Nervous system（nervous system）It is the most important regulatory system in the human body and plays a leading role in all life systems of the human body. With the increasing pressure of modern people and the aging of the population, insomnia, depression, Alzheimer's disease（AD）, Parkinson's disease, ischemic stroke and other neurological diseases（nervous system disease）It has become a serious disease endangering human health. base on2003—2016The investigation and analysis of insomnia in various provinces in China showed that the overall incidence of insomnia in China was15.0%, and a higher incidence in young adults[1]Insomnia is one of the important causes of depression. Depression is one of the most common mental disorders, with a population incidence of2%～3%, with the highest incidence especially in the adolescent population[2]Traditional Chinese medicine (TCM) is widely used in nerve diseases for its green, safe and effective characteristicsTreatment of systemic diseases[3]For example, the total effective rate of qiyeshen'an tablet with Panax notoginseng saponin as the main raw material in the treatment of insomnia can reach88.9%[4]; ginsenosideRb1Has been used as a potential treatmentADDrug development research[5-6]。
Semen ziphi Spinosae is a plant belonging to the genus Zizyphus Spinosae of rhamniaceaeZiziphus jujuba Mill. var. spinosa (Bunge) Hu ex H. F. ChouDried mature seeds of[7]According to the records of famous doctors, semen Ziziphi Spinosae "can cure restlessness, sweating, thirst, tonify the middle and benefit liver qi". Semen Ziziphi Spinosae is the first choice of traditional Chinese medicine in the clinical treatment of insomnia[8]At present, the compounds isolated and identified from semen Ziziphi Spinosae have exceeded130More than species, including saponins, flavonoids, alkaloids, fatty acids and other components[9]Zizyphus jujuba saponins can be further divided into tetracyclic triterpenes and pentacyclic triterpenes according to different aglycone structures2Types. Modern pharmacological research shows that semen ziphi Spinosae saponin is the main pharmacodynamic component of its tranquilization and tranquilization. In addition, it also shows a wide range of pharmacological activities in the nervous system, immune system, cardiovascular and cerebrovascular system, etc[10]In this paper, the structure and distribution of Zizyphus jujuba saponins were systematically summarized, and the pharmacological effects of Zizyphus jujuba saponins in the nervous system were reviewed, so as to provide a scientific reference for the discovery and development of new drugs for the treatment of nervous system diseases from Zizyphus jujuba saponins.
1 Saponins from semen ziphi Spinosae
from20century30Since the s, scholars at home and abroad have systematically studied the chemical components of different parts of wild jujube, such as seeds, pulp, leaves, roots and so on. So far, it has been isolated and identified from semen ziphi Spinosae and different parts of ziphi Spinosae51Saponins, including tetracyclic triterpenoid saponins20Pentacyclic triterpenoid saponins31.
1.1 Tetracyclic triterpenoid saponins
Tetracyclic triterpenoid saponins are a class of compounds widely existing in nature, which have important pharmacological effects such as anti-tumor, immune regulation, anti-inflammatory, anti-aging, improving memory and so on. Dammarane type tetracyclic triterpenoid saponinsIt is the main active ingredient of ginseng, Panax notoginseng, American ginseng and other valuable traditional Chinese medicines[11-12]Zizyphus spinosa saponin, which belongs to dammarane type, was first isolated from Zizyphus spinosa (seed) and is also the most important saponin in Zizyphus spinosa. At present, it was co isolated and identified from semen Ziziphi Spinosae20According to the different structure of dammarane type mother nucleus, gemmarane type saponins can be preliminarily divided into Zizyphus spinosaponin typeC-16Keto type andC-17Side chain variant3Types.
