Research progress on effective chemical constituents of Sijunzi Decoction and mechanism of prevention and treatment of digestive system diseases

ZHANGYu, HUANG Mei-zhen, PAN Chun-qu, RUAN Qing-ting, TAN Jin-jing, XIE Sheng,✉

1.Graduate School of Guangxi University of Traditional Chinese Medicine,Nanning 530001, China;

2.The First Affiliated Hospital of Guangxi University of Traditional Chinese Medicine, Nanning 530001, China

ABSTRACT Sijunzi Decoction, as one of the classic Chinese traditional prescriptions, has been used clinically by major physicians since the Song Dynasty.This article reviewed and sorted out the literature on the effective chemistry of Sijunzi Decoction and the mechanism of its prevention and treatment of digestive system diseases.At present, its effective chemical components are derived from the saponins and flavonoids in ginseng and licorice, and are effective for gastrointestinal mucosal injury diseases and malignant digestive system.Digestive system diseases such as tumors, functional gastrointestinal diseases, non-alcoholic fatty liver, acute liver injury, and liver failure show a multi-path, multi-target effect mechanism.This article reviews the effective chemical components and research of Sijunzi Decoction and the related mechanisms of prevention and treatment of digestive system diseases, and provides valuable clues for the follow-up research of Sijunzi Decoction.

Keywords:

Sijunzi Decoction

Effective chemical constituents

Mechanism of digestive system

diseases

Research progress

1.Introduction

Sijunzi Decoction is recorded in the "Taiping Huimin Hejiju Prescription" compiled and annotated by the Song Tai Medical Bureau.It is composed of ginseng, atractylodes, tuckahoe, and a small amount of licorice.It is the cornerstone of later "spleen and stomach" medicines, such as different powers.San, Liujunzi Decoction, Xiangsha Liujunzi Decoction, etc.are all tailored from this.Looking at the historical evolution of the application of Sijunzi Decoction, since the Song Dynasty until now, the function of Sijunzi Decoction is mainly to "tonify the spleen and nourish the qi".The "Medical Prescriptions Jijie" records: "This hand, foot,Taiyin, and foot Yang Ming medicine.Ginseng is sweet and warm,and it is the king of vitality.Atractylodes is bitter and warm, dry spleen and nourishes qi as a minister.Poria is sweet and weak,oozing dampness and reducing heat.Zuo.Liquorice is sweet and smooth, and Zhongyitu is also used.The vitality is sufficient for the spleen and the food is doubled.The remaining viscera will be shaded, and the color and body will be strong." The prescription can play a significant role in the treatment of various diseases with weakness of the spleen and stomach as the main syndrome.Modern pharmacology shows that Sijunzi Decoction has the effects of regulating gastrointestinal function, enhancing immunity, anti-tumor and anti-aging [1].

At present, the pharmacological mechanism of Sijunzi Decoction shows the advantages of multiple targets and multiple pathways in the prevention and treatment of digestive system diseases.After analysis and summary, ginseng and licorice are the main components of Sijunzi prescription compound activity, and Sijunzi is used in the treatment of gastrointestinal mucosal injury diseases.The mechanism of gastrointestinal epithelial cells has gradually become clear, mainly including promoting gastrointestinal epithelial cell migration and proliferation, maintaining tight junctions between gastrointestinal mucosal epithelial cells, inhibiting gastrointestinal mucosal epithelial cell apoptosis, resisting oxidative stress, and enhancing and inhibiting gastrointestinal mucosal immune response, Regulate the intestinal flora and other aspects.In addition, Sijunzi Decoction also shows a good mechanism of action on malignant tumors of the digestive system, functional gastrointestinal diseases,non-alcoholic fatty liver, acute liver injury and liver failure.This article summarizes the effective components of Sijunzi Decoction and its mechanism of preventing and treating the digestive system in the past 10 years, and provides a strong theoretical basis for the follow-up of the classic Sijunzi Decoction in the study of the digestive system.

