Rikkunshito ameliorates cachexia associated with bleomycin-induced lung fibrosis in mice by stimulating ghrelin secretion

Tsubouchi, Hironobu; Yanagi, Shigehisa; Miura, Ayako; Mogami, Sachiko; Yamada, Chihiro; Iizuka, Seiichi; Hattori, Tomohisa; Nakazato, Masamitsu

doi:10.1016/j.nutres.2014.08.014

Cited by 19 publications

(13 citation statements)

References 36 publications

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“…The administered dose of RKT is approximately equivalent to a typical clinical dose when converted based on body surface area (as recommended by the FDA) and this dose has previously been reported to show ameliorative effects in a mouse model of anorexia13144041. Cumulative food intake was determined at 1, 3 and 6 h after stress exposure.…”

Section: Methodsmentioning

confidence: 99%

CRF receptor 1 antagonism and brain distribution of active components contribute to the ameliorative effect of rikkunshito on stress-induced anorexia

Mogami

Sadakane

Nahata

et al. 2016

Sci Rep

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Rikkunshito (RKT), a Kampo medicine, has been reported to show an ameliorative effect on sustained hypophagia after novelty stress exposure in aged mice through serotonin 2C receptor (5-HT2CR) antagonism. We aimed to determine (1) whether the activation of anorexigenic neurons, corticotropin-releasing factor (CRF), and pro-opiomelanocortin (POMC) neurons, is involved in the initiation of hypophagia induced by novelty stress in aged mice; (2) whether the ameliorative effect of RKT is associated with CRF and POMC neurons and downstream signal transduction; and (3) the plasma and brain distribution of the active components of RKT. The administration of RKT or 5-HT2CR, CRF receptor 1 (CRFR1), and melanocortin-4 receptor antagonists significantly restored the decreased food intake observed in aged male C57BL/6 mice in the early stage after novelty stress exposure. Seven components of RKT exhibited antagonistic activity against CRFR1. Hesperetin and isoliquiritigenin, which showed antagonistic effects against both CRFR1 and 5-HT2CR, were distributed in the plasma and brain of male Sprague-Dawley rats after a single oral administration of RKT. In conclusion, the ameliorative effect of RKT in this model is assumed to be at least partly due to brain-distributed active components possessing 5-HT2CR and CRFR1 antagonistic activities.

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Section: Methodsmentioning

confidence: 99%

CRF receptor 1 antagonism and brain distribution of active components contribute to the ameliorative effect of rikkunshito on stress-induced anorexia

Mogami

Sadakane

Nahata

et al. 2016

Sci Rep

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“…In the same model of lung fibrosis, the traditional Japanese herbal medicine rikkunshito, known to stimulate a strong secretion of ghrelin, reduces lung fibrosis and ameliorates the systemic cachectic condition [ 87 ]. However, rikkunshito effects are only partially due to the associated ghrelin increase, since it maintains its protective effects also in mice devoid of the ghrelin gene [ 88 ].…”

Section: Acylated and Unacylated Ghrelin As Antifibrotic Factorsmentioning

confidence: 99%

Antifibrotic Activity of Acylated and Unacylated Ghrelin

Angelino

Reano

Ferrara

et al. 2015

International Journal of Endocrinology

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Fibrosis can affect almost all tissues and organs, it often represents the terminal stage of chronic diseases, and it is regarded as a major health issue for which efficient therapies are needed. Tissue injury, by inducing necrosis/apoptosis, triggers inflammatory response that, in turn, promotes fibroblast activation and pathological deposition of extracellular matrix. Acylated and unacylated ghrelin are the main products of the ghrelin gene. The acylated form, through its receptor GHSR-1a, stimulates appetite and growth hormone (GH) release. Although unacylated ghrelin does not bind or activate GHSR-1a, it shares with the acylated form several biological activities. Ghrelin peptides exhibit anti-inflammatory, antioxidative, and antiapoptotic activities, suggesting that they might represent an efficient approach to prevent or reduce fibrosis. The aim of this review is to summarize the available evidence regarding the effects of acylated and unacylated ghrelin on different pathologies and experimental models in which fibrosis is a predominant characteristic.

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“…18, 19, 20, 21, 22 Of the 43 major chemical compounds contained in rikkunshito, atractylodin shows a marked increase in ghrelin/GHS-R-binding activity and ghrelin-induced cytosolic calcium ion (Ca 2+ ) concentration in GHS-R-expressing cells through an allosteric mechanism. Atractylodin is a major ingredient detected in the plasma of rikkunshito-treated healthy volunteers.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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.

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Rikkunshito ameliorates cachexia associated with bleomycin-induced lung fibrosis in mice by stimulating ghrelin secretion

Cited by 19 publications

References 36 publications

CRF receptor 1 antagonism and brain distribution of active components contribute to the ameliorative effect of rikkunshito on stress-induced anorexia

CRF receptor 1 antagonism and brain distribution of active components contribute to the ameliorative effect of rikkunshito on stress-induced anorexia

Antifibrotic Activity of Acylated and Unacylated Ghrelin

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

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