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Article ; Online: Diagnostic Value of GSTP1, RASSF1, AND RASSF2 Methylation in Serum of Prostate Cancer Patients.

Aykanli, Emre / Arisan, Serdar / Arisan, Elif Damla / Yavuzsan, Abdullah Hizir

2024

Abstract: Purpose: Considering the inadequacy of PSA measurement in the diagnosis of prostate cancer, it is aimed to establish a potential liquid biopsy diagnostic panel.: Materials and methods: 39 patients who underwent TRUS-biopsy and 15 healthy volunteers ... ...

Abstract	Purpose: Considering the inadequacy of PSA measurement in the diagnosis of prostate cancer, it is aimed to establish a potential liquid biopsy diagnostic panel. Materials and methods: 39 patients who underwent TRUS-biopsy and 15 healthy volunteers were included. Approximately 15 ml of venous blood samples taken from healthy volunteers and patients before biopsy were separated as plasma. Hypermethylation status of GSTP1 and RASSF1:RASSF2 genes was revealed in cfDNA materials collected from plasma samples. Correlation of this epigenetic change detected in PCa, BPH and healthy volunteer groups with pathology results was examined. Results: Pathology reports of 39 patients included were 13 PCa, 3 ASAP, 3 HGPIN, and 20 BPH. In total, 3 of the patients with PCa had positive GSTP1, 4 had RASSF1 and 9 had positive RASSF2 methylation. It was seen that RASSF2 had the highest sensitivity (69%), specificity (39%) and NPV (80%), while RASSF1 had the highest PPV (30%). When the binary combinations of genes were examined it was observed that the GSTP1:RASSF1 combination had the highest sensitivity (46%), specificity (76%) and NPV (82%). When the methylation of all three genes was examined, it was observed that the sensitivity was quite low (8%), but the specificity (83%) increased significantly. Conclusion: Although we observed that the GSTP1 and RASSF1 methylation positivity rates that we examined in our study were higher in patients without prostate cancer, we found that the RASSF2 methylation rate was higher in patients with prostate cancer. randomized controlled studies are needed.
Language	English
Publishing date	2024-03-17
Publishing country	Iran
Document type	Journal Article
ZDB-ID	2251940-3
ISSN	1735-546X ; 1735-1308
ISSN (online)	1735-546X
ISSN	1735-1308
DOI	10.22037/uj.v20i.8014
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Article ; Online: Palbociclib suppresses the cancer stem cell properties and cell proliferation through increased levels of miR-506 or miR-150 in Panc-1 and MiaPaCa-2 cells.

Rencüzoğullari, Özge / Arisan, Elif Damla

Turkish journal of biology = Turk biyoloji dergisi

2022 Volume 46, Issue 5, Page(s) 342–360

Abstract: The prognostic characteristics of pancreatic cancer (PC) are determined by the contributing factors from the tumor microenvironment. Leptin is a critical oncogenic factor released by adipocytes as an adipokine into the tumor microenvironment, where it ... ...

