Co-Existence of Hypertensive and Anti-Hypertensive Constituents, Synephrine, and Nobiletin in Citrus unshiu Peel

Kim, Jung-Joon; Kim, Keunyoung; Jung, Yong‐Keun; Bian, Yiying; Ngo, Thien; Bae, Ok‐Nam; Lim, Kyung Min; Chung, Jin

doi:10.3390/molecules24071197

Cited by 14 publications

(10 citation statements)

References 28 publications

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“…These data suggest that citrus unshiu peel is an agonist of OX1R. In an aqueous extract mixture of NYT, the main ingredients of citrus unshiu peel were hesperidine, nobiletin, tangeretin, heptamethoxyflavone, naringin, and synephrine (53)(54)(55). Some studies on blood pharmacokinetics indicated that these ingredients are absorbed into the blood in humans after oral administration (56,57).…”

Section: Discussionmentioning

confidence: 94%

Japanese Herbal Medicine Ninjinyoeito Mediates Its Orexigenic Properties Partially by Activating Orexin 1 Receptors

Miyano¹,

Ohshima

Suzuki

et al. 2020

Front. Nutr.

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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 TM system, which detects the activation of GPCRs as a change in intracellular impedance ( Z). NYT increased the Z 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 Z 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 Z in OX1R-expressing cells. Contrarily, the selective NPY1R antagonist BIBO3340 failed to inhibit the NPY-induced increase in Z 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.

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Section: Discussionmentioning

confidence: 94%

Japanese Herbal Medicine Ninjinyoeito Mediates Its Orexigenic Properties Partially by Activating Orexin 1 Receptors

Miyano¹,

Ohshima

Suzuki

et al. 2020

Front. Nutr.

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“…Relative contents of different bioactive chemical components also lead to different pharmacological activities. For instance, a previous study has mentioned that the relative contents of synephrine and nobiletin coexisted in citrus, significantly affecting the vasoconstriction pattern since synephrine and nobiletin competitively blocked or activated the same contractile targets (Kim et al., 2019 ). Therefore, the differences in the phytochemicals of CER, CREA, and CFR were further clarified in this study, which might provide the chemical basis for explaining the different pharmacological activities and rational development of them.…”

Section: Discussionmentioning

confidence: 99%

Comparative analysis of chemical constituents in Citri Exocarpium Rubrum, Citri Reticulatae Endocarpium Alba, and Citri Fructus Retinervus

Yang

Liu

Chen

et al. 2022

Food Science & Nutrition

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Citri Exocarpium Rubrum (CER), Citri Reticulatae Endocarpium Alba (CREA), and Citri Fructus Retinervus (CFR) are used as medicine and food, which derive from three different parts of the pericarp of Citrus reticulata Blanco through natural drying. To systematically investigate similarities and differences in phytochemicals about the three herbs, a series of analytic approaches were applied for the qualitative and quantitative analysis of chemical constituents in them. The results indicated a total of 48 volatile compounds were determined representing 99.92% of the total relative content of CER extracts, including 24 alkenes, 11 alcohols, 6 aldehydes, 2 ketones, and 2 phenols, while volatile compounds were not extracted from CREA and CFR. CER was abundant in volatile components that mainly existed in the oil gland. And a total of 32, 35, and 28 nonvolatile compounds were identified from CER, CREA, and CFR extracts, respectively. The total content of flavonoids and phenolic, and hesperidin in CFR was the highest, followed by CREA and CER. Conversely, CER was a rich source of polymethoxyflavones (PMFs), and the total polymethoxyflavone content (TPMFC), the content of nobiletin, 3,5,6,7,8,3′,4′‐heptamethoxyflavone (HMF), tangeretin, and 5‐hydroxy‐6,7,8,3′,4′‐pentamethoxyflavone (5‐HPMF) in CREA and CFR were extremely low. Besides, CER and CREA had a higher concentration of synephrine than CFR. The phytochemicals of CER, CREA, and CFR were significantly different, which might provide chemical evidence for the comparative pharmacological activities’ research and rational application of them.

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“…the intestines [3][4][5]. However, some animal experiments and clinical results indicated that the decoctions or aqueous extracts of Zhishi and Zhiqiao probably connoted some pharmacological effects contrary to synephrine and N-methyltyramine [6].For example, (1) transiently or inapparently raising, or sometimes even declining the blood pressure [7,8]; (2) various cardiovascular protections [9,10]; (3) an excitatory effect to the in vitro and in vivo uteruses of pregnant and nonpregnant rabbits [11]; (4) a two-way regulating effect on gastrointestinal smooth muscle, namely not only exciting the gastrointestinal tract and enhancing its peristalsis, but also reducing the tension of gastrointestinal smooth muscle and relieve spasm [12]. These facts showed that there are probably some other ingredients with cholinergic or anti-cholinergic activities in the decoctions or aqueous extracts of Zhishi and Zhiqiao although some reports indicated that citrus flavonoids and essential oil should play a certain role in these complicated functions [13][14][15].…”

Section: Of 25mentioning

confidence: 99%

Stachydrine and Synephrine, a Pair of Bioactive Equilibrists in Four Chinese Herbs from <em>Citrus</em> Genus

Sun¹,

Xia²,

Yuan³

et al. 2023

Preprint

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Four Chinese herbs Zhishi, Zhiqiao, Qingpi and Chenpi from Citrus genus were widely used for treating various cardiovascular and gastrointestinal diseases. Although many pharmacological functions of these herb decoctions can be clarified from the bioactivities of identified ingredients, some of them remain confusing. To clarify the reasons of those confusing functions, depending on the extended structure-activity relationships of cholinergic and anti-cholinergic agents, here a simple method for quickly discovering possible choline analogs was established using a specific TLC method, and then stachydrine and choline were first identified from these Citrus herb decoctions based on their NMR and HRMS data. After this, two TLCS methods were first established respectively for the quantitatively analyses of stachydrine and choline, and the contents of both two ingredients and synephrine in 39 samples were determined using the valid TLCS and HPLC methods, respectively. The results showed the contents of stachydrine were 2.4 times to those of synephrine in Zhiqiao while about 1/3 to 2/3 in Zhishi, Qingpi and Chenpi. Simultaneously, the contents of stachydrine, choline and synephrine in these herbs present similar changing trends along with the delay of harvest time. However, the contents of synephrine decrease most rapidly, while those of stachydrine decrease most slowly. Based on these above, comparing with the pharmacological activities and pharmacokinetics reported of stachydrine and synephrine, it indicated that stachydrine and synephrine can be considered as a pair of bioactive equilibrists, especially in the cardio-cerebrovascular protection from these citrus herbs. Simultaneously, it confirmed that stachydrine should play an important role in the pharmacological functions, especially in dual-directionally regulating the uterus and various beneficial effects on cardio-cerebrovascular system, kidney and liver, of these citrus herbs.

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Co-Existence of Hypertensive and Anti-Hypertensive Constituents, Synephrine, and Nobiletin in Citrus unshiu Peel

Cited by 14 publications

References 28 publications

Japanese Herbal Medicine Ninjinyoeito Mediates Its Orexigenic Properties Partially by Activating Orexin 1 Receptors

Japanese Herbal Medicine Ninjinyoeito Mediates Its Orexigenic Properties Partially by Activating Orexin 1 Receptors

Comparative analysis of chemical constituents in Citri Exocarpium Rubrum, Citri Reticulatae Endocarpium Alba, and Citri Fructus Retinervus

Stachydrine and Synephrine, a Pair of Bioactive Equilibrists in Four Chinese Herbs from <em>Citrus</em> Genus

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