2.Effective chemical components of Sijunzi Decoction

As the basic method of traditional Chinese medicine to treat diseases, its curative effect is very important.Therefore, the current research focuses on the therapeutic mechanism of traditional Chinese medicine, while ignoring the research on the effective material basis of traditional Chinese medicine.At present, the chemical components of ginseng, atractylodes, tuckahoe, and licorice have gradually become clear.The compound Sijunzi soup composed of them has the characteristics of diversity and complexity under the complex chemical reaction in the decoction process, and its main components are not It is not a simple oneplus-one-equal-to-two algorithm for the ingredients of a single medicine.Therefore, to clarify the effective chemical ingredients of a Chinese medicine compound is a prerequisite for proving the treatment of diseases with multiple components and multiple targets in traditional Chinese medicine.Shang Ruxia[2] and others determined the chemical components of Sijunzi Decoction by high performance liquid chromatography (HPLC)-mass spectrometry,and analyzed the mass spectra to count 10 chemical substances in Sijunzi Decoction decoction, which are divided into ginsenosides Rb1, Re, Rg1, Rb2 , Rd, Rg3, Glycyrrhizic acid 7 kinds of saponins and Glycyrrhizin, Glycyrrhizin, Glycyrrhizin, Glycyrrhizin and 3 flavonoids.Xu Qiuxiang[3] et al.proved that ginsenosides Rb1,Re, Rg1 and glycyrrhizic acid are the four index components of Sijunzi Decoction.Wang Ke[4] et al.established HPLC fingerprint to determine the chemical components of Sijunzi Decoction,and analyzed the fingerprint to find chemical substances such as Atractylodes lactone Ⅲ, glycyrrhizin, glycyrrhizin, glycyrrhizic acid, uridine and so on.Wang Cancan[5] et al.analyzed the seven components of Sijunzi Decoction by ultra performance liquid chromatography (UPLC), which are ginsenosides Rg1, Re, Rf,Rb1, Rd, glycyrrhizic acid, and Atractylodes Ⅲ.Zhao[6] et al.found that by constructing Sijunzi Decoction to treat rats with spleen-qi deficiency syndrome, the metabonomics of TCM prescriptions found that the malonyl-ginsenoside Rb2, ginsenoside Ro of ginseng, the dehydrotomonic acid of Poria cocos, and dihydroxy wool Stetenetriene-21-acid, glycyrrhizic acid, isoglycyrrhizin, glycyrrhetinic acid of licorice, and Atractylodes Ⅱ of Atractylodes macrocephala are the main components of the therapy.An[7] et al.identified the active ingredients in Sijunzi Decoction 10 by ultra performance liquid chromatography-diode array detector (UPLC-PDA), which are ginsenosides Rg1, Re, Rb1, glycyrrhizin, glycyrrhizin, glycyrrhizin,Atractylodes lactone Ⅰ, atractylodes lactone Ⅱ, atractylodes lactone Ⅲ, poriaic acid.Qu[8] et al.used the pharmacokinetics of Sijunzi Decoction in rat plasma and identified six effective Sijunzi Decoctions by UHPLC-ESI-Q-TOF/MS (UHPLC-ESI-Q-TOF/MS)The ingredients are Atractylenolide Ⅲ, Poriaic acid, Ginsenoside Rb1, Re, Glycyrrhizic acid, Glycyrrhetinic acid.Huang et al.[9]used HPLC-DAD-ELSD analysis and used peak retention time,ultraviolet spectroscopy and mass spectrometry data to identify the main components of 23 Sijunzitang decoctions.The 12 saponins were ginsenosides Rb1, Rb2, Rc, Re, Rg1, Rg2, Ro and glycyrrhizic acid, glycyrrhizin A3, 22 β-acetyl glycyrrhizin acid, glycyrrhizin G2, cloud glycoside E2, 9 kinds of flavonoids are glycyrrhizin,glycyrrhizin, apisiso Glycyrrhizin, isoliquiritin, formononetin,glycyrrhizin, isoliquiritin, formononetin and xanthophyllin, as well as two kinds of lactones Atractylenolide I and Atractylenolide Ⅲ.In summary, the existing research shows that the effective chemical components of Sijunzi Decoction are mainly derived from ginseng and licorice.

Table 1 Main chemical components of Decoction

3.Related mechanisms of Sijunzi Decoction in preventing and treating digestive system diseases

3.1 Prevention and treatment of gastrointestinal mucosal injury and related disease mechanisms

As a part of the immune system, the gastrointestinal mucosa plays a role in maintaining the homeostasis of life.The immune deficiency and excessive immune response caused by the damage of the gastrointestinal mucosa are part of the gastrointestinal diseases such as peptic ulcer and inflammatory bowel.The basic pathogenesis and main pathological links of disease, intestinal obstruction, etc.,so repairing the damaged gastrointestinal mucosa is the key to treatment.Sijunzi Decoction can promote gastrointestinal epithelial cell migration and proliferation, maintain tight junctions between gastrointestinal mucosal epithelial cells, inhibit gastrointestinal mucosal epithelial cell apoptosis, resist oxidative stress, enhance and inhibit gastrointestinal mucosal immune response, and regulate the intestinal tract The flora can repair the gastrointestinal mucosa.

