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.

Clinical Analysis of "Different Diseases Saring Same Syndrome" Concept in End Stage of Different Hip Diseases / 中国实验方剂学杂志

The traditional Chinese medicine (TCM) concept that "different diseases may share the same TCM syndrome" is a unique theory explaining the relationship between diseases and TCM syndromes, which originally means that different diseases sharing the same TCM pathogenesis may develop the same syndrome. It accords with the theory of treatment based on syndrome differentiation. In clinical practices, this concept explains why the same herbal formula can be used to treat different diseases. With the development of a novel strategy to integrate the disease diagnosis and TCM syndrome differentiation, the meaning of "different diseases may share the same TCM syndrome" has also changed. It means that different diseases share the same TCM pathogenesis during their progression may show the same syndrome. Osteonecrosis of the femoral head （ONFH）, hip osteoarthritis (HOA), and hip rheumatoid arthritis (HRA) are three different diseases that occur in the bones, cartilage, and synovium of the hip joint, respectively. However, they share similar clinical symptoms and TCM symptoms if they had progressed to the end-stage. In the end-stage of the disease, hip pain, restricted activity, signs of waist and knee pain, and weakened walking function, whether it is symptoms or signs or TCM syndromes, all show their similarities, reflecting the concept of different diseases may share the same TCM syndrome. This article discusses the similarity of the three diseases from the aspects of syndrome characteristics, radiographic findings, syndrome differentiation, etiology and pathogenesis, as well as clinical treatments. We found that, in addition to similar clinical signs and symptoms, the three hip osteoarthropathies in the end-stage see articular cartilage degeneration, joint space stenosis, joint effusion, synovial thickening, bone hyperplasia, and subchondral bone cystic degeneration, etc. similar X-ray performance， kidney sperm, bone marrow, only kidney sufficiency, muscles and bones can be filled with bone marrow, liver blood, main muscles, liver and blood are sufficient to support the muscles and bones, and the disease is in the advanced stage， ONFH， HOA and HRA are closely related to liver and kidney dysfunction. Insufficient liver and kidney, meridian muscle, and bone malnutrition are three common pathological mechanisms of late hip bone disease. Deficiency, waist and knee weakness, and weakness in walking have also become common symptoms. It not only provides a theoretical basis for the "same syndrome",but also helps the differential diagnosis of "different diseases", improves the fracture level of hip diseases, and enriches the connotation of "different diseases sharing the same syndrome" in Chinese medicine.

Meta-analysis of RCT studies on clinical efficacy of single administration of Tripterygium Glycosides Tablets or combined administration with methotrexate against rheumatoid arthritis / 中国中药杂志

To evaluate the clinical efficacy of single administration of Tripterygium Glycosides Tablets(TGT) or combined administration with methotrexate(MTX) against rheumatoid arthritis(RA) based on American College of Rheumatology(ACR) efficacy standard. Six databases, namely CNKI, WanFang, VIP, PubMed, Embase and Cochrane Library, were retrieved for randomized controlled trials(RCT), and clinical trials were screened out according to the preset inclusion and exclusion criteria. Then, the study quality was evaluated by the risk assessment tools. Data extraction and analysis were performed by using RevMan 5.3 software for Meta-analysis. Sensitivity analysis and publication bias analysis were made to test the stability and reliability of results. Until December 2018, a total of 1 709 articles were obtained, and finally 10 clinical RCT studies with a total of 1 184 patients were included. As a result, the single administration of TGT showed a significantly better ACR efficiency(RR=1.31, 95%CI[1.15, 1.49], P<0.000 1) than methotrexate(MTX). The combined administration of TGT and MTX showed a significantly better ACR efficiency(RR=1.28, 95%CI[1.20, 1.38], P<0.000 01) than the single administration of MTX. In conclusion, the single administration of TGT and the combined administration of TGT and MTX were more effective in achieving ACR20, ACR50, ACR70 compliance than the single administration of MTX. Further validations based on more RCT studies with high-quality are required.

