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Öğe Comparative evaluation of relaxant effects of three prangos species on mouse corpus cavernosum: Chemical characterization and the relaxant mechanisms of action of P. pabularia and (+)-oxypeucedanin(Elsevier Ireland Ltd, 2022) Sevin, Gulnur; Alan, Elif; Demir, Serdar; Albayrak, Gokay; Demiroz, Tugce; Yetik-Anacak, Gunay; Baykan, SuraEthnopharmacological relevance: Erectile dysfunction (ED) is the most common form of sexual dysfunction which has been the topic of great interest through the history by all cultures. It is now among the most treated health problems in men of all ages that develop under the influence of lifestyle factors and some diseases. Plants are extensively used to cure sexual dysfunction for centuries. Roots of Prangos sp. have been used to improve sexual performance in Anatolian traditional medicine and are rich of coumarin, furanocoumarin and their derivatives. Scientific research is necessary to support and validate the ethno-traditional uses of these plants. Aim of the study: The aim of this study is to investigate the effects of the root extracts of P. pabularia, P. uechtritzii and P. heyniae on erectile function and to isolate and identify the chemical compounds of the most active extract and reveal possible pharmacological mechanism of the major compound of the extract with the strongest relaxant effect in mouse corpus cavernosum (MCC). Materials and methods: The roots of plants were extracted with chloroform, n-hexane and methanol. The compounds were isolated from the extract by column chromatography and structures were identified by NMR and MS. The relaxant effects of extracts (10(-7)-10(-4) g/mL), (+)-oxypeucedanin (10(-7) -10(-4) M) and Na 2 5 (10(-7) -3 x 10(-3) M) were tested in MCC strips by DMT myograph. To investigate the mechanism, the synthesis inhibitors of aminooxyacetic acid (AOAA, 10(-2) M) and nitro-L-arginine methyl ester (L-NAME, 10(-4) M) were used, respectively. H2S formation was evaluated basal and L-cysteine (L-cyst)-stimulated conditions by H2S microsensor. Results: All extracts relaxed MCC in a concentration dependent manner. The maximum relaxing effects were achieved with chloroform extracts. Chloroform extract of P. pabularia (Pp-CE) was more potent than the others. Pp-CE-induced relaxations were significantly decreased by AOAA and L-NAME. (+)-Oxypeucedanin, the major compound of Pp-CE, induced relaxant responses and this effect was inhibited by AOAA, but not L-NAME. The relaxation of (+)-oxypeucedanin was found to be similar in view of E-m(ax) to positive control H2S donor Na2S(+)-Oxypeucedanin increased L-cyst-stimulated H2S formation. Augmentation of H2S synthesis with (+)-oxypeucedanin was inhibited by AOAA. Conclusions: Pp-CE has the strongest effect on relaxation of MCC and this result supports the traditional aphrodisiac use of P. pabularia root extract in Anatolia. The pharmacological mechanisms of Pp-CE to relax MCC involve NO and H2S formation. (+)-Oxypeucedanin could be responsible for the H2S-mediated relaxations of Pp-CE in MCC.Öğe Cycloartane-type sapogenol derivatives inhibit NF kappa B activation as chemopreventive strategy for inflammation-induced prostate carcinogenesis(Elsevier Science Inc, 2018) Debelec-Butuner, Bilge; Ozturk, Mert Burak; Tag, Ozgur; Akgun, Ismail Hakki; Yetik-Anacak, Gunay; Bedir, Erdal; Korkmaz, Kemal SamiChronic inflammation is associated to 25% of cancer cases according to epidemiological data. Therefore, inhibition of inflammation-induced carcinogenesis can be an efficient therapeutic approach for cancer chemoprevention in drug development studies. It is also determined that anti-inflammatory drugs reduce cancer incidence. Cell culture-based in vitro screening methods are used as a fast and efficient method to investigate the biological activities of the biomolecules. In addition, saponins are molecules that are isolated from natural sources and are known to have potential for tumor inhibition. Studies on the preparation of analogues of cycloartane-type