Sinomenium wilfordii, also known as Hedysarum wilfordii and Sinomenium wilfordii, is a plant of the family tetrandridaceae, Sinomenium wilfordiiSinomenium acuturn (Thunb) Rehd et Wils.And celastrolS. acutum (Thunb) Rehd. et Wils. var. cinereumRehd. et Wils.. According to Chinese Pharmacopoeia2020According to the records in the edition of, Sinomenium wilfordii has the effects of dispelling wind dampness, unblocking meridians, promoting urination, etc. it is mainly used in clinic to treat rheumatism, arthralgia, joint swelling, paralysis and itching^[1]In recent years, with the popularization of Sinomenium Wilfordii in clinical application, there are more and more studies on its pharmacological effects and mechanisms. However, its quality evaluation method is a key clinical problem that needs to be solved urgently. Sinomenine is the highest content and the most active compound in the effective components of Sinomenium wilfordii, which is often used as the quality evaluation index of Sinomenium wilfordii. Network pharmacology predicted that not only multiple compounds of sinomenine act on the same target protein, but also a single compound acts on multiple target proteins and multiple pathways to exert efficacy. Therefore, it is obviously imperfect to only use a single component sinomenine as a quality control index^[2-3]。Therefore, this paper aims to review the research progress of the chemical constituents and pharmacological effects of Sinomenium sinense, and according to the quality marker of traditional Chinese medicine（quality marker，Q-Marker）To provide scientific basis for the quality evaluation and related product research and development of Sinomenium wilfordii.

1  chemical composition

Sinomenium wilfordii contains a variety of chemical components, mainly including alkaloids, volatile oils, lipids, anthraquinones, Phenanthrenes, steroids and phenols, among which alkaloids are currently the research focus, volatile oils, anthraquinones and other components are relatively few, and the research on lipids, steroids and other substances needs to be further strengthened^[4-5]。

1.1  alkaloid

Alkaloids are currently considered to be the main pharmacologically active components in Sinomenium wilfordii, from which they have been extracted63Alkaloids, whose structural types mainly include Isoquinolines, aporphines, morphanes and other skeleton alkaloids, have immunomodulatory, analgesic, anti-inflammatory and other effects^[5]Isoquinolines and aporphine alkaloids, including magnoliane, can reverse multidrug resistance; Morphine alkaloids such as2,2′-Sinomenine has a weak inhibitory effect on tumor cells; Other alkaloids with skeleton structure include protoberberine alkaloids such as SinomenineH, liannane alkaloids such as SinomenineK, oxidized isoprofene alkaloids such as SinomenineD, benzoquinoline alkaloids such as SinomenineFProto aporphine alkaloids such as SinomenineMAccording to the structure of alkaloid series, the phenanthrene core structure is its commonness, and this series of alkaloids have certain commonalities in biosynthesis and pharmacological effects^[6-7]With more in-depth research on Sinomenium wilfordii,13New alkaloid structures have also been discovered^[8-10]. whereAlkaloids represented by sinomenine are the compounds with the highest content of active ingredients and the strongest activity in sinomenine. See table for some alkaloids in sinomenine1，The chemical structures of some alkaloids are shown in Fig1。

1.2  volatile oil

There are few studies on volatile oils in Sinomenium chinense. According to the latest research, through gas chromatography-The volatile oil components in Sinomenium wilfordii were separated and identified by mass spectrometry, and a total of matching compounds were identified63The main components are fatty acids, sterols, alkenes and a small amount of aldehydes, and the most abundant are octadecanoic acid and hexadecanoic acid^[11]The study found that esters have an effect on biological activity according to their chain length and show a certain regularity. The longer the chain length, the more obvious inhibition of nitric oxide production without obvious cytotoxicity, and can inhibit tumor necrosis factor-α（tumornecrosis factor-α，TNF-α）And interleukinelement-6（interleukin-6，IL-6）Production of other inflammatory cytokines^[12]，See table for compound names2。1.3  other

LV Haining et al^[13]Isolated from Sinomenium wilfordii19Non alkaloid compounds, including3Phenanthrene compounds（3-hydroxyl-2,6,7-Trimethoxyphenanthrene3,5-Dihydroxy-2,6-Dimethoxyphenanthrene, Croton Flavin)6Anthraquinones (emodin, obtusin, orange Cassia obtusifolia6,8-Dihydroxy-1,2,7-Trimethoxy-3-Methyl anthraquinone, cassia, cassia flavescens) and10Phenolic compounds [p-hydroxybenzaldehyde, vanillin, eugenol, acetovanillone, isoacetovanillone, propyl eugenone, methyl Syringate, ethyl Syringate3,4,5-Trimethoxyphenol(E)-3,3′-Dimethoxy-4,4′-. The above studies suggest that Sinomenium wilfordii contains a variety of effective ingredients and may become a new potential research direction.

2  pharmacological action

Sinomenium wilfordii has a variety of biological activities. According to the records of Chinese Pharmacopoeia, Sinomenium wilfordii has the effects of dispelling wind dampness, dredging meridians and diuresis. With the deepening of modern pharmacological research, it is found that Sinomenium wilfordii also has anti-inflammatory, analgesic, immunosuppressive and other pharmacological effects, and can play a certain role in the treatment of tumor, cardiovascular, immune and nervous system diseases through a variety of ways.

