Hyperactivated RAGE in Comorbidities as a Risk Factor for Severe COVID-19—The Role of RAGE-RAS Crosstalk

Chiappalupi, Sara; Salvadori, Laura; Donato, Rosario; Riuzzi, Francesca; Sorci, Guglielmo

doi:10.3390/biom11060876

Cited by 30 publications

(41 citation statements)

References 137 publications

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“…Recent studies have suggested the activation of an HMGB1-RAGE cascade in COVID-19 pathogenesis [56] , [57] and an association with disease severity [21] , [58] . In this respect, our results showed an overexpression of HMGB1 and RAGE proteins in the plasma of patients with COVID-19, confirming that this effect is a common finding in the most severe forms of the disease.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress and inflammatory markers in patients with COVID-19: Potential role of RAGE, HMGB1, GFAP and COX-2 in disease severity

Passos

Heimfarth

Monteiro

et al. 2022

International Immunopharmacology

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Background SARS-CoV-2 infection can lead to the abnormal induction of cytokines and a dysregulated hyperinflammatory state that is implicated in disease severity and risk of death. There are several molecules present in blood associated with immune cellular response, inflammation, and oxidative stress that could be used as severity markers in respiratory viral infections such as COVID-19. However, there is a lack of clinical studies evaluating the role of oxidative stress-related molecules including glial fibrillary acidic protein (GFAP), the receptor for advanced glycation end products (RAGE), high mobility group box-1 protein (HMGB1) and cyclo-oxygenase-2 (COX-2) in COVID-19 pathogenesis. Aim To evaluate the role of oxidative stress-related molecules in COVID-19. Method An observational study with 93 Brazilian participants from September 2020 to April 2021, comprising 23 patients with COVID-19 admitted to intensive care unit (ICU), 19 outpatients with COVID-19 with mild to moderate symptoms, 17 individuals reporting a COVID-19 history, and 34 healthy controls. Blood samples were taken from all participants and western blot assay was used to determine the RAGE, HMGB1, GFAP, and COX-2 immunocontent. Results We found that GFAP levels were higher in patients with severe or critical COVID-19 compared to outpatients (p = 0.030) and controls (p < 0.001). A significant increase in immunocontents of RAGE (p < 0.001) and HMGB1 (p < 0.001) were also found among patients admitted to the ICU compared to healthy controls, as well as an overexpression of the inducible COX-2 (p < 0.001). In addition, we found a moderate to strong correlation between RAGE, GFAP and HMGB1 proteins. Conclusion SARS-CoV-2 infection induces the upregulation of GFAP, RAGE, HMGB1, and COX-2 in patients with the most severe forms of COVID-19.

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Section: Discussionmentioning

confidence: 99%

Oxidative stress and inflammatory markers in patients with COVID-19: Potential role of RAGE, HMGB1, GFAP and COX-2 in disease severity

Passos

Heimfarth

Monteiro

et al. 2022

International Immunopharmacology

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“…The RAGE interacts with effectors of the renin–angiotensin system (RAS), promoting the progression of a “cytokine storm” in macrophages and splenocytes; causing endothelial dysfunction on account of increased capillary permeability and release of damage-associated molecular pattern components (DAMP); increasing the production of ROS and the formation of atherosclerotic plaques; increasing the risk of thrombosis by inducing the formation and release of extracellular traps by neutrophils (NET), with further thrombocyte aggregation; and causing muscle wasting, stimulating apoptosis, increasing protein degradation and decreasing protein synthesis. The combined effects of RAGEs and AT1R occur in the vessels and parenchyma of the lungs, brain, heart and kidneys, and in the cells of the immune system, causing irreversible damage to many organs [ 259 ]. The question of what is still primary (cause) and what is secondary (consequence), in this case, not only has the right to be asked, but deserves serious attention on the part of scientists and physicians.…”

Section: Role Of Modified Albumin In Pathogenesis Of Diseasesmentioning

confidence: 99%

Serum Albumin in Health and Disease: Esterase, Antioxidant, Transporting and Signaling Properties

