Investigation on the pharmacological mechanisms of Shirebi granules in treating gouty arthritis with damp-heat syndrome based on crosstalk of Wnt/β-catenin signaling / 药学学报

Gouty arthritis is a type of metabolic rheumatic disease caused by autoimmune abnormalities. Currently, the use of Western medicine in the clinical treatment of gouty arthritis has been associated with a high risk of adverse reactions. Therefore, there is a growing interest in exploring therapeutic drugs from traditional Chinese medicine as a potential alternative. According to the theory of traditional Chinese medicine, gouty arthritis has been classified as damp-heat arthralgia syndrome. Shirebi granules has been found to have good clinical efficacy in treating gouty arthritis. However, its underlying pharmacological mechanisms remain unclear. To address this problem, the study first established the interaction network of candidate targets for Shirebi granules, which is used to treat damp-heat syndrome of gouty arthritis. Then, the key candidate targets of Shirebi granules for treating gouty arthritis with damp-heat syndrome were screened by calculating the topological features of the network nodes. Then, the functional mining of the key candidate targets revealed that the candidate targets of Shirebi granules may intervene in the biological process of inflammatory response and lipid metabolism through the crosstalk of Wnt/β-catenin signaling. To verify the effectiveness of Shirebi granules in treating gouty arthritis with damp-heat syndrome, a rat model was established. The results demonstrated that the granules significantly improved the severity of arthritis in rats with this condition, reduced joint inflammation, gait score, swelling index, increased mechanical pain threshold (P < 0.05), and reduced the content of serum inflammatory factors IL-1β, IL-6, and TNF-α in gouty arthritis rats with damp-heat syndrome (P < 0.01) gouty. It was also found that Shirebi granules effectively alleviated the symptoms of dampness heat syndrome such as local joint fever and dry mouth by reducing the temperature of the joints in acute gouty arthritis with damp-heat syndrome (AD) rats, increasing the threshold of heat pain, increasing water intake (P < 0.01), and inhibiting abnormal changes in the content of fatty acid oxidation related enzymes (P < 0.01). Western blot analysis showed that Shirebi granules increased the protein expression levels of Wnt and β-catenin (P < 0.01) while decreasing the protein expression of p65, p-p65 and PPARγ (P < 0.01) in rats with gouty arthritis and damp-heat syndrome. The results showed that Shirebi granules may reverse the "inflammation-immune" imbalance and lipid metabolism disorder by regulating the crosstalk of Wnt/β-catenin signaling, and play a role in alleviating the severity of the disease. This study provides a methodological reference for elucidating the pharmacological mechanisms of traditional Chinese medicine formulas. It also presents research ideas for the appropriate clinical use of Chinese patent medicines and the development of new clinical drugs for gouty arthritis therapy. The animal welfare and experiment procedures of this study were performed in accordance with the regulations of the Experimental Animal Ethics Committee of Experimental Research Center, China Academy of Chinese Medical Sciences (grant No. ERCCACMS11-2302-08).

Exploring biological connotation of blood stasis syndrome of rheumatoid arthritis and establishment of improved animal models based on syndrome-symptom mapping / 药学学报

Blood stasis syndrome is one of the core clinical syndrome of rheumatoid arthritis (RA), but the biological connotation of this syndrome is not clear, and there is a lack of disease improved animal models that match the characteristics of this disease and syndrome. The aim of this study was to screen the candidate biomarker gene set of blood stasis syndrome of RA, reveal the biological connotation of this syndrome, and explore and evaluate the preparation method of the improved animal model based on the characteristics of "disease-syndrome-symptom". The study was approved by the ethics committee of Guang'anmen Hospital, Chinese Academy of Traditional Chinese Medicine (No. 2019-073-KY-01) and the First Affiliated Hospital of Tianjin University of Traditional Chinese Medicine (No. TYLL2021[K]018), and the study subjects gave their informed consent. Animal welfare and experimental procedures followed the regulations of the Experimental Animal Ethics Committee of the Chinese Academy of Traditional Chinese Medicine (No. IBTCMCACMS21-2207-01). The whole blood samples were collected clinically from RA patients with blood stasis syndrome (3 cases) or other syndromes (7 types, 3 cases/type), and healthy volunteers (4 cases), and then transcriptome sequencing, KEGG, gene set enrichment analysis (GSEA) and weighted correlation network analysis (WGCNA) analysis were performed. 126 pivotal genes were screened, and their functional annotation results were significantly enriched in "immune-inflammation" related pathways and lipid metabolism regulation (sphingolipids, ether lipid metabolism and steroid biosynthesis). Syndrome-symptom mapping of hub gene set to the TCM primary and secondary symptoms, Western phenotypic symptoms and pathological links showed that joint tingling, abnormal joint morphology, petechiae and abnormal blood circulation are representative of blood stasis syndrome of RA. The results of the improved animal model showed that the rats in the collagen-induced arthritis + adrenaline hydrochloride (CIA+Adr) 3 model group had increased blood rheology, coagulation, platelet function and endothelial function abnormalities compared with the CIA-alone model group, suggesting that the rats with blood stasis syndrome of RA may be in a state of "blood stasis". The results of the study can help to advance the objective study of the evidence of blood stasis syndrome in RA, and provide new ideas for the establishment of an animal model that reflects the clinical characteristics of the disease and syndrome.

