1. The extracorporeal perfusion of the swine uterus as an experimental model: The effect of tocolytic drugs
Theodoros Maltaris, Charalampos Dragonas, Inge Hoffmann, Andreas Mueller, Ralf L Schild, Werner Schmidt, Matthias W Beckmann, Ralf Dittrich Eur J Obstet Gynecol Reprod Biol. 2006 May 1;126(1):56-62. doi: 10.1016/j.ejogrb.2005.07.026. Epub 2005 Oct 3.
Objective: Comparison of the effect of tocolytic drugs on isolated swine uterus preparations. Study design: Forty swine uteri were perfused with the aim to preserve a viable organ, which should be responsive to oxytocic hormones and tocolytic pharmaca. An intrauterine catheter recorded the pressure changes. After initiation of rhythmical uterine contractions we administered known tocolytic drugs (fenoterol, ritodrine, terbutaline, propofol, acetylsalicylic acid, alcohol, atosiban, verapamil, and glyceryl trinitrate) in various concentrations. Results: Perfusate pH and lactate, partial oxygen and carbon dioxide tensions, and oxygen saturation in the perfusate showed good preservation of the organ for up to 8h. All substances showed a tocolytic effect on the swine uterus. The effect varied substantially with regard to the length of the contraction free intervals, which was our main effect parameter. Fenoterol, acetylsalicylic acid, and alcohol showed the most and glyceryl trinitrate the least powerful effect. Conclusions: A direct comparison of various tocolytic substances in the same experimental model showed the best effect for fenoterol. Furthermore, we could demonstrate that the swine uterus perfusion system is a suitable model to study the influence of various conditions like the administration of drugs or the induction of oxidative stress on the uterus function.
2. Agonist/Antagonist Activity of Oxytocin Variants Obtained from Free Cyclic Peptide Libraries Generated via Amino Acid Substitution
Remi Kinoshita, Ikko Kozaki, Kazunori Shimizu, Takahiro Shibata, Akihito Ochiai, Hiroyuki Honda ACS Omega. 2021 Nov 8;6(46):31244-31252. doi: 10.1021/acsomega.1c04982. eCollection 2021 Nov 23.
We established a method for synthesizing a free cyclic peptide library via peptide array synthesis to demonstrate the sequence activity of cyclic peptides. Variants of the cyclic nonapeptide oxytocin (OXT) were synthesized via residue substitution. Natural amino acids (AAs) were classified into eight groups based on their physical properties and the size of their side chains, and a representative AA from each group was selected for residue substitution. All OXT variants were systematically evaluated for agonist/antagonist activity. Consequently, no improvement in agonist activity was observed, although substitution of the P4 and P8 residues resulted in decreased activity due to AA substitution. A few OXT variants exhibited antagonistic activity. In particular, the variants with P2 Leu residue substitution (Y2L) and Phe substitutions at residues 4 (Q4F), 5 (N5F), and 7 (P7F) showed high antagonistic activity. Variant Y2W was found to have the highest inhibitory effect, with a dissociation constant of 44 nM, which was comparable to that of the commercial antagonist atosiban (21 nM). Therefore, a free cyclic peptide library constructed via substitution with a natural AA residue was confirmed to be a powerful tool for bioactive peptide screening.
3. Anti-inflammatory effects of nesfatin-1 in rats with acetic acid - induced colitis and underlying mechanisms
C C Ozturk, S Oktay, M Yuksel, D Akakin, A Yarat, O Kasimay Cakir J Physiol Pharmacol. 2015 Oct;66(5):741-50.
Mucosal balance impairment, bacterial over-proliferation, cytokines, inflammatory mediators are known as responsible for inflammatory bowel disease. Besides known anorexigenic, neuroprotective, and anti-apoptotic effects, the major effect of nesfatin-1 on colitis is unknown. Our aim was to investigate the possible anti-inflammatory effects of nesfatin-1 in acetic acid induced colitis model and potential underlying mechanisms. Male Spraque-Dawley rats were anesthetized by intraperitoneal ketamine (100 mg/kg) and chlorpromazine (0.75 mg/kg). For nesfatin-1 and antagonist applications some of the rats were intracerebroventricularly (i.c.v.) cannulated. In colitis group, intrarectally (i.r.) 4% acetic acid solution (1 ml) and 10 minutes later i.c.v. nesfatin-1 (0.05 μg/5 μl) or vehicle (5 μl) were administered. Treatments continued for 3 days. In control group, physiological saline solution was used intrarectally. To identify the underlying effective mechanism of nesfatin-1, rats were divided into 3 subgroups, 5 minutes following colitis induction; i.c.v. atosiban (oxytocin receptor antagonist), SHU9119 (melanocortin receptor antagonist) or GHSR-1a antagonist (ghrelin receptor antagonist) were administered, 5 minutes later nesfatin-1 was administered for 3 days. On the fourth day, rats were decapitated, and colon tissues were sampled. Macroscopic and microscopic damage scores of distal colon, and colonic tissue malondialdehyde, glutathione, myeloperoxidase, superoxide dismutase, catalase, luminol and lucigenin chemiluminescence measurements were analysed. The increased myeloperoxidase activity, malondialdehyde levels, luminol and lucigenin chemiluminescence measurements, macroscopic and microscopic damage scores with colitis induction (P < 0.05 - 0.001) were decreased with nesfatin-1 treatment (P < 0.05 - 0.001). Nesfatin-1 may show this effect by inhibiting neutrophil infiltration through tissues and by decreasing formation of free oxygen radicals. Atosiban and GHSR-1a administration alleviated the protective effect of nesfatin-1 from microscopic and oxidant damage parameters and lipid peroxidation (P < 0.05 - 0.001). The results of the study suggest that nesfatin-1 had a protective effect from colitis induction, and the anti-inflammatory and antioxidant effects of nesfatin-1 on colitis might occur via oxytocin and ghrelin receptors.