Abstract	The prognostic characteristics of pancreatic cancer (PC) are determined by the contributing factors from the tumor microenvironment. Leptin is a critical oncogenic factor released by adipocytes as an adipokine into the tumor microenvironment, where it promotes tumor development by activating cancer stem cell (CSC) molecular regulators Notch, Hedgehog, and Wnt/β-catenin signaling. One of the downstream targets of these pathways is CDK4/6 and cyclin D which is controlled by P16 INK4A that is highly mutated in PC. Therefore, the purpose of this study was to determine the effect of a CDK4/6 inhibitor, palbociclib, on Leptin-induced PC cells and to target the Notch, Hedgehog, and Wnt/β-catenin signaling pathways via miR-150, miR-506, and miR-208 modulation. Leptin treatment increased the ability of Panc-1, MiaPaCa-2, and Capan-2 cells to proliferate and decreased the effect of palbociclib. Additionally, tumorspheres were generated from Leptin-treated (Leptin+) and Leptin-untreated (Leptin-) Panc-1 and MiaPaCa-2 cells and transfected with miR-506, miR-150 (tumorsuppressor miRNAs), or anti-miR-208 (oncomiR), followed by palbociclib treatment. Forced expression of miR-506 or miR-150 significantly increased the susceptibility of Leptin+ cells to palbociclib treatment by inhibiting colony and tumor spheroid formation, and CD44 expression in Panc-1 and MiaPaCa-2 cells. Additionally, the increased miR-150 expression is more effective at inhibiting N-cadherin, β-catenin, p-GSK3β, Notch, and Wnt5a/b expression in Leptin-/+ Panc-1 and MiaPaCa-2 cells. As a result, palbociclib suppressed the CSC profile induced by leptin treatment, inhibiting both tumorsphere forms and leptin-targeted signaling pathways, thereby disabling the Panc-1 and MiaPaCa-2 cells' resistance mechanism. Increased expression of miR-506 or miR-150 and inhibition of miR-208 enhanced sensitivity of Panc-1 and MiaPaCa-2 Leptin-/+ cells to palbociclib treatment. As a result, this study proved that combining inhibitors of CSC molecular regulators with palbociclib improves the success rate of inhibition of PC cell proliferation.
Language	English
Publishing date	2022-07-18
Publishing country	Turkey
Document type	Journal Article
ZDB-ID	2046470-8
ISSN	1303-6092 ; 1303-6092
ISSN (online)	1303-6092
ISSN	1303-6092
DOI	10.55730/1300-0152.2622
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Article ; Online: Design of Cinnamaldehyde- and Gentamicin-Loaded Double-Layer Corneal Nanofiber Patches with Antibiofilm and Antimicrobial Effects.

Cesur, Sumeyye / Ilhan, Elif / Tut, Tufan Arslan / Kaya, Elif / Dalbayrak, Basak / Bosgelmez-Tinaz, Gulgun / Arısan, Elif Damla / Gunduz, Oguzhan / Kijeńska-Gawrońska, Ewa

ACS omega

2023 Volume 8, Issue 31, Page(s) 28109–28121

Abstract: In this study, two-layer poly(vinyl alcohol)/gelatin (PVA/GEL) nanofiber patches containing cinnamaldehyde (CA) in the first layer and gentamicin (GEN) in the second layer were produced by the electrospinning method. The morphology, chemical structures, ... ...

Abstract	In this study, two-layer poly(vinyl alcohol)/gelatin (PVA/GEL) nanofiber patches containing cinnamaldehyde (CA) in the first layer and gentamicin (GEN) in the second layer were produced by the electrospinning method. The morphology, chemical structures, and thermal temperatures of the produced pure (PVA/GEL), CA-loaded (PVA/GEL/CA), GEN-loaded (PVA/GEL/GEN), and combined drug-loaded (PVA/GEL/CA/GEN) nanofiber patches were determined by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy, and differential scanning calorimetry, respectively. Their mechanical properties, swelling and degradation behavior, and drug release kinetics were investigated. SEM images showed that both drug-free and drug-loaded nanofiber patches possess smooth and monodisperse structures, and nanofiber size increase occurred as the amount of drug increased. The tensile test results showed that the mechanical strength decreased as the drug was loaded. According to the drug release results, CA release ended at the 96th hour, while GEN release continued until the 264th hour. The antibacterial and antibiofilm activities of PVA/GEL, PVA/GEL/CA, PVA/GEL/GEN, and PVA/GEL/CA/GEN nanofiber patches against
Language	English
Publishing date	2023-07-26
Publishing country	United States
Document type	Journal Article
ISSN	2470-1343
ISSN (online)	2470-1343
DOI	10.1021/acsomega.3c00914
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Article ; Online: Synthesis and characterization of novel ssDNA X-aptamers targeting Growth Hormone Releasing Hormone (GHRH).