1.1.1 Zizyphus spinosa sapogenin type Zizyphus jujuba saponin, ginsenoside and Notoginsenoside belong to dammarane type tetracyclic triterpenoid saponins, but the structure is slightly different from Zizyphus jujuba saponin（jujubogenin）The mother nucleus has2Ether bonds, i.eC-16Bitwise ANDC-30BitC-16Bitwise ANDC-23The chemical structure containing ether bond is usually unstable and prone to oxidation reaction. Zizyphus jujuba saponins by chemical reactionSmith-de MayThe real Zizyphus jujubosigenin can be obtained by degradation reaction; If acid is used（5% H2SO4）Hydrolyze to obtain the secondary metabolite ibilin lactone（ebelin lactone）The specific structure is shown in Fig1。
As early as1978Japanese scholarOtsukaetc.[13]Isolated from semen ziphi SpinosaeZizyphus jujuba saponinA（jujuboside A，JuA，1）AndZizyphus jujuba saponinB（jujubosideB，JuB，2）2Dammarane saponins were planted and elucidated by acid hydrolysis and enzymatic hydrolysis methodsJuAThe glycosyl composition of is arabinosyl-Xylosyl-Rhamnosyl-Glucosyl1∶1∶1∶2，JuBThe glycome of becomes1∶1∶1∶1After that, scholars at home and abroad successively isolated from semen Ziziphi Spinosae10AndJuA、JuBDammarane saponins with the same aglycone but different sugar chain structure are JujubosideB1（jujuboside Bl，JuBl，3）, Zizyphus JujubosideA1（jujuboside Al，JuAl，4）, Zizyphus JujubosideC（jujuboside C，JuC，5）, Jujuboside acetylateB（acetyljujuboside B，6）, Zizyphus JujubosideD（jujuboside D，JuD）. Subsequently, by Wangjianzhong et al[14]Also proved thatJuDWithJuA1Is the same compound. Liupengpeng[15]Jujuboside was isolated from semen Ziziphi SpinosaeI（zizyphus saponin I，7）, jujube saponinII（zizyphus saponin II，8）, jujube saponinIII（zizyphus saponin III，9）, this3.2013yearWangetc.[16]andLeeetc.[17]Zizyphus spinosa saponins were isolated from semen Zizyphus SpinosaeI（jujuboside I，JuI，10）, Zizyphus JujubosideA2（jujuboside A2，JuA2，11）。
1.1.2 C-16Keto type Zizyphus jujuba saponin C-16The keto dammarane type Zizyphus jujuba saponins are a class of tetracyclic triterpenoid saponins with novel structures, which are characterized byC-16Position with a keto substitution, which is currently found in semen Ziziphi Spinosae5Saponins of this type.1999yearMatsudaetc.[18]Zizyphus jujubosigenin（protojujubogenin）Maternal3Three new dammarane saponins, namely, protozaoren saponinA（protojujubosideA，PJuA，12）, jujube saponinB（protojujuboside B，PJuB，13）, jujube saponinB1（projujuboside B1，PJuB1，14）。PJuAstayC-16There is a keto substitution at position, exceptC-3In addition to the common glycosyl substitutions at position 1, itsC-23There is still a glucosyl substitution at position 1, which has6Sugar substituted triterpenoid saponins. Studies have shown that protozaoren saponin inβ-Under the catalysis of glucosidase, it can be dehydrated and converted into Zizyphus spinosaponin.PJuA、PJuB、PJuB1The sugar chains on the left side of the aglycone correspond toJuA、JuB、JuB1The sugar chains are completely consistent. Wang Jianzhong et al[14,19]Isolated2Three structurally novel dammarane saponins, namely, semen Ziziphi Spinosae saponinH（jujuboside H，JuH，15）, Zizyphus JujubosideG（jujuboside G，JuG，16）, surprisinglyJuHWithJuAThe sugar chains of,JuGWithJuBThe sugar chains of are completely consistent, and it is preliminarily presumed thatJuHandJuGProbablyJuAandJuBthroughC-16Bitwise ANDC-23The reaction product after the ring opening of the oxygen-containing heterocycle at position.
