Miyano Kanako, Ohshima Kaori, Suzuki Nozomi, Furuya Saho, Yoshida Yuki, Nonaka Miki, Higami Yoshikazu, Yoshizawa Kazumi, Fujii Hideaki, Uezono Yasuhito
Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan.
Laboratory of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan.
Front Nutr. 2020 Feb 27;7:5. doi: 10.3389/fnut.2020.00005. eCollection 2020.
Cancer cachexia is highly prevalent in patients with progressive cancer and is characterized by decreased food consumption, and body weight. Japanese herbal medicine Ninjinyoeito (NYT), composed of 12 herbal crude drugs, is prescribed in Asian countries to improve several symptoms such as anorexia and fatigue, which are commonly observed in patients with cancer cachexia. However, the action mechanisms of NYT in improving anorexia or fatigue in patients with cancer are not clear. Therefore, in the present study, we examined the effects of NYT on the activities of several G-protein-coupled receptors (GPCRs), which activate hyperphagia signaling in the central nervous system, using an assay with the CellKey™ system, which detects the activation of GPCRs as a change in intracellular impedance (ΔZ). NYT increased the ΔZ of human embryonic kidney 293 (HEK293) cells expressing orexin 1 receptor (OX1R) and those expressing neuropeptide Y1 receptor (NPY1R) in a dose-dependent manner. On the contrary, NYT did not significantly increase the ΔZ of HEK293A cells expressing growth hormone secretagogue receptor (GHSR) and those expressing NPY5R. The selective OX1R antagonist SB674042 significantly decreased the NYT-induced increase in ΔZ in OX1R-expressing cells. Contrarily, the selective NPY1R antagonist BIBO3340 failed to inhibit the NPY-induced increase in ΔZ in NPY1R-expressing cells. Additionally, we prepared modified NYT excluding each one of the 12 herbal crude drugs in NYT and investigated the effects on the activity of OX1R. Among the 12 modified NYT formulations, the one without peel failed to activate OX1R. A screening of each of the 12 herbal crude drugs showed that peel significantly activated OX1R, which was significantly suppressed by SB674042. These finding suggest that NYT and peel could increase food intake via activation of orexigenic OX1R-expressing neurons in the hypothalamus. This study provides scientific evidence to support the potential of NYT for cancer patients with anorexia.
癌症恶病质在进展期癌症患者中非常普遍，其特征是食物摄入量和体重下降。由12种草药粗提物组成的日本草药制剂人参养荣汤（NYT），在亚洲国家被用于改善一些症状，如厌食和疲劳，这些症状在癌症恶病质患者中很常见。然而，NYT改善癌症患者厌食或疲劳的作用机制尚不清楚。因此，在本研究中，我们使用CellKey™系统检测法，通过检测细胞内阻抗变化（ΔZ）来检测G蛋白偶联受体（GPCR）的激活，研究了NYT对几种GPCR活性的影响，这些GPCR在中枢神经系统中激活食欲亢进信号。NYT以剂量依赖的方式增加了表达食欲素1受体（OX1R）的人胚肾293（HEK293）细胞和表达神经肽Y1受体（NPY1R）的细胞的ΔZ。相反，NYT没有显著增加表达生长激素促分泌素受体（GHSR）的HEK293A细胞和表达NPY5R的细胞的ΔZ。选择性OX1R拮抗剂SB674042显著降低了NYT诱导的表达OX1R细胞中ΔZ的增加。相反，选择性NPY1R拮抗剂BIBO3340未能抑制NYT诱导的表达NPY1R细胞中ΔZ的增加。此外，我们制备了不含NYT中12种草药粗提物中每一种的改良NYT，并研究了其对OX1R活性的影响。在12种改良NYT制剂中，不含陈皮的制剂未能激活OX1R。对12种草药粗提物逐一进行筛选表明，陈皮显著激活OX1R，而SB674042可显著抑制这种激活。这些发现表明，NYT和陈皮可通过激活下丘脑表达产食欲性OX1R的神经元来增加食物摄入量。本研究为支持NYT对厌食癌症患者的潜在作用提供了科学证据。
