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    Avanafil as a Novel Therapeutic Agent Against LPS-Induced Acute Lung Injury via Increasing CGMP to Downregulate the TLR4-NF-?B-NLRP3 Inflammasome Signaling Pathway
    (Springer, 2022) Aydin, Pelin; Magden, Zeynep Berna Aksakalli; Uzuncakmak, Sevgi Karabulut; Halici, Hamza; Akgun, Nurullah; Mendil, Ali Sefa; Mokhtare, Behzad
    Aim We demonstrate the effect of PDE5 inhibitors in cases of acute lung injury via the relationship between cGMP/NO and the TLR4-NF-kappa B-NLRP3 pathway. Materials and Methods This study was performed with 30 male Wistar albino rats. Lipopolysaccharide (LPS) was administered intratracheally to the rats and acute lung injury (ALI) was induced. Twelve hours after LPS administration, avanafil, prepared at suitable doses according to the body weights of the animals, was administered by oral gavage. Lung tissue samples of all groups were examined histopathologically and by immunochemical staining (IL-1 beta, iNOS, TLR4, and NF-kappa B). The iNOS, NLRP3, and IL-1B mRNA expression levels in the lung tissues were measured by RT-PCR. The left upper lobes of the rat lungs were dried at 70 degrees C for 48 h and lung water content was calculated. Result Statistically significant increases in iNOS, NLRP3, and IL-1 beta mRNA expressions were observed in the rats with ALI compared to the healthy controls (p < 0.0001). Those increased expressions were reduced at both doses of avanafil (p < 0.0001). This reduction was found to be greater at 20 mg/kg (p < 0.0001). IL-1 beta, iNOS, TLR4, and NF-kappa B immunopositivity was moderate/severe in the ALI group and mild in the group with ALI + avanafil at 20 mg/kg (p < 0.05). When the wet/dry lung ratios were calculated, a statistically significant increase was seen in the ALI group compared to the healthy rats (p < 0.05). That increase was decreased with both avanafil doses (p < 0.05). Conclusion We suggest that avanafil may prevent the progression of ALI and be effective in its treatment. We hope that this study will be supported by future clinical studies to yield a new indication for avanafil.
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    Comparison of Serum Adropin Levels in Patients with Diabetes Mellitus, COVID-19, and COVID-19 with Diabetes Mellitus
    (Ataturk Univ, 2022) Aydin, Pelin; Uzuncakmak, Sevgi Karabulut; Tor, Ibrahim Hakki; Bilen, Arzu; Ozden, Ayse
    Objective: In the present study, the relationship between a poor prognosis and adropin levels in diabetic patients with coronavirus disease 2019 was investigated by measuring serum adropin levels and levels of D-dimer, C-reactive protein, and ferritin, which are considered prognostic factors for coronavirus disease 2019. Materials and Methods: Hundred volunteer participants treated in the Erzurum Regional Training and Research Hospital were included in this study. Serum adropin levels were measured by enzyme-linked immunosorbent assay. The relationship between serum adropin level and C-reactive protein, ferritin, and D-dimer levels was analyzed by correlation analysis. Results: The participants' serum adropin levels differed between the groups (P=.0007). The control group had the highest adropin levels among groups. The lowest adropin levels were in the COVID + diabetes mellitus group. Adropin levels of diabetes mellitus, COVID, and diabetes mellitus + COVID groups were significantly decreased when compared to the control (P<.05). There was a significant negative correlation between adropin and C-reactive protein, D-dimer, and ferritin. Conclusion: Adropin can be used as an auxiliary biomarker, a prognostic factor in the early management of coronavirus disease 2019 patients with diabetes mellitus. We think that our study will guide future studies conducted in this field.
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    Evaluation of IGFBP5 expression and plasma osteopontin level in COVID-19 patients
    (Elsevier Urban & Partner Sp Z O O, 2023) Uzuncakmak, Sevgi Karabulut; Aksakal, Alperen; Kerget, Ferhan; Aydin, Pelin; Halici, Zekai
    Purpose: The aim of this study is to investigate insulin-like growth factor binding protein 5 (IGFBP5) expression in coronavirus disease 2019 (COVID-19) patients and its relationships with COVID-19 laboratory findings and plasma osteopontin (OPN) levels.Materials and methods: We enrolled 60 patients with COVID-19 and 30 healthy individuals in this study. mRNA expression of IGFBP5 was measured by RT-PCR. Plasma OPN levels were measured via the ELISA method.Results: Plasma OPN levels were higher and IGFBP5 expression levels were lower in COVID-19 patients than in the healthy individuals (p = 0.0057 and p = 0.0142, respectively). Critically ill patients had higher OPN and lower IGFBP5 than non-critically ill patients. Patients with affected lungs demonstrated increased OPN and decreased IGFBP5 (p = 0.00032 and p = 0.044, respectively). Receiver operating characteristic (ROC) analysis indicated that IGFBP5 expression and OPN levels can be used discriminate non-critically from critically ill patients (p = 0.049; p = 0.0016, respectively).Conclusion: This study demonstrated that patients with a poor prognosis had increased OPN and decreased IGFBP5. High values of OPN and low values of IGFBP5 may be considered as signs of disease severity. Tissue -specific IGFBP5 expression may contribute to understanding the role of IGFBP5 in the lungs in COVID-19 cases.