1.1.3 C-17Side chain changing Zizyphus Jujuboside Wild jujube kernel also contains aC-17Tetracyclic triterpenoid saponins with subtle changes in side chains, which are rare saponins in semen ziphi Spinosae.2003Nian Bai Yanjing et al[20]Isolated1A novel saponin from semen Ziziphi SpinosaeE（jujuboside E，JuE，17）。JuESimilar to Jujuboside6Glycosyl substitution, andC-23Bitwise ANDC-16The ether bond between the positions breaks and opens the ring. What is more peculiar is thatJuEOfC-3The sugar chain of position andJuAAre completely consistent.2013yearWangetc.[16]Isolated from semen ziphi Spinosae3A new structural saponin, Zizyphus JujubosideII（jujuboside II，JuII，18）, Zizyphus JujubosideIII（jujuboside III，JuIII，19）, Zizyphus JujubosideIV（jujuboside IV，JuIV，20）。JuII、JuIII、JuIVThe special feature of isosaponin is its aglyconeC-23Bit isRConfiguration, while jujubosigeninC-23Bit isSConfiguration. In addition to this structural change,JuIIStructure vsJuBCompletely consistent;JuIIIWithJuIVPage5RingsERings are all five membered rings, andJuIIIThe sugar chain ofJuBCompletely consistent; andJuIVThe sugar chain ofJuA.
The chemical structure of tetracyclic triterpenoid saponins in semen ziphi Spinosae is shown in Fig2。
1.2 Distribution of tetracyclic triterpenoid saponins
By comparing the tetracyclic triterpenoid saponins in the seeds, pulp, leaves, roots and other different parts of Zizyphus jujuba, it was found that they were mainly distributed in the seeds (kernels) of Zizyphus jujuba, but rarely distributed in the pulp and leaves of Zizyphus jujuba. See the table for details1At present, there are few reports on dammarane type tetracyclic triterpenoid saponins in the pulp and leaves of Zizyphus jujuba, which can only be seen in a few literature reports. Guosheng et al[21]Isolated and identified from the ethanol extract of Zizyphus jujuba pulp2Gedammarane saponinIandIIHowever, tetracyclic triterpenoid saponins in wild jujube leaves have only been reported2011yearGuoetc.[22]utilizeHPLC-PDA-MS/ ELSDJujube saponins were identified from wild jujube leaves by HPLCIandII 2Dammarane saponin.
1.3 Pentacyclic triterpenoid saponins
Pentacyclic triterpenoid saponins are a class of saponins composed of30Pentacyclic terpenoids, composed of carbon atoms, are a class of natural products with great research and development value due to their wide range of pharmacological activities[11]It was co isolated and identified from different parts of Zizyphus jujuba Mill31Five pentacyclic triterpenoid saponins are mainly divided into oleanane according to different aglycone structures（oleanane）Type I, arbutine（ursane）Type, lupane（lupane）Typeceanothanetype4Types. The chemical structure of pentacyclic triterpenoid saponins is shown in Fig3。
1.3.1 Oleanane type The basic carbon frame of oleanane saponins is the pentacyclic parent nucleus of polyhydropine, which has8Methyl substitutions, and the sites of structural modification are mainly concentrated inARingCRing andC-28Bitwise[24]At present, it is co isolated from different parts of wild jujube7Oleanane saponins, all in free state, are oleanolic acid（oleanolic acid，21）, oleanolic acid（oleanonic acid，22）, hawthorn acid（maslinicaicd，23）、3-O-CIS-P-coumaroyl hawthorn acid（3-O-cis-p-coumaroyl maslinicacid，24），3-O-Trans-P-coumaroyl hawthorn acid（3-O-trans-p-coumaroylmaslinic acid，25）, hydroxyoleanolic acid lactone（hydroxyoleanonic acid lactone，26）, saikosaponinII（azukisaponin II，27）。
1.3.2 Ursane type The structure of Ursane saponins is basically the same as that of oleanane saponins, but the difference is that the structure of Ursane saponins inC-19Bitwise sumC-20Each has its own1Methyl groups. At present, it is co isolated from different parts of wild jujube6Ursane saponins, respectively3-Keto ursolic acid（3-ketoursolic acid，28）, ursolic acid（ursolicacid，29）, pomonoic acid（pomonic acid，30）（pomolic acid，31）, corosolic acid（corosolicacid）/2α-Hydroxyursolic acid（2α-hydroxyursolic acid）（32）、cecropiacicacid（33）。