Investigation of pharmacological characteristics and mechanisms of Qufeng Gutong Cataplasm based on a "disease-syndrome-symptom-formula" association network analysis / 药学学报

Growing clinical evidence shows that Qufeng Gutong Cataplasm may exert a significant analgesic effect. However, the pharmacological characteristics and mechanisms underlying this prescription are still unclear. In the current study, a "disease-syndrome-symptom-formula" association network analysis was performed to explore the pharmacological characteristics and mechanisms of Qufeng Gutong Cataplasm against osteoarthritis (OA), neuropathic pain (NP), chronic inflammatory pain (CIP) and myofascial pain syndrome (MPS) by integrating clinical phenomics data, transcriptomics data and biological interaction network mining. As a result, the three functional modules (Qufeng Sanhan-QFSHG, Shujin Huoxue-SJHXG and Xiaozhong Zhitong-XZZTG) enriched by the drug network targets were all related to the pharmacological effects of Qufeng Gutong Cataplasm, including dispersing cold and relieving pain, activating blood and relieving pain, reducing swelling and relieving pain. In addition, the main pharmacological effects of QFSHG and XZZTG were dispelling wind and dispersing cold and dehumidifying, promoting Qi and reducing swelling and relieving pain, respectively. In terms of reversing the imbalance of "immune-inflammation-vascular axis", the main pharmacological effects of SJHXG were regulating the liver and promoting Qi, activating blood circulation and removing stasis. Mechanically, the key network targets of Qufeng Gutong Cataplasm against OA, NP, CIP and MPS may play a therapeutic role in relieving hyperalgesia and paresthesia by reversing the "neuro-endocrine-immune" imbalance system during the occurrence and progression of diseases. In conclusion, our data indicate that Qufeng Gutong Cataplasm may relieve the pain and wind-cold-dampness arthralgia syndrome related symptoms by regulating the "neuro-endocrine-immune" system, neurological and endocrine disorders and reversing the imbalance of "immunity-inflammation". The relevant results may provide a network-based evidence for clinical positioning of Qufeng Gutong Cataplasm, and offer a direction for further clinical and experimental validation.

Exploring the potential mechanism of artesunate in intervening with U87 cells and U251 cells with distinct therapeutic effects on the basis of transcriptome sequencing and network pharmacology / 药学学报

Artesunate possesses the potential of intervening with glioma, however, its pharmacological mechanisms remain unclarified. Firstly, the effects of artesunate on cell activity, proliferation and apoptosis of U87 and U251 human glioma cells were explored. It was found that artesunate exerted stronger inhibitory effects on the activity and proliferation of U87 cells than U251 cells. It could significantly promote apoptosis in U87 cells (P < 0.05), while only high dose of artesunate can promote that of U251 cells (P < 0.01), detected by Hoechst and TUNEL cell apoptosis staining. Further, the differential expression gene sets between artesunate-sensitive and non-sensitive cell line, as well the therapeutic effects-related genes of artesunate were obtained through transcriptome sequencing and differential data analysis by using the lysates of U87 and U251 cells before and after artesunate treatment, aiming to explore the molecular mechanism of distinct artesunate sensitivity to two types of cells. Then, key putative targets that related to therapeutic effects were screened by constructing the interaction network of differential genes of three above comparison groups, and calculating their topological characteristics. Pathway enrichment analysis showed that those key putative targets were significantly enriched in several signaling pathways that were closely associated with the main pathological changes of glioma, among which apoptosis-related activating transcription factor 4 (ATF4)-DNA damage induced transcript 3 (DDIT3)- polyadenosine diphosphate ribose polymerase 1 (PARP1) signaling axis was the most enriched in. Molecular docking indicated that artesunate had fine binding affinities with ATF4 and DDIT3. Above all, this study preliminarily revealed that ATF4-DDIT3-PARP1 signaling axis is the target pathway of artesunate intervening with U87 glioma cells, and PARP1 may be an important gene for U251 cells to develop resistance to artesunate. Our results not only provide fundamental experimental evidence for artesunate as a potential therapeutic drug in glioma treatment, but shed light into overcoming drug resistance in its clinical therapy.

Characteristics and trends of adolescents health risk behaviors in Shanghai from 2004 to 2019 / 中国学校卫生

Objective@#To analyze the trend of adolescent health risk behaviors in Shanghai, and to provide reference for the comprehensive intervention of middle school students health risk behaviors.@*Methods@#Based on the health risk behavior questionnaire of Chinese Center for Disease Control and Prevention, the questionnaire was adapted according to the actual monitoring needs. It was divided into junior high school version and senior high school version. From 2004 to 2019, using the method of multistage stratified cluster random sampling, 59 209 middle school students who completed the questionnaire in 6 surveys were selected for analysis. @*Results@#From 2004 to 2019, in the 7 days prior to the survey, 9.2%-50.6% of middle school students drank a glass of soda more than or equal to once a day and 54.2%-76.1% of middle school students reported eating dessert twice or more. Within 7 days, 48.3%-60.7% of middle school students had≥60 min of exercise per day for less than or equal to 3 days, and 16.1%- 35.2% of middle school students reported too much extracurricular activities, and the reporting rate increased year by year with the annual percent change ( APC ) of 5.15%( t =9.28, P <0.01). The reporting rate of long time online learning was 6.0%-13.6%, which showed an upward trend among high school students, with the APC of 5.35%( t =3.14, P <0.05). The reporting rate of middle school students pedestrian safety problems decreased from 69.1% in 2004 to 27.6% in 2019, with the APC of -6.28%( t =-8.18, P <0.01), but the reporting rate of cycling safety problems have increased in recent years. The reporting rate of intentional injury behaviors decreased by year such as fighting, bullying, etc. The reporting rate of initial smoking age ≤13 years old decreased, but attempted drinking behavior increased in junior middle school students, and the APC was 1.61%( t =3.48, P <0.05). A total of 1.6%-3.4% of middle school students had an Internet addiction behavior tendency. The detection rate of Internet addiction tendency was increasing in high school students and girls, and APC was 6.59% and 10.29% respectively( t =6.37, 8.62, P <0.01).@*Conclusion@#From 2004 to 2019, unintentional injury behavior, intentional injury behavior and substance addiction behavior of middle school students in Shanghai have improved. However, unhealthy diet and physical inactivity are still high. In the follow up. It need to focus on adverse diet and lack of physical activity behavior and take comprehensive intervention measures to control them.

