Potentiation of ghrelin signaling attenuates cancer anorexia-cachexia and prolongs survival.
Potentiation of ghrelin signaling attenuates cancer anorexia-cachexia and prolongs survival.
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DOI：
10.1038/tp.2011.25
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发表时间：
2011-07-26
影响因子：
6.8
通讯作者：
Inui A
中科院分区：
文献类型：
--
作者：
Fujitsuka N;Asakawa A;Uezono Y;Minami K;Yamaguchi T;Niijima A;Yada T;Maejima Y;Sedbazar U;Sakai T;Hattori T;Kase Y;Inui A
癌症厌食-恶病质综合征的特征是食物摄入量减少、体重减轻、肌肉组织消耗和心理困扰，该综合征是癌症患者发病率和死亡率增加的主要原因。本研究旨在阐明参与该综合征发病机制的肠-脑肽，并确定癌症厌食-恶病质的有效治疗方法。我们发现在荷瘤大鼠中观察到生长素释放肽不足和抵抗。促肾上腺皮质激素释放因子（CRF）降低了酰基生长素释放肽的血浆水平，而其受体拮抗剂α-螺旋CRF则增加了这些大鼠的食物摄入量。 5-羟色胺 2c 受体 (5-HT2cR) 拮抗剂 SB242084 降低下丘脑 CRF 水平，改善厌食、胃肠 (GI) 运动障碍和体重减轻。生长素释放肽受体拮抗剂 (D-Lys3)-GHRP-6 会加重荷瘤大鼠的厌食症并加速死亡。 Ghrelin 在短期内减轻了厌食-恶病质，但未能延长生存期，SB242084 给药也是如此。此外，草药 rikkunshito 可以改善动物和癌症患者的厌食症、胃肠道运动障碍、肌肉萎缩和焦虑相关行为，并延长生存期。 (D-Lys3)-GHRP-6 阻断了 rikkunshito 的食欲刺激作用。六金子、橙皮苷和苍术素的活性成分分别增强生长素释放肽和受体信号传导，并且苍术素可延长荷瘤大鼠的生存期。我们的研究表明，癌症厌食-恶病质的综合机制涉及由于 5-HT 与 CRF 通过 5-HT2cR 的下丘脑过度相互作用而导致的 ghrelin 信号降低。增强生长素释放肽受体信号传导可能是治疗厌食症、肌肉萎缩和延长癌症厌食-恶病质患者生存期的一种有吸引力的治疗方法。
Cancer anorexia–cachexia syndrome is characterized by decreased food intake, weight loss, muscle tissue wasting and psychological distress, and this syndrome is a major source of increased morbidity and mortality in cancer patients. This study aimed to clarify the gut–brain peptides involved in the pathogenesis of the syndrome and determine effective treatment for cancer anorexia–cachexia. We show that both ghrelin insufficiency and resistance were observed in tumor-bearing rats. Corticotropin-releasing factor (CRF) decreased the plasma level of acyl ghrelin, and its receptor antagonist, α-helical CRF, increased food intake of these rats. The serotonin 2c receptor (5-HT2cR) antagonist SB242084 decreased hypothalamic CRF level and improved anorexia, gastrointestinal (GI) dysmotility and body weight loss. The ghrelin receptor antagonist (D-Lys3)-GHRP-6 worsened anorexia and hastened death in tumor-bearing rats. Ghrelin attenuated anorexia–cachexia in the short term, but failed to prolong survival, as did SB242084 administration. In addition, the herbal medicine rikkunshito improved anorexia, GI dysmotility, muscle wasting, and anxiety-related behavior and prolonged survival in animals and patients with cancer. The appetite-stimulating effect of rikkunshito was blocked by (D-Lys3)-GHRP-6. Active components of rikkunshito, hesperidin and atractylodin, potentiated ghrelin secretion and receptor signaling, respectively, and atractylodin prolonged survival in tumor-bearing rats. Our study demonstrates that the integrated mechanism underlying cancer anorexia–cachexia involves lowered ghrelin signaling due to excessive hypothalamic interactions of 5-HT with CRF through the 5-HT2cR. Potentiation of ghrelin receptor signaling may be an attractive treatment for anorexia, muscle wasting and prolong survival in patients with cancer anorexia–cachexia.
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影响因子：
29.4
作者：
Date, Y;Murakami, N;Nakazato, M
通讯作者：
Nakazato, M
影响因子：
4.8
作者：
Gyengesi, Erika;Liu, Zhong-Wu;Diano, Sabrina
通讯作者：
Diano, Sabrina
影响因子：
3.1
作者：
Jatoi, A;Yamashita, J;Loprinzi, CL
通讯作者：
Loprinzi, CL
影响因子：
5.3
作者：
Heisler, Lora K.;Pronchuk, Nina;Tecott, Laurence H.
通讯作者：
Tecott, Laurence H.
影响因子：
11
作者：
Inui, A
通讯作者：
Inui, A