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Öğe A bioactive product lipoxin A4 attenuates liver fibrosis in an experimental model by regulating immune response and modulating the expression of regeneration genes(2019) Kurtoğlu, Elçin Latife; Kayhan, Başak; Gül, Mehmet; Kayhan, Burçak; Akdoğan Kayhan, Meral; Karaca, Zeynal Mete; Yeşilada, ElifAbstract: Background/Aims: Lipoxin A4 (LXA4), an anti-inflammatory lipid mediator, regulates leukocyte cellular activity and activates gene transcription. The therapeutic effect of LXA4 on liver fibrosis and its mechanism on the immune system are largely unknown. Because the regenerative capacity of hepatocytes in acute and chronic liver failure models of mouse increases by silencing MKK4, we aimed to investigate the effect of parenteral administration of LXA4 on the genes responsible for regeneration of liver, namely MKK4, MKK7, and ATF2, and visualize the therapeutic effects in an experimental model. Materials and Methods: Fibrosis was induced in mice by administration of thioacetamide (TAA). LXA4 was administered during the last two weeks of fibrosis induction. The fibrosis level was measured by Knodell scoring. The liver function was measured by analyzing serum ALT, AST, and AP levels. Expression levels of genes responsible for liver fibrosis (TGF-?) and cell regeneration (MKK4, MKK7, and ATF2) have been measured by RT-PCR analysis. Inflammatory and anti-inflammatory cytokine levels were measured in serum samples and liver homogenates by Enzyme Linked Immunosorbent Assay (ELISA). Ultrathin sections were examined using a transmission electron microscope and analyzed. Results: We observed significant healing in liver of the LXA4-treated group, histologically. This finding was in parallel with reduction of serum ALT, AST, but not AP levels. TGF-? and MKK4 expressions were significantly reduced in the LXA4-treated group. Administration of LXA4 caused significant elevation of IL-10 in systemic circulation; however, that elevation was not detected in liver homogenates. Nevertheless, significant reductions in TNF-? and IL-17 have been observed. Conclusion: The anti-inflammatory effect of LXA4 maintains the regenerative capacity of liver during fibrosis in an experimental liver fibrosis model. LXA4 may be therapeutically beneficial in liver fibrosis.Öğe Chronic liver fibrosis induction in aging causes significant ultra-structural deterioration in liver and alteration on immune response gene expressions in liver-spleen axis(Taylor & Francis Inc, 2024) Karaca, Zeynal Mete; Karaca, Gamze; Kayhan, Basak; Gul, Mehmet; Ersan, Veysel; Bag, Harika Gozukara; Yesilada, ElifThe relationship between damage to the liver and spleen by aging and the immune response status in these two organs, which are anatomically and immunologically interconnected, is unknown. The authors investigated the histopathological, ultrastructural, and immunological effects of aging in young and aged fibrotic mice by using an experimental model. Four groups were planned, with 10 mice in each experimental group. The levels of fibrosis and ultrastructural destruction in the liver were determined by alpha-SMA staining and TEM analysis. Expression levels of immunity genes (Il2, Il4, Il6, Il10, Il12, Il17, Tnf, Ifng, Tgfb1, Gata3, Rorc, Tbx21, Foxp3, Ccl2, Ccr2, Cxcr3, Pf4, Cxcl10) were carried out by qRT-PCR. While structural disorders were detected in the mitochondria of aged healthy group, cellular destruction in the fibrosis-induced elderly group was at a dramatic level. Fibrosis induction in aged mice caused an elevation in the expression of chemokines (CCl2, CXCL10, CCR2) and cytokine (IL-17a) genes that induce autoinflammatory response in the liver. Unlike the cellular pathology and genes activated in fibrosis in youth and the natural occurrence of fibrosis with aging, induction of fibrosis during aging causes deterioration in the liver and expression of genes responsible for autoimmunity in both the liver and spleen.