Research

13 pages, 1589 KiB

Open AccessArticle

The JAK1/2 Inhibitor Baricitinib Mitigates the Spike-Induced Inflammatory Response of Immune and Endothelial Cells In Vitro

by Amelia Barilli, Rossana Visigalli, Francesca Ferrari, Giulia Recchia Luciani, Maurizio Soli, Valeria Dall’Asta and Bianca Maria Rotoli

Biomedicines 2022, 10(9), 2324; https://doi.org/10.3390/biomedicines10092324 - 19 Sep 2022

Cited by 6 | Viewed by 1737

Abstract

The purpose of this study was to examine the effect of the JAK-STAT inhibitor baricitinib on the inflammatory response of human monocyte-derived macrophages (MDM) and endothelial cells upon exposure to the spike S1 protein from SARS-CoV-2. The effect of the drug has been [...] Read more.

The purpose of this study was to examine the effect of the JAK-STAT inhibitor baricitinib on the inflammatory response of human monocyte-derived macrophages (MDM) and endothelial cells upon exposure to the spike S1 protein from SARS-CoV-2. The effect of the drug has been evaluated on the release of cytokines and chemokines from spike-treated MDM, as well as on the activation of endothelial cells (HUVECs) after exposure to conditioned medium collected from spike-activated MDM. Results obtained indicate that, in MDM, baricitinib prevents the S1-dependent phosphorylation of STAT1 and STAT3, along with the induction of IP-10- and MCP-1 secretion; the release of IL-6 and TNFα is also reduced, while all other mediators tested (IL-1β, IL-8, RANTES, MIP-1α and MIP-1β) are not modified. Baricitinib is, instead, poorly effective on endothelial activation when HUVECs are exposed to supernatants from S1-activated macrophages; the induction of VCAM-1, indeed, is not affected by the drug, while that of ICAM-1 is only poorly inhibited. The drug, however, also exerts protective effects on the endothelium by limiting the expression of pro-inflammatory mediators, specifically IL-6, RANTES and IP-10. No effect of baricitinib has been observed on IL-8 synthesis and, consistently, on neutrophils chemiotaxis. Our in vitro findings reveal that the efficacy of baricitinib is limited, with effects mainly focused on the inhibition of the IL-6-mediated inflammatory loop. Full article

(This article belongs to the Special Issue Non-antiviral Agents for Treatment of COVID-19)

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10 pages, 965 KiB

Open AccessArticle

“CAPA in Progress”: A New Real-Life Approach for the Management of Critically Ill COVID-19 Patients

by Nieves Carbonell, María Jesús Alcaráz, Ainhoa Serrano-Lázaro, María Rodríguez-Gimillo, David Sánchez Ramos, Francisco Ros, Josep Ferrer, María Luisa Blasco, David Navarro and María Ángeles Clari

Biomedicines 2022, 10(7), 1683; https://doi.org/10.3390/biomedicines10071683 - 13 Jul 2022

Cited by 1 | Viewed by 1460

Abstract

(1) Background: COVID-19-associated pulmonary aspergillosis (CAPA) has worsened the prognosis of patients with pneumonia and acute respiratory distress syndrome admitted to the intensive care unit (ICU). The lack of specific diagnosis criteria is an obstacle to the timely initiation of appropriate antifungal therapy. [...] Read more.

(1) Background: COVID-19-associated pulmonary aspergillosis (CAPA) has worsened the prognosis of patients with pneumonia and acute respiratory distress syndrome admitted to the intensive care unit (ICU). The lack of specific diagnosis criteria is an obstacle to the timely initiation of appropriate antifungal therapy. Tracheal aspirate (TA) has been employed under special pandemic conditions. Galactomannan (GM) antigens are released during active fungal growth. (2) Methods: We proposed the term “CAPA in progress” (CAPA-IP) for diagnosis at an earlier stage by GM testing on TA in a specific population admitted to ICU presenting with clinical deterioration. A GM threshold ≥0.5 was set as the mycological inclusion criterion. This was followed by a pre-emptive short-course antifungal. (3) Results: We prospectively enrolled 200 ICU patients with COVID-19. Of these, 164 patients (82%) initially required invasive mechanical ventilation and GM was tested in TA in 93 patients. A subset of 19 patients (11.5%) fulfilled the CAPA-IP criteria at a median of 9 days after ICU admittance. The median GM value was 3.25 ± 2.82. CAPA-IP cases showed significantly higher ICU mortality [52.6% (10/19) vs. 34.5% (50/145), p = 0.036], as well as a much longer median ICU stay than those with a normal GM index [27 (7–64) vs. 11 (9–81) days, p = 0.008]. All cases were treated with a pre-emptive systemic antifungal for a median time of 19 (3–39) days. (4) Conclusions: CAPA-IP highlights a new real-life early approach in the field of fungal stewardship in ICU programs. Full article

