Rehmannia glutinosa belongs to Scrophulariaceae（Scrophulariaceae）RehmanniaRehmannia Libosch. ex Fisch. etMey.Plant Rehmannia glutinosaRehmannia glutinosa Libosch.The fresh or dried root tubers, first published in the Shennong materia medica classic, are listed as top-grade. They are one of the famous "four Huaiyao" and have been used for thousands of years. Rehmannia glutinosa is cold in nature and tastes sweet and bitter. It can restore heart, liver and kidney meridians. It has the effect of nourishing yin and tonifying kidney. It is quite beneficial for those with Yin deficiency, blood deficiency and kidney deficiency^[1]Rehmannia glutinosa is divided into fresh rehmannia glutinosa, raw Rehmannia glutinosa and cooked Rehmannia glutinosa according to different processing methods^[2]Rehmannia glutinosa is commonly known as fresh rehmannia glutinosa, which has the effects of clearing away heat and generating fluid, cooling blood and dispersing blood stasis, detoxifying and relieving pain. It is used for heat disease hurting Yin, tongue crimson and thirsty, hair spots and rashes, hematemesis, bleeding, sore throat; Roast Rehmannia glutinosa slowly until it is about 80% dry. When used as medicine, it is known as raw Rehmannia glutinosa, which clears heat and cools blood, nourishes Yin and generates fluid. It is used for hot diseases, such as purplish tongue and thirst, internal heat due to yin deficiency, bone steaming and fever, internal heat to quench thirst, hematemesis, bleeding and rash^[1]The raw Rehmannia glutinosa wine is made and dried, and then used as medicine. It is used for nourishing yin and blood, tonifying essence and filling marrow. It is used for liver and kidney yin deficiency, waist and knee soreness and softness, bone steaming hot flushes, night sweats and spermatorrhea, internal heat and thirst quenching, blood deficiency and yellowing, palpitations and palpitations, irregular menstruation, metrorrhagia and blood leakage, dizziness, tinnitus and premature white beard^[1].

1  chemical composition

So far, compounds have been isolated and identified from fresh rehmannia glutinosa, raw Rehmannia glutinosa, cooked Rehmannia glutinosa, Rehmannia glutinosa leaves and Rehmannia callus200More than species, mainly iridoids, Ionones and phenylethanol compounds, in addition to triterpenoids, flavonoids, lignans, phenolic acids and other compounds.

1.1  Iridoids

Iridoids are the most abundant and abundant compounds in Rehmannia glutinosa. See table for specific names1The chemical structure is shown in Fig1Catalpol, a representative compound in this class, is the main component in Rehmannia glutinosaFractions and active ingredients, 《Chinese Pharmacopoeia》2015Annual edition vs2020It is listed as an index component under the item of identification and content determination in the annual edition^[1,3]。The basic skeleton of these compounds is mainly Leonurus glycosides, and most of the glycosyl ligands contained are glucose, mainly including digitalis glycoside a,Digitalis DAccording to the literature^[30]The content of these compounds varies greatly during the processing of Rehmannia glutinosa. The possible reason is related to the number of glycosyls attached to these compounds: when the compound is attached with3; Danglianyou2The content of sugar decreased with the processing process, and finally decreased to the original content of1/3; when the company has1.

1.2  Ionones

The Ionones found in Rehmannia glutinosa are mainly monoterpenes and sesquiterpenes5The hydroxyl group can form glycosides with glucose, and rarely polymerize with iridoid compounds. The specific names of Ionone compounds isolated from Rehmannia glutinosa are shown in table2The chemical structure is shown in Fig2。

1.3  Phenylethanol compounds

Most of the phenylethanol compounds in Rehmannia glutinosa exist in the form of glycosides, and their structural characteristics are as follows:β-Glucose is the linker, phenylethanol and Phenylacetyl are the substituents, which are connected to different parts of sugar by glycosidic bonds. Its representative compound verbascoside is Chinese Pharmacopoeia2015Annual Edition^[38]The specified index components of Rehmannia glutinosa and Rehmannia glutinosa, in addition to Cistanche glycoside A andCistanche glycoside fSee table for phenylethanol compounds isolated from Rehmannia glutinosa3The chemical structure is shown in Fig3。

