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Upregulation of the MAP2K4 gene triggers endothelial-mesenchymal transition in COVID-19

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Esra Yilmaz at Tokat Gaziosmanpaşa Üniversitesi
Esra Yilmaz
Dilek Yilmaz
Dilek Yilmaz
Dilek Yilmaz
  • This person is not on ResearchGate, or hasn't claimed this research yet.
Can Gokay Yildiz
Can Gokay Yildiz
Can Gokay Yildiz
  • This person is not on ResearchGate, or hasn't claimed this research yet.
Ercan Cacan at Tokat Gaziosmanpaşa Üniversitesi
Ercan Cacan
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Abstract and Figures

Background SARS-CoV-2 infection is marked by an excessive inflammatory response, leading to elevated production of pro-inflammatory cytokines through activation of intracellular pathways like mitogen-activated protein kinase (MAPK). Viruses can use the MAPK signaling pathway to their advantage, but the relationship of this pathway to the severe SARS-CoV-2 period has not been fully elucidated. MAP2K4 is involved in the MAPK signaling pathway and affects cellular processes such as cell-cell junction, cell proliferation, differentiation and apoptosis. Methods and results In this study, we sought to determine the associated biomarkers that are involved in the MAP2K4 pathway and elucidate its possible roles in terms of some clinical features associated with COVID-19. We evaluated the expressions of MAP2K4, SNAI1, SLUG, ZEB1 and E-Cadherin. For this purpose, we prospectively recruited 66 individuals, 39 of whom were women and had a mean age of 65 years. The results revealed that MAP2K4 upregulation increased SNAI1 gene expression level whereas E- Cadherin level was decreased in SARS-CoV-2 positive participants. In addition, negative correlations were determined with PLT, Lymphocyte and CKMB and E- Cadherin levels in positive participants. We also observed a negative correlation between the MAP2K4 and AST, and a positive correlation between SLUG and BUN, ZEB1 and CK. Conclusions We conclude that SARS-CoV-2 infection triggers fibrosis by increasing MAP2K4 regulation. Additionally, this is the first study to demonstrate the possible contribution of MAP2K4 in influencing COVID-19 clinical features, which may be relevant for identifying COVID-19 positive participants with severe complications.
SARS-CoV-2 infection upregulates MAP2K4 gene expression. MAP2K4 transcript levels in severe COVID-19 patients, individuals 6–12 months post-infection (recovered), and control group. Graphed data with error bars denoting standard error of the mean (SEM). Statistical significance was assessed using the One-way ANOVA followed by Dunnett’s post hoc test for multiple comparisons: *p ≤ 0.01, **p ≤ 0.001 and ***p ≤ 0.0001
SARS-CoV-2 infection upregulates MAP2K4 gene expression. MAP2K4 transcript levels in severe COVID-19 patients, individuals 6–12 months post-infection (recovered), and control group. Graphed data with error bars denoting standard error of the mean (SEM). Statistical significance was assessed using the One-way ANOVA followed by Dunnett’s post hoc test for multiple comparisons: *p ≤ 0.01, **p ≤ 0.001 and ***p ≤ 0.0001
… 
End-MT-related Snail gene expression increases while E-cadherin level decreases in patients with SARS-CoV-2 infection. Snail and E-Cadherin in transcription levels of target genes in severe COVID-19 patients, individuals 6–12 months post-infection, and control group. The graph presents the data with error bars representing the standard error of the mean (SEM). Statistical significance was evaluated using non-parametric Mann-Whitney U test and One-way ANOVA followed by Dunnett’s post hoc test for multiple comparisons. Statistical significance levels are denoted as: *p ≤ 0.01, **p ≤ 0.001 and ***p ≤ 0.0001
End-MT-related Snail gene expression increases while E-cadherin level decreases in patients with SARS-CoV-2 infection. Snail and E-Cadherin in transcription levels of target genes in severe COVID-19 patients, individuals 6–12 months post-infection, and control group. The graph presents the data with error bars representing the standard error of the mean (SEM). Statistical significance was evaluated using non-parametric Mann-Whitney U test and One-way ANOVA followed by Dunnett’s post hoc test for multiple comparisons. Statistical significance levels are denoted as: *p ≤ 0.01, **p ≤ 0.001 and ***p ≤ 0.0001
… 
End-MT-related Slug and Zeb1 gene expression levels differ in patients with SARS-CoV-2 infection. Zeb1 and Slug transcription levels of target genes in severe COVID-19 patients, individuals 6–12 months post-infection, and control group. The graph presents the data with error bars representing the standard error of the mean (SEM). Statistical significance was assessed using the non-parametric Mann-Whitney U test, with significance levels denoted as: *p ≤ 0.01, **p ≤ 0.001 and ***p ≤ 0.0001