2.1  antiinflammatory

Based on its anti-inflammatory, analgesic and immunosuppressive effects, Sinomenium wilfordii plays a significant role in the treatment of autoimmune diseases. The role of traditional Chinese medicine has long been documented. According to the compendium of Materia Medica of the Ming Dynasty, "rheumatic flow, calendar Festival crane knee, paralysis and itching, injury and swelling, used in alcohol medicine". In the Qing Dynasty, Zhang inherited the "materia medica is easy to read", which recorded that "all vines can pass through the meridians and enter the collaterals. This material is good at curing wind diseases, so all calendar paralysis can be cured. Soaking wine is especially wonderful. With wind Qi to the liver, it enters the liver, wind prevails over dampness, and moisture also passes through the spleen". It is also recorded in the medicinal property test of Longbai in the Qing Dynasty that "dampness, arthralgia, leg cramping, wind flaccidity of crane knees, numbness and wind pain, boiling cream and soaking wine can effectively treat wind".

According to this, the traditional efficacy of Qingfengteng based on dispelling wind dampness and dredging meridians was first used in the treatment of rheumatic diseases by the ancients. With the deepening of modern research, Sinomenium wilfordii has gradually been applied to the treatment of more immune system diseases.

Studies have shown that sinomenine has anti-inflammatory effects on protein, chemical, bacterial and other types of inflammation, and alkaloids have good anti-inflammatory effects, of which sinomenine is the main anti-inflammatory substance. Identification of anti inflammation in Sinomenium chinense by spectral effect relationship and chemometric methodsThe results showed that sinomenine, magnoliane, Dauricine and stephanine were the main anti-inflammatory components of sinomenine^[10]Through the network pharmacology method, the pharmacological mechanism of Sinomenium Wilfordii in the treatment of rheumatoid arthritis was explored, and it was found that the components of Sinomenium Wilfordii in the treatment of rheumatoid arthritis may be razmanine, stephanineβ-Sitosterol, sinomenine, etc^[3]Magnoline can regulate nuclear factorκB（nuclearfactor kappa-B，NF-κB）Mitogen activated egg（mitogen-activated protein kinases，MAPK）And phosphatidylinositol-3-kinase/protein kinaseB（phosphatidylinositol- 3-hydroxykinase/protein kinase B，PI3K/Akt）Signal communicationLu Er exerts immunosuppressive effects against inflammation and can delay cartilage degradationAnd prevention of osteoarthritis^[14-15]. microsomal prostaglandinsESynthases1（microsomalprostaglandin E synthase-1，mPGES-1）It's prostaglandinsE₂Terminal synthase, which catalyzes cyclooxygenase-1（cyclooxygenase-1，COX-1）AndCOX-2Derived prostaglandinsH₂Conversion to prostaglandinsE₂It is expressed in rheumatoid arthritis, cancer, atherosclerosis and other chronic diseases,Zhouetc.^[16]Studies have shown that sinomenine ismPGES-1Through animal experiments and cell culture verification, sinomenine can inhibit the production of inflammatory mediators and cytokines by lipopolysaccharide activated macrophages without affecting cell viability, and can selectively down regulate lipopolysaccharide activated macrophagesmPGES-1Expression and inhibition of inflammation in rat paw tissuemPGES-1Expression of; The excessive proliferation of fibroblast like synoviocytes and inflammatory reaction lead to the proliferation of synovial tissue in patients with rheumatoid arthritis, which increases the burden of patients. Wang Zhongyang et al^[17]It was found that different concentrations of sinomenine could inhibit the proliferation of fibroblast like synoviocytes induced by lipopolysaccharide in a concentration dependent manner.Lipopolysaccharide is an important inflammatory substance. Sinomenine can exert anti-inflammatory effect by reducing lipopolysaccharide induced toxicity, and its mechanism may be its regulationmiR-101、miR-192, mitogen activated protein kinase phosphatase-1And should activate the protein kinase pathway to alleviate lipopolysaccharide induced inflammatory injury and lipopolysaccharide mediated chondrocytesATDC5damage^[18-20]。Zhaoetc.^[21]A novel derivative of sinomenine was synthesized by chemical modification method, hairNow it can significantly inhibit inflammatory factors more than SinomenineIL-1βandIL-6Expression at the transcriptional and translational levels, and in3.250 mg/kgThe dose of 0.5% can reduce the local ear edema caused by xylene in mice, showing significant anti-inflammatory activity.Nietc.^[22]Synthesis of sinomenine by chemical modification-4-hydroxyl-Palmitate, which was found to promote macrophage reprogramming toM2Like phenotype, and can reduce the occurrence of endotoxemia in mice.

