Rheumatoid arthritis belongs to arthralgia syndrome in the theory of traditional Chinese medicine， and cold-dampness obstruction syndrome and dampness-heat obstruction syndrome are core syndromes and main syndrome differentiation types of this disease. Fine therapeutic effects have been obtained in the long-term clinical practice of many famous traditional Chinese medicine practitioners following the syndrome differentiation and treatment based on the guiding principles of cold and heat. To adapt to the clinical diagnosis practice of combining disease differentiation and syndrome differentiation， and to better carry out basic research on integrated Chinese and Western medicine and preclinical study on new traditional Chinese medicines， Guidelines for Establishing Animal Models of Rheumatoid Arthritis with Cold-Dampness Obstruction Syndrome and Dampness-Heat Obstruction Syndrome （hereinafter referred to as the Guidelines） were compiled by our research group， in cooperation with the renowned experts in research fields including traditional Chinese medicine， clinical medicine， zoology and evidence-based medicine， which provide a meaningful reference for scientific research， teaching and clinical applications. The compilation process of the Guidelines was guided by the theory of disease and syndrome integration and the principles of "evidence takes the main place， consensus plays an auxiliary role， and experience serves as the reference". Based on the comprehensive evaluation of pathogenesis homology， behavioral phenotypic consistency， and drug treatment predictability compared between animal models and human diseases， by the nominal group method， "recommendations" were formed for recommendations supported by evidence， and "consensus recommendations" were formed for recommendations not supported by evidence. Guidelines were formed involving content such as animal types， arthritis modeling methods， external stimulation conditions， and modeling assessment indicators during the establishment of the animal models of rheumatoid arthritis with cold-dampness obstruction syndrome and dampness-heat obstruction syndrome. The Guidelines are applicable for the disease and syndrome research on rheumatoid arthritis， investigation of therapeutic mechanisms， and development of new traditional Chinese medicine. The Guidelines also provide a reference for the establishment of guidelines on other types of diseases and syndromes combined with animal models to further promote the modernization of traditional Chinese medicine research and its integration with international academic development.

The Guidelines for Establishing Animal Models of Rheumatoid Arthritis with Cold-dampness Obstruction Syndrome and Dampness-heat Obstruction Syndrome （hereinafter referred to as the Guidelines） （No. T/CACM1567-2024） was published by Chinese Association of Chinese Medicine on January 11， 2024. To assist researchers and medical workers in understanding and applying the Guidelines more accurately， and also to provide reference and assistance for the establishment of guidelines on other types of diseases and syndromes combined with animal models， this paper made a declaration of the workflow， technological links， development references， promotion of its application and after-effect evaluation of the Guidelines that has been made according to the requirements of "Draft Group Standard of the Standardization Office of the Chinese Association of Traditional Chinese Medicine".

ObjectiveTo unveil the mechanism of Jianpi Huogu prescription （JPHGP） in ameliorating the dyslipidemia of steroid-induced osteonecrosis of the femur head （SONFH） by oxylipidomics combined with transcriptomics. MethodsSixty SD rats were assigned into normal， model， low-， medium-， and high-dose （2.5， 5， 10 g·kg^-1， respectively） JPHGP， and Jiangushengwan （1.53 g·kg^-1） groups. Lipopolysaccharide was injected into the tail vein at a dose of 20 μg·kg^-1 on days 1 and 2， and methylprednisolone sodium succinate was injected at a dose of 40 mg·kg^-1 into the buttock muscle on days 3 to 5. The normal group received an equal volume of normal saline. Drug administration by gavage began 4 weeks after the last injection， and samples were taken after administration for 8 weeks. Hematoxylin-eosin staining was conducted to reveal the histopathological changes of the femoral head， and the number of adipocytes， the rate of empty bone lacunae， and the trabecular area were calculated. Micro-computed tomography was used for revealing the histological and histomorphometrical changes of the femoral head. Enzyme-linked immunosorbent assay was employed to measure the serum levels of triglyceride （TG）， total cholesterol （TC）， low-density