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Abirateron ve Docetaxel Tedavileri Metastatik Prostat Kanseri Hücrelerinde Phospho-PTEN Ekspresyonunu Arttırır
(2023) Soylu, Hakan; Istıl, Kübra Aksu; Ustunel, Ismail; Karaçor, Kayıhan; Beyazçiçek, Özge
Amaç: Prostat kanseri erkeklerde kanser ile ilişkili ölümlerde ikinci sırada yer almaktadır. Kastrasyona dirençli metastatik prostat kanseri tedavilerinde dosetaksel ve abirateron asetat yaygın olarak kullanılmaktadır. Phospho-PTEN, onkojenik Akt hiperaktivasyonuna sebep olarak hücrelerde proliferasyon, migrasyon, angiyogenez ve hayatta kalmayı tetikler. Bu çalışmada prostat kanseri tedavisinde yaygın olarak kullanılan dosetaksel ve abirateron asetat ajanlarının onkogenic yolağı uyaran phospho-PTEN ekspresyonu üzerine etkisinin araştırılması amaçlanmışır. Gereç ve Yöntemler: In vitro olarak antijen reseptör (+) ve androjen reseptör (-) metastatik prostat kanseri hücre hatlarında dosetaksel ve abirateron acetat’ın phospho-PTEN expresyonu üzerine etkisi immünofloresan yöntemi ile araştırılmıştır. Bulgular: Antijen reseptör (+) ve androjen reseptör (-) metastatik prostat kanseri hücre hatlarının her ikisinde de bulgular birbiriyle uyumluydu. Kontrol ve abirateron asetat grupları arasında phospho-PTEN ekspresyonununda istatistiksel olarak anlamlı bir fark gözlenmedi. Dosetaksel ve abirateron asetat+dosetaksel gruplarında phospho-PTEN ekspresyonu kontrole göre istatistiksel olarak anlamlı şekilde arttı. Bu artış iki ajanın birlikte verildiği kombine grupta dosetaksel grubuna kıyasla istatistiksel olarak anlamlı şekilde daha fazlaydı. Sonuç: Dosetaksel ve kombine tedavi gruplarında belirgin şekilde phospho-PTEN artışı gözlendi. Phospho-PTEN’in artışı onkojenik Akt hiperaktivasyonuna neden olmaktadır. Bu bilgilere göre, dosetaksel ve kombine ilaç tedavileri hastalarda phospho-PTEN artışına sebep olarak hücrelerde onkojenik yolağı destekliyor olabilir. Hastalarda bu etkilerinin bertaraf edilebilmesi için PTEN’i defosforile edici ajanlar ya da defosforilasyonu sağlayan yolakların uyarılmasını sağlayacak ajanların verilmesi hastaların toplam hayatta kalma sürelerini artırabilir.
Characterization of Apelin/APJ Axis Expression in Normal Testicular Tissue, Germ Cell Neoplasia in Situ, and Testicular Seminoma
(2023) Soylu, Hakan; Ünal, Betül; Aksu, Kubra; Karacor, Kayihan; Beyazçiçek, Özge; Üstünel, İsmail
Aim: A testicular germ cell tumour is not observed widely, but its incidence and mortality rates have increased in recent years. One of the most common forms of this tumour is seminoma. Germ cell neoplasia in situ (GCNIS) is the precursor of seminoma. The apelin/APJ axis is increased in many cancers and is a pathway that plays an active role in angiogenesis, lymphangiogenesis, tumour growth, and migration. This study investigated the cellular distributions of apelin and APJ protein expressions in normal testicular tissue (TT), GCNIS, and seminoma.Material and Methods: Tissues from 18 patients who had undergone orchiectomy were used in this study. These tissues include areas of normal TT, GCNIS, and seminoma. Immunolocalisation of apelin and APJ were identified through the immunohistochemical method.Results: Apelin expression was significantly increased in seminoma and GCNIS compared to normal. Apelin expression were the same in GCNIS and seminoma. APJ expression was significantly increased in seminoma compared to normal and GCNIS. Normal and GCNIS APJ expressions were similar.Conclusion: Expressions of apelin and APJ proteins were significantly increased in seminoma in our study. Our findings were consistent with the results of relevant studies as increased expression of apelin/APJ has been observed in many different cancers. It can be predicted that the increase of this pathway in seminoma may support angiogenesis, lymphangiogenesis, migration, and metastasis. Therefore, the increase in mortality rates in seminoma patients may be related to apelin/APJ axis. Ultimately, the use of inhibitors of this pathway in these patients may reduce their mortality rate. New studies are needed before these inhibitors can be used clinically.
