Study on the pharmacological mechanism of chaihu shugan powder in the treatment of hepatocellular carcinoma

Xun Sun ,Jin-Wen Chai

1Laizhou Hospital of Traditional Chinese Medicine,Laizhou 261400,China.

Abstract:Liver depression and qi stagnation type liver cancer accounts for a high proportion of primary liver cancer,western medicine has no special treatment for this type of liver cancer in addition to routine treatment,while patients with this type of liver cancer often show pain in the right flank,mass under the right side,chest depression and other clinical symptoms seriously affect the quality of life of patients with liver cancer and bring great trouble to patients and their families.Chaihu Shugan San,which originated from the General order of Medicine in the Ming Dynasty,has a serious impact on the quality of life of patients with liver cancer and brings great trouble to patients and their families.It is the representative prescription of soothing the liver and regulating qi in traditional Chinese medicine.in recent years,its clinical application and pharmacological action in liver cancer have been studied more and more deeply,but the anti-tumor pharmacological research and effective components of Chaihu Shugan Powder are still lack of systematic summary.Based on the relevant studies at home and abroad,this paper summarizes the anti-tumor mechanism and possible effective components of Chaihu Shugan Powder,so as to provide further pharmacodynamic material basis and mechanism reference for the further clinical application of primary liver cancer.

Keywords:Chaihu Shugan Powder;liver depression and qi stagnation;primary liver cancer;clinical application

Introduction

Primary liver cancer,one of the most common malignant tumors in China,has the characteristics of late discovery,rapid development,difficult treatment and poor prognosis.Its early symptoms are hidden,many patients have reached the middle and late stage,only a small number of patients have the opportunity of surgical resection,even if surgical resection,the postoperative recurrence and metastasis rate is also very high.Western medicine alone is not effective in the treatment of liver cancer,while traditional Chinese medicine has congenital advantages in the treatment of liver cancer.Integrated traditional Chinese and western medicine is an important means to improve the efficacy of liver cancer.

Liver cancer belongs to the categories of "liver accumulation","bulging" and "jaundice" in traditional Chinese medicine."difficult classics 56 difficult" said:"the accumulation of the liver,known as fat qi,under the threat,such as covering the cup,head and foot,do not heal for a long time,people do not recover their limbs,jaundice,diet is not for." The theory of the origin of various diseases said:"it is diagnosed that the liver accumulates,the pulse is string and thin,the pain under the two sides,the evil under the heart,the cold of the foot and the shin,and the pain under the side leads to the lower abdomen.The body has no ointment,likes to turn tendons,and the claws are withered and black." "Taiping Huimin and Medicine Bureau"said:"the heart and belly accumulate,chronic disease,block as big as a cup and bowl,jaundice,persistent food,vomiting,support for upper qi,abdominal distension from time to time,hard under the heart." The hypochondriac pain,abdominal distension,jaundice,epigastric mass,nausea and vomiting described above are similar to the clinical symptoms of liver cancer.The incidence of liver cancer is mostly caused by emotional injury,improper diet or unclean diet,congenital deficiency of liver and kidney loss,resulting in qi stagnation,blood stasis,phlegm and toxin accumulation,accumulation over time,and liver accumulation.

Analysis of Pathogenesis of traditional Chinese Medicine

The pathogenesis of liver cancer is complex,which is caused by the liver or other visceral diseases.The loss of the liver and catharsis is the key link in the evolution of the pathogenesis.The disease is located in the liver,because there is a close control relationship between the liver and the spleen,the spleen and the stomach,and the homology of the liver and kidney,so the incidence of liver cancer is closely related to the gallbladder,spleen,stomach and kidney.In the early stage,the pathogenesis is mainly due to qi stagnation,blood stasis,damp-heat and other excess pathogens,while the course of the disease takes a long time to see deficiency of qi and blood,deficiency of both yin and yang,which becomes the syndrome of deficiency and excess.Liver loss and catharsis can cause stagnation of qi and blood,so qi stagnation and blood stasis can lead to hypochondriac pain and hepatomegaly;liver loss and catharsis can also lead to abnormal bile secretion and excretion,so the clinical manifestations are jaundice and anorexia;liver loss and catharsis affect the operation of qi,and then affect the rise and fall of spleen and stomach,which leads to the dysfunction of spleen and stomach,biochemical deficiency of qi and blood,and then clinical manifestations such as anorexia,fatigue and emaciation.The loss of liver and the stagnation of qi and blood can lead to abnormal water metabolism if it affects the function of regulating waterways of spleen,lung and kidney,so abdominal fullness and edema can be seen in clinic.It can be seen that liver depression and qi stagnation and cathartic dysfunction play an important role in the occurrence and development of liver cancer.Chaihu Shugan Powder is a classic prescription for soothing the liver and relieving depression.Its main components include:Bupleurum,Paeonia lactiflora,Fructus Aurantii,grilled licorice,tangerine peel,Chuanxiong,Xiangfu and so on.In the prescription,Chaihu soothes the liver wood to relieve depression,white peony collects liver yin to soften blood,Chuanxiong turns blood clotting to return to the liver,Fructus Aurantii breaks stagnation qi,tangerine peel,incense adjusts qi and relieves qi depression,peppermint relieves depression and soothes the liver,licorice soothes the liver and fire;all medicines are used to soothe the liver,activate blood circulation and relieve pain.Therefore,as a classic basic prescription for soothing the liver and relieving depression,Chaihu Shugan Powder plays an indispensable role in the treatment of liver depression and qi stagnation type of liver cancer.