lipoprotein （LDL）， high-density lipoprotein （HDL）， apolipoprotein A1 （ApoA1）， and apolipoprotein B （ApoB）. At the same time， the femoral head was collected for oxylipidomic and transcriptomic detection. The differential metabolites and differential genes were enriched and analyzed， and the target genes regulating lipid metabolism were predicted. The predicted target proteins were further verified by molecular docking， immunohistochemistry， and Western blot. ResultsCompared with the normal group， the model group showcased thinning of the femoral head， trabecular fracture， karyopyknosis， subchondral cystic degeneration， increases in the number of adipocytes and the rate of empty bone lacunae （P<0.01）， a reduction in the trabecular area （P<0.01）， decreases in BMD， Tb.Th， Tb.N， and BV/TV， and increases in Tb.Sp and BS/BV （P<0.01）. Compared with the model group， the JPHGP groups showed no obvious thinning of the femoral head or subchondroidal cystic degeneration. The high- and medium-dose JPHGP groups presented declines in the number of adipocytes and the rate of empty bone lacunae， an increase in the trabecular area （P<0.05， P<0.01）， rises in BMD， Tb.Th， Tb.N， and BV/TV， and decreases in Tb.Sp and BS/BV （P<0.05， P<0.01）. Compared with the normal group， the model group showcased raised serum levels of TG， TC， LDL， and ApoB and lowered serum levels of HDL and ApoA1 （P<0.01）. Compared with the model group， the JPHGP groups had lowered serum levels of TG， TC， LDL， and ApoB （P<0.05， P<0.01） and a risen serum level of ApoA1 （P<0.05， P<0.01）. Moreover， the serum level of HDL in the high-dose JPHGP group increased （P<0.01）. A total of 19 different metabolites of disease set and drug set were screened out by oxylipidomics of the femoral head， and 119 core genes with restored expression were detected by transcriptomics. The enriched pathways were mainly concentrated in inflammation， lipids， apoptosis， and osteoclast differentiation. Molecular docking， immunohistochemistry， and Western blot results showed that compared with the normal group， the model group displayed increased content of 5-lipoxygenase （5-LO） and peroxisome proliferator-activated receptor γ （PPARγ） in the femoral head （P<0.01）. Compared with the model group， medium- and high-dose JPHGP reduced the content of 5-LO and PPARγ （P<0.05， P<0.01）. ConclusionJPHGP can restore the levels of oxidized lipid metabolites by regulating the 5-LO-PPARγ axis to treat SONFH in rats. Relevant studies provide experimental evidence for the efficacy mechanism of JPHGP in the treatment of SONFH.

ObjectiveTo unveil the mechanism of Jianpi Huogu prescription （JPHGP） in ameliorating the dyslipidemia of steroid-induced osteonecrosis of the femur head （SONFH） by oxylipidomics combined with transcriptomics. MethodsSixty SD rats were assigned into normal， model， low-， medium-， and high-dose （2.5， 5， 10 g·kg^-1， respectively） JPHGP， and Jiangushengwan （1.53 g·kg^-1） groups. Lipopolysaccharide was injected into the tail vein at a dose of 20 μg·kg^-1 on days 1 and 2， and methylprednisolone sodium succinate was injected at a dose of 40 mg·kg^-1 into the buttock muscle on days 3 to 5. The normal group received an equal volume of normal saline. Drug administration by gavage began 4 weeks after the last injection， and samples were taken after administration for 8 weeks. Hematoxylin-eosin staining was conducted to reveal the histopathological changes of the femoral head， and the number of adipocytes， the rate of empty bone lacunae， and the trabecular area were calculated. Micro-computed tomography was used for revealing the histological and histomorphometrical changes of the femoral head. Enzyme-linked immunosorbent assay was employed to measure the serum levels of triglyceride （TG）， total cholesterol （TC）， low-density lipoprotein （LDL）， high-density lipoprotein （HDL）， apolipoprotein A1 （ApoA1）， and apolipoprotein B （ApoB）. At the same time， the femoral head was collected for oxylipidomic and transcriptomic detection. The differential metabolites and differential genes were enriched and analyzed， and the target genes regulating lipid metabolism were predicted. The predicted target proteins were further verified by molecular docking， immunohistochemistry， and Western blot. ResultsCompared with the normal group， the model group showcased thinning of the femoral head， trabecular fracture， karyopyknosis， subchondral cystic degeneration， increases in the number of adipocytes and the rate of empty bone lacunae （P<0.01）， a reduction in the trabecular area （P<0.01）， decreases in BMD， Tb.Th， Tb.N， and BV/TV， and increases in Tb.Sp and BS/BV （P<0.01）. Compared with the model group， the JPHGP groups showed no obvious thinning of the femoral head