Current Application Status of Citrus Peel (Chenpi) in the Prevention and Treatment of Cardio-Cerebrovascular Diseases

Chenpi is the dried and mature peel of the plant Citrus reticulata Blanco, belonging to the Rutaceae family, and its cultivated varieties. Chenpi is mainly distributed in regions such as Xinhui, Guangdong; Nanfeng, Jiangxi; Wenzhou, Zhejiang; and Wuzhou, Guangxi, with the most extensive research currently focused on Xinhui Chenpi from Guangdong. Guang Chenpi is characterized by its three-petal shape, and its processing typically involves three steps: peeling, turning, and drying. The peeling process utilizes either the three-knife method or the symmetrical two-knife method. Turning the peel should be done on sunny days, where the peeled mandarin peels are placed in a well-ventilated area to dry naturally, allowing their moisture to evaporate naturally. Once the texture softens, the peel is turned so that the white pith faces outwards. Drying can be achieved through either natural sun-drying or oven-drying (at a temperature generally below 45°C). Only Chenpi that has been aged naturally for three years or more can achieve medicinal efficacy.

The main active components of Chenpi include flavonoids, volatile oils, alkaloids, and some trace elements. Flavonoids primarily exist in the form of glycosides or aglycones, encompassing compounds such as flavones, hesperidin, neohesperidin, and naringin. The use of different excipients in processing Chenpi can affect the dissolution of flavonoid active ingredients to varying degrees. The volatile oil in Chenpi is a mixture, primarily comprising citral, d-limonene, hesperidin, nobiletin, and inositol, among others, accounting for 1.9% to 3.5% of Chenpi's chemical composition. Volatile oils exhibit antioxidant, antiasthmatic, and digestive fluid secretion-promoting effects. The content of volatile oil in Chenpi is related to both its origin and processing method. Synephrine, an alkaloid found in citrus peels, is the most abundant alkaloid present. In addition, N-methyltyramine is another major alkaloid in citrus peels. Chenpi polysaccharides are relatively difficult to extract, with a maximum extraction yield of 6.01% using hot water extraction methods. Moreover, significant differences exist in the polysaccharide content among different varieties of Chenpi. Chenpi polysaccharides possess antioxidant and antitumor properties. Pectin and pigments are also active components of Chenpi. Pectin can reduce lipid deposition in organs, making Chenpi effective in addressing arteriosclerosis caused by high-fat diets.

1. Blood Lipid Regulation and Prevention of Fatty Liver

The effects of Chenpi on regulating blood lipids and preventing fatty liver are primarily achieved through mechanisms such as reducing hepatic or blood lipid levels, enhancing fatty acid oxidation, and protecting the liver. Studies have found that Chenpi as a whole herbal medicine and its components (mainly flavonoids) have the ability to lower hepatic or blood lipid levels. Chenpi extracts can improve lipid metabolism, reduce lipoprotein, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and hepatic lipid levels in ovariectomized rats, and antagonize hepatic lipid deposition. Hesperidin can reduce serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels in hyperlipidemic rats while increasing high-density lipoprotein cholesterol (HDL-C) levels. Furthermore, its aglycone hesperetin promotes apolipoprotein-A1 (Apo-A1)-mediated cholesterol efflux, thereby further elevating HDL-C levels.

Citrus flavonoids can prevent hepatic steatosis and lipid metabolism disorders by inhibiting hepatic fatty acid synthesis and enhancing fatty acid oxidation. Hesperetin and naringenin promote fatty acid oxidation and the tricarboxylic acid cycle, reducing the amount of fatty acids in the liver and exhibiting strong antioxidant effects. Sudachitin, a polymethoxyflavone, has been shown to reduce TG and free fatty acid (FFA) levels in db/db mice, improve glucose tolerance, and ameliorate insulin resistance. Flavonoids from sweet oranges can inhibit insulin-stimulated glucose absorption and enhance fatty acid β-oxidation.

Total citrus flavonoids can reduce hepatic TG and serum AST levels in non-alcoholic steatohepatitis (NASH) mice, enhancing hepatic antioxidant capacity. The addition of 1.5% polymethoxyflavone to a high-cholesterol diet significantly reduces AST and ALP activities, as well as serum creatine kinase (CK) and lactate dehydrogenase (LDH) levels, indicating its potential for treating or preventing liver injury.