2.2  analgesia

At present, sinomenine and its derivatives, which are alkaloids, are the main pharmacodynamic substances for sinomenine to exert analgesic effect, while other substances have not been further studied. ^[23]And it has certain effects on central, peripheral pain and cancer pain. Sinomenine can reduce synovial inflammatory factors byTNF-αTo effectively relieve joint pain in adjuvant arthritis rats^[24]。Gaoetc.^[25]Sinomenine combined with gabapentin or tetramethylpyrazine hydrochloride was used in mice with photochemically induced sciatic nerve injury and rats with photochemically induced spinal cord injury. The effectiveness of the combined treatment was evaluated. It was found that sinomenine could enhance the efficacy of gabapentin or tetramethylpyrazine hydrochloride in rodent models of peripheral and central neuropathic pain, without tolerance and other obvious adverse reactions. In addition, sinomenine could also inhibit voltage-gated sodium current in a dose-dependent manner to exert peripheral analgesic effect^[26]。N-Demethylsinomenine is SinomenineN-Demethylated product, a natural component extracted from sinomenine, has been identified as the main metabolite of sinomenine,Ouetc.^[27]Found through animal experimentsN-Demethylsinomenine has dose related sustained analgesic effect on postoperative mechanical pain and allodynia in mice, and does not produce analgesic tolerance and residual effect. Some studies have found that sinomenine also has significant analgesic activity on postoperative pain in rats, which indicates that both have the potential to control postoperative pain^[28]. purinergic receptorsP2X₃It is a double transmembrane protein that plays a role in many diseases involving nerve signaling, such as pain,Raoetc.^[29]Studies have shown that sinomenine has inhibitory effect on diabetic neuropathic pain through2Administration of sinomenine to type 2 diabetic rats revealed that sinomenine could inhibitP2X₃Upregulation of the receptor, and can alleviate the effect ofp38 MAPKActivated and enhanced hyperalgesia^[30]Sinomenine also has certain potential in inhibiting cancer pain,Chenetc.^[31]Through experiments, it was found that it can inhibit microglia non receptor tyrosine protein kinase（Janus kinase 2，JAK2）/Signaling and activating transcription factors3（signal transducers and activators of transcription 3，STAT3）And neuronal calmodulin kinaseII（calmodulin-dependent kinase II，CAMKII）/CAMP response element binding protein（cAMP response element binding protein，CREB）.

2.3  Immunosuppression

Sinomenine has a variety of immunomodulatory effects, which can inhibit the activation and proliferation of lymphocytes, protect damaged organs and so on. At present, research mainly focuses on the effects of sinomenine and its derivatives onTThe proliferation of lymphocytes and the inhibition of inflammatory cytokine secretion, while other pharmacodynamic substances are less studied. Sinomenine can inhibit the signaling pathway related to osteoclast differentiation, regulate a variety of inflammatory cytokines and monocytes by reducing cytokine levels/The secretion of macrophage subsets and the inhibition of the classical activation pathway of macrophages play an immunosuppressive role in the treatment of rheumatoid arthritis^[32-34]Sinomenine has immunosuppressive effect on lymphocytes stimulated by allogeneic islets, and its maintenance of islet cell activity and secretion function is better than tacrolimus, and can reduce the immune injury of islets at the same time^[35]By administering sinomenine to mice with allergic rhinitis, it was found that the levels oftransforming growth factor-β（transforming growth factor-β，TGF-β）The expression level increased and the related symptoms decreased^[36]Sinomenine may also have certain potential in the treatment of chronic asthma. Through animal experimental studies, it was found that Sinomenine100 mg/kgIt can improve all histopathological changes of airway remodeling, and its mechanism may be related to its regulationTh2Derived cytokines are associated with the inhibition of airway epithelial apoptosis^[37]。Fuetc.^[38]Using the pressure overload caused by aortic constriction as the heart failure model, we found that sinomenine has a protective effect on pressure overload heart failure, which can reduce the serum central natriuretic peptide level and inhibit theI、IIIThe protein andmRNALevel, improveIL-10/IL-17.Yanetc.^[39]Discovery of sinomenine derivatives1032Can act on dendritic cells to blockIL-6Generation, terminationTh17Cell development, thereby significantly reducing encephalitisTCell response and the improvement of animal model of experimental autoimmune encephalomyelitis induced by sinomenine derivatives1032May be a new typeOf anti-inflammatory agents. In addition, sinomenine can regulate a variety of inflammatory factors such asIL-1β、TGF-βIt has good potential and prospect in the treatment of osteoarthritis, ankylosing spondylitis and gouty arthritis^[40-42]。

2.4  Anti cardiovascular disease

With the deepening of modern research, more and more studies have shown that Sinomenium wilfordii has good potential in the treatment of cardiovascular system diseases, but the current research on sinomenine, the main bioactive base of sinomenine wilfordii, and its derivatives, has mainly focused on sinomenine and its derivatives, while other substances have not yet been reported. Whether it also has this effect can be one of the directions for further research in the future.

Sinomenine can inhibit atherosclerosis by regulating inflammatory factors, leukocyte recruitment, migration and proliferation of smooth muscle cells, and plaque formation^[43]It can inhibit voltage dependent calcium channels and regulated longitudinal calcium channels in vascular smooth muscle cells, reduce the level of free calcium in vascular smooth muscle cells of rabbits, and regulate the protein kinase of vascular smooth muscle cells under ischemia and hypoxiaCActivity of^[44]It has been studied that sinomenine and its derivative Sinomenine4-Hydroxylinolenate was molecularly docked with the related proteins of ischemic stroke and found to have potential targets in anti ischemic stroke^[45]And animal experiments have found that sinomenine also has a significant effect in stress-induced heart failure in mice, which has the potential to become a new anti heart failure drug^[38]. sugarUropathy cardiomyopathy is a serious complication of diabetes,Jiangetc.^[46]Studies have found that sinomenine can block the immune response mediated by inflammatory cytokines and makeNF-κBInactivation can significantly improve the cardiac function of diabetic rats.

