Browsing by Author "Kocak, Ayse"

Now showing 1 - 7 of 7

Citation - WoS: 6
Citation - Scopus: 5
Antioxidant Effect of Epigallocatechin-3 in a Bleomycin-Induced Scleroderma Model
(Turkish League Against Rheumatism, 2019) Kocak, Ayse; Harmancı, Duygu; Cavdar, Zahide; Ural, Cemre; Birlik, Merih; Sarioglu, Sulen; Yilmaz, Osman; Akdoğan, Gül
Objectives: This study aims to evaluate the antioxidant effects of epigallocatechin-3-gallate (EGCG) in a bleomycin (BLM)-induced scleroderma model. Materials and methods: Thirty-two healthy female Balb-c mice (6-8-week-old; weighing 22 +/- 5 g) were used in this study. The mice were randomly divided into four groups: control (n=8), BLM (n=8), BLM+EGCG (n=8), and EGCG (n=8). Skin tissue specimens were collected at the end of the experiments. Histopathological examinations of skin tissues were performed. Skin samples were assessed for total superoxide dismutase (SOD) activity and malondialdehyde (MDA) content. The phosphorylation of p-38 mitogen-activated protein kinase and Akt protein (the serine-threonine protein kinase encoded by the AKT), as well as the nuclear factor-kappa B (NF-kappa B) levels, were analyzed by western blotting. Results: Epigallocatechin-3-gallate-treated groups were observed to have reduced connective tissue fibrosis in the dermis area using Masson's trichrome staining method. Pp-38 and NF-kappa B were found to decrease significantly in the BLM + EGCG group compared with the BLM group. Parallel to these findings, phosphorylated Akt protein was found to increase in the BLM + EGCG group compared with the BLM group. SOD activity was increased in the EGCG group and content of MDA level was decreased in EGCG groups. Conclusion: The results of the present study demonstrated that EGCG represses pp-38 and NF-kappa B signaling pathways, exerting a protective effect for scleroderma through its anti-oxidative role.
Citation - WoS: 2
Citation - Scopus: 4
Effects of Epigallocatechin-3 (egcg) on a Scleroderma Model of Fibrosis
(Walter De Gruyter Gmbh, 2018) Kocak, Ayse; Harmancı, Duygu; Birlik, Merih; Sarioglu, Sulen; Yilmaz, Osman; Cavdar, Zahide; Akdoğan, Gül
Objective: The aim of the present study was to evaluate the potential protective effects of epigallocatechin-3-gallate (EGCG) on fibrosis in bleomycin induced scleroderma model. Materials and methods: Thirty-two healthy female Balb-c mice with the average body weight of 22 +/- 5 g were used in this study. The mice were randomly divided into four groups as control (n=8), Bleomycin (n=8), Bleomycin+ EGCG (n =8) and EGCG (n =8). Skin tissue samples were collected to quantify matrix metalloproteinases (MMP-1, MMP-8, MMP-13), p-SMAD 2/3 and SMAD 2/3 in protein homogenates by western blotting. TGF-beta 1 expression was determined by real-time PCR. Immunohistopathological and histopathological examinations of skin tissues were also done. Results: When measured with Masson Trichrome, EGCG treatment was found to decrease fibrosis in connective tissue compared to the BLM injected control. EGCG was decreased dermal fibrosis. Bleomycin + EGCG group showed a significant reduction in fibrosis at the dermal surface area using hematoxylin measurements compared with the BLM group. MMP-1, MMP-8 protein levels were increased and p-SMAD 2/3 protein level was decreased. TGF-beta mRNA expression was decreased in the EGCG + BLM group compared with the BLM group. Conclusion: These results suggest an antifibrotic role for EGCG.