1.4  Triterpenoids

Triterpenoids in Rehmannia glutinosa mainly exist in leaves, and no relevant reports have been found in other parts. 9The structural types are oleanane type and Ursane type. See table for triterpenoids in Rehmannia glutinosa4The chemical structure is shown in Fig4。

1.5  Flavonoids

. The compounds isolated from Rehmannia glutinosa are shown in table5The chemical structure is shown in Fig5。

1.6  Sugars

The carbohydrate compounds in Rehmannia glutinosa are mainly divided into monosaccharides and polysaccharides2. Monosaccharides mainly includeD-GlucoseD-GalactoseD-Fructose, sucrose, raffinose, mannotriose, stachyose, verbascose, andD-mannose^[49]The content of stachyose in Rehmannia glutinosa is the highest, and the mass fraction of stachyose in its water extract can reach48.3%^[49]Rehmannia glutinosa polysaccharides mainly includea, Rehmannia glutinosa polysaccharideb^[50], Rehmannia glutinosa polysaccharideSRPⅠ, Rehmannia glutinosa polysaccharideSRPⅡ^[51]And byL-ArabinoseD-GalactoseL-RhamnoseD-Galacturonic acid press10∶10∶1∶1With14∶7∶3∶8The proportion of2Acid polysaccharide^[52]The relative molecular mass of these polysaccharides is huge, and most of them are10 000Above.

1.7  Other classes

In addition to the above types of ingredients, there are many other types of ingredients in Rehmannia glutinosa, such as lignans, phenolic acids, amino acids^[30,56-57]Volatile oil^[32,58]And inorganic elements^[56]Et al. See table for the names of lignans and phenolic acids6The structure is shown in Fig6。

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2  pharmacological action

Rehmannia glutinosa has a long history of medicinal use and a wide range of pharmacological effects in China. Modern pharmacological studies have shown that Rehmannia glutinosa has significant effects on the human blood system, cardiovascular and cerebrovascular system, central nervous system and immune system. In additionIt also has the functions of regulating blood glucose and lipid, anti-aging, anti-tumor, bacteriostasis, anti gastric ulcer and protecting gastric mucosa.

2.1  Effect on blood system

Prepared rehmannia glutinosa is an important blood tonic commonly used in clinic, which can enhance the body's hematopoiesis, Huang Xia et al^[61]By observing the effects of Rehmannia glutinosa polysaccharide on peripheral blood picture, bone marrow hematopoietic stem cells and bone marrow nucleated cells of model mice, it was found that Rehmannia glutinosa polysaccharide had antagonistic effects on peripheral blood picture and bone marrow nucleated cells decline of mice with different blood deficiency models, and it could promote the proliferation and differentiation of mouse hematopoietic stem cells; In addition, liupeijian et al^[62]Studies have shown that Rehmannia glutinosa polysaccharide can increase the serum granulocytes of mice with deficiency of both qi and blood by-Macrophage colony stimulating factor level to maintain the proliferation and differentiation of hematopoietic precursor cells and mature blood cells, thereby promoting bone marrow hematopoiesis; After administration of Rehmannia extract to anemic rats, xuelijun et al^[63]It was found that the number of red blood cells and bloodErythropoietin was significantly elevated, and plasma erythropoietin（erythropoietin，EPO）Improved level, brainEPOAnd its receptor levels were significantly up-regulated, which confirmed that Rehmannia glutinosa can act on the bone marrow hematopoietic system of rats, promote hematopoiesis, improve anemia, and thus play an important role in the treatment of anemiaTherapeutic effects in rats. Rehmannia glutinosa also has the effect of cooling blood and hemostasis. It is reported that fresh rehmannia glutinosa can reduce the related symptoms of tongue, lung and stomach bleeding injury in rats with blood heat hemorrhage, improve abnormal Hemorheology and coagulation system indicators, and has the effect of cooling blood and hemostasis^[64]The study also found that the raw landYellow, fried raw and cooked Radix Rehmanniae carbons can shorten the bleeding time and coagulation time in mice, and have a certain hemostatic effect^[65]. Wang Mei et al^[66]According to the experimental study on the pharmacodynamic material basis of the hemostatic effect of Rehmannia glutinosa, the pharmacodynamic active substances of the hemostatic effect of Rehmannia glutinosa are related to sugars and iridoid glycosides, and the specific mechanism of action needs further study.