The effect of apelin-13 on gastric ischemia/reperfusion injury: the roles of sensory nerves and vagus nerve
(Canadian Science Publishing, 2020) Birsen, Ilknur; Izgut-Uysal, V. Nimet; Soylu, Hakan; Ustunel, Ismail
Apelin is a peptide that plays a role in physiological processes such as angiogenesis, apoptosis, and proliferation. The aim of this study was to investigate the role of capsaicin-sensitive afferent neurons and vagus in the effect of apelin against ischemia/reperfusion (I/R) injury. The experimental groups were (1) control, (2) I/R, (3) apelin + I/R, (4) vagotomy + I/R, (5) vagotomy + apelin + I/R, (6) capsaicin + I/R, (7) capsaicin + apelin + I/R, (8) lorglumide + I/R, and (9) lorglumide + apelin + I/R. To test the potential gastroprotective effect of apelin-13, apelin-13 (2 mg/kg i.v.) was administered just before both ischemia and reperfusion. A vagotomy was performed 1 week before I/R in the vagotomized groups; capsaicin (125 mg/kg s.c.) was administrated 2 weeks before I/R in the capsaicin-treated groups and lorglumide (5 mg/kg i.p.) was administered 30 min before I/R in the lorglumide-treated groups. After I/R, a variety parameters in gastric tissue were analyzed. cfos expression was determined in brainstem samples. In the I/R group, the lesion index, myeloperoxidase activity, lipid peroxidation, nitric oxide, and tumor necrosis factor-alpha increased, and mucosal blood flow, prostaglandin-E2, and calcitonin gene related peptide decreased. Apelin prevented the damaging effects of I/R and increased cfos expression in brainstem areas. Vagotomy, capsaicin, and lorglumide largely eliminated the gastroprotective effects of apelin-13. This study showed that sensory nerves and the vagus play regulatory roles in apelin-induced gastroprotection. Cholecystokinin may play a role in the effect of apelin through sensory neurons.
Effect of Hydroxytyrosol on Prdx6 Expression in Diabetic Rat Liver
(Duzce Univ, Fac Medicine, 2023) Almali, Eda Nur; Karacor, Kayihan; Soylu, Hakan
Aim: Oxidative stress caused by hyperglycemia, which is the most important complication of diabetes mellitus, causes liver damage. Hydroxytyrosol is a polyphenolic compound abundant in olive oil that protects the liver against oxidative damage. Peroxiredoxin 6 (Prdx6) is an anti-oxidative enzyme known to exist in the liver. The aim of this study was to investigate the effect of hydroxytyrosol on Prdx6 expression in diabetes-induced liver injury. Material and Methods: Male Wistar rats were grouped into four as the control group (n=10), hydroxytyrosol group (n=10), streptozotocin group (n=10), and hydroxytyrosol+streptozotocin group (n=10). Blood glucose levels of the animals were measured after streptozotocin injection and at the end of the experiment. The general structure of the liver was examined with a hematoxylin-eosin stain. Prdx6 protein expression was determined with an immunohistochemical method. Results: In the streptozotocin+hydroxytyrosol group, blood glucose level was found to be lower when compared with the streptozotocin group (p<0.001), and histopathological findings in hepatocytes were found to decrease. Prdx6 expression was found to be similar in the control and hydroxytyrosol groups (p=0.590). However, it was found to be higher in streptozotocin and streptozotocin+hydroxytyrosol groups (p<0.001). Prdx6 expression of the streptozotocin+hydroxytyrosol group was found lower than the streptozotocin group (p<0.001). Conclusion: Hydroxytyrosol, the anti-oxidative activity of which has been proven in many studies, was found to relieve blood glucose levels in diabetic rats, cause histopathological changes in hepatocytes, and decrease anti-oxidative Prdx6 expression. This decrease suggested that instead of inhibiting Prdx6, hydroxytyrosol reduced oxidative stress irrespective of Prdx6.
