Abstract
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 in vitro 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 citrus unshiu peel failed to activate OX1R. A screening of each of the 12 herbal crude drugs showed that citrus unshiu peel significantly activated OX1R, which was significantly suppressed by SB674042. These finding suggest that NYT and citrus unshiu 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.
Highlights
Cancer cachexia, which is characterized by a decrease in body weight and food consumption, occurs in 80% of patients with progressive cancer, causing at least 20% of cancer-related deaths [1,2,3]
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 (CNS)
With respect to GPCR-activating hyperphagia signaling, we focused on activated appetitestimulating receptors, such as growth hormone secretagogue receptor 1a (GHSR), neuropeptide Y1 receptor (NPY1R), neuropeptide Y5 receptor (NPY5R), and orexin 1 receptor (OX1R) [17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32]
Summary
Cancer cachexia, which is characterized by a decrease in body weight and food consumption, occurs in 80% of patients with progressive cancer, causing at least 20% of cancer-related deaths [1,2,3]. This syndrome decreases the quality of life (QOL) and attenuates the efficacy of chemotherapy [4,5,6,7]. Several studies have shown that some herbal crude drugs of NYT improved appetite in a cancer cachexia model of animals or patients with cancer [12,13,14,15,16]. The action mechanisms of NYT in improving anorexia and/or fatigue in cancer cachexia–anorexia syndrome are not clear
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