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AMAÇ: Sepsis, sistemik inflamasyon ve yaşamsal organların disfonksiyonu ile tanımlanan yıkıcı bir hastalıktır. Phoenixin’in (PNX-14) çoğunlukla hipotalamusta ve kalpte eksprese olduğu ve iskemiyi takiben kardiyoproteksiyon sağladığı gösterilmiştir. Çalışmanın amacı, PNX-14'ün sepsis kaynaklı kardiyopulmoner hasar üzerinde yararlı etkisinin olup olmadığını değerlendirmek ve vagal liflerin bu etkiye katkısını açıklamaktır. YÖNTEMLER: Ketamin anestezisi altında, erkek SpragueDawley sıçanlara (310-390 g) taklit cerrahi (n=8) veya sepsisi indüklemek için çekal ligasyon ve ponksiyon (n=23) yapıldı. Sepsis yapılmadan önce, serum fizyolojik veya PNX-14 (50 µg/kg/gün) son 36 saat içinde tekrarlayan 3 doz şeklinde intraperitoneal olarak uygulandı. PNX-14 tedavisi alan sıçanların yarısında ek olarak vagal stimülasyon (VS) yapılırken diğerlerine VS yapılmadı. VS amacıyla sıçanlara, sepsisten 7 gün önce başlayarak, diazepam (5mg/kg) anestezisi altında aurikula konkalarındaki elektrotlar aracılığıyla düşük seviyeli transkutanöz VS (20 Hz, 0,2ms, 2mA, 30 dk/gün) uygulandı. Sepsisin 16. saatinde serum TNF-α ve IL-6 düzeylerini ölçmek için kardiyak ponksiyonla kan alındı, histolojik değerlendirme ve miyeloperoksidaz aktivitesi, glutatyon, katalaz, süperoksit dismutaz (SOD), malondialdehit seviyelerinin belirlenmesi için kalp ve akciğer örnekleri alındı. Veriler Student t-testi ve tek-yönlü ANOVA kullanılarak analiz edildi. BULGULAR: Sepsis, her iki dokuda hipotermiye, serum TNF-α ve IL-6 seviyelerinde artışa, her iki dokuda miyeloperoksidaz aktivitesinde ve histolojik hasar skorlarında artışa neden olurken, katalaz ve glutatyon seviyelerinde azalmaya neden oldu (p

Amaç: Çalışmada doğal yaşlanma sürecinde ya da D-galaktoz ile taklit edilenyaşlanma modelinde; 1- egzersizin torasik aortada endoteliyal fonksiyon üzerindekirolünü araştırmak, 2- iki farklı yaşlanma modelinin yağ dokusundaki irisindüzeylerini nasıl etkilediğini ortaya koymak ve yaşlanma ile ortaya çıkan olasıvasküler bozukluklardaki rolünü göstermek hedeflenmiştir.Gereç ve Yöntem: Bu çalışmada 12 haftalık (3 aylık) dişi (250-300 gr) SpragueDawley sıçanlar kullanılmıştır. Deney grupları 3 aylık sedanter (Genç; n=10), 3 aylıkegzersiz (Genç+E; n=10), 18 aylık doğal yaşlı sedanter (DY; n=10), 18 aylık doğalyaşlı egzersiz (DY+E; n=10), D-Galaktoz ile yaşlandırılmış sedanter (D-Gal; n=10)ve D-Galaktoz ile yaşlandırılmış egzersiz grubu (D-Gal+E; n=10) olmak üzereplanlanmıştır. Biyokimyasal, histopatolojik ve immunhistokimyasal analizler içinkalp ve aort dokusu alınmıştır. Plazma ve PVAD irisin düzeylerinin tayiniyapılmıştır. Vücut yağ oranı tespiti ve ayrıca torasik aortadan perivasküler adipozdoku içeren/içermeyen (PVAD+/-) halkalar ayrı ayrı izole organ banyolarındaçalışılmıştır.Bulgular: Yaşlanma gruplarının kalp dokusunda hem DY hem de D-Gal gruplarındaher ikisinde de oksidatif hasarda anlamlı şekilde artış ile birlikte antioksidankapasitede anlamlı şekilde azalma tespit edilmiştir. Egzersiz ile birlikte buparametrelerde anlamlı iyileşme kaydedilmiştir. Yaşa bağlı ortaya çıkan vaskülerdisfonksiyonun