Öğe Dexmedetomidine improves ultrastructural view of renal damage and biochemical parameters during an experimental inflammatory bowel disease(2018) Karaca, Zeynal Mete; Gül, Mehmet; Kayhan, Başak; Erdoğan Kayhan, GülayAbstract: Abstract Investigation of the effect of Dexmedetomidine (Dex) on inflammatory bowel diseases (IBD) induced renal damage by using an experimental model. IBD frequently cause reduction in renal function and renal failure. Since perioperative anesthesia and postoperative conditions in intensive care can cause acute kidney injury and reduction on renal function; deciding on a sedative and anesthetic agent without side effects would reduce IBD caused renal damage. We investigated histopathological, electron microscopic analyzes and antioxidant effects of Dex on kidney tissue during trinitrobenzene sulfonic acid (TNBS) induced damage in BALB/c mice at two different concentrations of Dex; 5?g/kg and 30?g/kg. Blood samples were collected to analyze creatinine levels. The levels of malondialdehyde (MDA) and activity of antioxidant enzymes glutathione (GSH) and superoxide dismutase (SOD) were measured in tissue homogenates. Histopathological and ultrastructural changes in kidney following TNBS induction were significantly reduced in Dex treatment groups. Administration of Dex significantly reduced creatinine levels. MDA levels were significantly reduced in Dex groups. Administration of Dex brought back GSH level to control level. Administration of Dex significantly 1.48 and 1.96 times increased SOD activity at 5?g/kg and 30 ?g/kg, respectively. Dexmedetomidine treatment may have benefits to prevent IBD induced renal damage.Öğe Effect of caffeic acid phenethyl ester (CAPE) on vascular endothelial growth factor a (VEGF-A) gene expression in gentamicin-induced acute renal nephrotoxicity(2018) Çiğremiş, Yılmaz; Akgöz, Müslüm; Özen, Hasan; Karaca, Zeynal MeteAbstract: Vascular endothelial growth factor-A (VEGF-A) gene expression in an experimental gentamicin-induced nephrotoxicity and ameliorative effect of caffeic acid phenethyl ester (CAPE) was investigated in rats. Animals were divided into four groups (n=8); control (C) group animals were given 10% dimethylsulfoxide (DMSO); gentamicin (G) group animals were given 100 mg/kg/day gentamicin; CAPE group animals were given 30 mg/kg/day CAPE and CAPE+G group animals were given 100 mg/kg/ day gentamicin plus 30 mg/kg/day CAPE. Serum creatinine and BUN levels significantly increased in gentamicin group as compared to the control group (p<0.05) while CAPE treatment did not significantly lower the levels of either BUN or creatinine (p>0.05). Gene expression level of VEGF-A in gentamicin group significantly decreased as compared to the control group, however, CAPE treatment did not have any increasing effect on the gene expression level. According to histopathological investigation, gentamicin treatment caused prominent degeneration in kidney tissue and CAPE treatment had only slight beneficial effect on lowering the tissue degeneration. The results showed that gentamicin decreases VEGF-A gene expression and this might be related to the tissue degeneration at cellular level. However, CAPE treatment did not have significant ameliorative effect in lowering the gentamicin induced nephrotoxicity.Öğe False negative results in luminex panel reactive antibodyidentification assay: Should we be alert on them?(2021) Karaca, Zeynal Mete; Ersan, Veysel; Kayhan, Basak; Yilmaz, SezaiAim: Panel Reactive Antibodies (PRA) analysis is important not only in virtual cross-match of donors and recipients but also in follow-up of recipients immune response after transplantation. Although bead based tests give faster and more reliable, it may have false positive and negative results. We investigated HLA groups of patients with false negative results and the frequencies of antiHLA antibodies in all three false negative situations.Materials and Methods: PRA results of all patients were divided into 3 groups according to negative controls and samples results. First one is negative controls were false negative and samples were false negative (1st Situation); second one is negative