dinoprost and cobaltous-chloride

Carfilzomib's (Cfz) adverse events in myeloma patients include cardiovascular toxicity. Since carfilzomib's vascular effects are elusive, we investigated the vascular outcomes of carfilzomib and metformin (Met) coadministration.. Mice received: (i) saline; (ii) Cfz; (iii) Met; (iv) Cfz+Met for two consecutive (acute) or six alternate days (subacute protocol). Leucocyte-derived reactive oxygen species (ROS) and serum NO. Acutely, carfilzomib alone led to vascular hypo-contraction and increased ROS release. Subacutely, carfilzomib increased ROS release without vascular manifestations. Cfz+Met increased PGF2α-vasoconstriction and LC3-B-dependent autophagy in both young and aged mice. In vitro, Cfz+Met led to cytotoxicity and autophagy, while Met and Cfz+Met shifted cellular metabolism.. Carfilzomib induces a transient vascular impairment and oxidative burst. Cfz+Met increased vascular contractility and synergistically induced autophagy in all settings. Therefore, carfilzomib cannot be accredited for a permanent vascular dysfunction, while Cfz+Met exert vasoprotective potency.

Topics: Actins; AMP-Activated Protein Kinase Kinases; Animals; Antineoplastic Agents; Autophagy; Cell Survival; Cobalt; Dinoprost; Drug Therapy, Combination; Endoplasmic Reticulum; Glucose; Glycolysis; Humans; Male; Metformin; Mice; Mice, Inbred C57BL; Myocytes, Smooth Muscle; Nitric Oxide; Oligopeptides; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Kinases; Reactive Oxygen Species; Tumor Suppressor Protein p53

To evaluate whether unacylated ghrelin and obestatin were able to influence human luteal cell function. The effect of these two ghrelin-related peptides on progesterone (P4), prostaglandin (PG) F(2α), PGE(2), and vascular endothelial growth factor (VEGF) release and on VEGF expression in isolated human steroidogenic cells has been investigated.. Prospective laboratory study.. University hospital.. Corpora lutea were obtained from 23 normally menstruating patients in the midluteal phase of the menstrual cycle.. Human luteal cells were isolated from corpora lutea, and primary cultures were established.. P4 and PGs release was assayed by enzyme immunoassay, VEGF secretion by ELISA, and VEGF mRNA expression by real-time polymerase chain reaction.. P4 and VEGF release were significantly reduced by both unacylated ghrelin and obestatin. Moreover, the highest concentration of obestatin was able to reduce the release of PGE(2) and PGF(2α). VEGF mRNA expression was not affected by the incubation with any of these ghrelin-related peptides. As expected, CoCl(2) was able to induce VEGF release and mRNA expression in luteal cells.. Our results suggest that, similar to ghrelin, both unacylated ghrelin and obestatin might play a role in regulating the luteal cell function that affects both luteal steroidogenesis and luteotrophic/luteolytic imbalance. These results further underline the pivotal correlation between the ghrelin system and reproduction.

Topics: Acylation; Adult; Cells, Cultured; Cobalt; Dinoprost; Enzyme-Linked Immunosorbent Assay; Female; Ghrelin; Humans; Luteal Cells; Progesterone; Real-Time Polymerase Chain Reaction; RNA, Messenger; Vascular Endothelial Growth Factor A

Ghrelin, well-known modulator of food intake and energy balance, is a rather ubiquitous peptide involved in several endocrine and nonendocrine actions. A possible as-yet-unknown role for ghrelin in modulating luteal function has been suggested because both ghrelin and its receptor (GRLN-R) have been immunohistochemically detected in human corpus luteum.. We first investigated GRLN-R mRNA expression in midluteal phase human luteal cells. Ghrelin effect on basal and human chorionic gonadotropin (hCG)-stimulated progesterone (P) release was then analyzed. Finally, we investigated whether ghrelin could affect luteal release of vascular endothelial growth factor (VEGF), prostaglandin (PG) E(2), both luteotropic factors, and PGF(2alpha), luteolytic modulator. Ghrelin effect on both basal and hypoxia-stimulated VEGF luteal expression was analyzed.. Human luteal cells were incubated for 24 h with ghrelin (10(-13) to 10(-7) m) or hCG (100 ng/ml) or CoCl(2) (10 microm), chemical hypoxia, or with hCG or CoCl(2) in combination with ghrelin. Both GRLN-R mRNA and VEGF mRNA were evaluated by real-time RT-PCR. PGs and P release was assayed by RIA, whereas VEGF release by ELISA.. GRLN-R mRNA expression was demonstrated in human luteal cells. Both basal and hCG-stimulated P release was significantly decreased by ghrelin, which was able to reduce PGE(2) and increase PGF(2alpha) luteal release. Both basal and hypoxia-stimulated VEGF release was significantly decreased by ghrelin, which did not affect VEGF mRNA luteal expression.. The present in vitro study provides the first evidence of a direct inhibitory influence of ghrelin on human luteal function.

Topics: Adult; Cells, Cultured; Chorionic Gonadotropin; Cobalt; Data Interpretation, Statistical; Dinoprost; Dinoprostone; DNA Primers; Female; Fluorescent Dyes; Ghrelin; Humans; Luteal Cells; Luteolysis; Peptide Hormones; Receptors, G-Protein-Coupled; Receptors, Ghrelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vascular Endothelial Growth Factor A

The involvement of arachidonic acid and arachidonic acid metabolites in the control of oxytocin secretion by ovine corpus luteum was investigated, using slices of luteal tissue incubated in vitro. Oxytocin was secreted at steady rates by luteal slices, during 60-min incubations (315.0 +/- 45.3 pg/mg.h). The secretion of oxytocin was stimulated by arachidonic acid, phospholipase A2 (PLA2), and phospholipase C (PLC) in a dose-dependent manner. The highest doses of arachidonic acid, PLA2, and PLC used stimulated oxytocin secretion by 145.8 +/- 23.0% (P less than 0.01; n = 6), 331.5 +/- 42.4% (P less than 0.02; n = 4), and 955.5 +/- 278.6% (P less than 0.01; n = 4), respectively. Oxytocin secretion by luteal slices was not affected by either prostaglandin F2 alpha (PGF2 alpha) or PGE2 over a concentration range from 3-3000 nM. Furthermore, inhibitors of the cyclo-oxygenase pathway of arachidonic acid metabolism did not consistently affect arachidonic acid and PLA2-stimulated oxytocin secretion. Nordihydroguaiaretic acid, which inhibits 5-lipoxygenase, however, totally abolished arachidonic acid- and reduced PLA2-stimulated oxytocin secretion. The presence of CoCl2 in the incubation medium also significantly reduced basal and PLA2- and PLC-stimulated oxytocin secretion [P less than 0.05 (n = 5), P less than 0.05 (n = 5), and P less than 0.01 (n = 6), respectively]. We have shown that oxytocin secretion from slices of ovine corpus luteum incubated in vitro is stimulated by exogenous and endogenously released arachidonic acid. The data show that PGF2 alpha and PGE2 do not have a role in luteal oxytocin secretion in vitro and PG formation does not appear to be involved in the stimulation of oxytocin secretion elicited by arachidonic acid or PLA2. Arachidonic acid may have its effect via the lipoxygenase pathway.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Cobalt; Corpus Luteum; Dinoprost; Dinoprostone; Female; In Vitro Techniques; Kinetics; L-Lactate Dehydrogenase; Masoprocol; Oxytocin; Phospholipases; Phospholipases A; Phospholipases A2; Prostaglandins; Prostaglandins E; Prostaglandins F; Sheep; Type C Phospholipases