Biological connotation of four traditional Chinese medicine syndromes of rheumatoid arthritis based on "disease-syndrome-symptom" association network / 中国中药杂志

The present study explored the biological connotation of traditional Chinese medicine(TCM) syndromes of rheumatoid arthritis(RA) from the "disease-syndrome-symptom" association network. RA patients with four TCM syndromes(dampness-heat obstruction, phlegm-stasis obstruction, Qi-blood deficiency, and liver and kidney deficiency), three for each type, were assigned as the RA TCM syndrome group, and three healthy volunteers as the normal control group. The differential gene sets of four syndromes were screened out through transcriptome expression profiling and bioinformatics mining. The relevant gene sets of syndrome-related clinical symptoms were collected from TCMIP v2.0(http://www.tcmip.cn/). The "disease-syndrome-symptom" association networks of four RA syndromes were established by using the intersection genes of syndrome-related differential genes and symptom-related genes, and the key network target genes of each syndrome were screened out and the corresponding biological functions were mined through topological feature calculation and enrichment analysis. The genes associated with clinical symptoms such as vasculitis, joint pain, and fever in the damp-heat obstruction syndrome ranked the top, and the key network target genes of this syndrome were most significantly enriched in the pathways related to material and energy metabolism and thermal reaction biological processes. The clinical symptom-related genes of the phlegm-stasis obstruction syndrome were most significantly enriched in the pathways related to "immunity-inflammation", nervous system regulation, and sensory response. The clinical symptoms such as hypoglycemia, hypotension, weight loss, palpitation, and arrhythmia in Qi-blood deficiency syndrome were predominant, and its key network target genes were most significantly enriched in the pathways related to the nervous system and "immunity-inflammation" response. The abnormal symptoms in the liver and kidney in the liver and kidney deficiency syndrome were commonly seen, and its key network target genes were most significantly enriched in the "immunity-inflammation" regulatory pathways, and liver and kidney development and metabolic response. In conclusion, the differences and connections of the biological basis between different TCM syndromes of RA are in line with the theoretical interpretation of TCM on the etiology and pathogenesis of RA. This study summarized the objective essence of syndromes to a certain extent from the "disease-syndrome-symptom" association network and is expected to provide a theoretical basis for the discovery of serum biomarkers of RA syndromes.

Investigation on therapeutic potential and molecular mechanisms of Kunxian capsule against diabetic kidney disease via reversing the imbalance of "immune-inflammation" network / 药学学报

Drug repositioning provides new clinical indications for existing drugs. The imbalance between body's "immune-inflammation" regulation is one of the important factors in the occurrence and development of diabetic nephropathy (DN). Chinese patent medicine Kunxian capsule is clinically used for treating rheumatoid arthritis with satisfying immune-modulatory and anti-inflammatory actions. Notably, accumulating clinical evidence based on small cohorts had shown that Kunxian capsule may be used to treat DN. But the underlying pharmacological mechanisms remain unclear. Therefore, this study integrated "drug target-disease gene-biological pathway-function module" multi-level associated network analysis, and in vivo and in vitro experiments, to verify the pharmacological effects of Kunxian capsules in DN and to elucidate its molecular mechanisms. The experimental protocol was reviewed by the Laboratory Animal Welfare and Ethics Committee of China Academy of Chinese Medical Sciences, and it complies with the relevant regulations on laboratory animal welfare and ethics. As a result, the network analysis showed that the candidate targets of Kunxian capsule against DN were significantly involved into various functional modules which were related to modulation of immune-inflammation system, basement membrane lesion, abnormal hemorheology, energy metabolism and hormone metabolism, and the number of targets enriched by PI3K/AKT/NF-κB pathway is the largest. In addition, both in vivo and in vitro experiments demonstrated that Kunxian capsule by gavage effectively reduced blood glucose, improved insulin resistance, reduced blood lipid, inhibited renal extracellular matrix protein production and renal inflammation, improved renal function and pathological damages, and inhibited the activity of PI3K/AKT/NF-κB/TNF-α/IL-1β pathway in diabetic nephropathy rats. Collectively, these findings suggest the therapeutic potentials of Kunxian capsule to alleviate DN by regulating the imbalance of immune-inflammation system.