1.3.3 Lupane type Lupane type differs from oleanane type in that itsEThe ring is a five membered carbon ring, and is inEringC-19With isopropyl group at positionα-Configuration exists. At present, it is co isolated from different parts of wild jujube12Lupane saponins, betulinic acid（betulinic acid，34）, betulin（betulin，35）, mycolic acid（alhpitolicacid，36）, betulinic acid（betulonic acid，37）, lupeol（lupeol，38）, methyl ROSINATE（alphitiolcaicd methyl ester，39）（methyl betulinate，40）、platanic acid（41）、3-O-CIS-P-coumaroyl maltic acid（3-O-cis-p-coumaroyl alphitolic acid，42）、3-O-Trans-P-coumaroyl maltic acid（3-O-trans-p-coumaroyl alphitolic acid，43）、2-O-Protocatechol maltic acid（2-O-protocatechuoylaliphitolic acid，44）、2α-Hydroxy pyracanthic acid（2α-hydroxypyracrenicacid，45）。
1.3.4 ceanothanetype ceanothaneThe structure of type a saponin is basically the same as that of lupane type,ERings are all five membered rings, except thatceanothanetypeA. At present, it is co isolated from different parts of wild jujube6individualceanothaneType saponins, respectively, theanoic acid（ceanothic acid，46）（epiceanothicacid，47）、colubrinic acid/zizyberanalic acid（48）, isotheanoic acid（isoceanothic acid，49）、ceanothenicacid（50）、3-O-Protocatechol American tea acid（3-O-protocatechuoyl ceanothic acid，51）Among them, epicatechin was isolated from nature for the first time.
1.4 Distribution of pentacyclic triterpenoid saponins
A comparative analysis of the distribution of pentacyclic triterpenoid saponins in different parts of wild jujube shows that pentacyclic triterpenoid saponins are more distributed in the pulp of wild jujube, which is also an important reason for the sour taste of wild jujube pulp. At present, it has been isolated and identified from the flesh of Zizyphus jujuba Mill24Five pentacyclic triterpenoid saponins, of which oleanane type6Individual, Ursane type6Individual, lupane type8Piecesceanothanetype4PCs. Isolated from semen ziphi Spinosae10Five pentacyclic triterpenoid saponins, of which oleanane type2Individual, lupane type6Piecesceanothanetype2PCs. Isolated from wild jujube leaves10Pentacyclic triterpenoid saponins, oleanane type2Individual, Ursane type1Individual, lupane type3Piecesceanothanetype4PCs. The chemical constituents in the roots of Zizyphus jujuba were less studied, and only isolated from the roots of Zizyphus jujuba7Pentacyclic triterpenoid saponins, among which lupane type4Piecesceanothanetype3PCs. In addition, lupane type saponins are the most abundant pentacyclic triterpenoid saponins in Zizyphus spinosa, and a total of12It is widely distributed in the pulp, seeds, leaves and roots of wild jujube; While Ursane type saponins had the least species, and a total of6, mostly distributed in the pulp, and only identified in the leaves1PCs. The distribution of pentacyclic triterpenoid saponins in wild jujube is shown in table2。
2 Pharmacological activities of semen ziphi Spinosae on nervous system
Semen ziphi Spinosae has a variety of pharmacological activities, such as tranquilization, anti anxiety, anti depression, anti-tumor and myocardial protection, and is widely used in the treatment of diseases of the nervous system, immune system, cardiovascular system and so on. The commonly used traditional Chinese medicine compounds containing semen ziphi Spinosae, such as semen ziphi Spinosae decoction, Guipi Decoction, and Zaoren Anshen capsules, are widely used in the clinical treatment of nervous system diseases such as insomnia, forgetfulness, anxiety, depression, and neurasthenia, and have obvious clinical efficacy[36-38]The related research of semen Ziziphi Spinosae in recent years was reviewed. Semen Ziziphi Spinosae showed obvious advantages in the treatment of nervous system diseases. Therefore, this paper focused on the research progress of semen Ziziphi Spinosae saponins in nervous system pharmacology.
