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Existing traditional Chinese medicine (TCM)-related databases are still insufficient in data standardization, integrity and precision, and need to be updated urgently. Herein, an Encyclopedia of Traditional Chinese Medicine version 2.0 (ETCM v2.0, http://www.tcmip.cn/ETCM2/front/#/) was constructed as the latest curated database hosting 48,442 TCM formulas recorded by ancient Chinese medical books, 9872 Chinese patent drugs, 2079 Chinese medicinal materials and 38,298 ingredients. To facilitate the mechanistic research and new drug discovery, we improved the target identification method based on a two-dimensional ligand similarity search module, which provides the confirmed and/or potential targets of each ingredient, as well as their binding activities. Importantly, five TCM formulas/Chinese patent drugs/herbs/ingredients with the highest Jaccard similarity scores to the submitted drugs are offered in ETCM v2.0, which may be of significance to identify prescriptions/herbs/ingredients with similar clinical efficacy, to summarize the rules of prescription use, and to find alternative drugs for endangered Chinese medicinal materials. Moreover, ETCM v2.0 provides an enhanced JavaScript-based network visualization tool for creating, modifying and exploring multi-scale biological networks. ETCM v2.0 may be a major data warehouse for the quality marker identification of TCMs, the TCM-derived drug discovery and repurposing, and the pharmacological mechanism investigation of TCMs against various human diseases.
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ObjectiveTo explore the "efficacy-toxicity" association mechanisms of Tripterygium wilfordii polyglycoside tablets （TWPT） by establishing and analyzing an interaction network associated with the clinical efficacy of TWPT in the treatment of rheumatoid arthritis （RA） and TWPT-induced liver injury. MethodOn the basis of the TWPT efficacy-related gene expression profile and TWPT-induced liver injury-related protein expression profile which were both obtained from our clinical cohorts， the "efficacy-toxicity" association network of TWPT was constructed， and the key network targets were identified by calculating the topological values of the nodes， including the degree， closeness and betweenness. After that， the biological functions and pathways of the key network targets were investigated by enrichment analysis. ResultA total of 119 differentially expressed genes （58 up-regulated and 61 down-regulated） between RA patients with TWPT well and weak response were identified as TWPT efficacy-related genes by clinical transcriptomics， and 49 differentially expressed proteins （36 up-regulated and 13 down-regulated） were demonstrated to be TWPT-induced liver injury-related proteins by clinical proteomics. In addition， the clinical symptom enrichment analysis indicated that the TWPT efficacy-related genes were significantly associated with various clinical symptoms of arthralgia in traditional Chinese medicine and clinical phenotypes of modern medicine， and most of the TWPT-induced liver injury-related proteins were involved in digestive system abnormalities. Therefore， the aforementioned multi-omics data represented the main clinical symptoms of TWPT treating RA and inducing liver injury. Mechanically， the "efficacy-toxicity" association network revealed that both TWPT efficacy-related genes and TWPT-induced liver injury-related core proteins were involved in the "immune-inflammatory" imbalance， especially playing an important role in neutrophil degranulation， complement cascade reaction， and immune-inflammatory response mediated by protein post-translational modification. Notably， the above genes and proteins were also enriched in various signaling pathways related to cell proliferation and cell cycle regulation， such as RAS and mitogen-activated protein kinase （MAPK） signaling pathway， and in several liver functional processes， such as glycogen metabolism and redox reaction. ConclusionThis study systematically explained the "efficacy-toxicity" association characteristics and molecular mechanisms of TWPT by applying a research strategy integrating clinical phenomics， transcriptomics and proteomics， laying a good data foundation for exploring the "efficacy enhancing and toxicity-reducing" mechanisms of TWPT.
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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.