2.Antithrombotic Effects

Chenpi extracts, hesperidin, naringenin, and their derivatives can exert antithrombotic effects through mechanisms such as inhibiting platelet aggregation. Chenpi can inhibit platelet aggregation and reduce red blood cell aggregation in rats. Hesperidin, hesperetin, and their derivatives possess antiplatelet aggregation and anticoagulant properties. Hesperidin can also inhibit rat platelet aggregation induced by collagen, arachidonic acid, ADP, and thrombin both in vitro and in vivo, and prolong tail bleeding time in mice. Naringenin-7-glucoside (naringin) can inhibit platelet and red blood cell aggregation, improving blood rheology.

3.Anti-Atherosclerotic Effects

The active ingredients in Chenpi that contribute to its anti-atherosclerotic effects include flavonoids such as naringin and naringenin, polymethoxyflavones, and citrus pectins. Naringin's anti-atherosclerotic effects are manifested primarily through regulating blood lipids, LDL-C, Apo-B levels, and non-HDL-C levels by inhibiting the activities of hydroxymethylglutaryl-CoA reductase (HMGCR) and acyl-CoA cholesterol acyltransferase (ACAT). It also inhibits the expression of vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1), thereby suppressing macrophage infiltration, smooth muscle cell proliferation, immune cell adhesion, and endothelial dysfunction, ultimately reducing the development of vascular plaques in hyperlipidemic animals. Metabolites of hesperetin and naringenin can reduce monocyte adhesion to endothelial cells by inhibiting the expression of genes associated with atherosclerosis, such as those involved in inflammation, cell adhesion, and cytoskeleton organization. Furthermore, naringenin can inhibit the proliferation and migration of vascular smooth muscle cells (VSMCs) by promoting the expression and activity of heme oxygenase-1 (HO-1) in VSMCs, blocking the generation of reactive oxygen species (ROS), and thereby exerting anti-atherosclerotic effects.

4.Cardiomyoprotective Effects

Hesperidin, hesperetin, and their derivatives exhibit anti-apoptotic and inhibitory effects on coronary vessel proliferation and migration, demonstrating favorable actions in myocardial injury, cardiac remodeling, myocardial ischemia, and myocardial infarction. Hesperetin protects against cardiomyocyte apoptosis and damage by reducing the ratio of apoptotic cells and inhibiting the activities of caspase-3 and caspase-9. Naringenin can reduce the ratio of neointima to media in rat carotid artery balloon injury models and serum levels of 8-iso-prostaglandin F2α (8-iso-PGF2α), suggesting its potential use in preventing restenosis after cardiac valve angioplasty. Furthermore, naringenin can also mitigate myocardial injury induced by ischemia-reperfusion in acute infarction rats, thereby exhibiting cardiomyoprotective effects.

5.Neuroprotective Effects

Compounds like nobiletin and tangeretin found in Chenpi possess neuroprotective properties, providing protection against cerebral ischemia-reperfusion injury and improving motor cognition. Nobiletin can ameliorate learning and memory impairments caused by aging and age-related neurodegenerative disorders, as well as oxidative stress and tau hyperphosphorylation. It also activates the ERK pathway and its cyclic adenosine monophosphate (cAMP) transcription. Furthermore, nobiletin reduces the infarct size in rat models of cerebral ischemia-reperfusion, inhibits brain edema and neutrophil infiltration into ischemic regions, decreases apoptotic cell death in the ischemic hemisphere, activates cAMP response element-binding protein (CREB), and improves motor dysfunction in rats with cerebral ischemia, thereby protecting against cerebral ischemia-reperfusion injury.

Chenpi, a commonly used traditional Chinese medicine, not only finds applications in clinical settings but also serves as a weight-loss supplement, exemplifying its dual role as both medicine and food. Its high utilization value and versatile applications make Chenpi a promising candidate with vast potential for future development.

References:

[1] Zhang Yixin, Tan Linglong, Yu Huan, Zhong Lingyun, Gong Qianfeng. Research Progress on the Processing of Chenpi (Dried Orange Peel) [J]. Jiangxi Journal of Traditional Chinese Medicine, 2018, 49(07): 66-69.

[2] Yu Jingjing, Su Jie, Lv Guiyuan. Research Progress on the Related Pharmacological Effects of Chenpi (Dried Orange Peel) Against Cardiovascular and Cerebrovascular Diseases [J]. Chinese Traditional and Herbal Drugs, 2016, 47(17): 3127-3132.

About the Author

Xiaonisha, a food technology professional holding a Master's degree in Food Science, is currently employed at a prominent domestic pharmaceutical research and development company. Her primary focus lies in the development and research of nutritional foods, where she contributes her expertise and passion to create innovative products.