2.5  Antitumor

Modern pharmacological studies have found that Sinomenium wilfordii has certain efficacy in urinary and reproductive system tumors such as prostate cancer and bladder cancer, digestive system tumors such as liver cancer and gastric cancer, respiratory system tumors such as lung cancer, and many other tumors. The mechanism may be related to its induction of tumor apoptosis, inhibition of tumor cell invasion and migration, impact on tumor neovascularization, and reversal of tumor cell multidrug resistance^[47]However, the current research shows that the main substance of its pharmacological activity is sinomenine. Some studies have found that the glycosides extracted from Sinomenium wilfordii have the activity of inhibiting the proliferation of cancer cells, but its specific mechanism of action needs further study^[48]。

2.5.1  Urogenital tumors  . According to the records of Chinese medicinal plants, "dehumidification, wind dispelling, qi activating, diuresis, bladder edema, wind swelling, beriberi dampness swelling". And the "Zhejiang Tianmu yam planting records" also contained: "water diuresis, diarrhea scorched blood points dampness and heat". With the widespread clinical use of Sinomenium wilfordii and the in-depth study of its pharmacological effects, Sinomenium wilfordii has unique advantages in the treatment of urogenital system tumors.

Sinomenine can be regulated in vivomiR-23aAnd inhibition of prostate cancer in vitroDU145Cell proliferation and inhibit the proliferation, migration and invasion of prostate cancer cells, which provides a certain feasible basis for the possibility of Sinomenium Wilfordii in the treatment of prostate cancer^[49-50]; and can be activated byPI3K/AktSignaling pathway inhibits bladder cancer cell line epithelialization-Mesenchymal transformation, with concentration dependence^[51]。PI3K/Akt/Mammalian target of rapamycin（mammalian target of rapamyc，mTOR）Pathway is a classical autophagy pathway, which plays an important role in maintaining cell survival, structural remodeling and internal environment stability, whileDengetc.^[52]According to the experimental study, sinomenine canPI3K/Akt/mTORPathway enhances autophagy and promotes apoptosis of renal cancer cells, and its ability is dose related. Human ovarian cancer specifictranscription factor2（human ovariancancer-specifictranscription factor 2，HOST2）It is a long-chain noncoding protein highly expressed in both ovarian cancer cell lines and in situ cancer cell linesRNASinomenine hydrochloride is a water-soluble hydrochloride salt of sinomenine, and studies have shown that it can inhibitHOST2To play an anti ovarian cancer role^[53-54]。NF-κBCan regulate breast cancer epithelium-Sinomenine can block the transformation and metastasis of mesenchymeNF-κBAt the same time, it can inhibit the invasion and metastasis of breast cancer cells by reducing the inflammatory response in mice4T1Epithelium of cells-Mesenchymal transformation and cancer stem cell properties, inducing breast cancer cell death through reactive oxygen species dependent and independent pathways^[55-57]。

2.5.2  Digestive system tumor  With the gradual deepening of the research on Sinomenium wilfordii, more and more studies have found that Sinomenium wilfordii has a good effect in the treatment of digestive system tumors. Sinomenine hydrochloride can inhibit gastric cancer through mitochondrial pathwayBCG-823Cell proliferation exerts time - and concentration dependent inhibitory effects, and higher concentrations can promote its apoptosis, the mechanism may be that it can activate caspase dependent apoptosis^[58]。miR-204Through multiple signaling pathways, sinomenine plays a role in different cancers by enhancingmiR-204While significantly inhibiting human gastric cancerMKN45andSGC-7901Cell proliferation, but its role in vivo experiments needs further in-depth study^[59]And sinomenine can activate theCaspase, caspase（cystein-asparate protease，Caspase）-3, activatedCaspase-9andE-The expression of cadherin and vimentin were down regulated to significantly inhibit bile ductThe activity of cancer cells, which is more significant with the increase of concentration and time^[60]Sinomenine on human liver cancerHepG2The proliferation of cells has a concentration dependent inhibitory effect, and can activate the related factors of tumor apoptosis by interfering with tumor cell membrane receptors, promoting its apoptosis^[61]。In addition, sinomenine can inhibitCOX-2And tissue cell cycle and exert time concentration dependent inhibitory effects on intestinal cancer cells^[62]. by observing sinomenine and5-The tumor inhibitory effect of fluorouracil in mice and the effect of the combined application of the two drugs showed that not only sinomenine had inhibitory effect when applied alone, but the effect of the combined application of the two drugs was more obvious without obvious adverse reactions^[63]。

2.5.3  Respiratory system tumor  α7Nicotinic acetylcholine receptors are potential targets for the treatment of lung cancer,Baietc.^[64]By comparing the effects of sinomenine and atropine on mice, it was found that sinomenine could inhibitα7The expression of nicotinic acetylcholine receptor inhibits lung cancer,And it can also mediate hexokinase through downregulation in vivo2Of aerobic glycolysisInhibition of human non-small cell lung cancer^[65]Sinomenine regulates tumor suppressor genesp16andp53Expression to affect the activity of lung cancer cells, zhenghuajun et al^[66]Lung cancerWALKER-256Lung cancer in rats was induced by cell suspension. By comparing the effects of sinomenine, cyclophosphamide and normal saline on lung cancer rats, it was found that sinomenine could inhibit theWALKER-256Differentiation and proliferation of transplanted lung cancer cells.