Ayhan-Sahin, Burcu / Apaydın, Zeynep-Elif / Obakan-Yerlikaya, Pınar / Arisan, Elif-Damla / Coker-Gurkan, Ajda

PloS one

2022 Volume 17, Issue 1, Page(s) e0260144

Abstract: Background: Growth Hormone Releasing Hormone (GHRH), 44 amino acids containing hypothalamic hormone, retains the biological activity by its first 29 amino acids. GHRH (NH2 1-29) peptide antagonists inhibit the growth of prostate, breast, ovarian, renal, ...

Abstract	Background: Growth Hormone Releasing Hormone (GHRH), 44 amino acids containing hypothalamic hormone, retains the biological activity by its first 29 amino acids. GHRH (NH2 1-29) peptide antagonists inhibit the growth of prostate, breast, ovarian, renal, gastric, pancreatic cancer in vitro and in vivo. Aptamers, single-strand RNA, or DNA oligonucleotides are capable of binding to target molecules with high affinity. Our aim in this study is to synthesize and select X-aptamers against both GHRH NH2 (1-29) and GHRH NH2 (1-44) and demonstrate synthesized aptamers' target binding activity as well as serum stability. Methods and results: Aptamers against GHRH NH2 (1-44) and NH2 (1-29) peptides were synthesized, and binding affinity (Kd) of 24 putative X-aptamers was determined by the dot-blot method, co-immunofluorescence staining and, SPR analysis. The serum stability of TKY.T1.08, TKY1.T1.13, TKY.T2.08, TKY.T2.09 X-aptamers was 90-120 h, respectively. The dose-dependent binding of TKY1.T1.13, TKY.T2.08, TKY.T2.09 X-aptamers on GHRHR in MIA PaCa-2 was approved by co-IF assay results. Moreover, SPR analysis indicated the Kd (4.75, 1.21, and 4.0 nM) levels of TKY2.T1.13, TKY.T2.08, TKY.T2.09 putative X-aptamers, respectively. Conclusion: Our results illustrate the synthesis of 24 putative X-aptamers against both GHRH NH2 (1-44) and NH2 (1-29) peptides and TKY1.T1.13, TKY.T2.08, TKY.T2.09 X-aptamers have high serum stability, high target binding potential with low Kd levels.
MeSH term(s)	Growth Hormone-Releasing Hormone
Chemical Substances	Growth Hormone-Releasing Hormone (9034-39-3)
Language	English
Publishing date	2022-01-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0260144
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Article: A Novel Approach for the Fabrication of 3D-Printed Dental Membrane Scaffolds including Antimicrobial Pomegranate Extract.

Karabulut, Hatice / Ulag, Songul / Dalbayrak, Basak / Arisan, Elif Damla / Taskin, Turgut / Guncu, Mehmet Mucahit / Aksu, Burak / Valanezhad, Alireza / Gunduz, Oguzhan

Pharmaceutics

2023 Volume 15, Issue 3

Abstract: In this study, a dental membrane scaffold was fabricated using a 3D printing technique, and the antimicrobial effect of pomegranate seed and peel extract were investigated. For the production of the dental membrane scaffold, a combination of polyvinyl ... ...

Abstract	In this study, a dental membrane scaffold was fabricated using a 3D printing technique, and the antimicrobial effect of pomegranate seed and peel extract were investigated. For the production of the dental membrane scaffold, a combination of polyvinyl alcohol, starch, and pomegranate seed and peel extracts was used. The aim of the scaffold was to cover the damaged area and aid in the healing process. This can be achieved due to the high antimicrobial and antioxidant content of pomegranate seed and peel extracts (PPE: PSE). Moreover, the addition of starch and PPE: PSE improved the biocompatibility of the scaffold, and their biocompatibility was tested using human gingival fibroblast (HGF) cells. The addition of PPE: PSE into the scaffolds resulted in a significant antimicrobial effect on
Language	English
Publishing date	2023-02-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics15030737
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Article ; Online: Epibrassinolide impaired colon tumor progression and induced autophagy in SCID mouse xenograft model via acting on cell cycle progression without affecting endoplasmic reticulum stress observed in vitro.