or subchondroidal cystic degeneration. The high- and medium-dose JPHGP groups presented declines in the number of adipocytes and the rate of empty bone lacunae， an increase in the trabecular area （P<0.05， P<0.01）， rises in BMD， Tb.Th， Tb.N， and BV/TV， and decreases in Tb.Sp and BS/BV （P<0.05， P<0.01）. Compared with the normal group， the model group showcased raised serum levels of TG， TC， LDL， and ApoB and lowered serum levels of HDL and ApoA1 （P<0.01）. Compared with the model group， the JPHGP groups had lowered serum levels of TG， TC， LDL， and ApoB （P<0.05， P<0.01） and a risen serum level of ApoA1 （P<0.05， P<0.01）. Moreover， the serum level of HDL in the high-dose JPHGP group increased （P<0.01）. A total of 19 different metabolites of disease set and drug set were screened out by oxylipidomics of the femoral head， and 119 core genes with restored expression were detected by transcriptomics. The enriched pathways were mainly concentrated in inflammation， lipids， apoptosis， and osteoclast differentiation. Molecular docking， immunohistochemistry， and Western blot results showed that compared with the normal group， the model group displayed increased content of 5-lipoxygenase （5-LO） and peroxisome proliferator-activated receptor γ （PPARγ） in the femoral head （P<0.01）. Compared with the model group， medium- and high-dose JPHGP reduced the content of 5-LO and PPARγ （P<0.05， P<0.01）. ConclusionJPHGP can restore the levels of oxidized lipid metabolites by regulating the 5-LO-PPARγ axis to treat SONFH in rats. Relevant studies provide experimental evidence for the efficacy mechanism of JPHGP in the treatment of SONFH.

ObjectiveTo systematically and objectively characterize the pharmacological effects of Fufang Biejia Ruangan pills （FBRP） in the intervention of alcoholic liver disease （ALD） using acute and chronic ALD mouse models and to elucidate its molecular mechanisms. MethodFifty SPF-grade male BALB/c mice were randomly divided into the normal group， model group， and FBRP low-， medium-， and high-dose groups （9.6， 19.2， 38.4 mg·kg^-1）. Except for the normal group， the remaining groups were given 56° white wine by gavage to establish the acute ALD model， with samples collected after 4 weeks. Thirty SPF-grade male C57BL/6N mice were randomly divided into the normal group， model group， and FBRP medium-dose group （19.2 mg·kg^-1）. The chronic ALD mouse model was established using the Lieber-DeCarli method over a 10-week period. Inflammatory markers in liver tissues were assessed using hematoxylin-eosin （HE）， Sirius Red， oil red O staining， and enzyme-linked immunosorbent assay （ELISA）. Intoxication behaviors of each group were objectively evaluated through sobering-up time， net-catching， and pole-climbing tests. Further bioinformatics analyses based on clinical transcriptomic data were conducted to identify key targets and molecular mechanisms of FBRP in alleviating ALD through liver-brain dialogue， with experimental validation by ELISA， Western blot， and immunohistochemical staining. ResultCompared with the normal group, the levels of aspartate aminotransferase （AST） and alanine aminotransferase （ALT） in liver tissues of mice in the acute and chronic ALD model groups were significantly increased （P<0.05）. Compared with the model group， the levels of AST and ALT in liver tissue of mice in FBRP groups were significantly decreased （P<0.05）. Compared with the normal group， the time of grasping the net and climbing the pole in the acute ALD model group was significantly decreased within 4 weeks （P<0.01）. Compared with the model group， the grasping and climbing time of FBRP high dose groups increased significantly within 4 weeks （P<0.05）. Compared with the normal group， the expression of high mobility group protein B1 （HMGB1） protein in liver tissue and prefrontal lobe tissue of mice in the chronic ALD model group was significantly increased （P<0.01）. Compared with the model group， the expression of HMGB1 protein in FBRP medium dose group was significantly decreased （P<0.05，P<0.01）. Compared with the normal group， the expression of brain-derived neurotrophic factor （BDNF） protein and the release of γ-aminobutyric acid （GABA） in the prefrontal cortex of the model group were significantly decreased （P<0.01）. Compared with the model group, the expression of BDNF protein and the release of GABA in the FBRP medium dose group were significantly increased （P<0.05）. ConclusionThis study revealed that FBRP improved key pathological changes in ALD by modulating liver-brain dialogue mediated by the HMGB1-BDNF axis. These findings provide experimental evidence for the clinical use of FBRP in treating ALD and offer new insights for the development of ALD therapeutic agents.