The effects of hydroxytyrosol on Prdx6 and insulin expression in diabetic rat pancreases
(Springer, 2023) Soylu, Hakan; Karacor, Kayihan
Diabetes mellitus is a widespread endocrine disease worldwide, accompanying chronic hyperglycemia. In this study, we investigated the effect of hydroxytyrosol, which exerts an antioxidant effect, on the expressions of insulin and peroxiredoxin-6 (Prdx6), which protect cells against oxidative injury in diabetic rat pancreas. This experimental study had four groups with ten animals in each group: control (nondiabetic) group, hydroxytyrosol group [10 mg/kg/day intraperitoneal injection (ip) hydroxytyrosol for 30 days], streptozotocin group (single ip injection of 55 mg/kg streptozotocin), and streptozotocin + hydroxytyrosol group (single ip injection of streptozotocin and ip injection of 10 mg/kg/day hydroxytyrosol for 30 days). During the experiment, blood glucose levels were measured at regular intervals. Insulin expression was determined by immunohistochemistry and Prdx6 expression was determined by immunohistochemistry and western blot. Immunohistochemistry and western blot results were analyzed by one-way ANOVA with applied Holm-Sidak multiple comparison test, and blood glucose results were analyzed by two-way repeated measures ANOVA with applied Tukey's multiple comparison test. Blood glucose levels on days 21 and 28 were significantly lower in the streptozotocin + hydroxytyrosol group compared with the streptozotocin group (day 21, p = 0.049 and day 28, p = 0.003). Expression of both insulin and Prdx6 were lower in the streptozotocin and the streptozotocin + hydroxytyrosol groups compared with the control and hydroxytyrosol groups (p < 0.001). Insulin and Prdx6 expression in the streptozotocin + hydroxytyrosol group were higher compared with the streptozotocin group (p < 0.001). The immunohistochemical findings of Prdx6 and western blot were the same. In conclusion, hydroxytyrosol, which is an antioxidant compound, increased Prdx6 and insulin expression in diabetic rats. Insulin increased by hydroxytyrosol may have been effective in reducing blood glucose levels. Furthermore, hydroxytyrosol may exert its effect on insulin by increasing Prdx6 expression. Thus, hydroxytyrosol may decrease or prevent several hyperglycemia-dependent complications by increasing the expression of these proteins.
Effects of isotretinoin and acitretin on neuroregeneration in experimental spinal cord injury
(Turkish Assoc Orthopaedics Traumatology, 2023) Kilic, Guven; Polat, Omer; Sensoy, Dogan; Soylu, Hakan
Objective: This study aimed to determine whether isotretinoin and acitretin have beneficial effects on neural tissue damage following acute spinal cord injury. Methods: Thirty-six rats were randomly divided into 6 groups: control, sham spinal cord injury, spinal cord injury with isotretinoin 15 mg/ kg for 14 days, spinal cord injury with isotretinoin 15 mg/kg for 28 days, spinal cord injury with acitretin 10 mg/kg for 14 days, and spinal cord injury with acitretin 10 mg/kg for 28 days. The damage to the spinal cord was formed by the clip compression technique. A neurological evaluation was conducted on days 1, 14, and 28. All rats were sacrificed following the treatment period, and samples of their spinal cords were collected for histopathological analysis. Results: The inclined plane angle was significantly increased on the 14th and 28th days in the isotretinoin 15 mg and acitretin 10 mg groups, compared to the spinal injury group (P=.049 and P=.009, respectively). The Drummond-Moore criterion was significantly higher in the acitretin 10 mg group than in the injury group (P=.026). Cleaved Caspase-3 expression was similar in the isotretinoin 15 mg day 28 group and the control group (P > .05), but significantly decreased in the acitretin 10 mg 14th-day and acitretin 10 mg 28th-day groups compared to spinal injury isotretinoin 15 mg 14th-day and isotretinoin 15 mg 28th-day groups (P < .05). Conclusion: This was the first study elaborating that isotretinoin and acitretin reduced neuronal apoptosis and improved functional recovery after spinal cord injury. These neuroprotective effects might open a window of opportunity for patients.
Evaluation of angiogenic apelin/apelin receptor axis in normal prostate, high grade prostatic intraepithelial neoplasia and prostatic adenocarcinoma
(Malaysian Society of Pathologists, 2022) Soylu, Hakan; Ünal, B.; Aksu, K.; Avci, S.; Caylan, A.E.; Üstünel, İ.