2.2  Effect on cardiovascular and cerebrovascular system

. Yanghuanbin et al^[67]Through clinical experiments, it was observed that after giving Dihuang Yinzi to patients with coronary heart disease and angina pectoris, its therapeutic effect on angina pectoris was better than isosorbide mononitrate, and the effective rate of improving electrocardiogram was also significantly higher than that of the control group; Clinical studies also showed that the total effective rate of treating cerebral infarction with self-made addition and subtraction of Dihuang decoction reached86.5%And this method can nourish the kidney and unblock the collaterals, give consideration to both specimens, and achieve good therapeutic effect^[68]。

2.3  Effects on the central nervous system

The clinical manifestations of Alzheimer's disease are mental retardation, memory loss, cognitive dysfunction, mental behavior changes and social activity decline, which is the most common neurodegenerative disease leading to Alzheimer's disease. Studies have shown that Rehmannia glutinosa can be widely used to treat various neurodegenerative diseases and effectively improve cognitive and memory disorders.Leeetc.^[69]By treating ratsipScopolamine hydrobromide induced memory deficits. After successful modeling,ip 200mg/kgRehmannia extract,2Weeks later, it was found that Rehmannia extract not only significantly improved the memory impairment of rats, but also reduced the latency of rats to find a platform in the water maze. In addition, the study also showed that200 mg/kgRehmannia glutinosa extract can enhance cholinergic immune response related to memory and reduce interleukin in hippocampus（interleukin，IL）-1βAnd tumor necrosis factor-α（tumor necrosis factor-α，TNF-α）mRNAIt is suggested that Rehmannia extract may improve cognition and alleviate inflammatory response by stimulating cholinergic enzyme activity. Liuzhishou et al^[70]Similar studies also showed that Dihuang Yizhi formula has a certain preventive and therapeutic effect on senile dementia, and its mechanism may be related to its ability to improve the level of oxidative stress in brain tissue and the concentration of acetylcholine between nerve synapses. Xuelijun et al^[63]The anemia rat model was prepared by tail cutting bloodletting combined with cyclophosphamide injection,ig 3、6、10 g/kgRehmannia glutinosa aqueous extract,10 dIt was found that the spatial memory ability of Rehmannia glutinosa treatment group was significantly improved, the escape latency was significantly shortened, the number of crossing the platform in a certain time was significantly increased, and the expression of erythropoietin and its receptor in brain tissue was significantly increased, indicating that Rehmannia glutinosa aqueous extract significantly improved the spatial memory ability of anemia mice.

2.4  Impact on the immune system

The immune system is an important system for the body to carry out immune response and immune function. Immunocompromised patients are vulnerable to various diseases. Studies have reported that different doses of Rehmannia extract can improve the immune organ index, carbon clearance indexIL-2andTNF-αLevel, improveTLymphocyte ratio, serum hemolysin level and splenic lymphocyte proliferation rate, serum immunoglobulin of mice in different doses of Rehmannia extract groupG, immunoglobulinALevels were also increased to varying degrees, indicating that Rehmannia glutinosa extract can promote immune function in mice^[71]Xi Xiangjun et al^[72]The experimental study of mouse immunocompromised model showed that Dihuang Decoction could improve the immune function of mice by increasing the level of serumIL-1αIt can enhance immune function, regulate endocrine, and protect the morphology and structure of thymus and ovary.

2.5  Anti aging effect

Aging is closely related to free radicals in the body. Excessive free radicals can lead to cell damage and aging.Piątczaketc.^[73]Studies have shown that the methanol extract of Rehmannia glutinosa can inhibitH₂O₂/FeInduces plasma protein oxidation,50 μg/mLMethanol extract can inhibit the production of superoxide anion by resting platelets. Ma Rui et al^[74]Studies have shown that Rehmannia glutinosa can inhibitH₂O₂The induced lipid peroxidation and hemolysis of red blood cells in rat kidney inhibit lipid peroxidation and delay cell senescence by scavenging the production of free radicals.