ObjectiveTo identify the pharmacodynamic material basis of Ruyi Zhenbaowan in relieving neuropathic pain by integrating the calculation of biological network proximity and pharmacokinetic characterization. MethodThe interaction network of "drug candidate target-related gene of disease" was constructed by Cytoscape 3.8.2， and the average shortest path value of each drug putative target acting on neuropathic pain-related genes in this network was calculated by Pesca 3.8.0 tool so as to evaluate the network proximity between them， and screen prescription candidate targets with strong intervention efficiency and their corresponding potential effect components. After that， plasma and cerebrospinal fluid samples were collected from rats after administration of Ruyi Zhenbaowan at set time points， and the contents of potential effect components in samples was quantified by ultra performance liquid chromatography-quadrupole-ion trap mass spectrometry（UPLC-Q-TRAP/MS）， and drug concentration-time curves were plotted， then the pharmacokinetic parameters were calculated by DAS 2.1.1. ResultBy evaluating the network proximity between candidate targets and neuropathic pain-related genes in the interaction network， a total of 40 putative targets of Ruyi Zhenbaowan with strong intervention effects on neuropathic pain-related genes， such as estrogen receptor 1（ESR1）， cyclic adenosine monophosphate（cAMP）-dependent protein kinase catalytic subunit alpha（PRKACA） and protein kinase B1 （Akt1）， and 10 corresponding potential effect components， such as glycyrrhizic acid and betulinic acid， were obtained. Pharmacokinetic characterization showed that among the 10 potential effect components， gallic acid， apigenin-7-O-glucuronide， glycyrrhizic acid and apigenin were well absorbed and metabolized in plasma and cerebrospinal fluid， with long onset time and good bioavailability. ConclusionFrom the perspective of efficacy-target-constituent-pharmacokinetic， this study analyzes the main effective materials of Ruyi Zhenbaowan， such as glycyrrhizic acid， gallic acid， apigenin-7-O-glucuronide and apigenin， which have a high exposure in plasma or cerebrospinal fluid and have a strong intervention effect on neuropathic pain. The related results provide reliable experimental evidences for clarifying the material basis and developing quality standards of Ruyi Zhenbaowan.

ObjectiveTo identify the chemical constituents of Ruyi Zhenbaowan in vitro and in vivo. MethodThe chemical constituents of Ruyi Zhenbaowan were identified based on UHPLC-Q Exactive Orbitrap HRMS. A total of 12 male SD rats were randomized into two groups： control （pure water） and Ruyi Zhenbaowan （1.8 g·kg^-1）. The rats were administrated with the suspension of Ruyi Zhenbaowan or pure water by gavage. After 1.5 h， the plasma and cerebrospinal fluid were collected. Chromatographic separation was performed on a Waters ACQUITY UPLC BEH C₁₈ column （2.1 mm × 150 mm， 1.7 μm） with a mixture of 0.1% formic acid aqueous solution （A） and acetonitrile （B） as the mobile phase. Gradient elution was carried out according to the procedure of 0~15 min，97%~80%A；15~30 min ，80%~60%A；30~40 min，60%~30%A；40~45 min，30%~5%A. The ion source was electrospray ionization， and scan range was m/z 100-1 500. The prototype components and the components in the plasma and cerebrospinal fluid were analyzed qualitatively by scanning in positive and negative ion modes and identified by comparison with the data in published literature and the information of standard substances. ResultA total of 126 chemical constituents were identified from the 80% methanol solution of Ruyi Zhenbaowan， and 14 and 7 prototype constituents were detected in the plasma and the cerebrospinal fluid， respectively. In addition， the fragmentation rules of apigenin， apigenin-7-O-glucuronide， galangin， liquiritin， piperine， glycyrrhizic acid， eugenol， gallic acid， and cholic acid were deduced. ConclusionThis study achieved rapid multicomponent characterization and identification of Ruyi Zhenbaowan in vitro and in vivo， providing theoretical support for exploring active substances and performing quality control.l.