3.1.1 Promote migration and proliferation of gastrointestinal epithelial cells

The migration and proliferation of gastrointestinal epithelial cells is one of the key links in the repair of gastrointestinal mucosal damage.Li Tongming[10] and others established a spleen-deficiency rat model and confirmed that Sijunzi Decoction can up-regulate SMS mRNA expression to promote epithelial cell regeneration and protect gastrointestinal mucosa.Small intestinal epithelial cells (IEC-6 cells) have been a hot spot in the study of gastrointestinal mucosal repair in recent years.Tu Xiaohua et al.[11]found that by culturing rat IEC-6 cells in vitro, Sijunzitang polysaccharides can regulate the polyamine signaling pathway, influx calcium ions, promote the migration of IEC-6 cells, and achieve the effect of repairing damaged intestinal mucosa.Shi[12] and others further researched and found that Sijunzitang polysaccharides can increase the levels of STIM1 protein and STIM1/TRPC1 complex, reduce the levels of STIM2 protein and STIM1/STIM2 complex, and promote calcium ion influx to accelerate IEC-6.The effect of cell migration promotes the restoration of the intestinal epithelium and effectively reduces the damage of the intestinal mucosa.Research by Song Houpan[13,14] and others have shown that Sijunzi Tang medicated serum can significantly promote the migration and proliferation of IEC-6 cells, and its mechanism is related to activating the TLR-2/My D88 signaling pathway and promoting the expression of c-Myc mRNA and protein.Related.

3.1.2Maintain tight junctions between epithelial cells of the gastrointestinal mucosa

Claudin controls the tight junctions between gastrointestinal epithelial cells to maintain the normal function of gastrointestinal mucosal barrier.Wang Dongxu[15] et al.established a rat model of gastric mucosal injury by indomethphene, and confirmed that Sijunzi Decoction can increase gastric mucosal tight junction proteins ZO-1,Occludin, Claudin-3, and adhesion junction proteins E-cadherin, α-The expression of catenin improved gastric mucosal damage in rats.Research by Huang Xiaoyan[16] and others have shown that Sijunzi Decoction can increase the levels of Occludin and claudin-1m RNA in the colon tissue of mice to repair ulcers stimulated by dextran sodium sulfate.Mucosal barrier function in mice with colitis.Huang Liquan[17] used Sijunzi Decoction to intervene in mice with acute gastrointestinal dysfunction and confirmed that Sijunzi Decoction can up-regulate the expression of c-kit, claudin-2, and occludin to improve intestinal mucosal permeability and intestinal motility to maintain gastrointestinal mucosa Completeness.

3.1.3 Inhibit the apoptosis of gastrointestinal mucosal epithelial cells

The apoptosis of intestinal epithelial cells will reduce the barrier function of the intestinal mucosa and cause gastrointestinal mucosal damage.Huang Xiaoyan[18] and other studies have confirmed that Sijunzi Decoction can increase the activity of telomeres and increase the expression of TERT to prevent the apoptosis of intestinal epithelial cells, thereby repairing the damaged intestinal mucosal barrier function and alleviating the induced by dextran sodium sulfate.Gastrointestinal mucosal damage in mice with ulcerative colitis.Zhao Shengyun[19] and other studies have shown that Sijunzi Decoction reduces the apoptosis of gastric mucosal cells in spleendeficiency rats by reducing the expression of caspase-3, and reduces the occurrence of gastric mucosal diseases.Zou Menglong[20]and others used network pharmacology to construct the "active components of traditional Chinese medicine-targets-disease targets"relationship of Sijunzi Decoction in the treatment of ulcerative colitis and predicted 80 targets related to ulcerative colitis, among which IL -6.Caspase-3 targets are most closely related.At the same time,experimental verification was carried out.It was found that Sijunzi inhibited the apoptosis of intestinal epithelial cells and alleviated the intestinal mucosal damage in mice.The mechanism is indeed related to the reduction of IL-6 and caspase-3.Expression related.