sapogenols (9,19-cyclolanostanes) have so far been limited. Therefore we have decided to direct our efforts toward the exploration of new anti-tumor agents prepared from cycloastragenol and its production artifact astragenol. The semi-synthetic derivatives were prepared mainly by oxidation, condensation, alkylation, acylation, and elimination reactions. After preliminary studies, five sapogenol analogues, two of which were new compounds (2 and 3), were selected and screened for their inhibitory activity on cell viability and NF kappa B signaling pathway activity in LNCaP prostate cancer cells. We found that the astragenol derivatives 1 and 2 as well as cycloastragenol derivatives 3, 4, and 5 exhibited strong inhibitory activity on NF kappa B signaling leading the repression of NF kappa B transcriptional activation and suppressed cell proliferation. The results suggested that these molecules might have significant potential for chemoprevention of prostate carcinogenesis induced by inflammatory NF kappa B signaling pathway.Öğe Decreased eNOS relaxations and relation with hsp90 in hypercholesterolemic rabbit aorta(Federation Amer Soc Exp Biol, 2013) Ozsarlak-Sozer, Gonen; Arun, Mehmet; Sevin, Gulnur; Ertuna, Elif; Yilmaz, Zeynep; Ulasan, Sema; Yetik-Anacak, GunayÖğe Different Responses of RT-PCR Amplifications after Tumor Necrosis alpha (TNFa) Induction at Nuclear Factor kappa B (NFkB) Gene Silenced LNCaP Cells(Federation Amer Soc Exp Biol, 2013) Gonen-Korkmaz, Ceren; Sevin, Gulnur; Gokce, Goksel; Arun, Mehmet Z.; Yetik-Anacak, Gunay; Yildirim, Gokce; Reel, Buket; Ogut, Deniz; Kaymak, AysegulÖğe Functional significance of hsp90-eNOS interaction in penile tissues(Federation Amer Soc Exp Biol, 2013) Yetik-Anacak, Gunay; Ertuna, Elif; Ozsarlak-Sozer, Gonen; di Pascoli, Saadet Turkseven; Koylu, Ersin; Gozen, Oguz; Sevin, Gulnur; Arun, Mehmet; Un, IsmailÖğe H2S releasing sodium sulfide protects against pulmonary hypertension by improving vascular responses in monocrotaline-induced pulmonary hypertension(Elsevier, 2022) Turhan, Kumru; Alan, Elif; Yetik-Anacak, Gunay; Sevin, GulnurPulmonary arterial hypertension is caused by complex structural and functional changes in the endothelial and smooth muscle cells of pulmonary arteries. Hydrogen sulfide (H2S), a gasotransmitter, can potentially treat pulmonary hypertension by relaxing the pulmonary arteries and decreasing bronchial pressure. Although the role of H2S in systemic circulation has been examined, the H2S levels in pulmonary arteries, the role of H2S in endothelium-dependent vasorelaxation and the L-cysteine/H2S pathway in monocrotaline-induced pulmonary arterial hypertension have not been investigated. The rats were divided into control, monocrotaline, monocrotaline + Na2S, and Na2S groups. The right ventricular pressure and hypertrophy were evaluated. KCl, acetylcholine, and L-cysteine responses were obtained in the main pulmonary arteries by wire myograph. H2S levels were measured in pulmonary arteries and lungs by methylene blue assay. Right ventricular pressure and hypertrophy were increased by monocrotaline and ameliorated by Na2S. The KCl-induced contractions and relaxing responses to acetylcholine and L-cysteine in pulmonary arteries and H2S production in the lungs and pulmonary arteries were significantly attenuated in the monocrotaline group and augmented in the monocrotaline + Na2S group. These findings suggest that H2S levels were reduced, and L-cysteine-induced and endothelium-dependent relaxations were impaired in the pulmonary arteries in monocrotaline-induced pulmonary arterial hypertension. The H2S donor, Na2S, prevented endothelial dysfunction and increased pulmonary artery pressure and hypertrophy. Also, Na2S enhanced the L-cysteine-mediated responses and restored the diminished H2S levels in pulmonary arteries and the lungs. The treatments targeting H2S might be beneficial for promoting vascular alterations, i.e. endothelial dysfunction and impaired H2S-mediated relaxation in pulmonary arterial hypertension.