2.1 Calm down
Insomnia is a chronic, recurrent or persistent sleep disorder caused by autonomic dysfunction caused by increased sympathetic nerve activity[39]Semen Ziziphi Spinosae is the first choice of traditional Chinese medicine in the treatment of insomnia, and saponins of semen Ziziphi Spinosae are the main active ingredients to improve sleep[40]At present, the pharmacological research of Zizyphus spinosa saponins in the treatment of insomnia mainly focuses on the total saponins of Zizyphus spinosa（jujubosides）AndJuA、JuBAnd other monomer composition research.
2.1.1 Total saponins of semen Ziziphi Spinosae The sedative and hypnotic effects of saponins from semen Ziziphi Spinosae were initially studied with total saponins from semen Ziziphi Spinosae as the research object. Chenbaiquan et al[41]Shaking cage transducer method, glass plate tilt method and pentobarbital sodium were used（pentobarbital sodium，PS）Mouse model study of total saponins of semen ziphi Spinosae (including total saponins91.2%）Sedative hypnotic effect, the results showed that the total saponins of semen ziphi Spinosae at high, medium and low doses could significantly inhibit the number of activities of normal mice, inhibit the central excitatory effect of amphetamine, and significantly prolong the duration of administrationPSThreshold dose of sleep time in mice as well as increasedPSNumber of sleeping mice at subthreshold doses.Jiangetc.[42]The sedative and sedative effects of total saponins, total flavonoids and total polysaccharides in semen ziphi Spinosae were compared. The results showed that total saponins and total flavonoids in semen ziphi Spinosae could significantly inhibit the walking time and walking stability of mice, and significantly prolongPSModel mice sleep time and improve the rate of falling asleep. The study also showed that the sedative hypnotic effect of total saponins of semen ziphi Spinosae was significantly stronger than that of total flavonoids, while total polysaccharides of semen ziphi Spinosae had no obvious sedative hypnotic effect.Caoetc.[43]The effects of total saponins from semen ziphi Spinosae on normalICRThe results showed that total saponins of semen Ziziphi Spinosae could significantly increase the total sleep and REM sleep time of mice during the day（REM）（NREM）; meanwhilePSTherapeutic models and p-chlorophenylalanine（PCPA）. At present, the research on the sleep improving effect of total saponins of semen Ziziphi Spinosae mainly uses the saponin part of semen Ziziphi Spinosae crude extracted by ethanol, which has low purity and complex chemical composition. Only a simple evaluation of the pharmacodynamic effect has been made, but no in-depth study on its mechanism of action has been seen.