Belinskaia

Voronina

Шмурак

et al. 2021

IJMS

141

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Being one of the main proteins in the human body and many animal species, albumin plays a decisive role in the transport of various ions—electrically neutral and charged molecules—and in maintaining the colloidal osmotic pressure of the blood. Albumin is able to bind to almost all known drugs, as well as many nutraceuticals and toxic substances, largely determining their pharmaco- and toxicokinetics. Albumin of humans and respective representatives in cattle and rodents have their own structural features that determine species differences in functional properties. However, albumin is not only passive, but also an active participant of pharmacokinetic and toxicokinetic processes, possessing a number of enzymatic activities. Numerous experiments have shown esterase or pseudoesterase activity of albumin towards a number of endogeneous and exogeneous esters. Due to the free thiol group of Cys34, albumin can serve as a trap for reactive oxygen and nitrogen species, thus participating in redox processes. Glycated albumin makes a significant contribution to the pathogenesis of diabetes and other diseases. The interaction of albumin with blood cells, blood vessels and tissue cells outside the vascular bed is of great importance. Interactions with endothelial glycocalyx and vascular endothelial cells largely determine the integrative role of albumin. This review considers the esterase, antioxidant, transporting and signaling properties of albumin, as well as its structural and functional modifications and their significance in the pathogenesis of certain diseases.

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“…HMGB-1 is a damage-associated molecular pattern protein that, when is secreted by damaged cells, exerts a strongly inflammatory activity binding to receptors as receptor for advanced glycation end products (RAGE) and Toll-like receptors 3 and 4. The link between HMGB-1 and thrombosis appears to be focused on the interaction with platelets, NET and coagulation and fibrinolysis factors [ 42 , 43 , 44 ].…”

Section: Discussionmentioning

confidence: 99%

“…Some authors have proposed that the presence of aPL and thrombotic events in COVID-19 patients could represent a secondary form of APS [ 52 , 53 ]. The aPL associated with secondary APS caused by infections usually disappeared in a short period of time [ 7 , 43 , 44 , 45 ]. Xiao et al propose that the dynamics of aPL in COVID-19 are similar to those in other infections [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Anti-Phospholipid Antibodies and COVID-19 Thrombosis: A Co-Star, Not a Supporting Actor

et al. 2021

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Background: COVID-19 clinical features include a hypercoagulable state that resembles the antiphospholipid syndrome (APS), a disease characterized by thrombosis and presence of antiphospholipid antibodies (aPL). The relationship between aPL-presence and the appearance of thrombi as well as the transience or permanence of aPL in COVID-19 patients is not sufficiently clear. Methods: A group of 360 COVID-19 patients were followed-up for 6 months. Classic aPL, anti-B2GPI IgA, anti-phosphatidylserine/prothrombin IgG/M and anti-SARS-CoV-2 antibodies were determined at acute phase and >12 weeks later. The reference group included 143 healthy volunteers of the same age-range distribution. Results: aPL prevalence was similar in COVID-19 patients and the reference population. aPL presence in both determinations was significantly associated with thrombosis (OR: 2.33 and 3.71), strong agreement being found for classic aPL and anti-B2GPI IgA (Weighted kappa: 0.85–0.91). Thrombosis-associated aPL occurred a median of 17 days after hospital admission (IQR: 6–28) vs. 4 days for the rest (IQR: 3–7). Although anti-SARS-CoV-2 antibodies levels increased during convalescence, aPL hardly changed. Conclusions: Most COVID-19 patients would carry these aPL before the infection. At least two mechanisms could be behind thrombosis, early immune-dysregulation-mediated thrombosis after infection and belated-aPL-mediated thrombosis, with SARS-CoV-2 behaving as a second hit.

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Hyperactivated RAGE in Comorbidities as a Risk Factor for Severe COVID-19—The Role of RAGE-RAS Crosstalk

Cited by 30 publications

References 137 publications

Oxidative stress and inflammatory markers in patients with COVID-19: Potential role of RAGE, HMGB1, GFAP and COX-2 in disease severity

Oxidative stress and inflammatory markers in patients with COVID-19: Potential role of RAGE, HMGB1, GFAP and COX-2 in disease severity

Serum Albumin in Health and Disease: Esterase, Antioxidant, Transporting and Signaling Properties

Anti-Phospholipid Antibodies and COVID-19 Thrombosis: A Co-Star, Not a Supporting Actor

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