Introduction and Objectives: Prostate cancer is one of the most commonly diagnosed cancers in American men. Apelin is an endogenous peptide identified as the ligand of the G protein-associated apelin receptor. Apelin and apelin receptor have many tissues distribution and they participate in pathological processes, such as cancer. Apelin stimulates cancer angiogenesis. However, there are insufficient data in the literature regarding the role of apelin/apelin receptor in normal tissue, high-grade prostatic intraepithelial neoplasia, and prostatic adenocarcinoma tissues. Therefore, this study aimed to investigate the apelin and apelin receptor expression levels in tissues of normal prostate tissue, high-grade prostatic intraepithelial neoplasia, and prostatic adenocarcinoma. Materials and Methods: In this study, 38 samples of patients undergoing radical prostatectomy were used. Among 38 samples; 20 patients were with prostatic adenocarcinoma, 18 patients were with high-grade prostatic intraepithelial neoplasia and adjacent normal prostatic tissue areas. The immunolocalisation of apelin and apelin receptor in these tissues were determined immunohistochemically. Results: Apelin and apelin receptor expressions were higher in prostatic adenocarcinoma than normal prostate tissue and high-grade prostatic intraepithelial neoplasia. Apelin receptor expression was also increased in high-grade prostatic intraepithelial neoplasia compared to normal tissue. Conclusion: Apelin and apelin receptor are increase in the process of prostate carcinogenesis. This increase may adversely affect the clinical course of prostate cancer patients by stimulating angiogenesis, which is important for invasion and metastasis in prostate cancer. © 2022, Malaysian Society of Pathologists. All rights reserved.
Evaluation of angiogenic apelin/apelin receptor axis in normal prostate, high grade prostatic intraepithelial neoplasia and prostatic adenocarcinoma
(Malaysian Journal Pathology, 2022) Soylu, Hakan; Unal, Betul; Aksu, Kubra; Avci, Sema; Caylan, Ahmet Ender; Ustunel, Ismail
Introduction and Objectives: Prostate cancer is one of the most commonly diagnosed cancers in American men. Apelin is an endogenous peptide identified as the ligand of the G protein-associated apelin receptor. Apelin and apelin receptor have many tissues distribution and they participate in pathological processes, such as cancer. Apelin stimulates cancer angiogenesis. However, there are insufficient data in the literature regarding the role of apelin/apelin receptor in normal tissue, highgrade prostatic intraepithelial neoplasia, and prostatic adenocarcinoma tissues. Therefore, this study aimed to investigate the apelin and apelin receptor expression levels in tissues of normal prostate tissue, high-grade prostatic intraepithelial neoplasia, and prostatic adenocarcinoma. Materials and Methods: In this study, 38 samples of patients undergoing radical prostatectomy were used. Among 38 samples; 20 patients were with prostatic adenocarcinoma, 18 patients were with high-grade prostatic intraepithelial neoplasia and adjacent normal prostatic tissue areas. The immunolocalisation of apelin and apelin receptor in these tissues were determined immunohistochemically. Results: Apelin and apelin receptor expressions were higher in prostatic adenocarcinoma than normal prostate tissue and high-grade prostatic intraepithelial neoplasia. Apelin receptor expression was also increased in high-grade prostatic intraepithelial neoplasia compared to normal tissue. Conclusion: Apelin and apelin receptor are increase in the process of prostate carcinogenesis. This increase may adversely affect the clinical course of prostate cancer patients by stimulating angiogenesis, which is important for invasion and metastasis in prostate cancer.
Expression of nuclear factor-erythroid 2-related factor 2 (Nrf2) in mouse uterus during the peri-implantation period
(Taylor & Francis Ltd, 2023) Soylu, Hakan; Aksu, Kübra; Gölal, Ezgi; Ustunel, Ismail; Izgut-Uysal, V. Nimet; Acar, Nuray
Nuclear factor-erythroid 2-related factor- 2 (Nrf2) is a nuclear transcription factor that facilitates transcription of genes for detoxification enzymes and antioxidant proteins. We investigated the distribution and expression of Nrf2 during the peri-implantation period. We detected Nrf2 in uteri of mice during estrus (control) and on days 1, 4, 5, 6 and 8 of pregnancy using immunohistochemistry, quantitative real-time polymerase chain reaction and western blotting. Nrf2 immunostaining was significantly greater on days 1, 5 and 6 of pregnancy compared to controls, and on days 4 and 8 of pregnancy; western blotting results were consistent with immunohistochemical observations. Nrf2 mRNA levels on days 5 and 8 were significantly higher than for control uteri. Increased expression of Nrf2 on days 1, 5 and 6 of pregnancy may be important for uterine receptivity, implantation and decidualization by protecting the developing embryo and uterus from the adverse effects of oxidative stress.