controls were false negative but samples were true negative (2nd Situation); third one is negative controls were true negative but samples were false negative (3rd Situation). All serum samples were tested by bead based Luminex assay.Results: While anti-HLA-A68, A24, A32 were the most frequent antibodies for the first situation, anti-HLA-A03,24,32 were the most frequent three antibodies for the second situation. In case of anti-HLA-B antibodies; anti-HLA-B38, B44, B48 were detected for the first situation, and anti-HLA-B44, B58, B49 were detected for the second situation. In case of class II antibodies; we detected anti-HLA-DRB110, DRB115 and DRB151 antibodies as the most frequent three antibodies at 1st situation. Frequencies of anti-HLA antibodies of 120 patients with false negative results were determined in serum samples. In case of 3rd situation, while anti-A23, A68, A24; anti-B06, B04, B39 and anti-Cw07 were the most frequent anti-HLA Class I antibodies, anti-HLA DQ07, DQ05, DQ04 and anti-HLA-DRB152, DRB113, DRB153 were the most frequent HLA-Class II antibodies detected in serum samples.Conclusion: Samples with false negative PRA results should be repeated and these samples should be recorded in the laboratory for internal control system.Öğe İn vivo akut nefrotoksisitede böbrek vasküler endotelyal büyüme faktör (VEGF) geni ifadesi ve kafeik asit fenetil ester (CAPE)'nin etkisi(İnönü Üniversitesi, 2014) Karaca, Zeynal MeteBu tezde; gentamisin ile deneysel böbrek nefrotoksisitesi oluşturulmuş sıçanların böbrek dokusunda vasküler endotelyal büyüme faktör (VEGF-A) geni ifadesi ve kafeik asit fenetil esterin (CAPE) nefrotoksisitenin önlenmesindeki rolünün araştırılması amacıyla 32 adet Wistar cinsi dişi sıçan kullanıldı. Hayvanlar her grupta 8'er adet sıçan olmak üzere 4 gruba ayrıldı; Kontrol grubu (K; %10'luk dimetil sülfoksit (DMSO) intraperitonal yoldan verildi), Gentamisin grubu (G; 8 gün boyunca intraperitonal yolla 100 mg/kg/gün vücut ağırlığı dozunda gentamisin verildi), CAPE grubu (C; 30 mg/kg/gün vücut ağırlığı dozunda CAPE intraperitonal yolla 10 gün boyunca verildi), CAPE+Gentamisin grubu (C+G; 30 mg/kg/gün vücut ağırlığı dozunda CAPE ve 100 mg/kg/gün vücut ağırlığı dozunda gentamisin intaperitonal olarak beraber uygulandı). Deney sonunda gruplardan alınan böbrek dokularından VEGF-A gen ifadesi ve histopatalojik analizlerin yanısıra, serumdan BUN ve kreatinin analizleri yapıldı. Kontrol grubuna göre gentamisin uygulamasının böbrek VEGF-A gen ifadesini düşürdüğü (p<0,05), CAPE uygulamasının ise VEGF-A gen ifadesinde herhangi bir yükseltici etki yapmadığı gözlendi (p>0,05). Histopatolojik olarak kontrol grubuyla karşılaştırıldığında gentamisin uygulamasının böbrek dokusunda ciddi hasarlanmalara yol açtığı, CAPE uygulamasının ise bu hasarları kısmen iyileştirdiği tespit edildi. Kontrol grubuyla karşılaştırıldığında gentamisin uygulanan hayvanların serum kreatinin ve BUN değerlerinin anlamlı derece yükseldiği (p<0,05), CAPE uygulamasının yükselen serum ve BUN değerlerini düşürmede anlamlı bir etki yapmadığı bulundu (p>0,05). Sonuç olarak gentamisin uygulamasının böbrek VEGF-A gen ifadesini ciddi bir şekilde azalttığı, gentamisin kaynaklı böbrek hasarında VEGF-A'nın bozulan ifadesinin önemli bir rol oynayabileceği, CAPE uygulamasının ise gentamisin kaynaklı toksisitenin önlenmesinde önemli bir etkisi olmadığı kanaatine varıldı.Öğe Influence of Lipoxin-A4 Treatment on Cytokine, Chemokine Genes Expression, and Phenotypic Distribution of Lymphocyte Subsets During Experimental Liver Fibrosis(Aves, 2022) Karaca, Zeynal Mete; Kurtoglu, Elcin Latife; Gul, Mehmet; Kayhan, BasakObjective: Lipoxins are anti-inflammatory, pro-resolving molecules that are secreted by immune cells such as neutrophils and macrophages. Lipoxins are a metabolite of the arachidonic acid pathway that resolve inflammation in fibrotic liver by producing several anti-inflammatory molecules. In this study, phenotypic distribution activation markers of lymphocytes in the spleen and expression levels of chemokines (chemokine (C-X-C motif) receptor 3, chemokine (C-X-C motif) ligand 10) cytokines (interferon gamma, tumor necrosis factor alpha, interleukin-6, interleukin-10) in the liver of lipoxin A4-treated fibrotic mice were investigated. Materials and methods: Liver fibrosis was induced in BALB/c mice by thioacetamide administration. Lipoxin A4 was administered during last 2 weeks of induction. Fibrosis level was determined by using Knodell scoring. Lymphocytes were identified by flow-cytometry. Expression levels of genes were measured by quantitative real time polymerase chain reaction in liver homogenates. Results: Lipoxin A4 treatment caused an elevation of T-lymphocyte percentage in the spleen. Interestingly, administration of lipoxin A4 significantly reduced B-lymphocyte population in spleen of fibrotic group. CD8(+) cytotoxic T cell frequency significantly reduced in thioacetamide-induced mice; however, lipoxin A4 administration increased that percentage significantly. Lipoxin A4 treatment significantly reduced frequency of activated (CD8(+)CD69(+)) cytotoxic T cells. Expression levels of chemokines significantly reduced in the liver after lipoxin A4 treatment. While expression levels of interferon gamma, tumor necrosis factor alpha. and interleukin-6 significantly reduced in the liver after lipoxin A4 treatment, an anti-inflammatory cytokine interleukin-10 expression was almost at similar levels in all experimental groups. Conclusion: Lipoxin A4 performs its anti-inflammatory effect by reducing the frequency of activated T cells and expression levels of chemokines cytokines responsible from inflammatory immune response in the liver.Öğe Is hepatitis-B immunization effective during chronic liver fibrosis? Investigation of secretory and cellular immune responses on an experimental model(Taylor & Francis Ltd, 2023) Kayhan, Basak; Karaca, Zeynal Mete; Canpolat, Esra; Ersan, Veysel; Gul, Mehmet; Yologlu, Saim; Yilmaz, SezaiObjective Adults with end-stage of chronic liver diseases have lower antibody titers after hepatitis-B vaccination. We have less amount of knowledge about the effect of non-viral cause chronic liver fibrosis on vaccination. In this study, we investigated the effect of non-viral chronic liver fibrosis on hepatitis B vaccine and the effect of tetanous toxoid co-administration at the level of humoral and cellular immune responses in an experimental model. Methods Hepatitis B vaccine was administered either alone or in combination with tetanus toxoid in thioacetamide-induced fibrotic BALB/c mice. Fibrosis level was determined by Knodell scoring. Anti-HBsAg, biochemical parameters, inflammatory (IL-1 beta, TNF-alpha), and anti-inflammatory (IL-10) cytokine levels were investigated in serum samples by automated systems and ELISA; respectively. Frequencies of activated lymphocytes were determined in flow cytometer. Results Antibody titers significantly decreased after immunization of fibrotic mice. However, co-administration of toxoid significantly elevated antibody titer. The percentage of CD19(+)CD69(+) B lymphocytes was found to be lower in vaccinated fibrotic group compared to vaccinated naive group. Simultaneous administration of toxoid significantly increased the frequencies of CD4(+) and CD8(+) T cells expressing CD69 and CD127. Interestingly, CD19(+)CD5(+)CD1(high) Breg cells were significantly reduced in the group vaccinated with hepatitis B vaccine and toxoid, simultaneously. The reduction in Breg percentage did not expose a significant decrease in the level of IL-10. Conclusion Non-viral chronic liver fibrosis causes a reduction on specific antibody level after vaccination. Reduction on Breg cell frequency may have an effect on elevation of antibody level after co-administration of tetanus toxoid.