Objective To explore the optimization strategy of Qishen Granules in treating coronary heart disease with heart failure(CHD-HF)based on data mining and the pathogenic"toxin"theory,and to predict its active components and mechanisms using network pharmacology.Methods Literature on traditional Chinese medicine(TCM)for treating CHD-HF was collected from relevant databases,and prescriptions were screened and established into a database according to inclusion and exclusion criteria.Frequency,association rules,and hierarchical clustering analyses were performed using the Ancient and Modern Medical Case Cloud Platform.Network pharmacology techniques were applied to screen potential targets of the optimized combination for treating CHD-HF,and carry out the targets and pathways enrichment analysis.Results A total of 336 articles and 339 prescriptions involving 191 herbs were included,with 12 herbs used more than 100 times.The core drug combinations for treating CHD-HF included Astragali Radix,Poria,Salviae Miltiorrhizae Radix et Rhizoma,Glycyrrhizae Radix et Rhizoma,Chuanxiong Rhizoma,etc,while commonly used detoxifying herbs included Leonuri Herb,Coptidis Rhizoma,etc.Association rule analysis yielded 10 two-item associations and 17 three-item associations;clustering analysis grouped the data into 5 categories.Based on data mining and the pathogenic"toxin"theory,the combination for treating CHD-HF was optimized to include Astragali Radix,Salviae Miltiorrhizae Radix et Rhizoma,Aconiti Lateralis Radix Praeparata,Glycyrrhizae Radix et Rhizoma,Coptidis Rhizoma,and Taraxaci Herba.Network pharmacology analysis identified 366 common targets between the optimized combination and CHD-HF,with 16 core targets screened out.Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis revealed significant enrichment in pathways such as cancer pathways,lipid and atherosclerosis,Rap1 signaling pathway,hypoxia-inducible factor 1(HIF-1)signaling pathway,phosphatidylinositol-3-kinase/protein kinase B(PI3K/Akt)signaling pathway,Ras signaling pathway,and mitogen-activated protein kinase(MAPK)signaling pathway.Conclusion TCM treatment for CHD-HF primarily focuses on replenishing qi and warming yang,activating blood circulation and resolving fluid retention.Based on data mining results and the pathogenic"toxin"theory,the formulation strategy of Qishen Granules for treating CHD-HF was optimized,potentially exerting therapeutic effects through anti-inflammatory,anti-apoptotic,and anti-hypoxia physiological processes.

Objective To investigate the therapeutic mechanism of Nuanxin Capsules(NXC)in ischemic heart failure(IHF)using network pharmacology and in vivo experimental validation.Methods Active components of NXC were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP)and SwissTargetPrediction database.Potential IHF-related targets were predicted via OMIM and GeneCards databases.Shared targets between NXC and IHF were identified to construct a"NXC-shared targets-IHF"network.Key bioactive components were screened,and protein-protein interaction(PPI)networks were built using STRING database.Core target modules were analyzed via CytoHubba plugin in Cytoscape 3.7.2.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses were performed using Metascape.For in vivo validation,an IHF mouse model was established by permanent ligation of the left anterior descending coronary artery.After 4-week intervention,cardiac function/structure was assessed by echocardiography,histopathology by hematoxylin-eosin(HE)staining,lymphatic vessel density by immunofluorescence,and protein expression of vascular endothelial growth factor C(VEGFC)and vascular endothelial growth factor receptor 3(VEGFR3)by Western Blot.Results Network pharmacology identified 242 shared targets between NXC and IHF,with core components including apigenin,pongapin,naringenin,4',5,7,8-tetramethoxyflavone,and tangeretin.Four core molecular clusters were identified(e.g.,VEGFC,FLT4/VEGFR3).GO analysis revealed enrichment in cellular response to nitrogen compounds,positive regulation of cell migration/phosphorus metabolism,and inflammatory response modulation.KEGG pathways included cancer,lipid/atherosclerosis,and endocrine resistance pathways.In vivo experiments demonstrated that NXC significantly improved cardiac function,attenuated pathological changes and inflammatory infiltration,promoted lymphangiogenesis,and upregulated VEGFC/VEGFR3 protein expression in IHF mice.Conclusion NXC may ameliorate IHF by promoting cardiac lymphangiogenesis via VEGFC/VEGFR3 signaling.