3.1.4 Anti-oxidant stress

The oxidative stress reaction of the gastrointestinal mucosa can cause inflammatory infiltration of neutrophils, increase the secretion of proteases, and produce a large amount of oxidation products that damage the integrity of the gastrointestinal mucosa and cause damage to the gastrointestinal mucosa.Su Yanmei[21] and others constructed spleen-deficiency gastric ulcer rats and confirmed that Sijunzi Decoction can up-regulate MT and HSP70 levels to eliminate oxidative free radicals and protect the gastric mucosa of rats with gastric ulcer.Sang Weigang[22] and others constructed rats with gastrointestinal injury after intestinal obstruction was relieved, and found that Sijunzi can reduce the expression of DAO in rat serum and the expression of MDA and SCF in small intestine tissues,reducing the damage of intestinal mucosa caused by oxidative stress,and promoting intestinal The gastrointestinal movement of rats after the obstruction was relieved.

3.1.5 Enhance and inhibit gastrointestinal mucosal immune response

When a pathogen or foreign body invades the human body, it will intensify the lymphocytes in the body to produce humoral immunity and cellular immunity to make an immune defense against the invasion.YU[23] constructed a rabbit model of intestinal obstruction,showing that Sijunzi Decoction can improve the immune function of the intestinal mucosa and repair the damaged intestinal mucosa.The mechanism is related to increasing the proportion of CD4+cells and reducing the proportion of CD3+and CD8+T cells.Li Lin[24] constructed a rabbit model after the intestinal obstruction was relieved, and showed that the four gentlemen can regulate the immune function of the body by improving cellular and humoral immunity, and its mechanism is related to the increase of IL-2,IgG, IgM, IgA, C3, C4, CD The ratio of+4T and CD+4/CD+8 cells is correlated with decreasing the ratio of TNF-α and CD+8T cells.The research of Zhang Yanxiang[25] confirmed that Sijunzi Decoction can reduce the expression of IL-1β and up-regulate the expression of IL-4, regulate immunity, balance the homeostasis of inflammatory factors, and alleviate the intestinal mucosa of rats with ulcerative colitis induced by sodium dextran sulfate.damage.The inflammatory factors generated under excessive immune stimulation will break the immune balance of the gastrointestinal mucosa and cause gastrointestinal damage.Therefore, suppressing the excessive immune response can effectively restore the damaged intestinal mucosa.Li Jinan [26] et al.used Sijunzi Decoctioncontaining cerebrospinal fluid to interfere with intestinal mucosal lymphocytes in ulcerative colitis in vitro experiments showed that Sijunzi Decoction can inhibit and reduce the intestinal mucosa by reducing the secretion of IL-1, IL-6, and TNF-ɑ The proliferation of lymphocytes and the proportion of CD4+T cells.

3.1.6 Regulate the intestinal flora

The intestinal tract is the human body's largest storage organ for bacteria.The imbalance of intestinal flora caused by the decrease of probiotics and the increase of pathogenic bacteria is one of the important pathogenesis of gastrointestinal mucosal damage.Yang Litao[27] used rifampicin and rhubarb gavage to construct a spleendeficiency rat model, which showed that Sijunzi Decoction played a protective role by increasing the number of probiotic lactic acid bacteria in the intestine, reducing the number of pathogenic bacteria Escherichia coli, and increasing the content of sIgA.The role of intestinal mucosa.Cao Jing’s [28] research shows that Sijunzi Decoction can improve the number of intestinal probiotics Bifidobacterium and Lactobacillus, and reduce the number of pathogenic Enterobacter and Enterococcus, so as to coordinate the balance of intestinal flora.Protect the intestinal mucosa of rats with ulcerative colitis.

3.2 Prevention and treatment of malignant tumors of the digestive system related mechanisms

According to epidemiology in 2014, malignant tumors of the digestive system occupies 4 of the common malignant tumors in my country, and they are also among the highest in mortality[29].In the treatment of these malignant tumors, Sijunzi Decoction showed good anti-tumor activity.