Öğe Hydrogen sulfide compensates nitric oxide deficiency in murine corpus cavernosum(Academic Press Ltd- Elsevier Science Ltd, 2016) Yetik-Anacak, Gunay; Dikmen, Aycan; Coletta, Ciro; Mitidieri, Emma; Dereli, Mehmet; Donnarumma, Erminia; Bianca, Roberta d'Emmanuele di Villa; Sorrentino, RaffaellaErectile dysfunction (ED) is considered as a marker for cardiovascular diseases. Nitric oxide (NO) deficiency is the major cause of erectile dysfunction (ED). The role of hydrogen sulfide (H2S) in erection has recently been recognized and is receiving attention as a pharmacological target. Several studies have focused on the effect of H2S on NO-dependent relaxation, but the role of NO on H2S in penile tissue has not been studied yet. Unlike NO, H2S is mainly synthesized from smooth muscle cells rather than endothelial cells. We hypothesized that H2S may compensate for the decreased NO bioavailability and may be beneficial in severe ED where endothelial dysfunction is present. Thus we studied the effect of NO deficiency on H2S formation and vasorelaxation induced by L-cysteine, which is the substrate of the H2S producing enzymes in mice corpus cavernosum (MCC). NO deficiency induced by Nw-Nitro-L-arginine (L-NNA) was confirmed by the inhibition of acetylcholine-induced relaxation. L-cysteine, the substrate for the endogenous H2S production, caused a concentration-dependent relaxation that was reduced by CBS/CSE inhibitor aminooxyacetic acid (AOAA) in MCC strips. L-NNA caused a significant increase in L-cysteine-induced relaxation, and this effect was reversed by AOAA. On the contrary, no change in relaxation to NaHS (exogenous H2S donor) in MCC was observed. L-NNA increased H2S formation stimulated by L-cysteine in wild type MCC but not in CSE(-/-)mice. In parallel, the expression of both cysthationine gamma lyase (CSE) and 3-mercaptopyruvate sulphurtransferase (3-MST) was increased, whereas cysthationine-beta synthase (CBS) was decreased in eNIOS(-/-)MCC. We conclude that H2S plays a compensatory role in the absence of NO by enhancing the relaxation induced by endogenous H2S through CSE and 3-MPST in MCC, without altering downstream mechanisms. We suggest that H2S-targeting drugs may provide the maintenance of compensatory treatment in ED patients. This may be more relevant in ED with severe endothelial dysfunction, as H2S is mainly derived from smooth muscle. (C) 2016 Elsevier Ltd. All rights reserved.Öğe Hydrogen sulfide: A novel mechanism for the vascular protection by resveratrol under oxidative stress in mouse aorta(Elsevier Science Inc, 2016) Yetik-Anacak, Gunay; Sevin, Gulnur; Ozzayim, Ozge; Dereli, Mehmet Vehbi; Ahmed, AsifReactive oxygen species (ROS) decreases bioavailability of nitric oxide (NO) and impairs NO-dependent relaxations. Like NO, hydrogen sulfide (H2S) is an antioxidant and vasodilator; however, the effect of ROS on H2S-induced relaxations is unknown. Here we investigated whether ROS altered the effect of H2S on vascular tone in mouse aorta and determined whether resveratrol (RVT) protects it via H2S. Pyrogallol induced ROS formation. It also decreased H2S formation and relaxation induced by L-cysteine and in mouse aorta. Pyrogallol did not alter sodium hydrogensulfide (NaHS)-induced relaxation suggesting that the pyrogallol effect on L-cysteine relaxations was due to endogenous H2S formation. RVT inhibited ROS formation, enhanced L-cysteine-induced relaxations and increased H2S level in aortas exposed to pyrogallol suggesting that RVT protects against "H2S-dysfunctions" by inducing H2S formation. Indeed, H2S synthesis inhibitor AOAA inhibited the protective effects of RVT. RVT had no effect on Ach-induced relaxation that is NO dependent and the stimulatory effect of RVT on H2S-dependent relaxation was also independent of NO. These results demonstrate that oxidative stress impairs endogenous H2S-induced relaxations and RVT offers protection by inducing H2S suggesting that targeting endogenous H2S pathway may prevent vascular dysfunctions associated by oxidative stress. (C) 2016 Published by Elsevier Inc.