Obakan Yerlikaya, Pinar / Adacan, Kaan / Karatug Kacar, Ayse / Coker Gurkan, Ajda / Arisan, Elif Damla

The international journal of biochemistry & cell biology

2022 Volume 155, Page(s) 106360

Abstract: Epibrassinolide is a member of brassinosteroids with a polyhydroxysteroid structure similar to steroid hormones of vertebrates. It was shown that EBR decreased cell proliferation and induced apoptosis in different colon cancer cell lines without exerting ...

Abstract	Epibrassinolide is a member of brassinosteroids with a polyhydroxysteroid structure similar to steroid hormones of vertebrates. It was shown that EBR decreased cell proliferation and induced apoptosis in different colon cancer cell lines without exerting a cytotoxic effect in epithelial fetal human colon cells. This finding highlighted the potential of epibrassinolide in clinical therapeutic setup. In our previous studies, we showed that epibrassinolide was able to induce apoptosis via endoplasmic reticulum stress. Recently, we also showed that endoplasmic reticulum and apoptotic stresses can be prevented via autophagic induction in non-cancerous epithelial or aggressive forms of cancer cells. Therefore, here in this study, we evaluated the anti-tumoral effect of epibrassinolide as well as the autophagy involvement in the aggressive forms of colon cancer cell lines as well as in vivo SCID mouse xenograft colon cancer model for the first time. For this purpose, SCID mouse model was used for subcutaneous injection of colon cancer cells in matrigel formulation. We found that autophagy is induced in both in vitro and in vivo models. Following tumor formation, SCID mice were treated daily with increasing concentrations of epibrassinolide for two weeks. Our findings showed that EBR inhibited the volume and diameter of the tumor in a dose-dependent manner by causing cell cycle arrest. Therefore our data suggest that epibrassinolide exerts a cytostatic effect on the agrressive form of colon cancer model in vivo, without affecting endoplasmic reticulum stress and the induction of autophagy might have role in this effect of epibrassinolide.
MeSH term(s)	Mice ; Animals ; Humans ; Mice, SCID ; Heterografts ; Endoplasmic Reticulum Stress ; Colonic Neoplasms/drug therapy ; Colonic Neoplasms/metabolism ; Apoptosis ; Cell Proliferation ; Cell Division ; Autophagy ; Cell Line, Tumor
Language	English
Publishing date	2022-12-29
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1228429-4
ISSN	1878-5875 ; 1357-2725
ISSN (online)	1878-5875
ISSN	1357-2725
DOI	10.1016/j.biocel.2022.106360
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Article ; Online: Palbociclib negatively regulates fatty acid synthesis due to upregulation of AMPKα and miR-33a levels to increase apoptosis in Panc-1 and MiaPaCa-2 cells.

Rencuzogulları, Ozge / Yerlikaya, Pınar Obakan / Gürkan, Ajda Çoker / Arısan, Elif Damla / Telci, Dilek

Biotechnology and applied biochemistry

2021 Volume 69, Issue 1, Page(s) 342–354

Abstract: Fatty acids (FAs) synthesis mechanism has various regulators such as fatty acid synthase (FASN), AMP-regulated protein kinase (AMPK), or mammalian target of rapamycin (mTOR), which are aberrantly dysregulated in various pancreatic cancer cells. In this ... ...