2.6  Antitumor

Stachyose is a component of Rehmannia glutinosa oligosaccharide, which has anti-tumor effect in vitro. Stachyose inhibits human liver cancerHepG-2Cell, human gastric cancerSGC-7901The effect of stachyose combined with cyclophosphamide is positively correlated with the concentrationH₂₂Tumor bearing mice, tumor mass of mice was negatively correlated with stachyose concentration^[75]。

2.7  Regulate blood glucose and blood lipids

Caichunchen et al^[76]Studies have shown that the obese diabetic rat model induced by high-fat and high sugar diet combined with streptozotocin,ip 10、20、30 mg/kgRehmannia glutinosa polysaccharide4 dThe body weight, fasting blood glucose and insulin levels, triacylglycerol and total cholesterol of mice were significantly reduced, and glucagon like peptide-1And Glucose dependent insulin-releasing peptide content was significantly increased. Rehmannia glutinosa oligosaccharides can reduce the postprandial blood glucose level andα-Glucosidase activity and decreaseddb/db2Impaired glucose tolerance in type 2 diabetic mice,Rehmannia glutinosa oligosaccharides can inhibit liver in vitroH4IIEExpression of phosphoenolpyruvate carboxylation kinase gene in cells to inhibit hepatic gluconeogenesis^[77]。

2.8  Bacteriostasis

Rehmannia glutinosa ethyl acetate extract, n-butanol extract, chloroform extract of different concentrations have obvious antibacterial effect on Escherichia coli, Staphylococcus aureus, Bacillus subtilis, etc^[78]. yuan Huiming et al^[79]It was found that Rehmannia glutinosa could inhibit the activities of Bacillus subtilis, Staphylococcus aureus and Escherichia coli, and the inhibitory effect on Bacillus subtilis was the strongest. Its inhibitory effect was positively correlated with the concentration of Rehmannia glutinosa, but it had no obvious inhibitory effect on Saccharomyces cerevisiae, Candida, Aspergillus niger.

2.9  Anti gastric ulcer

Dried Rehmannia glutinosa80%Ethanol extractALiquid can significantly reduce the gastric mucosal damage caused by absolute ethanol and inhibit heat shock protein70The synthesis of β - Catenin increases gastric mucosal blood flow; HEStained sections showed that the gastric mucosa was severely damaged, and the gastric foveal cells and glandular cells were severely damaged, and the surface cortex fell off,AIn the liquid group, some cells fell off, and most of the gastric foveal cells and gland cells were intact^[80]。

2.10  other

2.10.1 Diabetic osteoporosis  Gongetc.^[81]The study found that the aqueous extract of Rehmannia glutinosa could improve the osteoporosis caused by diabetes. The aqueous extract of Rehmannia glutinosa can increase the activity of bone specific alkaline phosphatase in the serum of streptozotocin-induced diabetic model mice, reduce the serum osteocalcin, significantly improve the bone mineral density, three-dimensional calibrated trabecular thickness, trabecular number and connectivity density of the femur of diabetic rats, reduce the trabecular spacing and structural model index, and inhibit the bone loss and microstructure deterioration caused by diabetic rats. ; increaseRuntRelated transcription factors2And osteopontin expression, promoting osteoblast differentiation; By upregulating cytochromeP45017A1And aromatase, down regulated11β-The expression of hydroxysteroid dehydrogenase further interferes with sterol hormone biosynthesis and improves glucocorticoid induced metabolic imbalance in vivo^[82]。

2.10.2  Renal dysfunction caused by diabetes  Daietc.^[83]Diabetic nephropathy was prepared by intraperitoneal injection of streptozotocin combined with high-fat dietRat models were treated with total glycosides of Rehmannia glutinosa and total glycosides of Rehmannia glutinosa leaves capsules, respectively15 d, serum creatinine, urea nitrogen24 hUrinary protein quantification and the degree of renal interstitial fibrosis were significantly reduced, and human wingless typeMMTVIntegration site family members4、βCatenin, transforming growth factor-β1The expression was significantly reduced, protecting mesangial cells,2-Ketoglutamic acid, guanosine triphosphate, neochenodeoxycholic acid1-Sphingosine phosphate, thiamine triphosphateN-acetyl-D-Glucosamine6-Phosphoric acid, etc27The endogenous metabolites recovered to normal levels in different degrees.

