Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1.

Caloric restriction (CR) is known to retard aging and delay functional decline as well as the onset of diseases in most organisms. Ghrelin is secreted from the stomach in response to CR and regulates energy metabolism. We hypothesized that in CR ghrelin has a role in protecting aging-related diseases. We examined the physiological mechanisms underlying the ghrelin system during the aging process in three mouse strains with different genetic and biochemical backgrounds as animal models of accelerated or normal human aging. The elevated plasma ghrelin concentration was observed in both klotho-deficient and senescence-accelerated mouse prone/8 (SAMP8) mice. Ghrelin treatment failed to stimulate appetite and prolong survival in klotho-deficient mice, suggesting the existence of ghrelin resistance in the process of aging. However, ghrelin antagonist hastened death and ghrelin signaling potentiators rikkunshito and atractylodin ameliorated several age-related diseases with decreased microglial activation in the brain and prolonged survival in klotho-deficient, SAMP8 and aged ICR mice. In vitro experiments, the elevated sirtuin1 (SIRT1) activity and protein expression through the cAMP-CREB pathway was observed after ghrelin and ghrelin potentiator treatment in ghrelin receptor 1a-expressing cells and human umbilical vein endothelial cells. Furthermore, rikkunshito increased hypothalamic SIRT1 activity and SIRT1 protein expression of the heart in the all three mouse models of aging. Pericarditis, myocardial calcification and atrophy of myocardial and muscle fiber were improved by treatment with rikkunshito. Ghrelin signaling may represent one of the mechanisms activated by CR, and potentiating ghrelin signaling may be useful to extend health and lifespan.

An easy method for the intraluminal administration of peppermint oil before colonoscopy and its effectiveness in reducing colonic spasm.

BACKGROUND: Systemic administration of a cholinergic blocking agent or glucagon is used to reduce spasms, but it is inconvenient and sometimes causes side effects. This study is an evaluation of the intracolonic administration of peppermint oil during colonoscopy for the control of colonic spasm. METHODS: Each patient in the treated group (n = 409) was given approximately 200 mL of the solution (a mixture of 8 mL of peppermint oil and 0.2 mL of Tween 80 per 1 L of water with 0.04% indigo carmine) by using a hand pump attached to the accessory channel of the colonoscope. Changes in patient posture were made to distribute the solution. The patients in the control group (n = 36) were given the solution without peppermint oil. RESULTS: A satisfactory spasmolytic effect was seen in 88.5% of the treated patients and in 33.3% of those in the control group (p<0.0001). No adverse effect was observed. The mean time to onset was 21.6 +/- 15.0 seconds, and the effect continued for at least 20 minutes. In patients with irritable bowel syndrome, efficacy was significantly lower (p < 0.0001). CONCLUSIONS: The intraluminal administration of peppermint oil by using a hand pump is a simple, safe, and convenient alternative to the systemic injection of a cholinergic blocking agent or glucagon during colonoscopy.

Effect of TKS159, a novel 5-hydroxytryptamine4 agonist, on gastric contractile activity in conscious dogs.

A novel 5-hydroxytryptamine (5-HT)4 receptor agonist, TKS159, ¿4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-ethyl-2- hydroxymethyl-4-pyrrolidinyl] benzamide), has recently been developed as a gastroprokinetic drug. Cisapride is already used clinically to increase gastric contractions. The stimulatory effects of TKS159 and cisapride on gastric contractions were examined using force transducers chronically implanted on the vagally denervated pouch (Heidenhain pouch) and the vagally innervated main stomach in conscious dogs. Contractile activity was analysed by computer and expressed as a motor index. Intravenous administration of TKS159 or cisapride significantly increased the motor index in both the main stomach and the Heidenhain pouch during the fed and fasted states. Pharmacological characterization in the fasted state revealed that the contraction-stimulating activity of TKS159 and cisapride on the stomach was significantly inhibited by atropine, hexamethonium and a 5-HT4 receptor antagonist, SDZ 205-557. Granisetron (a 5-HT3 receptor antagonist) significantly inhibited cisapride-induced, but not TKS159-induced gastric contractions. The plasma motilin concentration was significantly increased after cisapride, but not after TKS159 injection. In conclusion, TKS159 has a contractile-stimulating effect on both the innervated and the denervated stomach. It is likely that a cholinergic pathway and 5-HT4 receptors are involved in producing the contractions, although other mechanisms cannot be excluded. Cisapride has almost the same characteristics, but the present findings suggest the involvement of motilin and 5-HT3 receptors in the effects of cisapride.