pick To:lotus leafNelumbo nucifera. Lotus leaf alkaloids are alkaloid active substances extracted from lotus leaves, which have antibacterial, lipid regulating, antispasmodic and other effects. In recent years, health problems caused by obesity have received great attention, so the lipid-lowering and weight loss efficacy of lotus leaf alkaloids has become a research hotspot. The composition, lipid-lowering mechanism and its application in drug development of lotus leaf alkaloids were reviewed, providing references for the development of lipid-lowering products of lotus leaf alkaloids and the in-depth study of lipid-lowering mechanism.
Lotus leaf is an aquatic plant of lotus in the lotus familyNelumbo nucifera Gaertn. The dried leaves are mainly produced in Hubei, Jiangsu, Zhejiang and other places[1]，2002It was listed as a food of the same origin as medicine and food by the Ministry of health in. Traditional Chinese medicine believes that the lotus leaf is pungent and cool, bitter and slightly salty, and has the functions of Promoting Yang clearing, hemostasis and diuresis, clearing heat and dampness, clearing the heart and removing heat[2]According to the compendium of Materia Medica, "lotus leaf clothes are thin and inferior. Taking them alone can eliminate Yang edema.". According to modern medicine, the bioactive substances in lotus leaves are mainly flavonoids and alkaloids, among which lotus leaf alkaloids have many activities such as anti-aging, anti-oxidation, bacteriostasis, lipid regulation and weight loss, and free radical scavenging[3-6]。
Obesity is closely related to hyperlipidemia, diabetes, atherosclerosis and other cardiovascular and cerebrovascular diseases. . Many scholars have explored the lipid regulating effect of lotus leaf alkaloids, but there is no systematic study on its lipid regulating mechanism. Therefore, this paper reviews the constituents of lotus leaf alkaloids, the possible lipid-lowering mechanism and its application in drug development, in order to provide references for the development of lotus leaf alkaloids lipid-lowering products and the in-depth study of lipid-lowering mechanism.
1 Alkaloids from lotus leaves and their classification
Lotus leaf alkaloid from20Since the middle and late 20th century, the lotus leafWas found.1961Years, nuciferine（nuciferine）, Liensinine（roemerine）、O-Demethyllotus leaf base（O-nornuciferine, also known asN-Methyl pavine[7]）3Monomeric components were first found in lotus leaves[8]Up to now, the alkaloid monomers found in dried lotus leaves and lotus leaf juice have27According to the biogenic pathway and chemical structure type, they can be classified as Isoquinolines in phenylalanine and tyrosine alkaloids. According to the different connecting groups on the parent nucleus of isoquinoline or tetrahydroisoquinoline, they can be subdivided into proto aporphineClass A, aporphine, oxidized aporphine, dehydroarphine, monobenzylisoquinoline, dibenzylisoquinoline, and other classes. The typical structural formula is shown in Fig1The names and substituents are shown in table1，; Neferine methyl;Liensinine; Isoliensinine; Liensinine; N-methyl lotus leaf base, etcThe diversity of chemical structures of lotus leaf alkaloids makes them have a wide range of biological activities. Summarizing and classifying the chemical structures is conducive to exploring new activities, and provides a theoretical basis for the research of this kind of compounds in artificial synthesis and clinical application.
2 Lipid regulating mechanism of alkaloids from lotus leaves
Lotus leaf is a medicinal material with lipid regulating effect clearly recorded in ancient books. Modern pharmacology has proved that alkaloids in lotus leaves are the main effective components to reduce blood lipids and body mass in hyperlipidemic rats[22-25]. the total alkaloids of lotus leaves were continuouslyigAdministration to hyperlipidemic rats40 dThe positive drug simvastatin was used as the control, and the levels of blood lipid and body fat in rats were foundLee’sThe index decreased in varying degrees, close to the level of the control group[26]Lotus leaf alkaloid salt also has significant lipid-lowering effect on hyperlipidemic rats[27]。Jongetc.[28]According to the experiment, lotus leaf alkaloids can significantly inhibit adipocyte differentiation and pancreatic lipase activity, among which benzylisoquinoline alkaloids have the strongest inhibitory effect, which can not only inhibit fat accumulation, but also reduce fat absorption. It can be seen that lotus leaf alkaloids can exert lipid-lowering effects from many aspects, including inhibiting lipid synthesis and absorption, inhibiting cell proliferation and differentiation, and interacting with proteins, as shown in Fig2。
2.1 Interaction with lipids
Yuanyang[29]adoptSDNonalcoholic fatty liver in rats（NAFLD）Model study found that lotus leaf alkaloids can alleviate lipid peroxidation damage and oxidative stress by regulating energy metabolism disorder and lipid metabolism, thereby inhibiting inflammatory response, hepatic fatty lesions and collagen deposition in ratsNAFLDIt has a certain therapeutic effect. Lotus leaf alkaloids can be densely arranged on the human intestinal wall, forming a layer of fat isolation membrane, preventing fat accumulation and absorption, making the human body disgusted with greasy food and actively reducing intake[30]Benzylisoquinoline alkaloids can inhibit fat accumulation and absorption, while other alkaloids focus on inhibiting fat absorption[28,31]. Hanxiao et al[32]Study on nuciferine by in vitro cell culture experiment（1）The results showed that it may play a role in lipid regulation by reducing the activity of cholesterol esterase, inhibiting cholesterol synthesis and increasing low-density lipoprotein receptor.