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

To systematically evaluate the adverse drug reaction(ADR) of Tripterygium Glycosides Tablets(TGT) in the treatment of rheumatoid arthritis(RA). Four Chinese databases(CNKI, VIP, WanFang, SinoMed) and three English databases(Cochrane Library, EMbase, PubMed), from the time of database establishing to August 2019, were systematically retrieved to collect literature on the treatment of all types of RA with TG. Screening literature and extracting data according to inclusion and exclusion criteria. All studies were assessed by using internationally recognized methodological quality assessment tools or reporting quality evaluation criteria, with data being extracted and Meta-analyzed. There were 79 studies included, randomized controlled trials(RCT) containing TGT in the treatment group, non-randomized controlled trials(non-RCT), case series, case reports, and RCT containing TGT only in the control group were covered. There were in the control group; 765 ADR of 2 214 patients in 30 RCT(treatment group given TGT), 11 non-RCT and 7 case reports. The results of Meta-analysis of these 48 literatures showed that the overall incidence of ADRs was 0.23(95%CI[0.22,0.24]); ADR mainly occured in the reproductive, gastrointestinal, skin and accessories, blood, hepatobiliary system damage and the incidence of ADR in systems mentioned about respectively were 0.14(95%CI[0.12,0.17]),0.07(95%CI[0.06,0.08]),0.06(95%CI[0.04,0.07]),0.04(95%CI[0.03,0.05]),0.04(95%CI[0.03,0.05]). Further subgroup analysis results showed that the incidence of total ADR, especially the gastrointestinal, reproductive and cutaneous ADR of patients with treatment alone was higher than that in those paients with MTX or MTX+LEF therapy; The incidence of ADR, especially the gastrointestinal ADR, was also positively correlated with daily dose and course of treatment, while the incidence of different systems ADR was also correlated with different drug manufacturers, for instance, damage on the female reproductive system occurs most frequently in Hunan manufacture TGT administration, same as the damage on skin and accessories induced by TGT from Jiangsu manufacture. Above all, The clinical treatment of TGT for RA will cause multi-system ADR, with the highest incidence in the reproductive system, followed by the gastrointestinal system, which is closely related to the way of medication(monotherapy), daily dose, course of medication and drug manufacturer. Therefore, it is recommended that, in the treatment of RA, using TGT in combination, low dose or short-course medication, take measures to protect the reproductive system, stomach and liver, and paying attention to the drug manufacturer as well response of patients during administration should be valued to avoid ADRs to the maximum possibility.

Systematic reviews of effects of Tripterygium Glycosides Tablets on pro-inflammatory factors in rheumatoid arthritis / 中国中药杂志

To systematically evaluate the effects of Tripterygium Glycosides Tablets alone or in combination with methotrexate(MTX) and leflunomide(LEF) on the levels of pro-inflammatory cytokines in patients or animal models with rheumatoid arthritis(RA), and to provide reference for clinical application and related basic research, this study systematically searched databases of CNKI, VIP, WanFang, PubMed, Embase and Cochrane Library, collected relevant clinical or animal experimental studies, used risk assessment tools to evaluate the quality of research, and used Revman 5.3 software to conduct Meta-analysis or descriptive analysis of the outcome indicators included in the literatures. Of the 1 709 papers retrieved, 3 clinical studies and 12 animal experiments were included. The results showed that compared with MTX alone, Tripterygium Glycosides Tablets combined with MTX could further reduce the expression levels of peripheral blood TNF-α(SMD=-8.88,95%CI[-10.77,-6.99],P<0.000 01),IL-1β(P<0.000 01) and IL-6(SMD=-8.63, 95%CI[-10.57,-6.69], P<0.000 01) in RA patients. Compared with LEF alone, the combination of Tripterygium Glycosides Tablets and LEF could not further reduce the expression levels of TNF-α(P=0.20), IL-1β(P=0.17), IL-6(P=0.31). In RA animal model, compared with model group, Tripterygium Glycosides Tablets could reduce the expression levels of peripheral blood IL-1β(SMD=-6.29,95%CI[-9.64,-2.93],P<0.000 2)in peripheral blood(SMD=-1.39,95%CI[-1.77,-1.02],P<0.000 01), joint fluid(P<0.000 01) and paw plasma(P=0.02), and also reduce the expression levels of TNF-α in RA animal model group. Compared with MTX alone, Tripterygium Glycosides Tablets alone reduced the same levels of TNF-α(P=0.42) and IL-6(P=0.08) in joint fluid, while Tripterygium Glycosides Tablets combined with MTX could further reduce the levels of IL-6(P=0.000 1) in joint fluid; compared with LEF alone, Tripterygium Glycosides Tablets have the similar effects on reducing the expression levels of peripheral blood TNF-α(P=0.16), IL-1β(P=0.32), IL-6(P=0.12), while Tripterygium Glycosides Tablets combined with LEF could further reduce the expression levels of TNF-α(P=0.008), IL-1β(P=0.02), IL-6(P<0.000 1) in peripheral blood. Therefore, Tripterygium Glycosides Tablets combined with MTX could further reduce the expression levels of pro-inflammatory cytokines in peripheral blood of RA patients. Tripterygium Glycosides Tablets alone could reduce the expression levels of pro-inflammatory cytokines in peripheral blood and local joint of RA animal models. Tripterygium Glycosides Tablets combined with MTX or LEF could further reduce the express levels of pro-inflammatory cytokines in peripheral blood of RA animal models. Due to the limitation of literature, this conclusion needs to be further validated.

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.

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.