Exploration on Biological Basis Underling Different Syndromes of Nontraumatic Osteonecrosis of Femoral Head Based on Network Pharmacology / 中国实验方剂学杂志

Objective:To explore the biological basis underlying the different syndromes of nontraumatic osteonecrosis of the femoral head (NONFH) according to the molecular interaction network associated with syndromes and the corresponding prescriptions. Method:A total of 30 NONFH patients and 10 healthy controls were enrolled in the present study. The gene expression profiles associated with different syndromes of NONFH were detected by microarray analysis. Then, the molecular interaction networks of the differentially expressed genes of different syndromes were constructed to identify the crucial syndrome-related genes. After collecting the phenotype-related genes and the candidate targets of the corresponding prescriptions of different syndromes from Integrative Pharmacology-based Research Platform of Traditional Chinese Medicine (TCMIP) v2.0 (http://www.tcmip.cn/), the molecular interaction network associated with syndromes and the corresponding prescriptions were constructed and the biological basis of each syndrome was analyzed by functional enrichment analysis. Result:The crucial genes associated with the phlegm-stasis blocking collateral syndrome were mainly involved into the bone and lipid metabolism, and the regulation of immune-inflammation balance and circulation. Consistently, the candidate targets of the corresponding prescription-Jianpi Huogu prescription might play roles in the metabolism of osteogenesis, dissipating phlegm, activating circulation to remove blood stasis, relieving pain and inflammatory response. In addition, our data revealed that the stagnation of meridians syndrome-related genes could be mainly involved into the regulation of circulation and inflammatory response, as well as the metabolism of lipid and bone. Accordingly, the corresponding prescription of this syndrome-Huoxue Tongbi Formula could exert the regulatory effects on osteogenesis and inflammatory response, as well as the activation of the circulation and qi-invigorating. Moreover, the crucial genes associated with the liver and kidney deficiency syndrome played roles in various pathological processes during NONFH, such as the abnormal bone and lipid metabolisms, the immune-inflammation imbalance, and the blocked blood circulation, which were in line with our findings on the pharmacological mechanisms of the corresponding prescription of this syndrome-Bushen Zhuanggu formula. Conclusion:The current study indicated that the phlegm-stasis blocking collateral syndrome may be mainly associated with the abnormal bone and lipid metabolisms. The molecular mechanisms underlying the stagnation of meridians syndrome may be the imbalance of "immune-inflammation" and the blocking circulation. Furthermore, the liver and kidney deficiency syndrome may be not only associated with the abnormal bone and lipid metabolisms, but also implicated into various biological pathways-related to inflammation and circulation. Interestingly, the pharmacological mechanisms of the corresponding prescriptions may be in accord to the biological basis of each syndrome.

Investigation on Anti-liver Cancer Potential and Compatibility Characteristics of Fufang Biejia Ruangan Pian from Network Perspective / 中国实验方剂学杂志

Objective:To explore the anti-liver cancer potential of Fufang Biejia Ruangan Pian （FBRP） and its compatibility characteristics from a network perspective， so as to provide a theoretical basis for the clinical repositioning of FBRP. Method:Three self-pairs of cancer and para-cancerous tissue samples were collected from three patients with primary liver cancer， and the whole genome expression profiling chip was used to detect the differential genes related to the development and progression of liver cancer. After collecting the phenotype-related genes and the candidate targets of the corresponding prescriptions of FBRP from The Encyclopedia of Traditional Chinese Medicine （ETCM） and Integrative Pharmacology-based Research Platform of Traditional Chinese Medicine （TCMIP） V2.0， the "differentially expressed genes related to liver cancer development-candidate targets of FBRP efficacy substance group" interaction network was constructed according to the interaction information between the above-mentioned differentially expressed genes related to liver cancer and the candidate targets of the FBRP efficacy group， and then the major network nodes were screened. After that， the enrichment analysis of the pathway was performed in order to explore the biological basis of various pharmacological efficacy groups of FBRP， including Xiaozheng Sanjie group （Trionycis Carapax and Curcumae Rhizoma）， Buxue Huoxue group （Paeoniae Radix Rubra， Angelicae Sinensis Radix and Notoginseng Radix et Rhizoma）， Yiqi Jianpi group （Codonopsis Radix and Astragali Radix）， Yuyin Yanggan group （Placenta Hominis and Cordyceps） and Qingre Jiedu group （Isatidis Radix and Forsythiae Fructus）. Result:The major network targets of the five efficacy groups may be involved into several common pathways but also associated with some special pathological processes. Those common pathways mainly contained the regulation of nervous system， the balance of immune-inflammatory system， the regulation of energy metabolism of various substances and cancer-related pathways， while the point was also reflected by the follows：①The regulating effects of Xiaozheng Sanjie group and Yiqi Jianpi group were summarized as promoting Qi circulation and relieving depression and replenishing Qi-blood， benefiting spirit. Buxue Huoxue group may also participate in the regulation of promoting Qi circulation and relieving depression and Yuyin Yanggan group may participate in the regulation of replenishing Qi-blood and benefiting spirit. ②The regulatory effects of the Xiaozheng Sanjie group and the Yuyin Yanggan group were summarized as essence， Qi and blood supplement. Buxue Huoxue group focused on the improvement of the immune-circulatory system. Qingre Jiedu group mainly regulated the balance of immune-inflammatory system by acting on T cell receptor signaling pathway. ③Yiqi Jianpi group was demonstrated to show the effects on various material and energy metabolisms. Yuyin Yanggan group exerted effects on lipid metabolism， carbohydrate metabolism， protein metabolism and hormone metabolism. Qingre Jiedu group was also involved into metabolism of nucleotide and hormone. ④In the aspect of alleviating the pathological changes of cancer， the regulatory effects of the five efficacy groups on cell cycle and other functions could be summarized as dispelling pathogenic factors. ⑤The whole prescription focused on the anti-liver cancer potential of FBRP as a whole， while each efficacy group emphasized that each efficacy group had its own functional characteristics. The two network analysis models complemented and verified each other. Conclusion:FBRP has the anti-hepatoma potential. By revealing the biological connotation of its efficacy and the rationality of the compatibility， the regulation mechanism of FBRP to correct the imbalance network of inflammation and cancer in liver is clarified， which can provide the possibility and biological basis for FBRP to increase the clinical indications for the prevention and treatment of liver cancer.