Abstract	Fatty acids (FAs) synthesis mechanism has various regulators such as fatty acid synthase (FASN), AMP-regulated protein kinase (AMPK), or mammalian target of rapamycin (mTOR), which are aberrantly dysregulated in various pancreatic cancer cells. In this study, we aim to understand the regulatory role of palbociclib, a CDK4/6 inhibitor, on the cellular energy metabolism through regulation of AMPK/mTOR signaling by modulation of intracellular miR-33a levels in Panc-1 and MiaPaCa-2 cells. Palbociclib downregulated FAs metabolism more effectively in MiaPaCa-2 cells than Panc-1 cells. Moreover, palbociclib treatment increased the levels of miR-33a in each cell line albeit a higher increase was evident in MiaPaCa-2 cells. Stress-mediated activation of mTOR signaling axis was found associated with palbociclib-mediated AMPKα activation and miR33a upregulation. These findings provided that a deeper understanding about possible interactions of cell cycle activity and reduction of FAs synthesis may facilitate the enhancement of cell death mechanisms in pancreatic cancer cells.
MeSH term(s)	AMP-Activated Protein Kinases/metabolism ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Fatty Acids ; MicroRNAs/genetics ; Piperazines ; Pyridines ; Up-Regulation
Chemical Substances	Fatty Acids ; MicroRNAs ; Piperazines ; Pyridines ; AMP-Activated Protein Kinases (EC 2.7.11.31) ; palbociclib (G9ZF61LE7G)
Language	English
Publishing date	2021-02-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	883433-7
ISSN	1470-8744 ; 0885-4513
ISSN (online)	1470-8744
ISSN	0885-4513
DOI	10.1002/bab.2113
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Article ; Online: MicroRNAs for Virus Pathogenicity and Host Responses, Identified in SARS-CoV-2 Genomes, May Play Roles in Viral-Host Co-Evolution in Putative Zoonotic Host Species.

Lange, Sigrun / Arisan, Elif Damla / Grant, Guy H / Uysal-Onganer, Pinar

Viruses

2021 Volume 13, Issue 1

Abstract: Our recent study identified seven key microRNAs (miR-8066, 5197, 3611, 3934-3p, 1307-3p, 3691-3p, 1468-5p) similar between SARS-CoV-2 and the human genome, pointing at miR-related mechanisms in viral entry and the regulatory effects on host immunity. To ... ...

Abstract	Our recent study identified seven key microRNAs (miR-8066, 5197, 3611, 3934-3p, 1307-3p, 3691-3p, 1468-5p) similar between SARS-CoV-2 and the human genome, pointing at miR-related mechanisms in viral entry and the regulatory effects on host immunity. To identify the putative roles of these miRs in zoonosis, we assessed their conservation, compared with humans, in some key wild and domestic animal carriers of zoonotic viruses, including bat, pangolin, pig, cow, rat, and chicken. Out of the seven miRs under study, miR-3611 was the most strongly conserved across all species; miR-5197 was the most conserved in pangolin, pig, cow, bat, and rat; miR-1307 was most strongly conserved in pangolin, pig, cow, bat, and human; miR-3691-3p in pangolin, cow, and human; miR-3934-3p in pig and cow, followed by pangolin and bat; miR-1468 was most conserved in pangolin, pig, and bat; while miR-8066 was most conserved in pangolin and pig. In humans, miR-3611 and miR-1307 were most conserved, while miR-8066, miR-5197, miR-3334-3p and miR-1468 were least conserved, compared with pangolin, pig, cow, and bat. Furthermore, we identified that changes in the miR-5197 nucleotides between pangolin and human can generate three new miRs, with differing tissue distribution in the brain, lung, intestines, lymph nodes, and muscle, and with different downstream regulatory effects on KEGG pathways. This may be of considerable importance as miR-5197 is localized in the spike protein transcript area of the SARS-CoV-2 genome. Our findings may indicate roles for these miRs in viral-host co-evolution in zoonotic hosts, particularly highlighting pangolin, bat, cow, and pig as putative zoonotic carriers, while highlighting the miRs' roles in KEGG pathways linked to viral pathogenicity and host responses in humans. This in silico study paves the way for investigations into the roles of miRs in zoonotic disease.
MeSH term(s)	Animals ; Biological Coevolution ; COVID-19/transmission ; COVID-19/virology ; Chickens ; Gene Regulatory Networks ; Genome/genetics ; Host Specificity ; Humans ; Mammals ; MicroRNAs/chemistry ; MicroRNAs/genetics ; MicroRNAs/metabolism ; SARS-CoV-2/genetics ; SARS-CoV-2/pathogenicity ; SARS-CoV-2/physiology ; Sequence Alignment ; Tissue Distribution ; Zoonoses/transmission ; Zoonoses/virology
Chemical Substances	MicroRNAs
Language	English
Publishing date	2021-01-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v13010117
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Article ; Online: miR27a, a fine-tuning molecule, interacts with growth hormone (GH) signaling and ornithine decarboxylase (ODC) via targeting STAT5.