Objective To establish the animal model of comorbidity of knee osteoarthritis(KOA)and hypertension with pattern of liver and kidney deficiency and evaluate its characteristics of comorbidity and pattern.Methods Wistar-Kyoto(WKY)rats and spontaneously hypertensive rats(SHR)were assigned to the WKY control group(control group),hypertension combined with KOA sham-operation group(sham-operation group),hypertension combined with KOA group(model group),hypertension combined with KOA and liver-kidney deficiency pattern group(LKD group).The animal model of KOA combined with hypertension was prepared by anterior cruciate ligament transection(ACLT)in spontaneously hypertensive rats.ACLT combined with intramuscular injection of hydrocortisone was performed to prepare an animal model of KOA with liver-kidney deficiency(LKD)pattern type,combined with hypertension.Then,the related indexes of LKD syndrome were detected in turn,including the contents of thyroid stimulating hormone(TSH),testosterone(T),corticosterone(CORT),adrenocorticotropic hormone(ACTH)in serum,and enzyme activities of alanine transaminase(ALT),aspartate transaminase(AST),and alkaline phosphatase(ALP)in serum,the mass ratio of liver,kidney,spleen,thymus to the brain,body weight,anal temperature,activity situation,and emotion.Systolic blood pressure,diastolic blood pressure,and other blood pressure-related indices were also detected.The levels of serum tumor necrosis factor-α(TNF-α)and interleukin-1β(IL-1β),plantar mechanical pain sensitivity threshold,weight difference score of both hind limbs,hind limb joint swelling,and quadruped gait parameters were also measured.Furthermore,hematoxylin-eosin,safranine-fast green,and Masson staining were performed to observe pathological changes,cartilage degeneration,and bone destruction of the knee joint,and the microstructure parameters of the tibia were detected by Micro-CT imaging.Results Compared to the model group,the contents of serum TSH,ACTH,T,CORT and the mass ratio of the kidney,spleen,and thymus to the brain in the LKD group decreased(P<0.05).Compared to the control group,the systolic blood pressure and diastolic blood pressure of the other three groups increased significantly(P<0.05).Compared to the sham-operation group,serum TNF-α and IL-1β levels increased,plantar mechanical pain threshold decreased,weight difference score of both hind limbs and joint swelling of the affected limb increased(P<0.05),and gait parameters(e.g.,gait length and standing time of the affected limbs)became abnormal in the model and LKD groups.Simultaneously,the cartilage surface defect of the rat knee joint was severe,the arrangement of the surface chondrocytes was altered,the cartilage layer became thinner,the muscle fibers increased,and the cartilage ossification was severe.Furthermore,the relative volume,thickness,and number of trabeculae of the knee joint decreased significantly(P<0.05).Conclusion The rat model established in this study is consistent with the clinical characteristics of integrated traditional Chinese and Western medicine in patients with comorbidities of hypertension and KOA with liver and kidney deficiency pattern.This rat model can characterize the typical symptoms of liver and kidney deficiency pattern.It has typical pathological changes in knee cartilage and subchondral bone tissues and can maintain a stable range of high systolic and diastolic blood pressure.It also explore the scientific connotation of simultaneous treatment of different diseases in traditional Chinese medicine,revealing the therapeutic mechanism and developing new drugs.

Objective This study systematically evaluated the clinical efficacy of Shangke Jiegu tablet in the treatment of fracture,and explored the mechanism of action of Shangke Jiegu tablet and the compatibility of each efficacy group from the"Disease-Symptom-Formula"perspective.Methods Clinical research literatures on the use of Shangke Jiegu tablet for fracture intervention were retrieved from Chinese databases(CNKI,Wanfang Database,VIP database)and English databases(PubMed,Cochrane Library,EMbase),covering the period from the inception of the databases to January 2024.Risk assessment tools were used to evaluate the literature's quality,and the data were extracted and analyzed using Stata 16.0 software.Gene sets associated with fracture symptoms were identified through the TCMIP platform(version 2.0).Differential gene expression related to fractures was obtained from the GEO database.Chemical composition and candidate target profiles of the 12 herbs in Shangke Jiegu tablets were collected from TCMIP v 2.0.An interaction network between fracture-related genes and drug candidate targets was established,and core network targets were screened based on topological features,with functional enrichment analysis performed.Results A total of 14 articles were incorporated into the Meta-analysis,encompassing a total sample size of 1 293 cases,indicating an overall response rate of Shangke Jiegu tablets in fracture therapy(RR=1.24,95%CI:1.18-1.31,P<0.001).The"Disease-Symptom-Formula"association network analysis indicated that the pathways related to the putative targets of Shangke Jiegu tablet were primarily involved in bone healing,nerve and blood system regulation,and immune-inflammation regulation.Different efficacy groups within the prescriptions showed varying emphases on these roles.Conclusions Shangke Jiegu tablet may facilitate fracture healing by regulating blood and nervous systems,correcting immune-inflammatory imbalances,and maintaining bone and energy metabolism.The comprehensive effects include the dissipation of blood stasis,the promotion of blood circulation,the alleviation of swelling and pain,the regeneration of muscles and bones,and the clearance of heat and detoxification.These findings support the clinical advantages and positioning of Shangke Jiegu tablet.