irisinin vazorelaksan yanıtlarına da etkili olduğu gösterilmiştir.Ayrıca yaşa bağlı bozulan irisin yanıtlarının düzenli egzersiz ile düzelebileceğiortaya konmuş, PVAD'nun irisine bağlı gevşeme yanıtlarındaki etkisi ilk defavurgulanmıştır. Yaşlanma ile birlikte aorta azalan irisin immune ekspresyonu ilebirlikte egzersiz ile artan ekspresyon gösterilirken PVAD'da egzersiz ile birlikteartan kahverengi yağ dokusundaki irisin ekspresyonu ifade edilmiştir. Artan PVADirisin düzeyleri ELİSA ile de teyit edilmiştir.Sonuçlar: Yaşlanma ile birlikte PVAD'da meydana gelen değişiklikler vesonucunda damar yanıtlarında doğan faklılıkların tartışıldığı çalışmadasonuçlarımızın egzersiz ile birlikte irisin'e verilen yanıtlarda PVAD'nun katkısınıaydınlattığını düşünmekteyiz. Objective (Aim): The aim of this study is to investigate possible effect of exerciseon endothelial function of thoracic aortae in both natural aging and D-galactosemimetic ageing models. The second aim of present study is to demonstrate the levelof irisin on these aging models and also elucidiate the role of irisin on vasculardysfunction resulted in ageing.Material and Methods: Female Sprague-Dawley rats were obtained; 3-month-old,young group (n=10), 3-month-old young exercise group (n=10), 18-month-old, agedgroup (n=10), 18-month-old, aged exercise group (n=10) groups, D-galactosemimetic aging group (n=10), D-galactose induced aging exercise group (n=10).Cardiac and aortic samples were collected for biochemical, histopathological andimmunohistochemistry examination. The body fat ratio was calculated and thoracicaortas were taken for contractile responses studies in the absence or presence ofperivascular adiposes tissue (PVAT+/-). The levels of irisin in both plasma andPVAT were detected.Results: Although there were concurrence between ageing models (natural aging andD galactose mimetic ageing) according to oxidative stress and decreased antioxidantcapacities, it was obtained that the time for developing vascular dysfunction and themechanism of action were different and inadequate in these models. Vasorelaxantresponses of irisin in age-related vascular dysfunction have also been shown. Inaddition, age-related impaired irisin responses were found to be improved by regularexercise and the effect of PVAT on irisin-induced relaxation responses wasemphasized for the first time. Immune expression of irisin decreased in aorta withaging and it was increased by exercise. Increased PVAD iris levels have also beenconfirmed with ELISA.Discussion: In conclusion our results show the differences in vascular function andPVAT in aging and the contribution of PVAT to the response of irisin with exercise.The changes in PVAT with ageing and their effects on vascular response werediscussed. The attribution of PVAT on response of irisin during exercise would beelucidiated according to these results. 172

ÖZETÇalışmada doğal yaşlanma sürecinde ya da D-galaktoz ile taklit edilenyaşlanma modelinde ABSTRACTThe aim of this study is to investigate possible effect of exerciseon endothelial function of thoracic aortae in both natural aging and D-galactosemimetic ageing models.