As a classic compound prescription for soothing the liver and relieving depression,Chaihu Shugan Powder has been widely used in the treatment of liver depression and qi stagnation type of liver cancer.At the same time,with the deepening of pharmacological research of modern traditional Chinese medicine,Chaihu Shugan Powder can regulate cytokines,neurotransmitters,endocrine system,nerve cell injury signal pathway,antioxidant stress and other multi-level mechanisms[1].Its important role in the treatment of liver depression and qi stagnation has been continuously confirmed.

Study on Anti-tumor Pharmacological effect of Chaihu Shugan Powder

Effect on inflammatory cytokines

The secretion of inflammatory cytokines such as interleukin and tumor necrosis factor-α in peripheral blood increases,which acts on the corresponding receptors in the brain region through the blood-brain barrier,stimulates microglia and macrophages to produce inflammatory response,and inhibits neuronal regeneration in the hippocampus,thus affecting the occurrence of liver cancer.Some studies have found that Chaihu Shugan Powder can regulate immunity.Yang Donghua et al.[2] found that the content of IL-4 in serum of rats with liver-qi stagnation syndrome of tail-clamping method decreased,while the content of interferon-γ increased,and helper T cells were transformed into Th1 cells.Oral administration of 3 g/kg Chaihu Shugan Powder twice a day for 2 weeks can up-regulate the expression of IL-4 and down-regulate the expression of interferon-γ,and improve the imbalance of Th1/Th2 cytokines,indicating that Chaihu Shugan San can alleviate the symptoms of liver depression by regulating cytokines to reduce the inflammatory response of the body.Qiu Juan et al found that 2-week administration of 5.9g/kg Chaihu Shugan Powder could reduce the contents of serum interleukin-6 and tumor necrosis factor-α,effectively inhibit hippocampal p38MAPK activated by pro-inflammatory cytokines,protect hippocampal neurons,and thus inhibit the differentiation of hepatocellular carcinoma cells.

Effect on oxidative stress

Oxidative stress is that when the body is stimulated,the regulatory mechanism of oxidation system and antioxidant system is out of balance,which leads to the increase of highly active molecules such as reactive oxygen species,but it can not be effectively eliminated by the tissue of the system.so that there are a large number of oxidative intermediates in the body and damage.Changes such as decreased function of endogenous antioxidant system and oxidative stress play an important role in the occurrence and development of liver depression and qi stagnation type of liver cancer [3].Network pharmacology confirmed that Chaihu Shugan Powder has a certain ability of scavenging free radicals in the body and can effectively improve the antioxidant stress ability of the body.Li Shuqi [4]detected the ability of Chaihu Shugan Powder to scavenge free radicals by a variety of free radical detection methods.It was found that Chaihu Shugan Powder could scavenge free radicals in vitro and reduce free radicals,reduce oxidative stress reaction and tissue damage,and increase the antioxidant capacity of the body.Wu Jinxia et al.[5] found that hesperidin,rutin and neohesperidin were the main components with significant antioxidant activity in Chaihu Shugan Powder.They have good binding ability to the molecules of related enzymes regulated by Chaihu Shugan Powder in the treatment of liver stagnation and qi stagnation,indicating that hesperidin,naringin and neohesperidin are the main effective components of in vitro antioxidant activity of Chaihu Shugan Powder.Liu Yi et al.[6]found that 20 mg/kg,40 mg/kg and 60 mg/kg luteolin could significantly increase the sugar water preference,reduce the immobility time of forced swimming and tail suspension,increase the levels of superoxide dismutase and glutathione and decrease the content of malondialdehyde in the brain of CUMS mice,indicating that luteolin can enhance the antioxidant capacity of the brain tissue of CUMS mice.Improve the imbalance between oxidation system and antioxidant system.

