The role of C-terminal part of ghrelin in pharmacokinetic profile and biological activity in rats

Ghrelin is an endogenous ligand for growth hormone secretagogue receptor 1a (GHS-R1a), and consists of 28 amino acid residues with octanoyl modification at Ser³. The previous studies have revealed that N-terminal part of ghrelin including modified Ser³ is the active core for the activation of GHS-R1a. On the other hand, the role of C-terminal (8-28) region in ghrelin has not been clarified yet. In the present study, we prepared human ghrelin, C-terminal truncated ghrelin derivatives and anamorelin, a small molecular GHS compound which supposedly mimics the N-terminal active core, and examined GHS-R1a agonist activity in vitro, pharmacokinetic (PK) profile and growth hormone (GH) releasing activity in rats. All compounds demonstrated potent GHS-R1a agonist activities in vitro. Although the lack of C-terminal two amino acids did not modify PK profile and GH releasing activity, the deletion of C-terminal 8 and 20 amino acids affected them, and ghrelin(1-7)-Lys-NH₂ exhibited very short plasma half-life and low GH releasing activity in vivo. In rat plasma, ghrelin(1-7)-Lys-NH₂ was degraded more rapidly than ghrelin, suggesting that C-terminal part of ghrelin protected octanoylation of Ser³ from plasma esterases. Subdiaphragmatic vagotomy significantly attenuated GH response to ghrelin but not to anamorelin. These results suggest that the C-terminal part of ghrelin has an important role in the biological activity in vivo. We also found that ghrelin stimulated GH release mainly via a vagal nerve pathway but anamorelin augmented GH release possibly by directly acting on brain in rats.     

Stress tolerance to stress escape in plants: role of the OXS2 zinc-finger transcription factor family

During dire conditions, the channelling of resources into reproduction ensures species preservation. This strategy of survival through the next generation is particularly important for plants that are unable to escape their environment but can produce hardy seeds. Here, we describe the multiple roles of OXIDATIVE STRESS 2 (OXS2) in maintaining vegetative growth, activating stress tolerance, or entering into stress-induced reproduction. In the absence of stress, OXS2 is cytoplasmic and is needed for vegetative growth; in its absence, the plant flowers earlier. Upon stress, OXS2 is nuclear and is needed for stress tolerance; in its absence, the plant is stress sensitive. OXS2 can activate its own gene and those of floral integrator genes, with direct binding to the floral integrator promoter SOC1. Stress-induced SOC1 expression and stress-induced flowering are impaired in mutants with defects in OXS2 and three of the four OXS2-like paralogues. The autoactivation of OXS2 may be a commensurate response to the stress intensity, stepping up from a strategy based on tolerating the effects of stress to one of escaping the stress via reproduction.