(This article belongs to the Special Issue Non-antiviral Agents for Treatment of COVID-19)

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11 pages, 1705 KiB

Open AccessEditor’s ChoiceArticle

Natural Polyphenols, 1,2,3,4,6-O-Pentagalloyglucose and Proanthocyanidins, as Broad-Spectrum Anticoronaviral Inhibitors Targeting Mpro and RdRp of SARS-CoV-2

by Young-Hee Jin, Jihye Lee, Sangeun Jeon, Seungtaek Kim, Jung Sun Min and Sunoh Kwon

Biomedicines 2022, 10(5), 1170; https://doi.org/10.3390/biomedicines10051170 - 18 May 2022

Cited by 10 | Viewed by 2081

Abstract

The natural plant dietary polyphenols 1,2,3,4,6-O-Pentagalloylglucose (PGG) and proanthocyanidin (PAC) have potent antioxidant activity and a variety of pharmacological activities, including antiviral activity. In this study, we examined the inhibitory effect of PGG and PAC on SARS-CoV-2 virus infection, and elucidated its mode [...] Read more.

The natural plant dietary polyphenols 1,2,3,4,6-O-Pentagalloylglucose (PGG) and proanthocyanidin (PAC) have potent antioxidant activity and a variety of pharmacological activities, including antiviral activity. In this study, we examined the inhibitory effect of PGG and PAC on SARS-CoV-2 virus infection, and elucidated its mode of action. PGG and PAC have dose-dependent inhibitory activity against SARS-CoV-2 infection in Vero cells. PGG has a lower IC₅₀ (15.02 ± 0.75 μM) than PAC (25.90 ± 0.81 μM), suggesting that PGG has better inhibitory activity against SARS-CoV-2 than PAC. The PGG and PAC inhibit similar Mpro activities in a protease activity assay, with IC₅₀ values of 25–26 μM. The effects of PGG and PAC on the activity of the other essential SARS-CoV-2 viral protein, RdRp, were analyzed using a cell-based activity assay system. The activity of RdRp is inhibited by PGG and PAC, and PGG has a lower IC₅₀ (5.098 ± 1.089 μM) than PAC (21.022 ± 1.202 μM), which is consistent with their inhibitory capacity of SARS-CoV-2 infection. PGG and PAC also inhibit infection by SARS-CoV and MERS-CoV. These data indicate that PGG and PAC may be candidate broad-spectrum anticoronaviral therapeutic agents, simultaneously targeting the Mpro and RdRp proteins of SARS-CoV-2. Full article

(This article belongs to the Special Issue Non-antiviral Agents for Treatment of COVID-19)

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Review

Jump to: Research, Other

18 pages, 1345 KiB

Open AccessReview

The Mito-Hormetic Mechanisms of Ozone in the Clearance of SARS-CoV2 and in the COVID-19 Therapy

by Salvatore Chirumbolo, Angelica Varesi, Marianno Franzini, Luigi Valdenassi, Sergio Pandolfi, Umberto Tirelli, Ciro Esposito and Giovanni Ricevuti

Biomedicines 2022, 10(9), 2258; https://doi.org/10.3390/biomedicines10092258 - 12 Sep 2022

Cited by 4 | Viewed by 3466

Abstract

An increasing body of evidence in the literature is reporting the feasibility of using medical ozone as a possible alternative and adjuvant treatment for COVID-19 patients, significantly reducing hospitalization time, pro-inflammatory indicators, and coagulation markers and improving blood oxygenation parameters. In addition to [...] Read more.