2.5.4  Other tumors  Sinomenium also has certain inhibitory effects on glioblastoma and multiple myeloma.sirtuin1It is a member of the nicotinamide adenine dinucleotide dependent deacetylase family and plays an important role in biological processes such as oxidative stress, inflammation, glucose metabolism, etc. sinomenine can promotep53Expression and downregulation ofsirtuin1The proliferation of glioma cells was inhibited by the expression of bcl-2by16 μmol/LTime to gliomaU87andU251The activity of cells is significantly inhibited, which can causeG₀/G₁Cell cycle arrest and apoptosis, but it is slightly cytotoxic to normal human astrocytes^[67]。Sinomenine is induced by reactive oxygen species generation and autophagy lysosome pathwayU87And human brain tumorsSF767Cell autophagy, and play an inhibitory role in vitro and in vivouse^[68]The cannabinoids isolated from the dried stems of sinomenia vines were foundGIt has a concentration dependent inhibitory effect on glioblastoma, which can blockThe migration of glioblastoma cells and the induction of apoptosis provide a basis for further development of Sinomenium wilfordii for the treatment of human glioma^[69]。Wangetc.^[70]Discovery of derivatives of SinomenineYL064Can be directly suppressedSTAT3It can inhibit the proliferation and viability of multiple myeloma cells in vitro and in vivo, which indicates thatYL064It may be a promising candidate compound for the treatment of multiple myeloma; Programmed cell death factor4（programmed cell death factor 4，PDCD4）Sinomenine is a tumor suppressor gene, which is widely expressed in a variety of human tissues and plays an important role in the occurrence and development of tumors. Sinomenine can regulatemiR-29/PDCD4To inhibit the proliferation, migration and invasion of breast cancer cells and prevent the formation and destruction of bone caused by breast cancer^[71-72],Xieetc.^[73]It was found that it can inhibit chemokine receptors by4andSTAT3OfPhosphorylation while downregulating matrix metalloproteinases-2, matrix metalloproteinases-9、NF-κBThe expression of receptor activating factor ligand and vascular endothelial growth factor causes osteosarcomaSPhase arrest, while inhibiting the proliferation and metastasis of osteosarcoma. .

2.6  Anti nervous system disease

A large number of studies have shown that Sinomenium wilfordii also has a certain effect in the treatment of nervous system diseases. Multiple sclerosis is a chronic neuroinflammatory disease. Sinomenine can significantly reduce the levels of proinflammatory cytokines in tissues and inhibit neuroinflammation^[74]And can reduce inflammation and neuronal cell death, regulationINK4Site antisense noncodingRNA/miR-626Pathway, which plays a role in the treatment of Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases^[75-76], and play a role in the treatment of spinal cord injury by inhibiting inflammation and oxidative stress^[77]In addition, sinomenine is effective in preventing morphine addictionFruit, which can be passed throughN-methyl-D-Aspartate receptor1/CAMKII/CREBPathway showed protective effects against morphine addiction in vitro and in vivo^[78]。Lietc.^[79]Through experiments, it was found that sinomenine also has a certain role in anti chronic unpredictable mild stress depression in rats and anti depression in mice, and it may also become a new choice for clinical treatment of epilepsy, which can interfere with the acquisition of kindling and nucleotide binding oligomerization domain like receptor protein1The inflammatory process of the inflammasome exerts anticonvulsant and neuroprotective effects, suggesting that this component has the potential to treat epilepsy^[80]Sinomenine also has certain potential for the treatment of insomnia,Yooetc.^[81]Through experiments, it was found that sinomenine could enhanceγ-The aminobutyric acid system thus enhanced the non REM sleep induced by pentobarbital, and when CO administered with pentobarbital, it shortened the sleep latency and increased the total sleep time in a dose-dependent manner.

2.7  other

Through the analysis of44The results showed that magnoliane had the highest growth inhibitory activity against Candida, and the minimum inhibitory concentration was50 μg/mL, which may be a new antifungal drug^[82]Sinomenine can alleviate oxidative stress and inflammatory reaction in vivo and in vitro, and can inhibit acute liver injury induced by carbon tetrachloride and acetaminophen in mice and acute liver injury induced by Escherichia coli in miceAll of them play a alleviating role in the treatment of acute lung injury^[83-85]Sinomenine eye drops can also be used for dry eye in experimental mice to reduce ocular surface inflammation^[86]。The study found that scopoletin extracted from Sinomenium wilfordii had antioxidant activity, indicating that this component has the potential to treat a variety of diseases^[87]Phytosterols are based on cyclopentanthophenyl3-Hydroxy compounds, similar in structure to animal cholesterol, studies have found that phytosterols can reduce cholesterol, cellular antioxidation, regulate immunity, maintain the stability of the internal environment, reduce the incidence of heart disease, and have a certain therapeutic effect in lung cancer, gastric cancer, breast cancer, prostate cancer and other cancers. However, whether sterols contained in Sinomenium wilfordii have this effect still needs further research^[88]In conclusion, the substances of sinomenine that exert pharmacological effects may involve sinomenineA variety of alkaloids such as magnoliane, stephanine, razmanine, glycosides, scopoletin and other chemical components, and with the in-depth research, more pharmacodynamic substances may be found, and sterols may be one of the important pharmacodynamic substances of Sinomenium wilfordii, which can be used as one of the directions for further research on the pharmacological effects of Sinomenium wilfordii.