2.1.2 JuA JuAIt is a saponin with the highest content in semen Ziziphi Spinosae[44], whileJuAIt is also one of the effective components in vivo of semen ziphi Spinosae in the treatment of insomnia[45]. sodium penicillin was prepared byγ-Aminobutyric acid（GABA）Pathway acting central nervous system agonists[46]，Shouetc.[47]The study found that high doses ofJuASignificantly in vitroInhibition of rat hippocampus induced by penicillin sodiumCA1The excitability of neurons can significantly reduce the excitability of postsynaptic potential and the amplitude of population peak potential of hippocampal dentate gyrus granule cells at the same timeJuAIs throughGABAPathway to exert the inhibitory effect of the central nervous system[48]. afterZhangetc.[49]Studied theJuAResponse to glutamate in hippocampal neurons（Glu）The regulatory role of signaling pathway, the results showed thatJuACan significantly inhibitGluInduction of intracellularCa2+Concentration increases, suggestingJuAWith a calmodulin like antagonist trifluoperazine（TFP）The neuroinhibitory effect of.Youetc.[50]Using semi quantitativeRT-PCRTechnology studies theJuATo rat hippocampal neuronal cellsγ-aminobutyric acidA（GABAA）ReceptorsmRNAsExpression, the results showed that low or high doseJuACan significantly affectGABAAreceptormRNAsOfα1、α5、β2Subtype gene expression; meanwhileJuACompared with diazepam, it is less addictive, so it is expected to become a new drug for the long-term treatment of insomnia.Wangetc.[51]utilizeUPLC/ESI-SYNAPT-HDMSAnd pattern recognition technologyJuAThe metabolic pathway profile of intervention insomnia, the results showed thatJuAAfter the insomnia model of Drosophila melanogaster was given, the metabolites related to insomnia could be significantly corrected to a healthy level,JuAIt may be through the regulation of ascorbic acid, tryptophan, starch-Sucrose, amino sugar-Ribose, pantothenate-coenzymeA, pentose-Glucuronic acid conversion and other metabolic pathways play their role in the treatment of insomnia.Wangetc.[52]The study also proved thatJuACan significantly increase the number ofGABAReceptor subtypemRNAExpression of; More importantlyJuACan down regulate the levels of relevant serotonin cytokines in the intestinal mucosal system, thereby interfering with the brain neuronal intercellular cytokine network, inferringJuAThe mechanism of improving sleep is similar to that of melatonin. In conclusion,JuAIt is the main active ingredient in semen ziphi Spinosae, which can significantly reduce the spontaneous activity of animals, accelerate the speed of falling asleep, and prolong the sleep time;JuAIt can regulate multiple metabolic pathways to improve sleep quality, whileJuATo the "gut-The regulatory mechanism of the "brain axis" cytokine network provides a new research window for explaining its sleep improving effect.
2.1.3 JuB With the "microbial-intestines-The regulatory mechanism of "brain axis" on central nervous system diseases is gradually clarified[53].JuBIt is one of the main active ingredients of semen ziphi Spinosae in the treatment of insomnia, and it is alsoJuAOne of the most important metabolites of gut microbiota[54]。Wangetc.[55]Based on metabolomics and biological data pathway analysis, the results showed thatJuBAfter giving the wild-type Drosophila melanogaster insomnia model, it can make it associated with insomnia12These differential metabolites are adjusted to a healthy level, which may play a role in the treatment of insomnia by regulating tryptophan metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, arachidonic acid metabolism and phenylalanine metabolism. WithJuA,JuAThe treatment of insomnia is mainly through the regulation of glucose metabolism pathway, whileJuBTreating insomnia can regulate fatty acid metabolism more.Songetc.[56]applicationHPLC-MS/MSAnalytical techniques also demonstrate thatJuByesJuAThe most important gut microbiota degrade metabolites while using real-time fluorescence quantitative reverse transcription polymerase chain reaction（RTFQ-PCR）JuBCan increase the cell membrane surface of hippocampal neuronsGABAAThe number of receptors expressed; At the same time, increase the frequency of chloride ion channel opening, so as to play a calming and tranquilizing role. The above research shows that,JuBAsJuAOf gut microbiota metabolites, which are more likely to beJuAPharmacodynamic substances that play the role of improving sleep after entering the human body; At the same time, it also suggests that we should pay attention to the important media role of intestinal flora in the treatment of nervous system diseases by jujube saponins.
2.2 Antidepressant
According to the prediction of the World Health Organization, by2020In, depression will become the second major disease endangering human health. （noradrenaline，NE）And5-Serotonin（5-hydroxytrptamine，5-HT）Caused by low nerve activity or conduction function. At present, the research on the antidepressant effect of Jujuboside A mainly focuses on the total saponins of Jujuboside. Zhaoqiduo et al[57]Through forced swimming and tail suspension experiments in mice, it was proved that the total saponins of semen ziphi Spinosae (total saponin mass fraction was53.75%）It has obvious antidepressant effect and can enhance the activity and reduce the despair immobility time of mice. Ren Liyan et al[58]. A large number of studies have proved that semen ziphi Spinosae has antidepressant effect, and pointed out that the antidepressant mechanism of semen ziphi Spinosae is through reducing the prefrontal lobe5-HTAnd dopamine content[59]According to the comprehensive analysis, Zizyphus jujuba saponin may also be through the regulation of5-HTPathway to exert antidepressant effects.