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Objective To evaluate the changes in the expression of isolectin B4 (IB4) and calcium gene-related peptide (CGRP) in neurons in dorsal root ganglion (DRG) of rats with neuropathic pain (NP).Methods Forty healthy male Sprague-Dawley rats,weighing 250-280 g,were divided into 2 groups (n =20 each) using a random number table method:solvent group (group S) and group NP.NP was induced by intraperitoneally injecting resiniferatoxin 210 μg/kg,and the solvent of resiniferatoxin was intraperitoneally injected in group S.The mechanical paw withdrawal threshold (MWT) and thermal paw withdrawal latency (TWL) were measured in 5 rats selected before establishing the model and at 1,3,7 and 42 days after establishing the model.Five rats were sacrificed at 1,3,7 and 42 days after establishing the model,and the L4-6 segments of the DRGs were removed to determine the expression of CGRP and IB4 in neurons using immunofluorescence.Results Compared with the baseline before establishing the model,the MWT was signilicantly decreased at 3,7 and 42 days after establishing the model,and the TWL was prolonged at 1,3,7 and 42 days after establishing the model in group NP (P＜0.05).Compared with group S,the MWT was significantly decreased at 3,7 and 42 days after establishing the model,the TWL was prolonged at 1,3,7 and 42 days after establishing the model,and the expression of IB4 and CGRP in neurons in DRGs was down-regulated at 1,3,7 and 42 days after establishing the model in group NP (P＜0.05).Conclusion Down-regulated expression of IB4 expression in neurons in DRGs may be involved in the development and maintenance of mechanical hypersensitivity to pain,and down-regulated expression of CGRP may be involved in the development and maintenance of thermal analgesia in rats with NP.
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Objective To investigate plasma level of soluble intercellular adhesion molecule-1 (sICAM-1)and soluble E-slectin (sES) in patients with Keshan disease (KD) accompanied by hypertension,and to further their relation to systolic blood pressure (SBP),diastolic blood pressure (DBP) and ejection fraction (EF) of left ventricle.Methods Patients with Keshan disease investigated in 2007 in Fuyu County,Heilongjiang Province were divided into two groups according to whether they were accompanied by hypertension or not:KDP group (n =17),the patients were diagnosed as Keshan disease accompanied by hypertension;KDN group (n =14),the patients were only diagnosed as Keshan disease.Healthy volunteers lived in the same area as the patients were included in the control group (CON group,n =10).The clinical data (such as age,sex and past medical history),SBP and DBP were recorded.EF was detected by echocardiography.Plasma sICAM-1 and sES concentrations were measured by ABC-enzyme-linked immunosorbent assay technique.Results Plasma level of sICAM-1 in the subjects was significantly elevated in KDP group as compared with that in CON group and KDN group [(399.84 ± 99.06) vs (323.06 ± 61.27) μg/L,P ＜0.05;(399.84 ± 99.06) vs (268.27 ± 72.88) μg/L,P ＜ 0.01].However,there was no statistical significance in plasma sICAM-1 between the KDN group and control group (P ＞ 0.05).The difference of plasma sES between the control group,KDN group and KDP group did not reach statistical significance [(76.31 ± 23.17),(72.26 ± 20.15) and (90.21 ± 19.21) μg/L,F =3.236,P ＞ 0.05].As compared with the KDN group,SBP and DBP were obviously higher in KDP group [(169 ± 27) and (121 ± 10) mmHg,(102 ± 17) and (81 ± 6) mmHg,1 mmHg =0.133 kPa,F =6.376,4.300,all P ＜ 0.01],and EF was not significantly increased [(58 ± 14)％ and (55 ± 14)％,F =0.789,P ＞ 0.05].Furthermore,correlation analysis showed plasma sICAM-1 was positively correlated with SBP (r =0.540 6,P ＜ 0.01)and DBP (r =0.461 2,P ＜ 0.01),but not with EF of left ventricle in subjects whir Keshan disease (r =0.073 4,P ＞0.05).Conclusion These data shows slCAM-1 may play a role in the development of Keshan disease accompanied by hypertension,providing an potential index for its risk assessment.
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As one of the most sensitive cells of endoplasmic reticulum stress,pancreatic βcells have an abundance of endoplasmic reticulum .It is the adaptive response of pancreatic β cells under Endoplasmic reticulum stress conditions.Internal and external factors in the environment such as oxidative damage,lipid toxicity and the effect of cytokines in the endoplasmic reticulum could breake the steady-state,resulting in barriers to folding or misfolding of protein,thereby to trigger endoplasmic reticulum stress.Serious and lasting stress will lead to β cell apoptosis,involved in a variety of metabohc diseases as well as a variety of diseases.This article gives a review on the injury effects of multi-factor induced endoplasmic reticulum stress on the pancreatic β-cell