3 Toxicity study

Studies have shown that Sinomenium wilfordii has a wide range of pharmacological effects, but with the widespread clinical application of Sinomenium wilfordii, its adverse reactions have attracted more and more attention. According to the Great Dictionary of traditional Chinese medicine, Sinomenium sinense has little poison, and as early as in20There have been relevant studies and reports on the toxic effects of Sinomenium wilfordii since the century. The study found that miceigSinomenine, its LD50 is（580±51）mg/kg，While dogs and monkeys, respectivelyig 45、95 mg/kgAfter sinomenine, there will be mild gastrointestinal reactions,iv 5～13.5mg/kgLater, there will be blood pressure drop, dyspnea and other manifestations^[89]。According to clinical observationSinomenineCan cause agranulocytosis in the patient, while the patient is stoppingSinomenineAfter treatment10 dAnd returned to normal granulocyte level within^[90]At the same time, giving patients a large dose of sinomenine will lead to allergic reactions and systemic urticaria. Therefore, when using sinomenine in a large dose, patients' reactions should be closely observed, such as bone marrow function and granulocyte level^[91]However, at present, there are few relevant research literatures on the toxicity of Sinomenium wilfordii, which can be considered as one of the directions for further research on Sinomenium wilfordii.

4  Q-MarkerPredictive analysis

At present, because sinomenine has good anti-inflammatory, analgesic and immunosuppressive effects, it is widely used in a variety of clinical diseases. Therefore, sinomenine is considered as the drug of sinomenine in Chinese Pharmacopoeia, Japanese Pharmacopoeia, Korean Pharmacopoeia and European PharmacopoeiaQ-MarkerHowever, there are obvious limitations in using only one component to reflect the quality of drugs containing multiple chemical components. In order to better solve the problems existing in the quality control system of traditional Chinese medicine at this stage, academician liuchangxiao^[92-93]to2016Proposed inQ-MarkerThis new concept is the indicator substance that controls the safety and effectiveness of traditional Chinese medicine, and it is a chemical substance that is closely related to the efficacy attributes of traditional Chinese medicine and traditional Chinese medicine products (including traditional Chinese medicine extracts, traditional Chinese medicine preparations, traditional Chinese medicine decoction pieces, traditional Chinese medicine decoction) or formed in the process of processing and preparation. On this basis, through the analysis and summary of a large number of relevant literature, this paper summarizes Sinomenium wilfordii from many aspects, andQ-MarkerAnalysis, speculate more possible indicators of quality evaluation, and provide references for the quality control methods of Sinomenium wilfordii.

4.1  Based on plant affinity and chemical composition specificityQ-MarkerPredictive analysis

The chemical composition of traditional Chinese medicine is complex and the distribution of chemical substances is extensive. The same medicinal material can contain a variety of different chemical components, and the same chemical component can also exist in a variety of different medicinal materials, which is difficult to reflect the specificity of medicinal materials. Therefore, the genetic relationship and chemical component specificity of Sinomenium wilfordii were analyzed, and its representative and unique chemical components were selected to further predict the quality control indicators and improve the pertinence and direction of quality control.

Sinomenium wilfordii is a plant of the family stephaniaceae, which has about65genus350More than species, mainly distributed in the tropics and subtropics, in China19genus78Species, mainly distributed in the mountainous areas in the South and southwest of China. This family of plants is dioecious, mostly rattan plants, and is a well-known medicinal plant group. The Chinese medicinal materials contained in it include tetrandra tetrandra, Rhizoma polygonatum, Stephania stephaniae, and orbicularia. Chemotype is one of the signs of the differences of different species of plants, and it is also the manifestation of the commonness and individuality of different species of tetrandriaceae. At present, alkaloids, flavonoids, anthraquinones and other chemical components have been isolated from them. Among them, alkaloids are the most important secondary metabolites of tetrandriaceae plants, which have a wide range of plant distribution and rich chemical structure types, mainly including dibenzylisoquinolines, protoberberines, aporphines, morphine and lotus alkanes. Studies have found that tetrandriaceae plants also contain pyrrole alkaloids, which are currently considered to be the main pharmacological active substances. However, plants of different chemical types may grow in the same environment, which is difficult to distinguish from each other only in morphology, because they are hybridized in the growth environment. However, due to genetic factorsThe decisive role of phytoalexins is different in the chemical types of plants, and their clinical uses are also different. However, before these ingredients become effective ingredients, they often go through a long process of synthesis and have certain biogenic precursors^[94-95]Therefore, the chemical composition of Sinomenium wilfordii was analyzed from its biogenic pathway to form a unique quality control method for Sinomenium wilfordiiQ-MarkerIt has practical significance.

Qu Falin et al^[96]By high-phase liquid chromatography3The alkaloids contained in a batch of sinomenine from different habitats were determined. It was found that there were differences in sinomenine contained in sinomenine from Hunan, Hubei, Jiangsu and other places, and the highest content was1.90%, while the lowest is0.58%. HPLC was used to analyze the alkaloid content of sinomenine in different regions of Shaanxi Province. It was found that the average content of sinomenine in sinomenine in Nanzheng town of Shaanxi Province was the highest, accounting for up to3%, while only in babamiao Town, Shaanxi Province1.97%And the study found that the content of sinomenine in different parts of the same Sinomenium wilfordii was also different. The content of sinomenine in the roots of the same sinomenine is about higher than that in the stems0.62%The content of sinomenine in different parts of roots is also different, and the sinomenine content of lateral roots is the highest, followed by fibrous roots, and the sinomenine content of main roots is the lowest^[97]The results also provide a reliable basis for more rational and effective use of Sinomenium resources and evaluation of Sinomenium quality.