Coker-Gurkan, Ajda / Koyuncu, Kadriye / Yerlikaya, Pinar Obakan / Arisan, Elif Damla

Amino acids

2021 Volume 54, Issue 1, Page(s) 71–84

Abstract: Autocrine growth hormone (GH) expression triggers cell proliferation, invasion-metastasis in vitro and in vivo models, but GH gene mutations inhibit postnatal growth. Natural polyamines (PA); putrescine, spermidine, spermine trigger cell growth and ... ...

Abstract	Autocrine growth hormone (GH) expression triggers cell proliferation, invasion-metastasis in vitro and in vivo models, but GH gene mutations inhibit postnatal growth. Natural polyamines (PA); putrescine, spermidine, spermine trigger cell growth and differentiation. The importance of miR27a has shown to exert a suppressive effect on ornithine decarboxylase (ODC) expression in dwarf mice models. We aimed to modulate the role of A13S, F166Δ, T24 GH gene mutations' impact on PA metabolism and epithelial-mesencyhmal transition (EMT) pathway through miR27a. Biologically active GH signaling triggered cell viability, growth, and colony formation, but T24A alteration significantly decreases aggressive profiles due to inactive GH signaling through a decline in STAT5 activity and expressions of STAT5, c-myc and ODC. Although statistically significant increase in intracellular PA levels in wt GH signaling HEK293 cells compared to HEK293 cells with a lack of GH signaling, a sharp decline in PA levels measured in each mutant GH expressing HEK293 cells. When we inhibited miR27a, proliferation and colony formation accelerated through a significant increase in putrescine levels and upregulation of ODC, STAT5 expression. In contrast, a substantial decline in GH-mediated colony enlargement observed via ODC, STAT5 downregulation, and PA depletion in both wt and mutant GH expressing HEK293 cell lines by miR27a mimic transfection. In conclusion, T24A mutant GH expression declines the GH signaling through STAT5 activity, and mutant GH signaling decreased cell proliferation, division, and colony formation via EMT inhibition. The autocrine GH-mediated proliferative profiles were under the control of miR27a that depletes intracellular putrescine levels via targeting ODC.
MeSH term(s)	Animals ; Growth Hormone/genetics ; Growth Hormone/metabolism ; HEK293 Cells ; Humans ; Mice ; Ornithine Decarboxylase/metabolism ; Ornithine Decarboxylase Inhibitors ; Putrescine/metabolism ; Putrescine/pharmacology ; STAT5 Transcription Factor/genetics ; STAT5 Transcription Factor/metabolism ; Spermidine/metabolism
Chemical Substances	Ornithine Decarboxylase Inhibitors ; STAT5 Transcription Factor ; Growth Hormone (9002-72-6) ; Ornithine Decarboxylase (EC 4.1.1.17) ; Spermidine (U87FK77H25) ; Putrescine (V10TVZ52E4)
Language	English
Publishing date	2021-11-26
Publishing country	Austria
Document type	Journal Article
ZDB-ID	1121341-3
ISSN	1438-2199 ; 0939-4451
ISSN (online)	1438-2199
ISSN	0939-4451
DOI	10.1007/s00726-021-03101-9
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Article ; Online: Putative Roles for Peptidylarginine Deiminases in COVID-19.