2.2 Interaction with cells
Liuxiaoqin[33]It was found that the alkaloid extract of lotus leaf could transfer preadipocytes3T3-L1Mitotic arrest atG0/G1Phase, delaying the entry of cellsSPhase, can effectively inhibit3T3-L1. amongO-Demethyllotus leaf base（7）Can block cells inG0/G1Phase, nuciferine andN-Demethyllotus leaf base（8）Can block cells inSPhase, pavine（4）Can block cells inG2/Mstage[34]. lotus leaf alkaloids on3T3-L1The inhibition of cell proliferation was concentration and time-dependent, and the inhibition rate also increased with the increase of mass concentration and action time[9]。4The activities of alkaloid monomers in promoting apoptosis were8＞4＞7＞1[34]. annonaceine（2）And liriodendrine（13）Can also significantly inhibit3T3-L1Cells differentiate into adipocytes, probably because they have a methylenedioxy structure[28]In addition, protophylline（26）AndO-Demethyllotus leaf base（7）Can significantly increase3T3-L1Glucose consumption when cells differentiate into mature adipocytes, which may be beneficial to blood glucose balance and lipid regulation[35]While in liver cancerHepG2In cells, nuciferine can regulatePASDomain filament/Threonine kinase（PASK）NAFLDAnd the process is similar toPASKThe expression levels of related genes are closely related[36]In addition, nuciferine can be activated by turning off potassiumATPEnzyme（K-ATP）Channel stimulation of pancreatic islets and rat insulinomaINS-1ECells secrete insulin[37].
2.3 Interaction with proteins
The essence of pancreatic lipase is an acidic protein molecule, which has a folded structure in space. This structure is easy to form gaps and small holes, so that small molecules in lotus leaf alkaloids may enter and combine with pancreatic lipase, causing changes in the structure of pancreatic lipase and its microenvironment, thereby accelerating energy consumption and lipid metabolism, inhibiting carbohydrate and lipid absorption, and ultimately significantly reducing the body weight of hyperlipidemic rats and the contents of triacylglycerol and total cholesterol in serum[38-39]. yolk antibody to pancreatic lipase can specifically bind to pancreatic lipase and inhibit its activity, niumengxian et al[39]. Studies have shown that alkaloids from lotus leaves can activate protein kinase by activating adenylate（AMPK）signaling pathway， Improve glucose and lipid metabolism in mature adipocytes, which may be the biological basis for lotus leaf alkaloids to play the role of lipid regulation and weight loss[35,40]. with nuciferine and protonuciferine（26）,AMPKPhosphorylation and glucose transporters（GLUT4）The expression levels were significantly enhanced, resulting in increased glucose uptake and decreased lipid accumulation, indicating thatAMPKThe signaling pathway may be involved in the process of aporphine alkaloids inhibiting lipogenesis[41]Some studies have shown that within a certain range,5-Serotonin（5-HT）The higher the activity of the receptor, the more likely it is to produce anorexia and satiety[42]，Munusamyetc.[43]Experiments proved that lotus leaf alkaloid and lotus root alkaloid（3）Activation selectivity5-HT2AReceptors, in which Liensinine has no effect on5-HT2AThe selectivity of the receptor is better than5-HT1A、D1andD2Receptor, which is due to the interaction between Liensinine and5-HT2AThere are stronger hydrogen bonds and dipoles between several key residues in the receptor binding site-Dipole interaction, suggesting that nuciferine and Liensinine can activate5-HT.Zhangetc.[44]It is believed that nuciferine can activate receptors by activating peroxisome proliferators（PPAR）/Peroxisome proliferator activated receptor coactivator1α（PGC1α）Pathway, improving the effect of high-fat diet combined with streptozotocin induced2Lipid distribution in type 2 diabetic mice, thereby reducing total cholesterol, triacylglycerol, low-density lipoprotein and the number of fat droplets in the liver, and reducing hepatic steatosis.