3.2.1 Prevention and treatment of gastric cancer related mechanisms

Gastric cancer refers to a malignant tumor derived from the epithelium of the gastric mucosa.Its pathological essence is that a variety of pathogenic factors break the dynamic balance between the proliferation and apoptosis of gastric mucosal cells and cause gene mutations.In vitro experiments by Jia[30] et al.found that rat serum containing Sijunzi Decoction can inhibit the proliferation of gastric cancer cell lines MKN-28 and HGC-27, reduce the colony-forming ability of MKN-28 and HGC-27, and up-regulate Bax.The level of caspase-3 and PARP down-regulate the level of bcl-2, promote the apoptosis of the side population of MKN-28 and HGC-27 cells, and achieve the purpose of treating gastric cancer.In vitro experiments by Li Jing[31] and others showed that rabbit serum containing Sijunzi Decoction can significantly inhibit the proliferation of the side population, non-side population and unsorted cells of the gastric cancer cell line SGC-7901; further experiments showed that it contains Sijunzi Decoction of rat serum can increase the levels of Bax and Bcl-2 related apoptotic proteins to achieve the proliferation of the side population cells of the gastric cancer cell line SGC-7901[32].Yu Junrong[33] and others used Sijunzi Decoction to interfere with the rat model of gastric precancerous lesions and found that the abnormal histopathology of gastric mucosal epithelium in rats has been significantly improved.The mechanism is to reduce the overexpression of MCT4 and CD147, thereby inhibiting lactic acid outflow.To improve the acidic microenvironment of gastric mucosal epithelium.

3.2.2 Prevention and treatment of liver cancer related mechanisms

The pathological nature of liver cancer is the imbalance of proliferation and apoptosis, the suppression of oncogene expression and tumor suppressor genes, and active blood vessel proliferation under the influence of a variety of pathogenic factors.Chen Limei[34]and others established a H22 liver cancer mouse model and found that Jiawei Sijunzi Decoction can up-regulate the expression of Bax,caspase-3 protein and the levels of TNF-α and IL-2, and downregulate the expression of Bcl-2 protein, and inhibit tumors by promoting cell apoptosis.Growth rate and enhancement of the body's immunity to achieve the role of treatment of liver cancer.Jin Tong[35]and others established a mouse model of H22 liver cancer and found that Jiawei Sijunzi Decoction can inhibit tumor tissue angiogenesis and tumor cell proliferation, induce tumor cell proliferation and apoptosis, and achieve the purpose of inhibiting tumor growth in mice.Its mechanism is related to reducing VEGF, The expression of VEGFR2 and TNF-α, thereby reducing the correlation of CD31 expression in tumor tissues.Shi Shengying [36] et al.extracted serum from rats containing Jiawei Sijunzi Decoction and intervened in hepatocarcinoma Hep-G2 cells in vitro and found that Jiawei Sijunzi Decoction can inhibit Akt and m TOR phosphorylation and achieve the purpose of blocking the PI3K/Akt/m TOR signaling pathway.When the Hep-G2 cell proliferation of liver cancer, it also induced the apoptosis of Hep-G2 cell.Lu Xiang[37] and others constructed a mouse model of lung metastasis of H22 liver cancer cells and found that Sijunzi Decoction can prevent the lung metastasis of H22 liver cancer cells by up-regulating the expression of IL-2 and down-regulating the expression of ICAM-1.Chen[38] and others constructed mice with H22 liver cancer cells and found that Sijunzi Decoction controlled the further deterioration of liver cancer by increasing the weight of mice, food intake and reducing ascites.Its mechanism and inhibition of TGF-b and IGF1 signaling pathways Related.Chen Yan[39] and others have shown that Sijunzi Decoction can increase the level of serum CD4+T cells and NK cells, and enhance immunity, thereby reducing the recurrence rate of liver cancer and improving the survival rate of patients after liver cancer surgery.