Discussion on Prescription Discovery and Molecular Mechanism of Portulacae Herba in Treating Diabetes Mellitus Based on Data Mining and Integrative Pharmacology / 中国实验方剂学杂志

Objective:A new prescription containing Portulacae Herba was created and the molecular mechanism of the new prescription for treating diabetes was clarified based on big data of traditional Chinese medicine （TCM）. Method:Taking Portulacae Herba as the key word， the TCM Inheritance Support System and Encyclopedia of TCM （ETCM） were used to excavate the most frequently used medicines combined with Portulacae Herba， and form a new prescription. Based on the basic theory of TCM， this paper analyzed the rationality of the new prescription in treating diabetes， and used the Integrative Pharmacology-based Research Platform of TCM （TCMIP） to predict the target of the new prescription， and constructed the interaction network between drugs and targets of diabetes-related diseases， the key targets of drug intervention were enriched and analyzed， and the network graph of TCM-chemical composition-key target-pathway was drawn. Result:There were 89 prescriptions containing Portulacae Herba in ETCM. The most frequently used medicines in combination with Portulacae Herba were Phellodendri Chinensis Cortex， Rehmanniae Radix and Saposhnikoviae Radix， the four medicines were combined into a new prescription. According to the new prescription to treat diabetes， 89 key core target information was obtained， among which there were 10 targets of drug and disease， including phosphoinositide-3 kinase regulatory subunit 1 （PIK3R1）， insulin （INS）， glucokinase （GCK）， etc. The new prescription treated diabetes by regulating growth hormone receptor signaling， protein kinase A （PKA） activation， adrenoceptors and other pathways. Conclusion:The therapeutic effect of new prescription containing Portulacae Herba created by big data analysis of TCM on diabetes reflects multi-component， multi-target， multi-pathway characteristics of TCM， which can provide scientific basis for explaining the mechanism and material basis of this new prescription in the treatment of diabetes.

Clinical symptoms effect of Tripterygium Glycosides Tablets alone or combined with methotrexate in treatment of rheumatoid arthritis: a Meta-analysis / 中国中药杂志

To systematically review the improvement effects of Tripterygium Glycosides Tables( TGT) alone or in combination with methotrexate( MTX) on the clinical signs and symptoms of rheumatoid arthritis( RA),and provide a basis for the rational use of TGT in clinic,in the current study,six literature databases including CNKI,Wan Fang,VIP,PubMed,EMbase,and Cochrane Library,were systematically searched,according to the inclusion and exclusion criteria. Review Manager 5.3 software was used to input the literatures,and we assessed the risk bias on the level of outcome indicators for each included literature. A total of 18 literatures were included,and the classification results showed that: compared with MTX,TGT alone can reduce the number of joint swelling( MD =0. 18,95%CI[-1.06,1.42],P = 0.78) and joint tenderness( MD =-0.06,95% CI[-1.69,1.56],P = 0.94) in RA patients with the same effect as MTX. In terms of drug combination,TGT combined with MTX had an advantage over MTX alone in lessening the morning stiffness time( MD = 18. 24,95% CI[12. 64,23. 84],P < 0. 000 01) of RA,joint tenderness( MD = 2. 65,95% CI[1. 85,3. 44],P<0.000 01) and joint swelling( MD = 3.01,95% CI[2.09,3.39],P< 0.000 01). In conclusion,this Meta-analysis suggest that TGT alone was superior to MTX in improving joint swelling and tenderness in RA patients,TGT combined with MTX may improve the clinical manifestation of RA patients better than MTX alone.

Meta-analysis of laboratory index of Tripterygium Glycosides Tablets in treatment of rheumatoid arthritis / 中国中药杂志

The aim of this study was to systematically evaluate the clinical efficacy of Tripterysium Glycosides Tablets( TGT) alone or in combination with methotrexate( MTX) in the treatment of rheumatoid arthritis( RA) based on the laboratory index criteria and to provide a basis for the clinical application of TGT against RA. Six databases including CNKI,Wan Fang,VIP,PubMed,EMbase and Cochrane were retrieved for randomized controlled trials( RCT) about TGT alone or combination with MTX in the treatment of RA.Then risk assessment tools were used for quality evaluation of the studies,and data extraction and analysis were conducted by using Rev Man 5.3 software for Meta-analysis. A total of 1 709 articles were retrieved,and finally 25 studies were included,with a total sample size of 2 507 cases. Meta-analysis results showed that between TGT alone and TGT alone,MDESR=-2. 66,95%CI[-8.17,2.86],P = 0.35; MDCRP=-2.38,95%CI[-9.01,4.24],P = 0.48; between TGT combined with MTX and MTX alone,MDESR= 8.74,95%CI[6.72,10.76],P<0.000 01; MDCRP= 5.37,95%CI[3.71,7.03],P<0.000 01; SMDRF= 1.05,95%CI[0.51,1.60],P = 0.000 1.The effect of TGT on decreasing CRP and ESR in RA patients was similar to the MTX. In addition,TGT combined with MTX were more effective in decreasing CRP,ESR,RF than MTX alone. However,due to the potential bias in the included studies,more and high-quality randomized controlled trials would be needed to improve the level of evidence.