Objectives: Studies have indicated that oxytocin (OT), a regulatory nonapeptide synthesized in the hypothalamic supraoptic and paraventricular nuclei, is endogenously released into blood following a fatty meal or by the stimulation of exogenous cholecystokinin (CCK). Despite OT’s acceleratory effect on gastric emptying, there are also experimental studies documenting its delaying action. Methods: Sprague Dawley rats were used to evaluate the effect of centrally or peripherally administered OT on the gastric emptying rate of a liquid meal in awake rats and to explain the interaction of OT and CCK-2 receptors in these effects. Under anesthesia, a group of rats was inserted intracerebroventricularly (icv) for drug applications, while some were inserted with stainless steel gastric cannulas for gastric emptying. Before gastric emptying tests were performed, rats were given intraperitoneally or icv saline, OT, OT antagonist atosiban (ATO) and/or CCK-2 antagonist L365,260. Following the drug injections, in another group that had no gastric cannula placement, rats were given orogastrically methylcellulose containing phenol red, and the gastric emptying rate was calculated.Results: Both central and peripheral injections of OT slowed the gastric emptying of physiological saline in rats with gastric cannula, while gastric emptying of methyl cellulose was accelerated at the 30th minute. It has been shown by using the receptor antagonist ATO that endogenous OT has an accelerating effect. The acceleratory effect of the exogenous OT on methyl cellulose in the late period was suppressed by ATO, but CCK-2 antagonist had no effect.Conclusion: In the experiments performed by using a viscous methyl cellulose meal and solutions through the gastric cannulas, exogenous OT inhibits gastric motility for a short term and then accelerates. Endogenous OT increases gastric emptying, while OT and CCK-2 receptors mediate these effects.Key words: Atosiban, CCK-2 receptors, gastric cannula, gastric emptying, Amaç: Hipotalamusta supraoptik ve paraventriküler çekirdeklerde sentezlenen düzenleyici bir nonapeptit olan oksitosinin (OT) yağlı bir öğün sonrası endojen olarak ya da kolesistokininin (CCK) eksojen olarak uyarılmasıyla kana verildiği gösterilmiştir. OT’nin sağlıklı bireylerde mide boşalma hızını artırdığını gösteren çalışmalara karşın, yavaşlattığını belgeleyen deneysel çalışmalar da bulunmaktadır.Yöntem: Santral veya periferik yolla verilen OT’nin ya da endojen OT’nin sıvı gıdanın mideden boşalma hızı üzerine etkisini uyanık sıçanlarda ölçmek ve bu etkilerde OT ve CCK-2 reseptörlerinin aracılığını açıklamak amacıyla Sprague Dawley sıçanlar kullanıldı. Anestezi uygulanan sıçanların bir grubuna ilaç uygulamaları için intraserebroventriküler (isv) kanül, bir gruba ise paslanmaz çelik mide kanülü yerleştirildi. Mide boşalma testleri öncesinde sıçanlara intraperitoneal veya isv olarak serum fizyolojik, OT, OT antagonisti atosiban (ATO) ve/veya CCK-2 antagonisti L365,260 enjeksiyonları yapıldıktan sonra mide boşalma testi uygulandı. Mide kanülü yerleştirilmeyen bir grup sıçanda ise ilaç enjeksiyonları sonrası fenol kırmızısı eklenmiş metil selüloz, orogastrik gavajla verilip mide boşalma hızları hesaplandı.Bulgular: Mide kanüllü sıçanlarda OT’nin hem santral hem de periferik enjeksiyonu fizyolojik tuzlu suyun mideden boşalmasını yavaşlatıp, metil selülozun mide boşalmasını 30. dakikada hızlandırdı. Reseptör antagonisti ATO verilerek endojen OT’nin hızlandırıcı etkili olduğu ortaya kondu. Eksojen verilen OT’nin geç dönemde metil selülozun boşalmasını hızlandırıcı etkisini ATO baskılarken, CCK-2 antagonistinin etkisi gözlenmedi.Sonuçlar: Sonuç olarak, ekzojen OT visköz bir sıvı olan metil selüloz ve mide kanülü aracığıyla yapılan deneylerde mide motilitesini kısa süreli olarak inhibe etmekte ve ardından hızlandırmakta, endojen OT ise mide boşalmasını artırıcı etki göstermekte ve OT ve CCK-2 reseptörleri OT’nin bu etkilerinde aracılık etmektedirler.Anahtar Kelimeler : Atosiban, CCK-2 reseptörleri, mide kanülü, mide boşalması