Objective:To explore the repairing effect and mechanism of tangeretin in rats with spinal cord injury.Methods:The rats were divided into sham-operation group, model group and tangeretin group according to random number table, with 8 rats in each group. Except for the sham-operation group, Allen hit method was used to make rat models in the other groups. After the model was successfully established, the tangeretin group was intragastrically administered with tangeretin 50 mg/kg, and the sham-operation group and the model group were intragastrically administered with an equal volume of normal saline once a day for 14 days. On days 0, 3, 7, and 14 after modeling, the motor function recovery of rats was assessed using the Basso-Beattie-Bresnahan (BBB) score; the morphological changes of the spinal cord tissues were observed using HE staining and Nissl staining; the SOD and GSH activities and MDA, IL-1β, TNF-α, and IL-10 levels in the spinal cord tissues of rats in each group were measured using ELISA kit detection; the GFAP and Neun expressions in the spinal cord tissues were detected by immunofluorescence; the IL-1β, TNF-α, IL-10, nuclear factor E2-related factor 2 (Nrf-2), and NAD (P) H-quinone oxidoreductase 1 (NQO-1) expressions in the spinal cord tissues were detected by Western blot.Results:Compared with the model group, the BBB score increased in the tangeretin group ( P<0.05), HE staining score decreased ( P<0.05), and the number of Nissl bodies increased ( P<0.05); the level of IL-10, SOD and GSH activities increased ( P<0.05), and IL-1β, TNF-α and MDA levels decreased in the spinal cord tissue ( P<0.05); GFAP fluorescence intensity decreased ( P<0.05) and NeuN fluorescence intensity increased ( P<0.05); the relative expression of IL-1β and TNF-α decreased ( P<0.05), and the relative expressions of IL-10, Nrf-2 and NQO-1 protein increased ( P<0.05). Conclusions:Tangeretin can exert anti-inflammatory and anti-oxidative stress effects through the Nrf2/NQO1 signaling pathway and alleviate early spinal cord injury in rats. On the other hand, it may promote the recovery of spinal cord injury by reducing glial scar generation and promoting neural cellogenesis.

OBJECTIVES: Malignant melanoma is a highly malignant and heterogeneous skin cancer. Although immunotherapy has improved survival rates, the inhibitory effect of tumor microenvironment has weakened its efficacy. To improve survival and treatment strategies, we need to develop immune-related prognostic models. Based on the analysis of the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Sequence Read Archive (SRA) database, this study aims to establish an immune-related prognosis prediction model, and to evaluate the tumor immune microenvironment by risk score to guide immunotherapy. METHODS: Skin cutaneous melanoma (SKCM) transcriptome sequencing data and corresponding clinical information were obtained from the TCGA database, differentially expressed genes were analyzed, and prognostic models were developed using univariate Cox regression, the LASSO method, and stepwise regression. Differentially expressed genes in prognostic models confirmed by real-time reverse transcription PCR (real-time RT-PCR) and Western blotting. Survival analysis was performed by using the Kaplan-Meier method, and the effect of the model was evaluated by time-dependent receiver operating characteristic curve as well as multivariate Cox regression, and the prognostic model was validated by 2 GEO melanoma datasets. Furthermore, correlations between risk score and immune cell infiltration, Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) score, immune checkpoint mRNA expression levels, tumor immune cycle, or tumor immune micro-environmental pathways were analyzed. Finally, we performed association analysis for risk score and the efficacy of immunotherapy. RESULTS: We identified 4 genes that were differentially expressed in TCGA-SKCM datasets, which were mainly associated with the tumor immune microenvironment. A prognostic model was also established based on 4 genes. Among 4 genes, the mRNA and protein levels of killer cell lectin like receptor D1 (KLRD1), leukemia inhibitory factor (LIF), and cellular retinoic acid binding protein 2 (CRABP2) genes in melanoma tissues differed significantly from those in normal skin (all P<0.01). The prognostic model was a good predictor of prognosis for patients with SKCM. The patients with high-risk scores had significantly shorter overall survival than those with low-risk scores, and consistent results were achieved in the training cohort and multiple validation cohorts (P<0.001). The risk score was strongly associated with immune cell infiltration, ESTIMATE score, immune checkpoint mRNA expression levels, tumor immune cycle, and tumor immune microenvironmental pathways (P<0.001). The correlation analysis showed that patients with the high-risk scores were in an inhibitory immune microenvironment based on the prognostic model (P<0.01). CONCLUSIONS The immune-related SKCM prognostic model constructed in this study can effectively predict the prognosis of SKCM patients. Considering its close correlation to the tumor immune microenvironment, the model has some reference value for clinical immunotherapy of SKCM.
Humans ; Melanoma/genetics* ; Skin Neoplasms/genetics* ; Tumor Microenvironment ; Prognosis

To investigate the relationship between serum C-reactive protein (CRP) levels and work impairment in patients with ankylosing spondylitis (AS) based on real-world evidence. Outpatients with confirmed AS at Chinese PLA General Hospital were recruited consecutively by Smart-phone SpondyloArthritis Management System (SpAMS) from April 2016 to April 2018. The relationship between CRP and work productivity and activity impairment questionnaire (WPAI) were evaluated. Five hundred and fifty-one outpatients with AS in paid employment were recruited. The presenteeism, overall work impairment, and activity impairment rates increased by 1.4% (1.1%, 1.8%), 1.1% (0.5%, 1.6%), and 1.7% (1.3%, 2.1%), respectively, for every 10 mg/L increase in the CRP level (all P value<0.01). However, the CRP level was not associated with absenteeism after adjusting for covariates [0.5%(-0.4%, 1.0%), P>0.05]. There is a significant association between increased serum CRP levels at baseline and the previous 7-day work impairment in patients with AS. Higher CRP levels contribute to worse presenteeism, overall work impairment, and activity impairment rates, which suggests the necessity of monitoring CRP on treatment, and also indicates that anti-inflammatory therapy may be effective for improving work productivity.