End-MT-related Slug and Zeb1 gene expression levels differ in patients with SARS-CoV-2 infection. Zeb1 and Slug transcription levels of target genes in severe COVID-19 patients, individuals 6–12 months post-infection, and control group. The graph presents the data with error bars representing the standard error of the mean (SEM). Statistical significance was assessed using the non-parametric Mann-Whitney U test, with significance levels denoted as: *p ≤ 0.01, **p ≤ 0.001 and ***p ≤ 0.0001
… 
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ORIGINAL ARTICLE
Molecular Biology Reports (2025) 52:180
https://doi.org/10.1007/s11033-025-10289-6
moderate, severe and critical pathology. Mild patients have
a fever, upper respiratory tract symptoms, sore throat and
gastrointestinal tract symptoms, while moderate and severe
patients have dyspnea, tachypnoea (respiratory rate > 24/
min), hypoxia (oxygen saturation (SpO2) < 95% in room
air), tachycardia (heart rate > 110/min) and fatigue. In
severe patients, oxygen saturation falls below 90%, hypo-
tension requires inotropic support and acute respiratory
distress syndrome (ARDS) develops. Respiratory fail-
ure, septic shock and multiple organ failure are observed
in critically ill patients [2]. Severe COVID-19 issues have
led to some patients being admitted to the intensive care
unit (ICU). Additionally, COVID-19 appears to be linked to
arrhythmic problems, and neurological consequences such
as headache, myalgia, dizziness, cerebral hemorrhage and
hyposmia. Furthermore, the presence of SARS-CoV-2 RNA
in the blood can cause severe heart damage and multiple
organ failure [1].
Introduction
According to the World Health Organization (WHO),
coronavirus disease 19 (COVID-19) is a disease caused
by SARS-CoV-2, which has infected more than 760 mil-
lion people and been associated with 6.887 million deaths
over the past three years [1]. Depending on the severity of
the disease, COVID-19 is divided into three categories:
Ercan Cacan
ercan.cacan@gop.edu.tr
1 Department of Molecular Biology and Genetics, Faculty of
Art and Science, Tokat Gaziosmanpasa University,
Tokat 60200, Türkiye
2 Department of Infectious Diseases and Clinical
Microbiology, Yozgat City Hospital, Tokat 66100, Türkiye
3 Department of Emergency Medicine, Tokat City Hospital,
Tokat 60200, Türkiye
Abstract
Background SARS-CoV-2 infection is marked by an excessive inammatory response, leading to elevated production of
pro-inammatory cytokines through activation of intracellular pathways like mitogen-activated protein kinase (MAPK).
Viruses can use the MAPK signaling pathway to their advantage, but the relationship of this pathway to the severe SARS-
CoV-2 period has not been fully elucidated. MAP2K4 is involved in the MAPK signaling pathway and aects cellular pro-
cesses such as cell-cell junction, cell proliferation, dierentiation and apoptosis.
Methods and results In this study, we sought to determine the associated biomarkers that are involved in the MAP2K4 path-
way and elucidate its possible roles in terms of some clinical features associated with COVID-19. We evaluated the expres-
sions of MAP2K4, SNAI1, SLUG, ZEB1 and E-Cadherin. For this purpose, we prospectively recruited 66 individuals, 39 of
whom were women and had a mean age of 65 years. The results revealed that MAP2K4 upregulation increased SNAI1 gene
expression level whereas E- Cadherin level was decreased in SARS-CoV-2 positive participants. In addition, negative corre-
lations were determined with PLT, Lymphocyte and CKMB and E- Cadherin levels in positive participants. We also observed
a negative correlation between the MAP2K4 and AST, and a positive correlation between SLUG and BUN, ZEB1 and CK.
Conclusions We conclude that SARS-CoV-2 infection triggers brosis by increasing MAP2K4 regulation. Additionally, this
is the rst study to demonstrate the possible contribution of MAP2K4 in inuencing COVID-19 clinical features, which may
be relevant for identifying COVID-19 positive participants with severe complications.
Keywords SARS-CoV-2 · MAPK pathway · MAP2K4 · SNAI1 · E-cadherin · End- MT
Received: 22 September 2024 / Accepted: 22 January 2025
© The Author(s), under exclusive licence to Springer Nature B.V. 2025
Upregulation of the MAP2K4 gene triggers endothelial-mesenchymal
transition in COVID-19
EsraYilmaz1· DilekYilmaz2· Can GokayYildiz3· ErcanCacan1
1 3
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
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