However, in terms of alkaloid compounds, they can be used as the main components of Rhizoma Corydalis, Rhizoma Chuanxiong, Rhizoma Coptidis and other medicinal materialsQ-MarkerReferences.Alkaloids are a class of nitrogen-containing organic compounds that widely exist in nature. They have anti-inflammatory, analgesic, antitumor and other pharmacological activities. Generally, according to the molecular structure of the compounds, alkaloids are divided into organic amines, pyridines, Isoquinolines, indoles, purines, etc^[98]。Sinomenine is an isoquinoline alkaloid with the strongest biological activity in Sinomenium wilfordii, which is widely considered as the most potent alkaloid in Sinomenium wilfordiiQ-Marker, with anti-inflammatory, analgesic, immunosuppressive and other pharmacological activities. However, due to the extensive existence of alkaloids, they are only used as theQ-MarkerLack of certain representativeness. However, according to the analysis of flavonoids and anthraquinones in different varieties of plants of tetrandriaceae, at present, flavonoids are only isolated from tetrandria tetrandra2The biflavonoids are tetrandrine A and tetrandrine B, respectively; Anthraquinones in the same family are only isolated from Stephania trifoliata1Anthraquinones (Aloe Emodin) and isolated from Sinomenium wilfordii6AnthraquinonesCompounds (emodin, obtusin, orange chamaecrisin6,8-Dihydroxy-1,2,7-Trimethoxy-3-Methyl anthraquinone, cassia, cassia flavescens). . Therefore, flavonoids and anthraquinones together with Sinomenine can be considered as the main components of SinomenineQ-MarkerSelect.

4.2 Validity basedQ-MarkerPredictive analysis

The same traditional Chinese medicine often has many different pharmacological effects, and different traditional Chinese medicines may also have the same efficacy^[99], therefore, a traditional Chinese medicine may have multipleQ-MarkerBased on the traditional efficacy of Sinomenium sinenseQ-MarkerPerform predictive analysis.

4.2.1  Based on the dehumidification effect  . In modern clinic, this effect is often used in the treatment of rheumatic diseases, mainly for the treatment of rheumatoid arthritis. According to the above pharmacological studies of sinomenine, its anti rheumatoid arthritis substances may be razmanine, stephanine, sinomenineβ-Sitosterol, Magnolia lactone, aconite epoxy lactone, l-stephanide, etc; And sinomenine, magnoliane, Dauricine, stephanine and other substances in sinomenine are the main anti-inflammatory compounds of sinomenine, which may be the material basis for anti rheumatoid arthritis. Q-MarkerReferences to.

4.2.2  Based on the effect of dredging meridians  . "Arthralgia syndrome" is caused by the invasion of external pathogens such as cold, dampness, heat, etc., which obstruct the meridians and blood circulation. It is a disease mainly characterized by soreness, numbness, heavy weight, unfavorable flexion and extension, or even joint enlargement and burning in muscles, bones and joints. Rheumatoid arthritis, ankylosing spondylitis, gout, hyperostosis, sciatica and scapulohumeral periarthritis in modern medicine belong to this category. At present, drugs containing Sinomenium wilfordii, such as tongfengting capsules, Huayu Xiaobi capsules, qinxitong tablets and Zhengqing Fengtongning sustained-release tablets, are used to treat and improve the symptoms of various immune system diseases, and are mainly used to treat rheumatoid arthritis, systemic lupus erythematosus and ankylosing spondylitis. The study found that sinomenine was the main active substance that exerted anti-inflammatory, analgesic and immunosuppressive effects^[6]。

And with the deepening of research, the efficacy of qingfengtengtong meridian is also used in the treatment of cancer and cardiovascular disease in modern clinic. Pharmacological studies have found that sterols can reduce cholesterol, cellular antioxidation, regulate immunity, maintain the stability of the internal environment, reduce the incidence of heart disease, and have a certain therapeutic effect in lung cancer, gastric cancer, breast cancer, prostate cancer and other cancers. Therefore, sinomenine and sterols can be considered as SinomenineQ-MarkerCandidates for.

4.2.3  Based on the diuretic effect  Diuresis is the expression of traditional Chinese medicine theory, that is, the diuretic effect of modern medicine. Poria cocos, plantain seed, chuanmutong and other medicinal materials have this effect, often containing sterols. At present, most drugs with diuretic effect are used for treatmentCardiovascular diseases such as hypertension. The study found that sterols and fatty acids in Akebia manshuriensis are one of the material bases for exerting diuretic effect^[100]。However, there is no in-depth study on the application of sinomenine in diuresis. However, it can be found from the traditional Chinese medicine works that its diuretic effect has been used in the treatment of urinary system diseases. With the research of modern pharmacology, sinomenine, which has the highest content, has a certain effect in urinary system tumors. Q-Marker.

4.3  Based on the property relatedQ-MarkerPredictive analysis

Four Qi and five flavor are the main content of traditional Chinese medicine property, and also one of the main basis of clinical medication and compatibility application, which can be used to determineQ-MarkerImportant basis for. Suwen first proposed the relationship between five flavors and efficacy. Five flavors not only summarize the taste of drugs, but also reflect the efficacy of drugs. Qingfengteng tastes pungent and bitter, has a flat nature, and belongs to the liver and spleen meridians. According to the property theory of traditional Chinese medicine, pungent drugs have the effect of dispersing and activating qi and blood. From the relationship between pungent drugs and viscera treatment, it can be concluded that pungent drugs mainly belong to liver, spleen, lung and stomach, and their chemical components are mainly volatile oil, followed by glycosides and alkaloids^[101]The bitter medicine has the effects of relieving heat, drying dampness, preserving Yin, and returning to the liver, lung, stomach, heart, large intestine, and kidney meridian. Its chemical components are mainly alkaloids, glycosides, and bitter substances^[102-103]It is independent of cold, heat, temperature and cool4A kind of property^[104], which are mentioned in Shennong materia medica classic, syndrome type materia medica and compendium of Materia Medica, and are listed in Chinese pharmacopoeia for the first time2010Edition. Studies have shown that volatile oil, steroids, alkaloids and other components are the important material basis of drugs^[105]According to this, it can be considered that the volatile oil, steroids, alkaloids and other components in Sinomenium wilfordii should be the main material basis for its nature, taste and meridian tropism, which can be used asQ-MarkerGlycosides and bitter substances can be used as the direction of further research on Sinomenium wilfordii.