Arisan, Elif Damla / Uysal-Onganer, Pinar / Lange, Sigrun

International journal of molecular sciences

2020 Volume 21, Issue 13

Abstract: Peptidylarginine deiminases (PADs) are a family of calcium-regulated enzymes that are phylogenetically conserved and cause post-translational deimination/citrullination, contributing to protein moonlighting in health and disease. PADs are implicated in a ...

Abstract	Peptidylarginine deiminases (PADs) are a family of calcium-regulated enzymes that are phylogenetically conserved and cause post-translational deimination/citrullination, contributing to protein moonlighting in health and disease. PADs are implicated in a range of inflammatory and autoimmune conditions, in the regulation of extracellular vesicle (EV) release, and their roles in infection and immunomodulation are known to some extent, including in viral infections. In the current study we describe putative roles for PADs in COVID-19, based on in silico analysis of BioProject transcriptome data (PRJNA615032 BioProject), including lung biopsies from healthy volunteers and SARS-CoV-2-infected patients, as well as SARS-CoV-2-infected, and mock human bronchial epithelial NHBE and adenocarcinoma alveolar basal epithelial A549 cell lines. In addition, BioProject Data PRJNA631753, analysing patients tissue biopsy data (n = 5), was utilised. We report a high individual variation observed for all PADI isozymes in the patients' tissue biopsies, including lung, in response to SARS-CoV-2 infection, while PADI2 and PADI4 mRNA showed most variability in lung tissue specifically. The other tissues assessed were heart, kidney, marrow, bowel, jejunum, skin and fat, which all varied with respect to mRNA levels for the different PADI isozymes. In vitro lung epithelial and adenocarcinoma alveolar cell models revealed that PADI1, PADI2 and PADI4 mRNA levels were elevated, but PADI3 and PADI6 mRNA levels were reduced in SARS-CoV-2-infected NHBE cells. In A549 cells, PADI2 mRNA was elevated, PADI3 and PADI6 mRNA was downregulated, and no effect was observed on the PADI4 or PADI6 mRNA levels in infected cells, compared with control mock cells. Our findings indicate a link between PADI expression changes, including modulation of PADI2 and PADI4, particularly in lung tissue, in response to SARS-CoV-2 infection. PADI isozyme 1-6 expression in other organ biopsies also reveals putative links to COVID-19 symptoms, including vascular, cardiac and cutaneous responses, kidney injury and stroke. KEGG and GO pathway analysis furthermore identified links between PADs and inflammatory pathways, in particular between PAD4 and viral infections, as well as identifying links for PADs with a range of comorbidities. The analysis presented here highlights roles for PADs in-host responses to SARS-CoV-2, and their potential as therapeutic targets in COVID-19.
MeSH term(s)	Betacoronavirus/isolation & purification ; COVID-19 ; Case-Control Studies ; Cell Line ; Coronavirus Infections/metabolism ; Coronavirus Infections/pathology ; Cytokines/metabolism ; Databases, Factual ; Epithelial Cells/cytology ; Epithelial Cells/metabolism ; Epithelial Cells/virology ; Extracellular Vesicles/metabolism ; Humans ; Isoenzymes/genetics ; Isoenzymes/metabolism ; Lung/enzymology ; Lung/pathology ; Lung/virology ; Pandemics ; Pneumonia, Viral/metabolism ; Pneumonia, Viral/pathology ; Protein Interaction Maps ; Protein-Arginine Deiminases/genetics ; Protein-Arginine Deiminases/metabolism ; RNA, Messenger/metabolism ; SARS-CoV-2
Chemical Substances	Cytokines ; Isoenzymes ; RNA, Messenger ; Protein-Arginine Deiminases (EC 3.5.3.15)
Keywords	covid19
Language	English
Publishing date	2020-06-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms21134662
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