Insights into the potential role of alpha1‐antitrypsin in COVID‐19 patients: Mechanisms, current update, and future perspectives

Marzouk, Saber; Attia, Noha; Mashal, Mohamed

doi:10.1111/crj.13406

Cited by 7 publications

(3 citation statements)

References 56 publications

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“…Indeed, several studies pointed to a tentative link between lower blood AAT levels and severe Covid‐19, suggesting that AAT deficiency contributes to Covid‐19 fatalities (Faria et al, 2021; Ferrarotti et al, 2021; Shapira et al, 2020; Shimi et al, 2021; Vianello & Braccioni, 2020). Indeed, bioengineered AAT, which is approved for treating lung inflammation in AAT deficient individuals, was proposed as potential therapeutic for Covid‐19 (Marzouk et al, 2021; Yang et al, 2020; Yang et al, 2021). As of July 2021, five clinical trials of AAT administration for Covid‐19 patients were listed on the http://clinicaltrials.gov website.…”

Section: Discussionmentioning

confidence: 99%

d‐Galactose treatment increasesACE2,TMPRSS2, andFURINand reducesSERPINA1mRNAexpression inA549human lung epithelial cells

Baristaite

Genevieve

2021

Drug Dev Res

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Several comorbidities including diabetes, immune deficiency, and chronic respiratory disorders increase the risk of severe Covid‐19 and fatalities among SARS‐CoV‐2 infected individuals. Severe Covid‐19 risk among diabetes patients may reflect reduced immune response to viral infections. SARS‐CoV‐2 initially infects respiratory tract epithelial cells by binding to the host cell membrane ACE2, followed by proteolytic priming for cell entry by the host cell membrane serine protease TMPRSS2. Additionally, the protease FURIN facilitates cell exit of mature SARS‐CoV‐2 virions. Alpha‐1 antitrypsin (AAT), the major plasma serine protease inhibitor, encoded by SERPINA1, is known to promote immune response to viral infections. AAT inhibits neutrophil elastase, a key inflammatory serine protease implicated in alveolar cell damage during respiratory infections, and AAT deficiency is associated with susceptibility to lung infections. AAT is implicated in Covid‐19 as it inhibits TMPRSS2, a protease essential for SARS‐CoV‐2 cell entry. Here we show that treatment of A549 human lung epithelial cells for 7 days with 25 mM d‐galactose, an inducer of diabetic‐like and oxidative stress cellular phenotypes, leads to increased mRNA levels of ACE2, TMPRSS2, and FURIN, along with reduced SERPINA1 mRNA. Together, the dysregulated transcription of these genes following d‐galactose treatment suggests that chronic diabetic‐like conditions may facilitate SARS‐CoV‐2 infection of lung epithelial cells. Our findings may in part explain the higher severe Covid‐19 risk in diabetes, and highlight the need to develop special treatment protocols for diabetic patients.

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Section: Discussionmentioning

confidence: 99%

d‐Galactose treatment increasesACE2,TMPRSS2, andFURINand reducesSERPINA1mRNAexpression inA549human lung epithelial cells

Baristaite

Genevieve

2021

Drug Dev Res

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“…In addition to inhibiting TMPRSS2, preventing the processing of the spike protein and cellular entry of SARS-CoV-2, AAT has a panoply of other activities that could antagonize both the intracellular virus and the multiple pathogenic mechanisms associated with severe COVID-19 ( Figure 2 and Table 1 ) [ 23 , 95 ]. Such host-directed activities are less likely to be affected by SARS-CoV-2 mutations.…”

Section: Other Activities Of Aat Could Mitigate Severity Of Covid-19mentioning

confidence: 99%

Alpha-1-antitrypsin antagonizes COVID-19: a review of the epidemiology, molecular mechanisms, and clinical evidence

Bai

Schountz

Buckle

et al. 2023

Biochemical Society Transactions

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Alpha-1-antitrypsin (AAT), a serine protease inhibitor (serpin), is increasingly recognized to inhibit SARS-CoV-2 infection and counter many of the pathogenic mechanisms of COVID-19. Herein, we reviewed the epidemiologic evidence, the molecular mechanisms, and the clinical evidence that support this paradigm. As background to our discussion, we first examined the basic mechanism of SARS-CoV-2 infection and contend that despite the availability of vaccines and anti-viral agents, COVID-19 remains problematic due to viral evolution. We next underscored that measures to prevent severe COVID-19 currently exists but teeters on a balance and that current treatment for severe COVID-19 remains grossly suboptimal. We then reviewed the epidemiologic and clinical evidence that AAT deficiency increases risk of COVID-19 infection and of more severe disease, and the experimental evidence that AAT inhibits cell surface transmembrane protease 2 (TMPRSS2) — a host serine protease required for SARS-CoV-2 entry into cells — and that this inhibition may be augmented by heparin. We also elaborated on the panoply of other activities of AAT (and heparin) that could mitigate severity of COVID-19. Finally, we evaluated the available clinical evidence for AAT treatment of COVID-19.

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“…Human bone morphogenetic protein 7 (hBMP7), a part of the transforming growth factor- (TGF-) β superfamily, is known to regulate cell proliferation, differentiation, apoptosis, and antagonize TGF-β signaling [ 164 ]. Therefore, it was characterized by its ability to induce the differentiation of brain tumor stem cells.…”

Section: Cell Therapy For Glioblastomamentioning

confidence: 99%

Cell-Based Therapy for the Treatment of Glioblastoma: An Update from Preclinical to Clinical Studies

Attia

Mashal

Pemminati

et al. 2021

Cells

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Glioblastoma (GB), an aggressive primary tumor of the central nervous system, represents about 60% of all adult primary brain tumors. It is notorious for its extremely low (~5%) 5-year survival rate which signals the unsatisfactory results of the standard protocol for GB therapy. This issue has become, over time, the impetus for the discipline of bringing novel therapeutics to the surface and challenging them so they can be improved. The cell-based approach in treating GB found its way to clinical trials thanks to a marvelous number of preclinical studies that probed various types of cells aiming to combat GB and increase the survival rate. In this review, we aimed to summarize and discuss the up-to-date preclinical studies that utilized stem cells or immune cells to treat GB. Likewise, we tried to summarize the most recent clinical trials using both cell categories to treat or prevent recurrence of GB in patients. As with any other therapeutics, cell-based therapy in GB is still hampered by many drawbacks. Therefore, we highlighted several novel techniques, such as the use of biomaterials, scaffolds, nanoparticles, or cells in the 3D context that may depict a promising future when combined with the cell-based approach.

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Insights into the potential role of alpha1‐antitrypsin in COVID‐19 patients: Mechanisms, current update, and future perspectives

Cited by 7 publications

References 56 publications

d‐Galactose treatment increasesACE2,TMPRSS2, andFURINand reducesSERPINA1mRNAexpression inA549human lung epithelial cells

d‐Galactose treatment increasesACE2,TMPRSS2, andFURINand reducesSERPINA1mRNAexpression inA549human lung epithelial cells

Alpha-1-antitrypsin antagonizes COVID-19: a review of the epidemiology, molecular mechanisms, and clinical evidence

Cell-Based Therapy for the Treatment of Glioblastoma: An Update from Preclinical to Clinical Studies

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