2.10.3 Antidepressant  Rehmannia glutinosa aqueous extract can improve chronic mild unpredictable stress（chronic mild unpredictable stress，CUMS）Gastric ulcer, antioxidant capacity and exercise ability of depressed mice alleviate depression in mice. CUMSThe level of malondialdehyde in the liver of model mice, and increase the activities of superoxide dismutase and catalase, reduce the body's oxidative damage^[84]。Ethanol extract of Rehmannia glutinosa onCUMSDepression model mice have antidepressant effect, which can relieve the depression caused byCUMSThe symptoms caused by the reduced preference for sucrose in mice can be recoveredCUMSThe abnormal increase of cortisol level in serum may be caused by inhibition of hypothalamus-pituitary-Hyperactivity of the adrenal axis increases central neurotransmitters5-Hydroxytryptamine, norepinephrine, improve brain-derived nervous systemOperating trophic factors and tropomyosin related kinasesBProtein expression^[85]。

2.10.4  Liver protection  Zhangetc.^[86]useCCl₄The liver injury model was prepared and Rehmannia glutinosa oligosaccharide was continuously administered21 dThe levels of alanine aminotransferase and aspartate aminotransferase in the serum of mice were significantly increased, while the levels of total cholesterol and triacylglycerol were significantly decreased; The liver oxidative damage was significantly improved, and the activities of glutathione, glutathione peroxidase and superoxide dismutase were increased.

3  Conclusion and Prospect

Rehmannia glutinosa, first published in the Shennong herbal classic, is listed as a top-grade drug. It is one of the famous "four Huaiyao" and has been used for thousands of years. With the continuous development of modern pharmacy and the in-depth study of Rehmannia glutinosa, more and more active ingredients in Rehmannia glutinosa have been excavated, such as iridoids, Ionones and phenylethanol, as well as triterpenoids, flavonoids and other compounds. However, Rehmannia glutinosa or Rehmannia glutinosa are often used in the form of water decoction, and the ingredients that exert efficacy in the decoction are mostly water-soluble ingredients with large polarity. Therefore, the research on the water-soluble components of Rehmannia glutinosa and Rehmannia glutinosa has important role and significance for its development and utilization. Pharmacological studies have found that Rehmannia glutinosa can significantly regulate the blood system, cardiovascular and cerebrovascular system, central nervous system and immune system. In addition, it can also regulate blood glucose and blood lipids, anti-aging, anti-tumor, bacteriostasis, anti gastric ulcer and protect gastric mucosa^[87]Although there are many pharmacological activities of Rehmannia glutinosa, the mechanism of action of the active substances has not been clearly studied. In addition, 《Chinese Pharmacopoeia》2020The quality control methods of Rehmannia glutinosa and prepared rehmannia glutinosa were also improved in the edition2015Edition, digitalis glycosides in neohyperplastic Rehmannia glutinosa and prepared rehmannia glutinosaDThe content determination of verbascoside was deleted^[1]. So follow upThe research work of Rehmannia glutinosa can be started from the following aspects:（1）Improve the existing extraction process of Rehmannia glutinosa and increase the amount of effective ingredients; The（2）PlusGreat efforts should be made to expand the research dimension and clarify the molecular mechanism of the pharmacological action of Rehmannia glutinosa, such as exploring new active ingredients and new targets and new pharmacological effects of existing active ingredients with the help of modern research methods such as molecular biology and network pharmacology; The（3）According to different therapeutic purposes and treatment methods, different active ingredients are selected, such as quality marker

Conflict of interest 

References (omitted)  

Come   Source: chenjinpeng, zhangkexia, Liu   Yi, gaixiaohong, Ren   Tao, Liu Suxiang, Tian Chengwang. Research progress on chemical constituents and pharmacological effects of Rehmannia glutinosa       [J] . Chinese herbal medicine, 2021, 52 (6): 1772-1784