Öğe New mechanism for the beneficial effect of sildenafil on erectile function: H2S(Academic Press Inc Elsevier Science, 2013) Dikmen, Aycan; Bianca, Roberta d'Emmanuele di Villa; Mitidieri, Emma; Donnarumma, Erminia; Sevin, Gulnur; Cirino, Giuseppe; Sorrentino, Raffaella; Yetik-Anacak, GunayÖğe Relaxation mechanisms of chloroform root extracts of Prangos heyniae and Prangos uechtritzii on mouse corpus cavernosum(Wiley, 2022) Alan, Elif; Albayrak, Gokay; Sevin, Gulnur; Yetik-Anacak, Gunay; Baykan, SuraErectile dysfunction (ED) is the inability to achieve/maintain an erection. Because of the side effects, interactions, or ineffectiveness of currently used drugs, novel drug discovery studies are ongoing. The roots of Turkish endemic plants Prangos uechtritzii and Prangos heyniae are traditionally used as aphrodisiacs in Anatolia and contain coumarin-like relaxant compounds. This study aims to reveal the relaxant effect mechanisms of chloroform root extracts of P. heyniae (Ph-CE) and P. uechtritzii (Pu-CE). Isolated organ bath experiments were performed on Swiss albino mouse corpus cavernosum by DMT strip myograph. Relaxant responses to extract (10(-7)-10(-4) g/ml) were obtained in the presence/absence of NO and H2S synthesis inhibitors nitro-l-arginine methyl ester (l-NAME, 100 mu M) and aminooxyacetic acid (AOAA, 10 mM) respectively. Sodium nitroprusside (SNP, 10(-9) to 10(-4) M) and Na2S (10(-6) to 3 x 10(-3) M)-induced relaxations and CaCl2 (10(-6) to 10(-4) M), KCl (10(-2.1) to 10(-0.9) M) and phenylephrine (3 x 10(-8) to 3 x 10(-5) M)-induced contractions were taken in the presence/absence of the extracts (10(-4) g/ml). Relaxations induced by Ph-CE but not by Pu-CE were inhibited in the presence of l-NAME and AOAA. Ph-CE increased Na2S- and SNP-induced relaxations. Ph-CE and Pu-CE decreased the contractions of KCl, phenylephrine, and CaCl2. It was concluded that NO and H2S synthesis/downstream mechanisms play roles in relaxations of Ph-CE but not in Pu-CE-induced relaxations. Inhibition of calcium influx appears to be involved in the relaxant effect of Ph-CE and Pu-CE. Since the extracts act directly by relaxing smooth muscle or through H2S as well as NO, they may be a potential therapeutic agent in diseases such as ED where the bioavailability of NO is impaired.Öğe The role of eNOS on the compensatory regulation of vascular tonus by H2S in mouse carotid arteries(Academic Press Inc Elsevier Science, 2017) Ertuna, Elif; Loot, Annemarieke E.; Fleming, Ingrid; Yetik-Anacak, GunayThe gasotransmitter nitric oxide (NO) has an important role in vascular function and a decrease in its bioavailability is accepted as a main pathological mechanism for cardiovascular diseases. However, other gasotransmitters such as hydrogen sulfide (H2S) are also generated by the endothelium and can also affect vascular tone and a crosstalk may exist between H2S and NO. We therefore investigated the consequences of deficiency, replacement or overexpression of endothelial nitric oxide synthase (eNOS) on H2S-induced vascular responses in murine carotid arteries. In pre-contracted carotid arteries from wild-type (WT) mice, L-cysteine elicited relaxation that was inhibited by the H2S synthesis inhibitor amino-oxyacetic acid (AOAA). Genetic deletion of eNOS increased L-cysteine-induced relaxation compared to WT, but the replacement of eNOS by adenoviral transfection or H2S synthesis inhibition by AOAA reversed it. Furthermore, eNOS deletion did not alter NaHS-induced relaxation in carotid arteries while eNOS overexpression/replacement increased NaHS-induced relaxation responses in carotid arteries from WT or eNOS(-/-). We suggest that, endogenously produced H2S can compensate for impaired vasodilatory responses in the absence of NO to maintain vascular patency; while, eNOS abundance can limit endogenous H2S-induced vascular responses in mice carotid arteries. Our result suggests that endogenous vs. exogenous H2S-induced relaxation are reciprocally regulated by NO in mice carotid arteries. (C) 2017 Elsevier Inc. All rights reserved.