ObjectiveTo systematically evaluate the safety of Chinese medicines combined with Tripterygium wilfordii polyglycoside tablets/Tripterygium wilfordii tablets （TWPT/TWT） in the treatment of rheumatoid arthritis （RA）， and to explore the network regulatory mechanisms of enhancing efficacy and reducing toxicity of commonly used combination regimes. MethodThe literature involving the adverse reactions of TWPT/TWT in treating RA was searched and collected from three Chinese databases （CNKI， Wanfang Data， VIP） and three English databases （PubMed， Cochrane Library， Embase） from the inception of the databases to July 2021. All studies were assessed by the Cochrane risk of bias tool， and the data were extracted and analyzed by Stata 15.0. Furthermore， Integrative Pharmacology-based Research Platform of Traditional Chinese Medicine 2.0 （TCMIP v2.0，http：//www.tcmip.cn/） was used to construct a "drug target-symptom gene of efficacy and toxicity" interaction network， to explore the underlying network regulatory mechanisms of enhancing efficacy and reducing toxicity of common T. wilfordii preparation combinations. ResultA total of 2 132 articles on Chinese medicines combined with TWPT/TWT in the treatment of RA were retrieved， and 18 of them were finally included. The systematic review showed that the adverse reactions of TWPT/TWT against RA mainly occurred in the digestive system， blood system， and reproductive system， of which digestive system had the highest incidence of damages. However， the combination with Chinese medicines effectively alleviated the adverse reactions caused by TWPT/TWT ［RR （95% CI）=0.45 （0.30， 0.66）， P<0.01］. In addition， the subgroup analysis indicated that the age of RA patients， course of disease， combination regimen， medication dosage and duration of treatment all affected the occurrence of adverse reactions of TWPT/TWT. It was found in clinical studies that total glucosides of paeony （TGP） and TWPT/TWT was most widely combined， and the effect of TGP in reducing TWPT/TWT-induced hepatotoxicity was also more significant than that of other Chinese medicines. Moreover， taking this combination regime as an example， this paper explored the "efficacy-toxicity" association mechanisms of TGP-TWPT/TWT against RA. The "drug target-symptom gene of efficacy and toxicity" interaction network revealed that the core network targets of TGP-TWPT/TWT enhanced efficacy and reduced toxicity mainly through regulating immunity-inflammation-related pathways， metabolic pathways and cell signal transduction. Especially， interleukin-4 （IL-4） and interleukin-13 （IL-13）， which were involved in the "immunity-inflammation" module， were the common targets of TGP-TWPT/TWT to enhance efficacy and reduce toxicity. The endogenous sterols， bile acids and bile salts， insulin secretion and other metabolic pathways in the "body metabolism" module were closely associated with the mechanisms of TWPT/TWT inducing hepatotoxicity and TGP reducing hepatotoxicity. While cell function regulation pathways， such as stem cell factor （SCF）/tyrosine kinase receptor （KIT） signaling pathway and phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt）signaling pathway were involved in both anti-RA effects and hepatotoxicity of TWPT/TWT. ConclusionClinical application of suitable Chinese medicines combined with TWPT/TWT in the treatment of RA can effectively improve the rheumatism and reduce the adverse reactions of TWPT/TWT， and TGP-TWPT/TWT has the most significant toxicity-reducing effect. Further biological network-based investigation indicates that the toxicity-reducing mechanism of TGP-TWPT/TWT may be related to the regulation of interleukin signaling pathway and bile acid metabolism pathway， and the synergistic efficacy-enhancing effect of the combination may be achieved by acting on interleukin signaling pathway and cell function regulation pathway.