A Preliminary Study of Possible Fibrotic Role of Meprin Metalloproteases in Scleroderma Patients
(Turkish League Against Rheumatism, 2021) Kocak, Ayse; Avsar, Aydan Koken; Harmancı, Duygu; Akdogan, Gul; Birlik, A. Merih
Objectives: This study aims to investigate the possible fibrotic role of meprin metalloproteases and possible fibrotic effects of activator protein-1 (AP-1) in scleroderma patients. Patients and methods: Between April 2018 and April 2019, a total of 85 scleroderma patients (9 males, 76 females; mean age: 54.9 +/- 12.1 years; range, 22 to 80 years) who met the 2013 American College of Rheumatology/European League Against Rheumatism criteria and 80 healthy control individuals (10 males, 70 females; mean age 42.9 +/- 10.2 years; range, 19 to 65 years) were included. Patients' data and blood samples were collected. Messenger ribonucleic acid expressions of interleukin (IL)-6, AP-1 subunits, and tumor necrosis factor-alpha (TNF-alpha) were analyzed by quantitative real-time polymerase chain reaction. Serum meprin alpha and beta protein levels were analyzed using the enzyme-linked immunosorbent assay. Results: Meprin alpha and meprin beta protein levels increased in scleroderma patients. The AP-1 subunits (c-Fos, c-Jun), IL-6, and TNF-alpha increased in scleroderma patients, compared to controls. Conclusion: Our results provide evidence showing that increased meprins levels may be related to AP-1 levels and increased meprins levels may responsible for increased inflammatory TNF-alpha and IL-6 levels. All these data suggest meprins as promising therapeutic targets to restore the balance between inflammation and extracellular matrix deposition in scleroderma.
Citation - WoS: 11
Citation - Scopus: 12
Protective Effects of Alpha-Lipoic Acid on Bleomycin-Induced Skin Fibrosis Through the Repression of Nadph Oxidase 4 and Tgf-Beta 1/Smad3 Signaling Pathways
(Sage Publications Ltd, 2022) Kocak, Ayse; Ural, Cemre; Harmancı, Duygu; Oktan, Mehmet Asi; Afagh, Aysan; Sarioglu, Sulen; Yilmaz, Osman; Akdoğan, Gül
The aim of this study was to determine the protective effects of alpha-lipoic acid (ALA), which is known as a powerful antioxidant, and the possible related molecular mechanisms that mediate its favorable action on skin fibrosis in the bleomycin (BLM)-induced scleroderma (SSc) model in mice. The experimental design was established with four groups of eight mice: Control, ALA (100 mg/kg), BLM (5 mu g/kg), and BLM + ALA group. BLM was administered via subcutaneous (sc) once a day while ALA was injected intraperitoneally (ip) twice a week for 21 days. Histopathological and biochemical analyses showed that ALA significantly reduced BLM-induced dermal thickness, inflammation score, and mRNA expression of tumor necrosis factor-alpha (TNF-alpha) in the skin. Besides, the mRNA expressions of the subunits of NADPH oxidase, which are Nox4 and p22phox, were found to be significantly induced in the BLM group. However, ALA significantly reduced their mRNA expression, which were in parallel to its decreasing effect on serum total oxidant status (TOS) level. Moreover, it was found that ALA downregulated the mRNA expressions of alpha-smooth muscle actin (alpha-SMA), collagen type I and fibronectin in the skin tissue of the BLM group. Additionally, it was shown that ALA reduced significantly the TGF-beta 1 and p-Smad3 protein expressions in the BLM + ALA group. On the other hand, ALA did not exhibit any significant effect on the p38 mitogen-activated kinase (MAPK) activation induced by BLM. All these findings point out that ALA may be a promising treatment for the attenuation of skin fibrosis in SSc patients.