In order to demonstrate the possible protective effects of estrogen receptor (ER)-alpha and ER beta receptor subtypes in the pathogenesis of colonic and gastric oxidant damage, experimental ulcer and colitis were induced by acetic acid, and the animals were randomly divided as colitis, ulcer, and their corresponding non-ulcer and non-colitis control groups. Each group of rats was treated intramuscularly with the vehicle, selective ER alpha agonist propylpyrazole-triol (1 mg/kg), ER beta agonist diarylpropionitrile (1 mg/kg), non-selective ER agonist 17 beta estradiol (E2; 1 mg/kg), or E2 plus non-selective ER antagonist ICI-182780 (1 mg/kg). The results revealed that induction of ulcer or colitis resulted in systemic inflammation as assessed by increased levels of plasma TNF-alpha and IL-6 levels. In both tissues, the presence of oxidant damage was verified by histological analysis and elevated myleoperoxidase activity. In the colitis and ulcer groups, both ER agonists and the non-selective E2 reversed the oxidative damage in a similar manner. These findings indicate that estrogen acts via both ER alpha- and ER beta-mediated and direct antioxidant mechanisms, where both ER subtypes play equal and efficient roles in the anti-inflammatory action of estrogen, in limiting the migration of neutrophils to the inflamed tissue, reducing the release and activation of cytokines and thereby alleviating tissue damage.

Background and Objectives:Obestatin and ghrelin are hormones derived from the same gene but have opposing effects. Ghrelin has anti-inflammatory activities; however, the role of obestatin in the inflammatory processes has not been clearly demonstrated yet. The aim of the study was to analyse and compare the anti-inflammatory effect of exogenous ghrelin and obestatin in a rat model of colitis.Methods:Acute and chronic colitis was induced in 96 rats by adding 3% dextran sulfate sodium to the drinking water for 5 and 10 days, respectively. Intraperitoneal pretreatment with ghrelin or obestatin was started before the induction of colitis, and continued for 5 and 10 days. Clinical signs of the disease and histopathological changes were evaluated. By-products of neutrophil activation, lipid peroxidation, and inflammatory and anti-inflammatory cytokines were measured in colonic tissues.Results:Obestatin and ghrelin significantly ameliorated clinical and histopathological severity of chronic colitis, whereas they were less effective in the acute form. Therapeutic effect of ghrelin and obestatin in acute colitis was associated with reduced lipid peroxidation and T(h)1-induced inflammatory response, whereas obestatin in chronic colitis was protective via the suppression of polymorphonuclear leukocyte infiltration and enhancement of glutathione synthesis. Moreover, therapeutic effects of ghrelin and obestatin in chronic colitis appear to be associated with inhibition of inflammatory and activation of anti-inflammatory cytokines.Conclusions:This study demonstrated the novel anti-inflammatory effect of obestatin and ghrelin in an experimental model of colitis. Although both obestatin and ghrelin exerted anti-inflammatory effects in chronic colitis, they were less effective in acute colitis.