3 Effects of lotus leaf alkaloids on lipid regulationuse
The lipid regulating function of lotus leaf alkaloids can assist in the treatment of a variety of cardiovascular diseases, such as atherosclerosis, hypercholesterolemia, etc., and has been usedIn a variety of compound preparations. Tongmai Jiangzhi tablet is a Chinese patent medicine for the treatment of hyperlipidemia contained in the drug standard of the Ministry of health. Xiong Dengke et al[45]The mass fraction of nuciferine was determined to be2.42 mg/gJiangzhining granules are mainly used to regulate blood lipids and soften blood vessels, fanchengtai et al[46]The mass fraction of nuciferine was determined by HPLC to be0.41 mg/gHedan granules are made of lotus leaf, Salvia miltiorrhiza, etc5Chinese patent medicine composed of traditional Chinese medicine for the treatment of hyperlipidemia caused by phlegm and blood stasis, zhulianghui et al[47]The mass fraction of nuciferine was determined by HPLC to be0.23 mg/gHugan Qingzhi granule is made of lotus leaf, Alisma orientalis, etc5The traditional Chinese medicine compound preparation composed of traditional Chinese medicine has the effect of activating blood circulation and regulating lipid. It can be used to treat hyperlipidemia and non-alcoholic fatty liver. Studies have found that it can significantly reduce blood lipid levels, prevent and improve inflammatory injury and steatosis, effectively inhibit liver lipid deposition and regulate lipid metabolism disorders[48]The mass fraction of nuciferine measured by thin-layer chromatography was0.15 mg/g[49]Tangzhiqing is a prescription composed of mulberry leaves, lotus leaves and other traditional Chinese medicinal materials, which has the functions of removing blood stasis, eliminating pimples, elevating clarity and reducing turbidityIt can be used to treat pre diabetes glucose and lipid metabolism disorders[50]Tangzhiqing compound has shown good lipid-lowering and hypoglycemic effects in clinic[51]，Under HPLC conditions,Lietc.[52]Chromatographic fingerprinting was usedThe content of nuciferine in tangzhiqing compound was determined to be1.75 mg/gZhimaikang capsule is Chinese Pharmacopoeia2015The Chinese patent medicine with lotus leaf as one of the main ingredients included in the edition has the effects of regulating blood lipids, activating blood vessels, supplementing qi and blood, and is clinically used to treat hyperlipidemia, arteriosclerosis and other diseases.
4 epilogue
Most chemically synthesized lipid-lowering drugs (such as liraglutide) act on the nervous system, making the body feel full or anorexic to achieve the effect of lipid-lowering and weight loss. Therefore, when drugs play the role of lipid regulation, they will also bring dizziness and headache, anxiety, nausea and vomiting and other side effects, and even cause serious damage to the human body (such as amirex). At present, lotus leaf alkaloids, which also have lipid-lowering effects, have no obvious adverse reactions. It has many advantages, such as natural green, wide sources, low cost, non-toxic and side effects, and is a better source of weight loss drugs.
Lotus leaf, as a kind of edible and medicinal plant in China, is not only cheap, rich in resources, but also has a wide range of biological activities. A large number of studies have shown that the extraction and separation technology of alkaloids from lotus leaves is becoming more and more mature, but the problems of low extraction rate, high cost and not suitable for industrial production need to be solved. （HIV）The processing method of the products is also very simple, and most of them are made into tea or powder into medicine. The fundamental reason is that the content of alkaloids in lotus leaves is low, and pure products are expensive, which hinders the development and utilization. Therefore, efforts should be made to synthesize lotus leaf alkaloids, improve genetic traits through genetic engineering or expand sources through artificial synthesis, and increase the yield of lotus leaf alkaloids, so as to further develop lotus leaf lipid-lowering products and benefit more high-fat people.
References (omitted)
Come Research Progress on Alkaloids from lotus leaves and their lipid regulating mechanism [j]. Chinese herbal medicine, 2019, 50 (8): 1998-2003