Citation - WoS: 6
Citation - Scopus: 6
Relationship of Wnt Pathway Activity and Organ Involvement in Scleroderma Types
(Wiley, 2020) Kocak, Ayse; Harmancı, Duygu; Akdoğan, Gül; Birlik, Merih
Objective Scleroderma (SSc) is a chronic inflammatory autoimmune disease characterized by fibrosis in the skin and internal organs. In SSc, the heart, lung, kidney, gastrointestinal (GIS) system, muscle, and peri-articular structures are damaged. There is no study of the relationship between SSc type, stage, pathogenesis, organ involvement, and Wnt signaling. In this study, we aimed to show the relationship of the Wnt gene family and antagonists in SSc subtypes and different organ involvement. Methods Eighty-five SSc patients and 77 controls were included in this study. The gene expressions and protein levels of the Wnt family and antagonists were analyzed from blood samples. The relationship between these parameters and disease stage, type, and organ involvement were evaluated. Results Wnt-1, Wnt-10b, Wnt-2, and Wnt-6 gene expressions are increased and Axin-2, DKK-1, and Kremen protein expressions are decreased in SSc. Wnt-3a and Wnt-10a gene expressions are increased in generalized SSc compared to limited SSc. Wnt-1, Wnt-2 gene expressions are increased significantly in pulmonary arterial hypertension (PAH)(+) SSc compared to PAH(-) SSc. There was a positive correlation between the modified Rodnan skin score and Wnt-2 in SSc. There was a significant positive correlation between GIS involvement score and Wnt-1, Wnt-2, Wnt-4, Wnt-8a, Wnt-9b in SSc. Conclusion Wnt-1 and Wnt-2 were found higher in scleroderma and organ involvement. They may play a role in the pathogenesis of the disease.
Citation - WoS: 37
Role of the Microrna-29 Family in Fibrotic Skin Diseases
(Spandidos Publ Ltd, 2017) Harmancı, Duygu; Erkan, Erdogan Pekcan; Kocak, Ayse; Akdoğan, Gül
Fibrotic skin diseases are characterized by the accumulation of collagen. The hallmarks of fibrotic skin diseases are unbalanced fibroblast proliferation and differentiation, extracellular matrix production and transforming growth factor- signalling. Numerous studies have investigated the possibility that microRNAs (miRNAs or miRs) are involved in the pathogenesis of certain fibrotic diseases, including skin, heart, lung and liver diseases. miRNAs are a class of small non-coding RNAs, which modify gene expression by binding to target messenger RNA (mRNA) and blocking the translation or inducing the degradation of target mRNA. The biological relevance of miRNAs has been investigated in physiological and pathological conditions, and there is increasing evidence that the miR-29 family is associated with fibrotic diseases. The aim of the present review is to provide an up-to-date summary of current knowledge on the latest developments associated with the miR-29 family and fibrotic skin diseases.
Citation - WoS: 1
Citation - Scopus: 2
Selective JAK-1 Inhibitor Upadacitinib and Peptide PD29 Modulate the JAK and TGF-β/Smad Signaling Pathways Reducing Experimental Dermal Fibrosis
(Pergamon-elsevier Science Ltd, 2025) Kocak, Ayse; Ural, Cemre; Cavdar, Zahide; Sarioglu, Sulen; Akdogan, Gul; Birlik, Merih
This study investigates the antifibrotic and anti-inflammatory effects of Janus kinase (JAK) inhibitors and the PD29 peptide in the context of systemic sclerosis (SSc), a condition characterized by dermal thickening, chronic inflammation, and excessive extracellular matrix deposition. Pulmonary arterial hypertension (PAH) and pulmonary fibrosis represent serious and often fatal complications associated with SSc. The pathogenesis of SSc involves dysregulation of immune responses and aberrant activation of signaling pathways, including TGF beta/Smad. The antifibrotic properties of upadacitinib, a selective JAK1 inhibitor, and PD29 peptide were evaluated using a bleomycin-induced SSc mouse model and primary human lung fibroblasts. Both agents, administered individually or in combination, significantly attenuated dermal thickening, myofibroblast transdifferentiation, collagen deposition, and activation of the TGF-beta 1 signaling axis. In vivo and in vitro analyses demonstrated that upadacitinib and PD29 downregulated key fibrotic markers, including alpha-SMA, JAK1, TGF-beta 1, Smad2, and collagen-1, at both the gene and protein levels. Furthermore, treatment significantly reduced systemic inflammatory cytokines, including IL-6 and TNF-alpha. Notably, combination therapy exhibited a more pronounced effect compared to monotherapy. These findings suggest that upadacitinib and PD29 exert potent antifibrotic and anti-inflammatory effects through suppression of TGF-beta 1-mediated Smad2/3 signaling, predominantly via inhibition of JAK1 activation. Consequently, JAK inhibitors and PD29 represent promising therapeutic candidates for the management of fibrosis in systemic sclerosis.