An exploration into the therapeutic effects and molecular mechanisms of paeoniflorin in the treatment of adjuvant-induced arthritis rats by a network pharmacology-based research strategy / 药学学报

Paeoniflorin (PAE), the major active compounds of Chinese herbs Radix Paeoniae Alba andChinese patent drug "Total Glucosides of Paeony Capsules", which is effective in the treatment of rheumatoid arthritis (RA), exerted multi-pharmacological activities, such as anti-inflammatory, immune-regulatory, etc. However, its potential action mechanisms remain unclear. Herein, we predicted the putative targets of Radix Paeoniae Alba and constructed an interaction network of putative targets of Radix Paeoniae Alba and known RA-related genes. A list of key putative targets was identified by calculating their topological features (degree, node betweenness and closeness) in the above pharmacological network. Importantly, pathway enrichment analysis revealed that these key putative targets were significantly enriched in several RA-related pathways, including cartilage damage-related IL1B-TNF-TLR2-JUN-MMP1-MMP3 signaling pathway. Further molecular docking simulation showed that PAE, the major active compounds of Radix Paeoniae Alba, has strong binding affinity with MMP1 and MMP3 proteins. Next, in vivo experiments based on the adjuvant-induced arthritis (AIA) animal models showed that PAE significantly alleviated the disease severity and the syndromes of severe redness or swelling in hind limbs of AIA rats, including decreasing the arthritis score, the diameter of the limbs, and elevating body weight and pain thresholds (all P<0.05). ELISA assay indicated that PAE obviously suppressed the abnormal up-regulation of serum inflammatory factors including IL-1β, TNF-α, IL-6, IL-17 and IFN-γ in AIA rats (all P<0.001). Western blot analysis found that PAE simultaneously modulated the abnormal up-regulation of MMP1 and MMP3 proteins in the ankle tissues of AIA rats (all P<0.001) (all procedures in the current study were performed in accordance with the ethical standards of the Center for Laboratory Animal Care, China Academy of Chinese Medical Sciences). In conclusion, PAE alleviated the cartilage damage and disease severity in the progressive process of RA via regulating the IL1B-TNF-TLR2-JUN-MMP1-MMP3 pathway. This study provided the theoretical basis of the PAE for its immune-regulatory effects, and as well provided references for the action mechanism study of extract compounds of Chinese herbs.

Investigation on the inflammation network mechanisms of Wutou decoction acting on neuropathic pain / 药学学报

Wu-tou decoction (WTD) was originally recorded in the synopsis of the golden chamber and it had been widely used for the treatment of neuropathic pain (NP) with exact therapeutic efficacy. However, the underlying molecular mechanisms still remain unclarified. Thus, in this research, we aimed at clarifying the underlying molecular mechanisms of WTD against NP by combining network analysis and experimental validation based on the spinal nerve ligation (SNL) model. Firstly, the network analysis indicated that key targets of WTD were significantly involved in the MAPK signaling pathway (P = 4.04E-12) and four important components of the above pathway, AKT kinase (AKT), MAP kinase kinase 4 (MKK4), c-Jun N-terminal kinase (JNK) and transcription factor AP-1 (JUN) had been reported to play a vital role in neuroinflammation during the disease process of NP. Then, experimental validation results proved that WTD markedly reduce the severity of mechanical allodynia (P<0.01) and cold hypersensitivity (P<0.05) of SNL rats. In addition, Western blot results provided evidence that the phosphorylated protein expression levels of AKT, MKK4, JNK and JUN in the superficial lamina of spinal cord of SNL rats were markedly increased (P<0.001), and WTD could improve the phosphorylated protein expression level of AKT (P<0.001) which was reported to be nerve protective and attenuate the phosphorylated protein expression levels of MKK4, JNK and JUN (P<0.01) which were closely involved into neuroinflammation. In conclusion, this study indicated that WTD might exert anti-hyperalgesia action through the inhibition of neuroinflammation mediated by AKT-MKK4-JNK-JUN which belong to the MAPK signaling pathway. These findings also provided scientific evidences that WTD might be a promising candidate for NP. Animal experiments in this study were approved by the Ethics Committee of Experimental Animals of the China Academy of Chinese Medical Sciences.