Neither HFD nor NES-1 changed methylcellulose emptying, but NES-1 delayed saline emptying in cannulated ND-rats. Inhibitory effect of NES-1 on gastric emptying in ND-rats was reversed by all antagonists, and abolished in HFD-rats. In HFD-rats, carbachol-induced contractility was enhanced in gastric, but inhibited in ileal strips. HFD increased body weight, while serum triglycerides, alanine transaminase, aspartate aminotransferase, glucose, and levels of malondialdehyde, glutathione, myeloperoxidase activity, and luminolchemiluminescence in hepatic, ileal, and adipose tissues were similar in ND- and HFD-rats, but only lucigenin-chemiluminescence was Background/Aims Gastrointestinal motility changes contribute to development and maintenance of obesity. Nesfatin-1 (NES-1) is involved in central appetite control. The aim is to elucidate effects of NES-1 and high-fat diet (HFD) on gastrointestinal motility and to explore myenteric neuron expressions of tyrosine hydroxylase (TH), vasoactive intestinal peptide (VIP), and neuronal nitric oxide synthase (nNOS) in HFDinduced oxidative injury. Methods Sprague-Dawley rats were fed with normal diet (ND) or HFD. Gastric emptying rate was measured following NES-1 (5 pmol/rat, intracerebroventricular) preceded by subcutaneous injections of glucagon-like peptide 1 (GLP-1), cholecystokinin 1 (CCK-1), and gastrin/CCK-2 receptor antagonists. In carbachol-contracted gastric and ileal strips, contractile changes were recorded by adding NES1 (0.3 nmol/L), GLP-1, CCK-1, and gastrin/CCK-2 antagonists. Results Neither HFD nor NES-1 changed methylcellulose emptying, but NES-1 delayed saline emptying in cannulated ND-rats. Inhibitory effect of NES-1 on gastric emptying in ND-rats was reversed by all antagonists, and abolished in HFD-rats. In HFD-rats, carbachol-induced contractility was enhanced in gastric, but inhibited in ileal strips. HFD increased body weight, while serum triglycerides, alanine transaminase, aspartate aminotransferase, glucose, and levels of malondialdehyde, glutathione, myeloperoxidase activity, and luminolchemiluminescence in hepatic, ileal, and adipose tissues were similar in ND-and HFD-rats, but only lucigenin-chemiluminescence was increased in HFD-rats. Vasoactive intestinal peptide (VIP) and TH immunoreactivities were depressed and nNOS immunoreactivity was increased in gastric tissues of HFD-rats, while VIP and TH were enhanced, but nNOS was reduced in their intestines. Conclusions HFD caused mild systemic inflammation, disrupted enteric innervation, enhanced gastric contractility, inhibited ileal contractility, and eliminated inhibitory effect of NES-1 on gastric motility. (J Neurogastroenterol Motil 2021;27:265-278)

In order to investigate the role of the vagus nerve in the possible gastroprotective effect of obestatin on the indomethacin-induced acute oxidative gastric injury, Sprague-Dawley rats of both sexes were injected subcutaneously with indomethacin (25 mg/kg, 5% NaHCO3) followed by obestatin (10, 30 or 100 μg/kg). In other sets of rats, surgical vagotomy (Vx) or selective degeneration of vagal afferent fibers by perivagal capsaicin was performed before the injections of indomethacin or indomethacin + obestatin (30 μg/kg). Gastric serosal blood flow was measured, and 4 h after ulcer induction gastric tissue samples were taken for histological and biochemical assays. Obestatin reduced the severity of indomethacin-induced acute ulcer via the reversal of reactive hyperemia, by inhibiting ulcer-induced neutrophil infiltration and lipid peroxidation along with the replenishment of glutathione (GSH) stores, whereas Vx abolished the inhibitory effect of obestatin on blood flow and lipid peroxidation, and worsened the severity of ulcer. On the other hand, serosal blood flow was even amplified by the selective denervation of the capsaicin-sensitive vagal afferent fibers, but obestatin-induced reduction in ulcer severity was not altered. In conclusion, the gastroprotective effect of obestatin on indomethacin-induced ulcer appears to involve the activation of the vagovagal pathway.