Expressions of Notch signalling pathway members during early pregnancy in mice
(Springer, 2023) Acar, Nuray; Soylu, Hakan; Avci, Sema; Ustunel, Ismail
Although pregnancy is initiated and maintained through highly complex mechanisms, it is essential to understand the events that occur before and during early pregnancy to understand a healthy implantation process. The Notch signal, thought to be involved in this process, is frequently the subject of research with its different aspects. To better understand the role of Notch signaling in the peri-implantation period of the mouse uterus, we investigated the state of expression and localization of Notch 3, Notch 4, Rbp-J, Hes1, Hes7, Hey2, HeyL, and Fbw7 in the uterus and implantation sites in early pregnancy. Balb/C mice were divided into groups D1, D4, D5, D6, and D8. For D5 and D6 groups, implantation sites were identified by intravenous injection of Chicago blue. IHC, WB, and QRT-PCR methods were used. Notch 3 was very strong positive on the 4th day of pregnancy. Notch 4 was highly expressed on days 4, 5, 6, and 8 of pregnancy when P-4 levels were high. Hes 1 level was at the lowest on the 4th day of pregnancy. Hes 7 protein expression gradually increased from D1 to D8 in the uteri and implantation sites. Hey 2 expression was at the highest level on the 1st and 4th days. Hey L expression was on the apical of the glands. Fbxw7 that expression was high on the 1st and 4th days of pregnancy. Notch signaling may play an essential role in regulating endometrial receptivity. In addition, our Hes7 results are new to the literature.
Misoprostol-Induced Modification of the Notch Signaling Pathway in the Human Cervix
(Sage Publications Inc, 2019) Avcı, Sema; Şimşek, Mehmet; Soylu, Hakan; Üstünel, İsmail
The complex and multifactorial mechanisms that initiate and sustain the early labor process in the human uterus and cervix are still not well defined. Cervical maturation or ripening is likely to play a key role in preparing for birth. Prostaglandins have many different functions, including the regulation of uterine contractility and structure during pregnancy. The prostaglandin E1 analogue misoprostol is frequently used as a uterotonic and cervical ripening agent. Notch is a transmembrane receptor family responsible for basic functions such as cell survival, cell-cell communication, and differentiation and decidualization in pregnancy. However, our understanding of the effect of Notch signaling on the cervical ripening process is limited. This study was conducted in 20 pregnant women aged at 12 to 20 weeks of gestation undergoing medical abortion for fetal or maternal indications. True-Cut needle biopsies were taken from the anterior cervix 4 hours after oral ingestion of 200-mu g misoprostol or before the ingestion of misoprostol in the control group. Cervical expression of Notch receptors and ligands changed during the early phase of prostaglandin-induced preterm labor. Four hours after the administration of misoprostol, it was seen that N1 expression increased in muscle, while DLL1 and J2 expression increased in blood vessels, and N4 expression increased in macrophages. Knowing the mechanisms that initiate preterm birth is the most important step in planning the treatments and actions to prevent premature birth. As a signal that affects and perhaps directs preterm labor, Notch is prone to be an important actor in this process.
The protective effect of docosahexaenoic acid on the stomach in Parkinson's disease induced by MPTP in male C57BL/6 mice
(Univ Zagreb Vet Faculty, 2022) Birsen, İlknur; Avci, Sema; Izgut-Uysal, V. Nimet; Soylu, Hakan; Özkan, Ayşe; Parlak, Hande; Acar, Nuray
The purpose of this study was to detect gastric changes in Parkinson's disease induced by 1-methyl-4-phenyl-1.2.3.6.-tetrahydropyridine (MPTP), and to investigate the protective effect of docosahexaenoic acid (DHA) against these changes in mice. The mice were divided into 4 groups (n=10 in per group) as control, DHA, Parkinson and DHA+Parkinson groups. DHA was administered by gavage for 30 days. On the 23th day of gavage treatment, the animals of the Parkinson and DHA+Parkinson groups were intraperitoneally injected with MPTP. Seven days after the injection of MPTP, their locomotor activity, bradykinesia and rotarod performance were measured. Tyrosine hydroxylase expression in substantia nigra and the apoptotic index, the concentrations of tumor necrosis factor-alpha and histamine, and the number of mast cells in the stomach were evaluated. Administration of DHA significantly prevented the reduction in motor functions (P<0.001) and nigral TH neurons (P<0.05), and apoptosis (P<0.05), and an increase in TNF-alpha concentration (P<0.01) in the stomach. An increase in the number of mast cells in the stomach wall was observed in PD (P<0.001). DHA prevented the increase in the number of mast cells (P<0.05) and the histamine level (P<0.01) due to PD. As a result, MPTP administration in mice caused changes in the stomach as well as impairment in motor functions, and DHA was observed to reduce these changes.
The Role of Cholecystokinin in the Gastroprotective Effect of Apelin Against to Ischemia/Reperfusion-Induced Injury
(Wiley, 2018) Birsen, İlknur; Uysal, V. Nimet İzgüt; Soylu, Hakan; Üstünel, İsmail
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