Effect on signal pathway of nerve cell injury

Studies have shown that Chaihu Shugan Powder can effectively enhance neuroplasticity.Du Yawei et al.[7] found that 2-week administration of 3.5g/kg Chaihu Shugan Powder could increase the number of positive cells of extracellular regulated protein kinase(extracellular regulated protein kinases-1) and phosphorylated extracellular signal-regulated kinase (phospho-excelluar signal-regulated ki-nase,p-ERK) in hippocampal CA3 and dentate gyrus (dentategyrus,DG) region of rats with liver-qi stagnation.It is suggested that Chaihu Shugan Powder may protect the neurons in the hippocampus,relieve the symptoms of liver depression and treat liver cancer through ERK1/2 and P-ERK signal pathways.Wu M et al.[8]found that 6 g/kg aqueous extract of Fructus Aurantii could reduce the immobility time of mice during forced swimming and tail suspension,and the aqueous extract of Fructus Aurantii and naringin,hesperidin,neohesperidin and nobiletin all had neuroprotective effects on corticosterone-induced neurotoxicity in PC12 cells,indicating that naringin,neohesperidin,naringin and hesperidin could protect nerve cells.Improve neural plasticity to achieve anti-tumor effect.

Effect on neuroendocrine

The occurrence of liver cancer is closely related to neuroendocrine.Shen Jianying et al used 3.6g/kg Chaihu Shugan Powder to treat rats with liver depression syndrome of peri-menopausal syndrome caused by chronic restraint for 3 weeks.the results showed that the expression of estrogen receptor α and β in ovary was up-regulated,indicating that Chaihu Shugan Powder can alleviate the abnormal state of endocrine by up-regulating the release of estrogen,so as to improve the symptoms of liver depression in peri-menopausal period.Chen X Q et al found that administration of 50 mg/kg and 100 mg/kg saikosaponin A for 4 weeks could reduce the immobility time of forced swimming in peri-menopausal rats of CUMS,down-regulate CRH in hypothalamus and GC in hippocampus,and restore the imbalance of HPA axis.Li H Y et al.[9] found that administration of 0.75mg/kg and 1.5mg/kg saikosaponin D for 3 weeks could reduce the expression of GR,reduce the content of corticosterone in serum and alleviate the dysfunction of HPA axis in CUMS rats.

Effect on neurotrophic factors

Neurotrophin can affect the survival,development and apoptosis of neurons,protect neurons [10],and promote the repair and regeneration of neurons.It is a kind of essential protein for the growth and development of nerve cells [11].Including nerve growth factor and brain-derived nutrition factor [12],and this kind of neurons play an important role in the occurrence and development of liver cancer.Chaihu Shugan Powder can regulate the expression of brain-derived nutrition factor (brain derived neumtrophic factor,BDNF) and its receptor tyrosine kinase receptor B in the brain.Deng Ying et al.[13] established a rat model of depression by CUMS combined with orphanage.The results showed that 5.9 g/kg Chaihu Shugan Powder could increase the sugar preference,increase the score of horizontal and vertical exercise,shorten the stay time in the central area,and up-regulate BDNF and tyrosine kinase receptor B in hippocampus,amygdala and frontal lobe of rats.It is suggested that the mechanism of Chaihu Shugan Powder in improving depression-like behavior in rats may be related to the increase of the expression of neurotrophic factor and its receptor.

Summary

There are complex biomolecule networks among cytokines,nervous system,endocrine system and immune system [14].Multi-components of Chaihu Shugan Powder play an important role in functional regulation and functional feedback respectively [15].Furthermore,it interacts and restricts each other with neurotransmitters,endocrine hormones and cytokines at a deeper level [16],which plays an overall anti-tumor effect.However,although more active components have been found in Chaihu Shugan Powder,the specific target of each component is not clear,and how the components work together is not clear.At present,with the in-depth study of Chaihu Shugan Powder,clinical and animal experiments have proved that clinical application of Chaihu Shugan Powder can achieve a better effect in the treatment of liver depression and qi stagnation type of liver cancer.and through the synergistic effect of multi-targets,multi-sites and multi-links to exert the anti-tumor effect.It involves a variety of pathways and pathways related to the pathogenesis of liver cancer,such as neurotransmitters,neuroplasticity,neuroendocrine,immune regulation,oxidative stress and energy metabolism[17-18].Therefore,the interaction of multi-components of Chaihu Shugan Powder is considered from many aspects.it is expected to fully clarify its pharmacological mechanism.