Identification of biomarkers to response of Tripterygium Glycosides Tablets acting on rheumatoid arthritis by integrating transcriptional data mining and biomolecular network analysis / 中国中药杂志

Growing clinical evidence shows that a partial rheumatoid arthritis( RA) patient treated with Tripterygium Glycosides Tablets( TGT) may fail to achieve clinical improvement. It is of great clinical significance to predict the therapeutic effect of TGT in RA. Therefore,the aim of the current study was to identify potential biomarkers for TGT treatment in RA. Affymetrix EG1.0 arrays were applied to detect gene expression in peripheral blood mononuclear cells obtained from 6 RA patients( 3 responders and 3 non-responders) treated with TGT. By integrating differential expression data analysis and biomolecular network analysis,360 mRNAs( 185 up-regulated and 175 down-regulated) and 24 miRNAs( 7 up-regulated and 17 down-regulated) which were differentially expressed between TGT responder and non-responder groups were identified. A total of 206 candidate target genes for the differentially expressed miRNAs were obtained based on miRanada and Target Scan databases,and then the miRNA target gene coexpression network and miRNA-mediated gene signal transduction network were constructed. Following the network analyses,three candidate miRNAs biomarkers( hsa-miR-4720-5 p,hsa-miR-374 b-5 p,hsa-miR-185-3 p) were identified as candidate biomarkers predicting individual response to TGT. Partialleast-squares( PLS) was applied to construct a model for predicting response to TGT based on the expression levels of the candidate gene biomarkers in RA patients. The five-fold cross-validation showed that the prediction accuracy( ACC) of this PLS-based model efficacy was 100.00%,100.00%,100.00%,66.67% and 66.67% respectively,and all the area under the receiver operating characteristic curve( AUC) were 1.00,indicating the highly predictive efficiency of this PLS-based model. In conclusion,the integrating transcription data mining and biomolecular network investigation show that hsa-mir-4720-5 p,hsa-mir-374 b-5 p and hsa-mir-185-3 p may be candidate biomarkers predicting individual response to TGT. In addition,the PLS model based on the expression levels of these candidate biomarkers may be helpful for the clinical screen of RA patients,which potentially benefit individualized therapy of RA in a daily clinical setting.

A comparative study on the mechanisms of two classical herbal formulae for rheumatoid arthritis applying cold and heat patterns based on target network / 药学学报

Wu-tou decoction (WTD) and Baihu-Guizhi decoction (BHGZD) as described in the Synopsis of the Golden Chamber have been used extensively for the treatment of rheumatoid arthritis (RA) with apparent therapeutic efficacy. However, characteristics of pharmacological effects and their underlying molecular mechanisms have not been fully elucidated due to a lack of appropriate scientific methodology. In the current study, we performed an integrative approach applying gene expression profiling and network analysis to examine the therapeutic effects and molecular mechanisms of WTD and BHGZD based on adjuvant-induced arthritis (AIA) animal model. Results demonstrated that both WTD and BHGZD could relieve the severity of arthritis in AIA rats, while the significant differences were observed in the changes of the withdrawal response scores and latency time of AIA rats treated with WTD and BHGZD. Mechanistically, our network pharmacology-based investigation demonstrated that the major candidate targets of WTD and BHGZD were significantly associated with several inflammation-immune regulatory pathways, such as Toll-like receptor signaling pathway, T cell receptor signaling pathway, cytokine-cytokine receptor interaction, chemokine signaling pathway, B cell receptor signaling pathway, antigen processing and presentation, Fc epsilon RI signaling pathway, natural killer cell mediated cytotoxicity, as well as leukocyte transendothelial migration. In particular, the major candidate targets of WTD were also involved in the regulation of hormone and energy metabolism, which might be imbalanced during RA progression. In conclusion, the current study revealed differences and similarities regarding the effects and network regulatory mechanisms of WTD and BHGZD. These findings may present a scientific basis for elucidation of mechanisms by which WTD and BHGZD alleviates RA.

Exploiture and application of an internet-based Computation Platform for Integrative Pharmacology of Traditional Chinese Medicine / 中国中药杂志

Recently, integrative pharmacology(IP) has become a pivotal paradigm for the modernization of traditional Chinese medicines(TCM) and combinatorial drugs discovery, which is an interdisciplinary science for establishing the in vitro and in vivo correlation between absorption, distribution, metabolism, and excretion/pharmacokinetic(ADME/PK) profiles of TCM and the molecular networks of disease by the integration of the knowledge of multi-disciplinary and multi-stages. In the present study, an internet-based Computation Platform for IP of TCM(TCM-IP, www.tcmip.cn) is established to promote the development of the emerging discipline. Among them, a big data of TCM is an important resource for TCM-IP including Chinese Medicine Formula Database, Chinese Medical Herbs Database, Chemical Database of Chinese Medicine, Target Database for Disease and Symptoms, et al. Meanwhile, some data mining and bioinformatics approaches are critical technology for TCM-IP including the identification of the TCM constituents, ADME prediction, target prediction for the TCM constituents, network construction and analysis, et al. Furthermore, network beautification and individuation design are employed to meet the consumer's requirement. We firmly believe that TCM-IP is a very useful tool for the identification of active constituents of TCM and their involving potential molecular mechanism for therapeutics, which would wildly applied in quality evaluation, clinical repositioning, scientific discovery based on original thinking, prescription compatibility and new drug of TCM, et al.

