not interfere with the IFN-induced antiviral pathway in human AMs. In contrast, PPARγ antagonist and knockdown of PPARγ in human AMs further enhanced virus-stimulated proinflammatory response. In a mouse model of influenza infection, flu virus dose-dependently reduced PPARγ transcriptional activity and decreased expression of PPARγ. Moreover, PPARγ agonist troglitazone significantly reduced high doses of influenza infection-induced lung pathology. In addition, flu infection reduced PPARγ expression in all mouse macrophages, including AMs, interstitial macrophages, and bone-marrow-derived macrophages but not in alveolar epithelial cells. Our results indicate that the influenza virus specifically targets the PPARγ pathway in macrophages to cause acute injury to the lung.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Influenza virus causes lung immunopathology through down-regulating PPARγ activity in macrophages

et al. 2022

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“…Observed increased CD36 gene expression in both survivors and non-survivors may be a consequence of PPARγ activation and here with remains increased after 7 days in the ICU. By targeting inflammation, ACE2 and the WNT/β-catenin pathway, PPARγ agonists were suggested to be interesting candi-dates for SARS-CoV-2 therapy due to modulation of the cytokine storm by pre-venting the cytokine overproduction [28,29].…”

Section: Discussionmentioning

confidence: 99%

The role of cholesterol metabolism in predicting clinical outcome of patients with severe COVID-19

Usenko

Miroshnikova

Bezrukova

et al. 2022

Preprint

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Transcriptomic analysis conducted by us previously revealed upregulation of genes involved in low-density lipoprotein particle receptor (LDLR) activity pathway in lethal COVID-19. Last data suggested the possible role of extracellular vesicles and exomeres in COVID-19 pathogenesis. The aim of the present study was to retro-spectively evaluate parameters of cholesterol metabolism as possible predictors of fatal outcome of COVID-19. Blood from 39 patients with severe COVID-19 (the main cohort) were collected at the time of admission to the intensive care unit (ICU) (T1) and 7 days after admission to the ICU (T2). After 30 days patients were divided into two subgroups according to outcome-21 non-survivors and 18 survivors. 28 patients (13 non-survivors and 15 survivors) with severe COVID-19 were included as the replication cohort. The study demonstrated that plasma low- and high-density lipoprotein cholesterol levels (LDL-C and HDL-C) were decreased and CCL20/MIP3?, IL-10, IL-15, IL-27 concentrations were increased in non-survivors compared to controls in T1. STAB1 gene expression was higher in non-survivors than in survivors (p=0.017) in T2. The conjoint fraction of exomeres and LDL particles measured by dynamic light scattering (DLS) was decreased in non-survivors com-pared to survivors in both the main and replication cohorts. We first showed that change of exomeres fraction may be critical in fatal outcome of COVID-19.

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Section: Fxr and Signaling Pathways In Covid-19mentioning

confidence: 99%

“…Furthermore, FXR agonists can provoke the expression of PPARα, which possesses potent immunomodulatory effects in SARS-CoV-2 infection (Fantacuzzi et al 2022 ). PPARα agonists can lessen pulmonary inflammation, lipotoxicity, and metabolic derangement induced by SARS-CoV-2 infection (Fantacuzzi et al 2022 ). Besides, in vitro study displayed that fenofibrate inhibits SARS-CoV-2-mediated cytopathic in Vero E6 cell lines at a concentration of 20 µM (Rodon et al 2021 ).…”

Section: Fxr and Signaling Pathways In Covid-19mentioning

confidence: 99%

A perspective study of the possible impact of obeticholic acid against SARS-CoV-2 infection

et al. 2022

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The causative agent of CoV disease 2019 is a new coronavirus CoV type 2, affecting the respiratory tract with severe manifestations (SARS-CoV-2). Covid-19 is mainly symptomless, with slight indications in about 85% of the affected cases. Many efforts were done to face this pandemic by testing different drugs and agents to make treatment protocols in different countries. However, the use of these proposed drugs is associated with the development of adverse events. Remarkably, the successive development of SARS-CoV-2 variants which could affect persons even they were vaccinated, prerequisite wide search to find efficient and safe agents to face SARS-CoV-2 infection. Obeticholic acid (OCA), which has anti-inflammatory effects, may efficiently treat Covid-19. Thus, the goal of this perspective study is to focus on the possible medicinal effectiveness in managing Covid-19. OCA is a powerful farnesoid X receptor (FXR) agonist possessing marked antiviral and anti-inflammatory effects. FXR is dysregulated in Covid-19 resulting in hyper-inflammation with concurrent occurrence of hypercytokinemia. Interestingly, OCA inhibits the reaction between this virus and angiotensin-converting enzyme type 2 (ACE2) receptors. FXR agonists control the expression of ACE2 and the inflammatory signaling pathways in this respiratory syndrome, which weakens the effects of Covid-19 disease and accompanied complications. Taken together, FXR agonists like OCA may reveal both direct and indirect impacts in the modulation of immune reaction in SARS-CoV-2 conditions. It is highly recommended to perform many investigations regarding different phases of the discovery of new drugs.

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PPAR Ligands Induce Antiviral Effects Targeting Perturbed Lipid Metabolism during SARS-CoV-2, HCV, and HCMV Infection

Cited by 21 publications

References 95 publications

Influenza virus causes lung immunopathology through down-regulating PPARγ activity in macrophages

Influenza virus causes lung immunopathology through down-regulating PPARγ activity in macrophages

The role of cholesterol metabolism in predicting clinical outcome of patients with severe COVID-19

A perspective study of the possible impact of obeticholic acid against SARS-CoV-2 infection

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