4.4  Based on the measurability of chemical compositionQ-MarkerPredictive analysis

The measurability of chemical components is a traditional Chinese MedicineQ-MarkerOne of the basic conditions of analysis. At present, the qualitative identification and quantitative determination of medicinal materials can be carried out by ultra-high performance liquid chromatography, chromatography and the establishment of fingerprints. Finally, based on the measurability of chemical components, theQ-MarkerReferences. The content of sinomenine in Shuangwu Zhentong capsules was determined by HPLC. The results proved that the content was stable, reliable and reproducible^[106]The content of sinomenine in Qingteng powder was determined by ultra performance liquid chromatography, and the results also showed that the content of sinomenine was stable and reliable^[107]. was isolated from Sinomenium wilfordii by HPLC3Phenolic compounds6Anthraquinones and10Phenolic compounds^[12]。

However, there are obvious limitations in using only one chemical component as an indicator of drug quality evaluation. In some animal experiments, the internal standard method was used to calculate the blood concentration of sinomenine in rabbits after injection. It was found that sinomenine has the characteristics of rapid distribution and rapid elimination^[108]In addition, studies have found that sinomenine has the characteristics of low oral bioavailability and large fluctuations in plasma concentration during high-dose administration; And the toxicity study of sinomenine found that it may be related to the occasional gastrointestinal toxicity and allergic reactions, which suggested that sinomenine still had some drawbacks when it played a therapeutic role, so the safety of its chemical composition should be taken into account^[109]Through gas chromatography-The components of the volatile oil in Sinomenium wilfordii were determined by mass spectrometry80Compounds, which match63Nos; In addition, some studies have used Soxhlet extraction method to extract total alkaloids from Sinomenium sinense, and gas phase-Identification of Sinomenium chinense by mass spectrometryTengine, amberline, stephanine4-(6-methyl-3-Cyclohexene carboxyl)-Morpholine(−)-6′-methyl-nitrogen-Taurine and3-Methoxy-nitrogen-Codeine6Alkaloids accounted for up to91.1%^[9,110]However, some studies have found that the three-dimensional fluorescence spectrum of Sinomenium sinense shows the characteristic fluorescence peak of Magnolia alkaloid through fluorescence analysis, so it is presumed that it may contain Magnolia alkaloid. -Quadrupole-The time-of-flight mass spectrometer found that the pharmacological activities of sinomenine, magnoliane, noraconitine, aconitine and tetrandrine well represented the main indications and biological activities of sinomenine, which could be used as the quality indicators of sinomenine, which provided more basis for the quality control indicators of sinomenine^[111]Therefore, these substances can be used together with Sinomenine as sinomenineQ-MarkerReferences to.

5  epilogue

Sinomenium wilfordii is a plant of tetrandriaceae, which contains alkaloids, lipids, volatile oils, steroids, glycosides, anthraquinones, phenols and other chemical components. At present, most of the research on sinomenine focuses on the bioactive alkaloids represented by sinomenine, and most of the research focuses on the therapeutic effect of sinomenine in the treatment of tumor, cardiovascular disease, immune disease and nervous system disease. However, other components such as lipids, volatile oils and steroids have not been studied in depth, and with the wide application of Sinomenium wilfordii, its toxic effects such as allergic reactions and gastrointestinal discomfort have attracted attention. On this basis, it is still debatable to use only a single active compound as the quality control and quality evaluation index of Sinomenium wilfordii. Therefore, it is of great significance to establish a scientific and reasonable quality control and evaluation method for comprehensively and accurately evaluating the effective components and clinical efficacy of Sinomenium wilfordii. On the basis of summarizing the chemical constituents and pharmacological effects of Sinomenium sinenseQ-MarkerGuided by the new concept, the plant phylogeny and chemical component specificity, effectiveness, property correlation, and chemical component measurability were analyzed. It was presumed that a variety of alkaloids, volatile oils, steroids, anthraquinones, phenanthrene, and phenols such as sinomenine, magnoliane, Dauricine, l-stephanine, stephanine, noraconitine, and tetrandrine in Sinomenium wilfordii could be used as quality evaluation indicators of Sinomenium wilfordii. In addition, the volatile oils, lipids, sterols, and other substances in Sinomenium wilfordii had good research prospects. With the deepening of research, more bioactive substances of Sinomenium wilfordii might be included as wind vineQ-MarkerProvide basis for the selection and determination of.

Conflict of interest 

References (omitted)   picture;

Come   Source: luoyanqun, shenxiaolan, caisanjin, meizhigang, fengzhitao. Research progress of chemical constituents and pharmacological effects of Sinomenium sinense and prediction analysis of quality marker (q-marker)   [J] . Chinese herbal medicine, 2022, 53 (3): 898-911