Network Pharmacology-based Approaches Capture Essence of Chinese Herbal Medicines / 中草药·英文版

Traditional Chinese Medicine (TCM), a crucial component of the current medical system, has been extensively used in clinical practice due to its valuable therapeutic efficacy, and its potentials as an important source of new pharmacophores. TCM is characterized by holistic theory, which emphasizes maintaining the balance of the patient's whole body using herbal formulae (fangji in Chinese) composed of mixtures of herbs with multiple bioactive ingredients. Because of the complex nature of these formulae, it is necessary to develop systematic methods to identify their bioactive ingredients and to clarify their mechanisms of action. With the rapid progress in bioinformatics, systems biology, and polypharmacology, "network pharmacology", which shifts the "one target, one drug" paradigm to the "network target, multi-component" strategy, has attracted the attention because it can not only reveal the underlying complex interactions between a herbal formula and cellular proteins but detect the influence of their interactions on the function and behavior of the system. Growing evidence shows that the network pharmacology strategy can be a powerful approach to modern research on TCM. The present paper focuses on the basis of network pharmacology and the recent progress in its methodology, illustrates its utility in screening bioactive ingredients and elucidating the mechanisms of action of TCM herbal formulae, analyzes its limitations and problems, and discusses its development direction and application prospects.

Valuation on analgesic, expectorant and antitussive effects of compatible use of Aconiti radix cocta and Fritillaria cirrhosa or Fritillaria thunbergii / 中国中药杂志

<p><b>OBJECTIVE</b>To study the analgesic, expectorant and antitussive effects of the compatible use of Aconiti Radix Cocta and Fritillaria cirrhosa or F. thunbergii with different matching ratio or dose in mice.</p><p><b>METHOD</b>The two-factor, seven-level uniform design method was adopted to observe the analgesic, expectorant and antitussive effects of the oral administration with the two combined decoctions in rats, with frequency of body torsions induced by acetum, secretion of phenol red in tracheas and frequency of coughs as indexes. Significant matching proportions and doses were collected for verification.</p><p><b>RESULT</b>The effect on the frequency of body torsions: The combined decoctions could effectively reduce the frequency of body torsions. According to a regression analysis, Aconiti Radix Cocta and F. cirrhosa had the synergistic effect, which was maximized with a ratio of 1: 1. The 1: 1 combined decoction played the least role in reducing the frequency of body torsions with a total dose of more than 5 g x kg(-1). The effect on the secretion of phenol red in tracheas. The combined decoctions could effectively increase the secretion of phenol red in tracheas. According to a regression analysis, Aconiti Radix Cocta and F. thunbergii had the antagonism, which was maximized at the ratio of 1: 1, and minimized with a total dose of less than 10 g x kg(-1) and a ratio of 5: 1 between F. thunbergii and Aconiti Radix Cocta. The effect on the frequency of coughs. The combined decoctions could effectively reduce the frequency of coughs. According to a regression analysis, Aconiti Radix Cocta and F. cirrhosa had the antagonism, which was maximized at the ratio of more than 1: 5 and less than 10: 1. There was no interaction between Aconiti Radix Cocta and F. thunbergii. F. thunbergii could reduce the frequency of coughs, whereas Aconiti Radix Cocta showed no effect.</p><p><b>CONCLUSION</b>The compatible application of Aconiti Radix Cocta and F. cirrhosa could enhance the analgesic effect of Aconiti Radix Cocta and reduce the expectorant and antitussive effects of F. cirrhosa, which vary according to different matching ratio and dose. The compatible application of Aconiti Radix Cocta and F. thunbergii shows no effect on the antitussive effect of F. thunbergii. This study provides experimental basis for in-depth studies on the combined effect of Aconiti Radix Cocta and Fritillaria--two of eighteen incompatible pairs.</p>

Study on efficacy of compatibility between aconiti radix cocta and Pinelliae Rhizoma on basis of uniform design method / 中国中药杂志

<p><b>OBJECTIVE</b>To study the effect of Aconiti Radix Cocta and Pinelliae Rhizoma with different matching proportions and doses on their analgic, anti-inflammatory, phlegm eliminating and cough relieving efficacies in mice.</p><p><b>METHOD</b>The two-factor, seven-level uniform design method was adopted to observe the effect of the oral administration with the combined decoction on the analgic, anti-inflammatory, phlegm eliminating and cough relieving efficacies, with frequency of body torsions induced by acetum, ear swelling degree induced by dimethylbenzene, secretion of phenol red in tracheas and frequency of coughs induced by aqueous ammonia as indexes. Significant matching proportions and doses were collected for verification.</p><p><b>RESULT</b>(1) The effect on the frequency of body torsions and ear swelling degree. The combined decoction could effectively reduce the frequency of body torsions and ear swelling degree. According to a regression analysis, Aconiti Radix Cocta and Pinelliae Rhizoma had the antagonism, which was maximized at the ratio of 10: 1, and minimized at the ratio of less than or equal to 1: 1. The frequency of body torsions and ear swelling degree increased first and then decreased along with the rise in the total dose; and a higher proportion of Aconiti Radix Cocta resulted in a faster speed in decrease or increase. (2) The effect on the secretion of phenol red in tracheas and frequency of coughs. The combined decoction could effectively increase the secretion of phenol red in tracheas and decrease the frequency of coughs. According to a regression analysis, Pinelliae Rhizoma and Aconiti Radix Cocta had the synergistic effect in the secretion of phenol red in tracheas, which was maximized with a total dose of more than 5 g x kg(-1) and a ratio of 1: 1.</p><p><b>CONCLUSION</b>The compatible application of Pinelliae Rhizoma and Aconiti Radix Cocta can decrease the analgesic and anti-inflammatory effects of Aconiti Radix Cocta and promote the cough-relieving effect of Pinelliae Rhizoma, which vary according to different matching ratio and dose. This study provides experimental basis for indepth studies on the combined effect of Aconiti Radix Cocta and Pinelliae Rhizoma--two of eighteen incompatible pairs.</p>