Study on the risk factors for the misdiagnosis of femoral head osteonecrosis / 中国骨伤

<p><b>OBJECTIVE</b>To evaluate the status and risk factors for the misdiagnosis of femoral head osteonecrosis, providing the basis for accurate diagnosis of osteonecrosis of femoral head.</p><p><b>METHODS</b>The data of 314 hospitalized patients were collected from March 2015 to March 2016, and the risk factors for osteonecrosis of femoral head were analyzed by Logistic regression model. Misdiagnosis was defined that the diagnosis given on the first time was different from that on the second time or that given by expert group with the same symptoms and signs. The general data, predisposing factors, time of onset, hospital visits, clinical manifestations, X-ray film of hip joint, MRI and other data were statistically analyzed.</p><p><b>RESULTS</b>Total 127 patients experienced misdiagnosis (up to 40.8%). Among them, the patients with osteonecrosis of femoral head misdiagnosed as other diseases accounted for 77.2% and the patients with other diseases misdiagnosed osteonecrosis of femoral head accounted for 22.8%. Statistical analysis showed that the predisposing factors, history of glucocorticoid and alcohol intake, diseased lower limb, pained lower limb, hidden disease attack, the level of first reception hospital and expert were significantly related with the misdiagnosis of femoral head osteonecrosis based on the logistic regression model (<0.05) . The relationship between misdiagnosis and gender, age, primary disease taking glucocorticoid, approach and time of glucocorticoid use, the type of alcohol, drinking time had no statistical significance(>0.05). The Logistic regression analysis showed that the hidden disease attack(OR=3.059) and level of first reception expert(OR=2.778) were the high risk factors associated with the misdiagnosis in which the femoral head necrosis was misdiagnosed as other diseases(<0.01), and glucocorticoid intake history was the low risk factors(OR=0.387)(<0.05). The Logistic regression analysis showed that the level of first reception expert (OR=3.573) was the high risk factor associated with the misdiagnosis in which the other diseases were misdiagnosed as necrosis of femoral head.</p><p><b>CONCLUSIONS</b>Misdiagnosis rate of femoral head necrosis is high. Hidden disease attack and low level of first reception expert are the high risk factors associated with the misdiagnosis in which the femoral head necrosis was misdiagnosed as other diseases, however, glucocorticoid intake history is the protective factor of misdiagnosis. Low level of first reception expert is the high risk factor associated with the misdiagnosis in which other diseases were misdiagnosed as necrosis of femoral head.</p>

Study on optimization of a fewest layer measuring method of osteonecrotic area in femoral head / 中国骨伤

<p><b>OBJECTIVE</b>To optimize a measuring method of osteonecrotic area by analyzing the average osteonecrotic areas and osteonecritic volume using multi layer MR images.</p><p><b>METHODS</b>The MRI images of 87 cases (120 hips) of ONFH(ARCO II) were collected retrospectively from January 2011 to January 2012 in Wangjing Hospital of China Academy of Chinese Medicine Science. PHILIPS Achieval 1.5T MR was used to obtain coronal TSE T1 weighted (T1W) images. The scanning parameters were shown as follows:slice thickness, 3.5 mm; gap, 0.3 mm; images repetition time(TR), 500 ms;echo time(TE), 20 ms;field of view (FOV), 374 mm;total 12 layers. According to the distribution rule of osteonecrotic lesion, the layer of coronal T1-weighted imaging showing most of femoral neck was marked as layer 0(L0). The layers before L0 were marked in sequence L1, L2, L3, L4... , and the layers after L0 were marked in sequence L-1, L-2, L-3, L-4... . Auto CAD 2007 was used to measure the percentage of osteonecrotic area and calcu late the average data, and then decreased the layer from low to high layer successively based on frequency of osteonecrotic occurrences. First, the layer with lowest frequency of osteonecrotic occurrenoses L3 was removed, then calculated the average osteonecrotic area of the ramaining 8 layers. L5, L4, L-2, L-1, L3 layers were gradually removed, resulting in the calculation of avereage osteonecrotic areas in 7, 6, 5, 4, 3 layers. These areas were compared to the osteonecrotic volume in MR imagings, leading to the optimization of the fewest layer measuring method of osteonecrotic area using a statistical analysis.</p><p><b>RESULTS</b>The percentage of osteonecrotic volume in 120 hips was 0.333±0.151. The average osteonecrotic areas of 9 to 3 layers were 0.321±0.117, 0.317±0.136, 0.312±0.147, 0.333±0.153, 0.348±0.172, 0.365±0.174, 0.377±0.202 respectively. There were no statistical differences of the average osteonecrotic areas and osteonecrotic volume in 9 to 3 layers(>0.05), but when the osteonecrotic layers were reduced to 3, there were statistical differences(<0.05). Total 120 hips were grouped according to osteonecrotic volume based on ARCO staging criteria, among them, 12 hips were grade A, 43 were B, 65 were C. According to average osteonecrotic areas of 4 layers, 10 hips were A grade, 32 were B, 78 were C. There were no statistical differences between two methods(>0.05). There was a high degree of concordance among two methods.</p><p><b>CONCLUSIONS</b>The results of 4(L0, L1, L2, L3) layers measuring method and osteonecrotic volume measuring method are similar. The 4 layers measuring method is an accurate, convenient, valuable method measuring the esteonecrotic area with the fewest layers, which is worth to be popularized in clinical application.</p>