BACKGROUND: The aim of this study was to evaluate the possible protective effects of dapagliflozin in an experimental sepsis model in rats. METHODS: Saline (1 mL/kg, p.o.) or dapagliflozin (10 mg/kg, p.o.) was administered to Sprague-Dawley rats for 5 days prior to the surgical procedures. Under anesthesia, sepsis was induced by cecal ligation puncture, while sham control groups underwent laparotomy only. Blood urea nitrogen, creatinine, and glucose levels were measured in serum samples and the levels of malondialdehyde (MDA), glutathione (GSH), myeloperoxidase (MPO), tumor necrosis factor alpha, interleukin 1 beta, caspase 8, and caspase 9 were determined in tissue samples (kidney, liver, and lung). Histological evaluation was also performed. RESULTS: The administration of dapagliflozin in a sepsis model reduced oxidative stress (MDA), increased antioxidant levels (GSH), and reduced inflammation (MPO) in the kidney (p

WOS: 000381406300002, PubMed ID: 27399230, Although endogenous estrogen is known to offer cardiac and vascular protection, the involvement of estrogen receptors in mediating the protective effect of estrogen on hypertension-induced cardiovascular and renal injury is not fully explained. We aimed to investigate the effects of estrogen receptor (ER) agonists on oxidative injury, cardiovascular and renal functions of rats with renovascular hypertension (RVH). Female Sprague-Dawley rats were randomly divided as control and RVH groups, and RVH groups had either ovariectomy (OVX) or sham-OVX. Sham-OVX-RVH and OVX-RVH groups received either ER agonist diarylpropiolnitrile (1 mg/kg/day) or ER agonist propyl pyrazole triol (1 mg/kg/day) for 6 weeks starting at the third week following the surgery. At the end of the 9(th) week, systolic blood pressures were recorded, cardiac functions were determined, and the contraction/relaxation responses of aortic rings were obtained. Serum creatinine levels, tissue malondialdehyde, glutathione, superoxide dismutase, catalase levels, and myeloperoxidase activity in heart and kidney samples were analyzed, and Na+, K+-ATPase activity was measured in kidney samples. In both sham-OVX and OVX rats, both agonists reduced blood pressure and reversed the impaired contractile performance of the heart, while ER agonist improved renal functions in both the OVX and non-OVX rats. Both agonists reduced neutrophil infiltration, lipid peroxidation, and elevated antioxidant levels in the heart, but a more ER-mediated protective effect was observed in the kidney. Our data suggest that activation of ER might play a role in preserving the function of the stenotic kidney and delaying the progression of renal injury, while both receptors mediate similar cardioprotective effects., Scientific Research Project Commission of Marmara University (BAPKO) [SAG-A-010710-0221], This work was supported by the Scientific Research Project Commission of Marmara University (BAPKO); Project No: SAG-A-010710-0221.

WOS: 000398070900028, PubMed ID: 27900560, Background The present study aimed to investigate the effects of Roux-en-Y gastric bypass (RYGB) and prosthesis placement on gastric emptying rate in conjunction with serum ghrelin-obestatin-leptin responses in non-obese rats with intact or denervated afferent innervation. Methods Under anesthesia, male Sprague-Dawley rats underwent either sham operation, RYGB, prosthesis, and/or Gregory cannula placement. Three weeks later, liquid or solid gastric emptying tests were performed and serum ghrelin, leptin and obestatin levels were measured. Results Both prosthesis placement and RYGB surgery delayed non-nutrient liquid emptying; while solid nutrient emptying was delayed only by RYGB. Nutrient-dependent (acid, hyperosmolal and peptone) delay in liquid emptying was abolished in rats with prosthesis. By vagal afferent denervation, delayed liquid emptying was abolished, while solid emptying was further delayed in rats with prosthesis. Ghrelin and obestatin levels were depressed in prosthesis-placed rats, but RYGB surgery had no impact on both levels. Leptin level was elevated in solid-food-given rats with prosthesis, but not changed in RYGB group, while it was reduced following liquid meal. All the changes observed in ghrelin, obestatin, or leptin levels in response to meal ingestion were reversed with vagal afferent denervation. Conclusions Both RYGB and prosthesis placement had delaying effects on gastric emptying rate of non-obese rats. Our results indicate that the short-term changes in gastric motility and hormone responses induced by volume reduction are reversed by afferent denervation, suggesting that sparing the vagal innervation could be essential for reaching optimum motility and hormone changes expected after bariatric surgery., Marmara University Research Fund, The authors acknowledge Merve Evren, PhD Candidate at Ege University Natural and Applied Sciences Department of Biotechnology, for the preparation of the excellent medical illustrations. This work was supported by a grant from Marmara University Research Fund.