3.2.3 Prevention and treatment of colorectal cancer related mechanisms

Colorectal cancer, also known as colorectal cancer, refers to a malignant tumor that occurs in the epithelium of the large intestine and is one of the common cancers in my country.Zhu Yueyi[40] et al.co-cultured the NK cells treated with Sijunzi Decoction with the human colon cancer cell line HCT116, and used Sijunzi Decoction to intervene in a mouse model of colon cancer subcutaneous tumor and found that Sijunzi Decoction can increase the activity of NK cells and inhibit colon cancer cells.The mechanism of growth is related to the suppression and control of STAT3 signal, thereby reducing the expression of IFN-γ and PD-1/PD-L1.Huang Xiaoyan[41] et al.used Sijunzitang medicated serum to interfere with colorectal cancer SW480 cells after RNA interference in vitro experiments and found that Sijunzitang effectively inhibited the proliferation of cancer cells.The mechanism was to induce autophagy and control inflammation, thereby reducing hTERT expression, telomerase activity, and telomere length are related.Li Ruizhi[42] and others found by constructing a rat model of colon cancer that Sijunzi Decoction can reduce the expression of COX-2, VEGF, and AQP-1,thereby preventing the formation of new blood vessels and lymphatic vessels, reducing tumor invasion and metastasis, and reducing tumor invasion and metastasis.Molecules of inflammatory factors achieve the purpose of treating the colon.Zhou[43] and others implanted colorectal cancer cells into the spleen of mice, confirming that Sijunzi Decoction can up-regulate the solubility of mouse serum GM-CSF, thereby increasing the number of macrophages in the spleen to clear the vascular system in colon cancer cells , To achieve the purpose of inhibiting liver metastasis of colon cancer.

3.3 Prevention and treatment of functional gastrointestinal diseases related mechanisms

Functional gastrointestinal disease is a non-organic digestive tract motility disorder due to brain-intestinal interaction.Its essence is the reduction of gastrointestinal emptying rate and intestinal propulsion rate caused by a variety of pathogenic factors.Tianrong[44,45] et al.established a spleen-deficiency rat model by bitter cold and dissolving qi method (gavage of rhubarb Zhishi Magnolia decoction), and proved that Sijunzi Decoction can reduce the small intestine tissue and increase the CaM/CaM KⅡ in the hippocampus.The expression of mRNA and protein can improve the gastric residual rate and small intestine propulsion rate of rats with spleen deficiency.Zhong Zishao[46] and others used iodoacetamide to construct a functional dyspepsia rat model.The body weight and gastric emptying rate of rats under the intervention of Sijunzi Decoction have been significantly improved.Serum CNP and gastric smooth muscle NPR-B, cGMP The content of succinate was significantly reduced, confirming that Sijunzi can treat functional dyspepsia by inhibiting the CNP-NPRB-cGMP pathway of gastric antral smooth muscle.Duan Yongqiang et al.[47,48] established a rat model of irritable bowel syndrome by gavage with senna leaves, and confirmed that Sijunzi Decoction can improve the stomach by upregulating the levels of NO and NOS in serum and small intestine tissue, and down-regulating the levels of MOT, CCK, and SP.The role of residual rate and small intestinal propulsion rate.Zhang Ting [49] et al.established a rat model of spleen deficiency through rhubarb gavage and found that Sijunzi Decoction can better regulate the balance between gastrointestinal contraction and diastolic functions.Its mechanism is related to increasing serum and intestinal tissue AchE levels and reducing NOS.Vitality is related.Wang Lu[50]and others have confirmed that Sijunzi Decoction can promote and shorten the gastric emptying time of rats by inhibiting the expression of 5-HIAA, and improve the digestion level of rats with spleen deficiency.Liu Fang[51] and others have confirmed that Sijunzi Decoction can significantly reduce the levels of 5-HT3 and 5-HT4 in the intestinal mucosa of patients with irritable bowel syndrome and the levels of serum IL-6, IL-8, and TNF-α inflammatory factors.Improve the patient's clinical symptoms.

3.4 Prevention and treatment of liver diseases related mechanisms

The liver is the human body's largest digestive gland and detoxification organ.Due to various factors such as poor living habits, excessive drinking, long-term staying up late, drugs, viruses and other factors, liver disease is becoming a frequently-occurring and common disease.