2.3 Anxiolytic
About4.1%Of people will suffer from anxiety disorders in their lifetime. If they do not receive treatment for a long time, there are40%～50%Of patients may further evolve into depression[60]The onset of anxiety disorder involves changes in the concentration of monoamine neurotransmitters in the synaptic space, endocrine system and immune dysfunction, etc[61]。Pengetc.[62]Sauteed jujube kernel95%Ethanol extractigAfter administration to anxiety disorder model mice, black and white experiments were performed（BWT）And maze（EPM）. Rongchunlei et al[63]It was found that the alcohol extract of semen ziphi Spinosae had obvious anxiolytic effect on the yin deficiency model of mice caused by thyroid tablets, and its anxiolytic mechanism may be related to the improvement of brainGABAContent, enhancedGABAAR1Expression, decreasedGluContent andN-methyl-D-Aspartate receptor1（NMDAR1）Expression related. Existing studies have preliminarily proved the anti anxiety effect of total saponins of semen ziphi Spinosae, but its mechanism of action and the active ingredients that exert anti anxiety effect need further explanation.
2.4 Improve memory
Mild cognitive impairment is characterized by memory dysfunction, which is also an important early symptom of senile dementia[64]。Zhangetc.[65]adoptYMaze test and passive avoidance test（PAT）It has been proved that the total saponin extract of semen Ziziphi Spinosae（JuAandJuBTotal content in9%The above) can improve the memory impairment caused by alcohol in mice, and help improve the learning ability of mice to a certain extent. It is preliminarily confirmed that the main active ingredient in the extract of semen ziphi Spinosae isJuAandJuB。
2.5 treatAD
In recent yearsADThe incidence rate is increasing year by year, and about70%byADIts pathogenesis mainly includes cholinergic theory andβ-Amyloid protein（β-amyloid peptide，Aβ）Doctrines[2]。2014yearLiuetc.[66]First injection through lateral ventricleJuAEvaluate its impact onβ-Amyloid peptide（1-42）（Aβ1-42）Effects of induced cognitive impairment. The results showed thatJuAMainly by reducing the amount ofAβ1-42And significantly inhibited acetylcholinesterase（AChE）AndNOOf activity, thereby achieving remission caused byAβ1-42The results of the study showed thatJuArightADIt has certain therapeutic effect,JuAPromising for development as a treatmentADNew natural drugs.
3 discuss
Zizyphus jujuba is a unique wild medicinal plant in China, with a huge resource reserve, and its seeds——. since20century30In the s, researchers at home and abroad began to carry out systematic research on the saponins and pharmacological effects of semen Ziziphi Spinosae. Co isolated and identified from wild jujube51Among them, dammarane type tetracyclic triterpenoid saponins were20, mainly distributed in semen Ziziphi Spinosae (seeds), while pentacyclic triterpenoid saponins Co31, mainly distributed in the pulp and leaves of Zizyphus spinosa. Zizyphus jujuba saponins in tranquilization, anti anxiety, anti depression, memory improvement, treatmentADAnd other nervous system diseases showed significant activity. However, because the saponins of semen Ziziphi Spinosae are not easy to obtain, the existing pharmacological models of the central nervous system are limited, and the chemical structure of saponins is complex, so the research progress of saponins of semen Ziziphi Spinosae in the treatment of nervous system diseases is relatively slow.