An increasing body of evidence in the literature is reporting the feasibility of using medical ozone as a possible alternative and adjuvant treatment for COVID-19 patients, significantly reducing hospitalization time, pro-inflammatory indicators, and coagulation markers and improving blood oxygenation parameters. In addition to the well-described ability of medical ozone in counteracting oxidative stress through the upregulation of the main anti-oxidant and scavenging enzymes, oxygen–ozone (O₂–O₃) therapy has also proved effective in reducing chronic inflammation and the occurrence of immune thrombosis, two key players involved in COVID-19 exacerbation and severity. As chronic inflammation and oxidative stress are also reported to be among the main drivers of the long sequelae of SARS-CoV2 infection, a rising number of studies is investigating the potential of O₂–O₃ therapy to reduce and/or prevent the wide range of post-COVID (or PASC)-related disorders. This narrative review aims to describe the molecular mechanisms through which medical ozone acts, to summarize the clinical evidence on the use of O₂–O₃ therapy as an alternative and adjuvant COVID-19 treatment, and to discuss the emerging potential of this approach in the context of PASC symptoms, thus offering new insights into effective and safe nonantiviral therapies for the fighting of this devastating pandemic. Full article

(This article belongs to the Special Issue Non-antiviral Agents for Treatment of COVID-19)

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15 pages, 1508 KiB

Open AccessReview

Adrenomedullin Therapy in Moderate to Severe COVID-19

by Toshihiro Kita and Kazuo Kitamura

Biomedicines 2022, 10(3), 533; https://doi.org/10.3390/biomedicines10030533 - 24 Feb 2022

Cited by 8 | Viewed by 2337

Abstract

The 2019 coronavirus (COVID-19) pandemic is still in progress, and a significant number of patients have presented with severe illness. Recently introduced vaccines, antiviral medicines, and antibody formulations can suppress COVID-19 symptoms and decrease the number of patients exhibiting severe disease. However, complete [...] Read more.

The 2019 coronavirus (COVID-19) pandemic is still in progress, and a significant number of patients have presented with severe illness. Recently introduced vaccines, antiviral medicines, and antibody formulations can suppress COVID-19 symptoms and decrease the number of patients exhibiting severe disease. However, complete avoidance of severe COVID-19 has not been achieved, and more importantly, there are insufficient methods to treat it. Adrenomedullin (AM) is an endogenous peptide that maintains vascular tone and endothelial barrier function. The AM plasma level is markedly increased during severe inflammatory disorders, such as sepsis, pneumonia, and COVID-19, and is associated with the severity of inflammation and its prognosis. In this study, exogenous AM administration reduced inflammation and related organ damage in rodent models. The results of this study strongly suggest that AM could be an alternative therapy in severe inflammation disorders, including COVID-19. We have previously developed an AM formulation to treat inflammatory bowel disease and are currently conducting an investigator-initiated phase 2a trial for moderate to severe COVID-19 using the same formulation. This review presents the basal AM information and the most recent translational AM/COVID-19 study. Full article

(This article belongs to the Special Issue Non-antiviral Agents for Treatment of COVID-19)

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16 pages, 1419 KiB

Open AccessReview

Drugs Modulating Renin-Angiotensin System in COVID-19 Treatment

by Jose L. Labandeira-Garcia, Carmen M. Labandeira, Rita Valenzuela, Maria A. Pedrosa, Aloia Quijano and Ana I. Rodriguez-Perez

Biomedicines 2022, 10(2), 502; https://doi.org/10.3390/biomedicines10020502 - 21 Feb 2022

Cited by 11 | Viewed by 4999

Abstract

A massive worldwide vaccination campaign constitutes the main tool against the COVID-19 pandemic. However, drug treatments are also necessary. Antivirals are the most frequently considered treatments. However, strategies targeting mechanisms involved in disease aggravation may also be effective. A major role of the [...] Read more.

A massive worldwide vaccination campaign constitutes the main tool against the COVID-19 pandemic. However, drug treatments are also necessary. Antivirals are the most frequently considered treatments. However, strategies targeting mechanisms involved in disease aggravation may also be effective. A major role of the tissue renin-angiotensin system (RAS) in the pathophysiology and severity of COVID-19 has been suggested. The main link between RAS and COVID-19 is angiotensin-converting enzyme 2 (ACE2), a central RAS component and the primary binding site for SARS-CoV-2 that facilitates the virus entry into host cells. An initial suggestion that the susceptibility to infection and disease severity may be enhanced by angiotensin type-1 receptor blockers (ARBs) and ACE inhibitors (ACEIs) because they increase ACE2 levels, led to the consideration of discontinuing treatments in thousands of patients. More recent experimental and clinical data indicate that ACEIs and, particularly, ARBs can be beneficial for COVID-19 outcome, both by reducing inflammatory responses and by triggering mechanisms (such as ADAM17 inhibition) counteracting viral entry. Strategies directly activating RAS anti-inflammatory components such as soluble ACE2, Angiotensin 1-7 analogues, and Mas or AT2 receptor agonists may also be beneficial. However, while ACEIs and ARBs are cheap and widely used, the second type of strategies are currently under study. Full article