3.4.1 Prevention and treatment of non-alcoholic fatty liver related mechanisms

The pathological nature of non-alcoholic fatty liver is due to excessive accumulation of lipids in liver cells caused by a variety of pathogenic factors, resulting in hepatocyte inflammatory necrosis and fibrosis.Zou Yanfei[52] et al.through a mouse model of abnormal lipid metabolism induced by a high-fat diet, confirmed that Sijunzi Decoction up-regulated the expression of PPARγmRNA in the liver tissues of mice, activated the expression of liver lipid metabolism enzymes, promoted fat oxidation, and improved mice.Serum TG,TC, LDL-C levels.Zhang Xiuting[53] et al., through a mouse model of abnormal lipid metabolism induced by a high-fat diet, confirmed that Sijunzi Decoction can effectively reduce the content of TG, TC,and LDL-C in the serum of mice, and regulate lipid metabolism.Its mechanism and inhibition of internal organs The expression of LPL in fat is related to reducing fat accumulation.Yang[54] et al.induced a non-alcoholic fatty liver rat model through a high-fat diet, confirming that Sijunzi Decoction can effectively improve liver fibrosis and reduce IL-6, IL-12, iNOS, TNF-α, IL- 1β level improves hepatocyte inflammatory response and achieves the effect of treating non-alcoholic fatty liver.The mechanism is related to the upregulation of PPAR-α and its downstream target molecules CPT-1 and CPT-2 protein expression, and down-regulation of LC3B and SREBP-1c protein expression.Yang Jiayao[55] and others observed in vitro experiments on the non-alcoholic fatty liver cell model constructed by the human normal liver cell line LO2 stimulated by oleic acid, and confirmed the mechanism of Sijunzi Decoction in the treatment of non-alcoholic fatty liver and the up-regulation of PCNA and Bcl- 2 protein, promote the proliferation of hepatocytes,and down-regulate cleaved caspase-3, cleaved caspase-8, cleaved caspase-9, Bax protein, and inhibit hepatocyte apoptosis.3.4.2 Prevention and treatment of acute liver injury and liver failure related mechanisms

Acute liver injury is a disease in which liver cell necrosis caused by a variety of reasons in a short period of time causes abnormal liver function.It continues to develop gradually and later to the late stage, which is manifested as acute liver failure with a high fatality rate.Wang Yang[56] and others used the method of concanavalin A injection to construct a mouse model of acute liver injury, which proved that Sijunzi Decoction can improve liver antioxidant capacity by reducing serum NO and MDA levels, and reduce ALT and AST.The level of protection on liver tissue.Huachen[57,58] constructed a rat model of liver ischemia-reperfusion injury, and confirmed that Sijunzi Decoction can up-regulate hepatocyte Bcl-2 protein and SOD levels, down-regulate the Bax protein expression, MDA and IL-6 levels, and have anti-inflammatory effects.Hepatocyte apoptosis,anti-oxidative damage and reducing the release of inflammatory factors improve the liver damage caused by liver ischemia and reperfusion.Ju Baoling[59,60] used D-galactosamine and endotoxin injection to construct a mouse model of acute liver failure, and found that Sijunzi Decoction can reduce enterobacteria The number of enterococci plays a role in repairing the intestinal barrier damage in mice with acute liver failure and protecting the liver.

4.Conclusion and outlook

Existing studies have proved that Sijunzi Decoction mainly contains saponins, flavonoids, lactones, triterpenes and other ingredients,and the main ingredients are active from saponins and flavonoids in ginseng and licorice.In the prevention and treatment of digestive system diseases, Sijunzi Decoction has shown multiple pathways and multiple targets for diseases such as gastrointestinal mucosal injury diseases, digestive system malignancies, functional gastrointestinal diseases, non-alcoholic fatty liver, acute liver injury and liver failure.Point effect mechanism.

The research on traditional Chinese medicine compound prescriptions is a key step in the modernization of traditional Chinese medicine, and has certain guiding significance for the clinical use of hidden prescriptions.Existing studies have shown that the rationality of the compound formula is the key to the superior efficacy of Sijunzi Decoction in treating digestive system diseases.However,due to the lack of current technology or insufficient attention, the research on the effective ingredients of Sijunzi mainly focuses on small molecular saponins and flavonoids, while ignoring the research on macromolecular compounds, such as Sijunzi polysaccharides.Sijunzi polysaccharides are the most abundant components of Sijunzi, and have good activity on the immune regulation of the intestinal tract[61].Therefore, future research on the chemical composition of Sijunzitang should mainly focus on polysaccharides.At present, it is reasonable to believe that the mechanism of Sijunzi Decoction to prevent and treat digestive system diseases is jointly regulated by multiple pathways, but it ignores the research on whether the pathways have mutual influence.Therefore, consider the interaction effects between pathways from multiple levels.It can fully explain the effect mechanism of Sijunzi Decoction, which is expected to provide modern biological research support for the concept of "treating different diseases at the same time" in traditional Chinese medicine.At the same time, the current research on the effect mechanism of Sijunzi on digestive system diseases is mainly focused on the gastrointestinal tract and liver, and the study on the effect mechanism on multiple diseases of the digestive system such as esophagus, bile duct, pancreas, etc.is missing.This is also one of the focus of future research of Sijunzi Decoction.