Öğe Kronik karaciğer fibrozu oluşturulan genç ve yaşlı farelerde inflamatuar ve anti-inflamatuar sitokin genlerinin ifade edilme düzeyinin araştırılması(İnönü Üniversitesi, 2020) Karaca, Zeynal MeteAmaç: Vücudumuzdaki en büyük organ olan karaciğerin immün sistem üzerindeki etkisi tam olarak bilinmemektedir. Projemizin amacı, kronik karaciğer fibrozu esnasında karaciğer ve sekonder lenfoid organ olan dalakta gelişen hücresel yanıtın moleküler düzeyde analizi ve ayrıca genç ve yaşlı deneklerden elde edilen verilerin karşılaştırılarak yaşlanmanın karaciğerdeki immün yanıt üzerine etkisinin araştırılmasıdır. Materyal ve Metot: Kronik fibroz modeli oluşturmak amacıyla BALB/c farelere ip. Thioacetamide enjeksiyonu yapılmıştır. Tüm gruplarda karaciğer ve dalak dokularında inflamatuar ve anti-inflamatuar sitokin genlerinin ifade edilme düzeyleri araştırılmış, karaciğer dokularında histolojik ve immünohistokimyasal analizler yapılmıştır. Bulgular: Genç fibrotik deneklerin karaciğer dokularında TNF-IL-10 ve TGF- gen ifade düzeyleri genç naive deneklere göre artış gösterirken, ROR-t,ve IFN- gen ifade düzeylerinde azalma saptanmıştır. Dalak dokularında ise GATA-3, FOXP3 ve TNF- gen ifade düzeyleri artış göstermiştir. Yaşlı fibrotik deneklerin karaciğer dokularında ROR-t, T-bet, IL-10 ve IFN- gen ifadeleri yaşlı naive deneklere göre azalmaktadır. Dalakta ise T-bet ve IFN- gen ifade seviyeleri azalmıştır. Yaşlanma ile beraber karaciğer dokusunda T-bet, IL-10 ve TGF- gen ifadelerinde artış saptanmıştır. Ayrıca yaşlı deneklerin dalaklarında TGF-IL-17, ROR-t ve IL-2 dışındaki tüm genlerin ifade düzeyleri artmıştır. Sonuç: Karaciğer fibrozu esansında genç bireylerde karaciğerin hem inflamatuar hem de anti-inflamatuar yanıtı desteklediği, dalakta ise anti-inflamatuar yanıtı desteklediği anlaşılmaktadır. Yaşlanmaya bağlı olarak fibroza karşı verilen immün yanıtın farklılık gösterdiği anlaşılmaktadır. Anahtar kelimeler: Fibrozis, Karaciğer, Dalak, SitokinÖğe Protective Effect of Canaboid Type 2 Receptor Agonist (JWH-133) Against Hepatic Endoplasmic Reticulum Stress Induced by Prangos Ferulacea Extract(Wiley, 2022) Celik, Mesut; Duzova, Halil; Karaca, Zeynal Mete; Tasidere, Asli Cetin; Gecibesler, Ibrahim Halil; Caliskan, Ali Riza[Abstract Not Available]Öğe The relationship between caspase-1 related inflammasome expression and serum inflammatory cytokine levels during acute brucellosis(Kare Publ, 2019) Karaca, Gamze; Karaca, Zeynal Mete; Kayhan, Basak; Bayindir, Yasar; Kayabas, Uner; Toplu, Sibel; Elmasdag, SirvanOBJECTIVE: Brucellosis is a zoonotic disease caused by Brucella in domestic and wild animals. It also causes systemic diseases with the involvement of different parts of the human body. An efficient innate immune response is crucial to cure brucellosis with optimum antibiotic treatment. The inflammasomes are innate immune system receptors and sensors that regulate the activation of cysteine-dependent aspartate specific protease-1 (caspase-1) and caspase-1-induced cell death process known as pyroptosis. The aim of the present study was to investigate the expression levels of CASPASE-1 and associated inflammasomes AIM2, NLRP3, and NLRC4 to analyze their relationship with the inflammatory cytokine interleukin (IL)-1 beta, IL-18, and interferon-gamma (IFN-gamma) in peripheral blood samples of patients with acute brucellosis with healthy controls. METHODS: Peripheral blood samples were obtained from 20 healthy volunteers and 20 patients with acute brucellosis. RNA and serum samples were isolated to examine the expression levels of AIM2, NLRP3, NLRC4, and CASPASE-1 by real-time polymerase chain reaction, and IL-1 beta, IL-18, and IFN-gamma were measured by enzyme-linked immunosorbent assay. RESULTS: In the acute brucellosis group, AIM2 and NLRC4 expressions were significantly higher than in healthy volunteers. A significant increase on caspase-1 expression in patients with acute brucellosis was not observed. Serum IL-18 and IFN-gamma levels were significantly higher in patients with acute brucellosis than in healthy controls. CONCLUSION: Caspase-1-related inflammasomes are sufficiently activated to induce the secretion of cytokines, such as IFN-gamma and IL-18, to induce cellular immune response. Caspase-1 activation level should be investigated at different periods of disease in a group with high number of patients to understand the role of pyroptosis and caspase-1 in brucellosis.