(This article belongs to the Special Issue Non-antiviral Agents for Treatment of COVID-19)

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18 pages, 2331 KiB

Open AccessReview

Human Milk Oligosaccharides: Potential Applications in COVID-19

by Somchai Chutipongtanate, Ardythe L. Morrow and David S. Newburg

Biomedicines 2022, 10(2), 346; https://doi.org/10.3390/biomedicines10020346 - 01 Feb 2022

Cited by 15 | Viewed by 6099

Abstract

Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has become a global health crisis with more than four million deaths worldwide. A substantial number of COVID-19 survivors continue suffering from long-COVID syndrome, a long-term complication exhibiting chronic inflammation and [...] Read more.

Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has become a global health crisis with more than four million deaths worldwide. A substantial number of COVID-19 survivors continue suffering from long-COVID syndrome, a long-term complication exhibiting chronic inflammation and gut dysbiosis. Much effort is being expended to improve therapeutic outcomes. Human milk oligosaccharides (hMOS) are non-digestible carbohydrates known to exert health benefits in breastfed infants by preventing infection, maintaining immune homeostasis and nurturing healthy gut microbiota. These beneficial effects suggest the hypothesis that hMOS might have applications in COVID-19 as receptor decoys, immunomodulators, mucosal signaling agents, and prebiotics. This review summarizes hMOS biogenesis and classification, describes the possible mechanisms of action of hMOS upon different phases of SARS-CoV-2 infection, and discusses the challenges and opportunities of hMOS research for clinical applications in COVID-19. Full article

(This article belongs to the Special Issue Non-antiviral Agents for Treatment of COVID-19)

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Other

Jump to: Research, Review

16 pages, 1748 KiB

Open AccessCase Report

First Recombinant High-Density Lipoprotein Particles Administration in a Severe ICU COVID-19 Patient, a Multi-Omics Exploratory Investigation

by Sébastien Tanaka, Floran Begue, Bryan Veeren, Alexy Tran-Dinh, Tiphaine Robert, Parvine Tashk, Brice Lortat-Jacob, Dorothée Faille, Luc de Chaisemartin, Nathalie Zappella, Enora Atchade, Laura Kramer, Philippe Montravers and Olivier Meilhac

Biomedicines 2022, 10(4), 754; https://doi.org/10.3390/biomedicines10040754 - 23 Mar 2022

Cited by 14 | Viewed by 3027

Abstract

High-density lipoproteins (HDLs) have multiple endothelioprotective properties. During SARS-CoV-2 infection, HDL-cholesterol (HDL-C) concentration is markedly reduced, and studies have described severe impairment of the functionality of HDL particles. Here, we report a multi-omic investigation of the first administration of recombinant HDL (rHDL) particles [...] Read more.

High-density lipoproteins (HDLs) have multiple endothelioprotective properties. During SARS-CoV-2 infection, HDL-cholesterol (HDL-C) concentration is markedly reduced, and studies have described severe impairment of the functionality of HDL particles. Here, we report a multi-omic investigation of the first administration of recombinant HDL (rHDL) particles in a severe COVID-19 patient in an intensive care unit. Plasma ApoA1 increased and HDL-C decreased after each recombinant HDL injection, suggesting that these particles were functional in terms of reverse cholesterol transport. The proportion of large HDL particles also increased after injection of recombinant HDL. Shotgun proteomics performed on HDLs isolated by ultracentrifugation indicated that ApoA1 was more abundant after injections whereas most of the pro-inflammatory proteins identified were less abundant. Assessment of Serum amyloid A-1, inflammatory markers, and cytokines showed a significant decrease for most of them during recombinant HDL infusion. Our results suggest that recombinant HDL infusion is feasible and a potential therapeutic strategy to be explored in COVID-19 patients. Full article

(This article belongs to the Special Issue Non-antiviral Agents for Treatment of COVID-19)

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