（synthetic biology）It provides a new technical means to solve the difficult problem of obtaining saponins from semen ziphi Spinosae. 20The century proposed that it is a new technology based on the engineering design concept, through the mining and design of biological components, the assembly and integration of components and functions, and the optimization and adaptation of systems, to obtain artificial life units or systems that meet the expected goals, and to transform existing natural systems or synthesize new artificial life systems from scratch[67]At present, synthetic biology has made breakthroughs in the synthesis of natural products, especially in the field of terpenoids such as artemisinin, paclitaxel and ginkgolide. For example, due to the low content and unstable structure of artemisinin, the traditional phytochemical extraction method takes a long time and the extraction rate is low, and the use of synthetic biology can solve this problem in artemisinin production. At present, there are mainly biological total synthesis and biological semi synthesis methods, which can make the total recovery of artemisinin reach46%, which greatly promoted the industrial production of artemisinin[68]. Further, the structure of Zizyphus jujuba saponins can be modified by synthetic biological technology to enrich the types of Zizyphus jujuba saponins, which will provide a powerful technical means to clarify the structure-activity relationship of Zizyphus jujuba saponins.
"Microorganisms-intestines-Brain axis theory believes that gut microbes, gut and brain3There is close information exchange between them, and the gut and brain central nervous system have biphasic regulation[69]Most saponins have long sugar chains, which inevitably have complex interactions with intestinal flora and intestines after oral administration. Therefore, the research on saponins should attach great importance to "microorganisms"-intestines-The mediating role of brain axis. It has been shown that ginsenosidesCompound KIt is the main metabolite of ginsenoside acting on intestinal bacteria, and has higher bioavailability than the ginsenoside prototype compound, which is important inADAnd animal models of cerebral ischemia,CompoundKIt has obvious neuroprotective and cognitive enhancing effects[70]。Zhangetc.[54]It is also proved by the study of rat intestinal floraJuAThe final metabolite is Zizyphus spinosaponin, and the metabolites of intestinal flora such as Zizyphus spinosaponin may be the real effective ingredients to exert the effect of calming and tranquilizing. However, how the metabolites of Zizyphus Jujuboside gut microbiota pass through the "microbial-intestines-The mechanism of brain axis regulating the nervous system is still unclear, and the ability and pathway of metabolites to cross the blood-brain barrier are still unclear. Therefore, the research on the pharmacological mechanism of saponins from semen ziphi Spinosae should be based on the existing research, combined with the "microbial-intestines-The latest research results of "brain axis" theory explore a new research direction for elucidating the mechanism of Zizyphus jujuba saponins in the treatment of nervous system diseases.
Saponins have highly complex chemical structures, unpredictable metabolic reactions and low concentration metabolites. These factors greatly limit the structural identification of saponins from semen Ziziphi Spinosae and the study of its mechanism of action in vivo. Therefore, new technologies are urgently needed for the structural identification of saponins from semen Ziziphi Spinosae. The latest LC-MS technology, especially the emerging new mass spectrometry detectors, such as hybrid high-resolution mass spectrometer（HRMS）, quadrupole time-of-flight mass spectrometry（Q-TOF）Linear ion trap mass spectrometer（LTQ-Orbitrap）With good sensitivity, high dynamic range and versatility, it has become the main analytical method for the analysis of unknown products. ReconnectionMass Frontier、Compound DiscovererThe mass spectrometric structure analysis software can automatically process and analyze the mass spectrometric data, predict the fragments and provide the pathway of fragment generation mechanism, so as to quickly and conveniently convert the mass spectrometric data into compound structure information, and speculate the structure of metabolites and unknown compounds. .
With the continuous progress of science and technology, the continuous integration and development of various disciplines, the continuous emergence of new methods such as the preparation of various natural products, structural analysis and pharmacological research models, will certainly accelerate the research on the effective components and mechanism of action of Zizyphus jujuba saponins in the treatment of nervous system diseases, and to a great extent promote the research on the pharmacodynamic components of Zizyphus jujuba seed into a new historical stage. It is believed that the research and development of new drugs for nervous system diseases based on Zizyphus jujuba saponins will be strongly promoted with the continuous clarification of the effective substances and the mechanism of action of Zizyphus jujuba saponins in the treatment of nervous system diseases.
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Come Source: duchenhui, cuixiaofang, peixiangping, Yan Yan, qinxuemei