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    The melatonin agonist ramelteon attenuates bleomycin-induced lung fibrosis by suppressing the NLRP3/TGF-?1/HMGB1 signaling pathway
    (Elsevier Urban & Partner Sp Z O O, 2023) Aydin, Pelin; Aksakalli-Magden, Zeynep B.; Civelek, Maide S.; Karabulut-Uzuncakmak, Sevgi; Mokhtare, Behzad; Ozkaraca, Mustafa; Alper, Fatih
    Purpose: The possible effects of ramelteon, a melatonin receptor agonist on bleomycin-induced lung fibrosis were analyzed via transforming growth factor beta 1 (TGF-beta 1), the high mobility group box 1 (HMGB1) and Nod-like receptor pyrin domain-containing 3 (NLRP3) which are related to the fibrosis process. Materials and methods: Bleomycin (0.1 mL of 5 mg/kg) was administered by intratracheal instillation to induce pulmonary fibrosis (PF). Starting 24 h after bleomycin administration, a single dose of ramelteon was administered by oral gavage to the healthy groups, i.e. PF + RM2 (pulmonary fibrosis model with bleomycin + ramelteon at 2 mg/kg) and PF + RM4 (pulmonary fibrosis model with bleomycin + ramelteon at 4 mg/kg) at 2 and 4 mg/kg doses, respectively. Real-time polymerase chain reaction (real-time PCR) analyses, histopathological, and immunohistochemical staining were performed on lung tissues. Lung tomography images of the rats were also examined. Results: The levels of TGF-beta 1, HMGB1, NLRP3, and interleukin 1 beta (IL-1 beta) mRNA expressions increased as a result of PF and subsequently decreased with both ramelteon doses (p < 0.0001). Both doses of ramelteon partially ameliorated the reduction in the peribronchovascular thickening, ground-glass appearances, and reticulations, and the loss of lung volume. Conclusions: The severity of fibrosis decreased with ramelteon application. These effects of ramelteon may be associated with NLRP3 inflammation cascade.
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    Suberosin Alleviates Sepsis-Induced Lung Injury in A Rat Model of Cecal Ligation and Puncture
    (Taylor & Francis Inc, 2023) Uzuncakmak, Sevgi Karabulut; Halici, Zekai; Karakaya, Songul; Kutlu, Zerrin; Saglam, Yavuz Selim; Bolat, Ismail; Aydin, Pelin
    Background/aims Sepsis is one of the major problems encountered in intensive care units, causing organ damage and increasing mortality. Suberosin (SBR) is a type of coumarin with antioxidant and anti-inflammatory activities. The goal of this study is to explore the protective effects of SBR on the lungs in a rat model of sepsis. Methods Male Wistar rats were utilized in this study. A cecal ligation and puncture (CLP) model was applied to induce sepsis. Rats were separated into six groups with nine animals in each group, including healthy control, SBR, CLP, and CLP + SBR (5, 10, and 20 mg/kg) groups. Superoxide dismutase (SOD), glutathione (GSH) enzyme activities, and malondialdehyde (MDA) level were measured via enzyme-linked immunosorbent assay (ELISA). The messenger RNA (mRNA) expressions of tumor necrosis factor alpha (TNF-alpha) and interleukin 1 beta (IL-1 beta) were evaluated by real-time polymerase chain reaction (RT-PCR). Histopathological changes in the lungs were investigated with hematoxylin and eosin (H&E). Results MDA levels and GSH and SOD enzyme activities were negatively affected in the CLP group, but SBR treatment ameliorated these oxidative stress parameters in the SBR1-3 groups (p< 0.05). The mRNA expressions of TNF-alpha and IL-1 beta were increased in the CLP group, and SBR treatment decreased those expression levels in a dose-dependent manner (p < 0.05). Organ damage and necrosis were seen in the CLP group and were alleviated in the SBR3 group. Immunohistochemical (IHC) analysis of lung tissues demonstrated decreased TNF-alpha and IL-1 beta immunopositivity in the SBR1-3 groups (p< 0.05). Conclusions SBR ameliorated sepsis-related lung injury in a dose-dependent manner. This compound has significant potential as a future agent in the treatment of sepsis.