BACKGROUND: Concerns exist regarding the potential development of tuberculosis in patients with rheumatoid arthritis (RA) treated with biological and targeted drugs. We assessed systematically whether biological therapy increased the risk of tuberculosis in patients with RA by meta-analysis of randomized controlled trials (RCTs). METHODS: A systematic literature search was conducted in PubMed, Embase, the Cochrane Library, and China Biology Medicine disc for RCTs evaluating biological therapy in patients with RA from inception through August 2021. Traditional meta-analysis and network meta-analysis were performed to compare the risk of tuberculosis for each biologics class in patients with RA. Peto odds ratio (Peto OR) and its 95% confidence interval (CI) were calculated as the primary effect measure. RESULTS: In total, 39 studies with 20,354 patients were included in this meta-analysis, and 82 patients developed tuberculosis. The risk of tuberculosis was increased in patients treated with biologics compared with non-biologics (Peto OR: 3.86, 95% CI: 2.36-6.32, P < 0.001). Also, tumor necrosis factor-α (TNF-α) inhibitors had a higher probability of developing tuberculosis than placebo (Peto OR: 3.98, 95% CI: 2.30-6.88, P < 0.001). However, network meta-analysis demonstrated that there was no significant difference in the risk of tuberculosis for each biologics class in patients with RA. Noticeably, tuberculosis was significantly more common in patients treated with a high dose compared with patients receiving a low dose of tofacitinib (Peto OR: 7.39, 95% CI: 2.00-27.31, P = 0.003). CONCLUSION This meta-analysis demonstrates the evidence of an elevated risk of tuberculosis in patients with RA treated with TNF-α inhibitors, and a dose-dependent elevated risk of tuberculosis in patients treated with tofacitinib.
Antirheumatic Agents/adverse effects* ; Arthritis, Rheumatoid/drug therapy* ; Humans ; Network Meta-Analysis ; Pharmaceutical Preparations ; Randomized Controlled Trials as Topic ; Tuberculosis/drug therapy*

Ankylosing spondylitis (AS) is a chronic inflammatory disease mainly affecting the sacroiliac joints, spine and peripheral joints. In China, standardized diagnosis and treatment of AS is still to be popularized. Based on the evidence and guidelines from China and other countries, Chinese Rheumatology Association developed standardization of diagnosis and treatment of AS. The purposes are: (1) to standardize the diagnosis and evaluation of AS; (2) to promote rational use of non-steroidal anti-inflammatory drugs, biological as well as traditional disease modifying anti-rheumatic drugs, so as to improve the patient′s quality of life.

To investigate the predictive value of [ 18F]fluorodeoxyglucose-positron emission computed tomography(PET)/CT for disease progression in patients with dermatomyositis (DM) and interstitial lung diseases (ILD). Sixty-seven DM patients who underwent [ 18F] FDG-PET/CT imaging were retrospectively analyzed from January 2012 to September 2017 at PLA General Hospital. Their clinical manifestations and imaging characteristics were recorded. Compared with those chronically progressed (C-ILD), patients with rapid progression (RP-ILD) had significantly higher erythrocyte sedimentation rate (ESR) and standardized uptake value (SUV) in lungs ( P<0.05). In patients with RP-ILD, SUV in lungs was positively correlated with age, disease course, and ESR. Receiver operating characteristic curve analysis suggested that when lung SUV cut off value was 2.25, the sensitivity and specificity to predict disease progression was 77.8% and 72.8%, respectively. Old age, longer disease course, low creatine kinase level, higher ESR, and high SUV are prognostic factors for DM-associated ILD.

Objective: To investigate the clinical and imaging characteristics of infectious sacroiliitis. Methods: A total of 110 patients diagnosed with infectious sacroiliitis were retrospectively analyzed between 2008 and 2017.Clinical manifestations and therapeutic responses, laboratory tests such as HLA-B₂₇, erythrocyte sedimentation rate (ESR), C reactive protein (CRP), T cell spot test for tuberculosis infection(TB-SPOT), Brucella agglutination test ect., blood culture of pathogens, pathological findings as well as magnetic resonance imaging were all recorded and analyzed. Results: Among the 110 patients, the male to female ratio was 44 to 66 with an average age 15-58(29.4±10.8) years and the course of disease 0.3-60 (5.7±13.2) months. As to the pathogens, 71 cases were pyogenic, 24 cases with tuberculous sacroiliitis, and 15 cases were brucellosis infections. The majority of patients (97.3%) had unilateral sacroiliac joint involvement. Ten (9.1%) patients suffered infectious sacroiliac arthritis after delivery. Hip pain was the main clinical manifestation (83/110,75.5%) and fever as the second (77/110,70.0%). HLA-B₂₇ was positive in 11 patients (10.0%). Both ESR and CRP were elevated in the majority. There were 103 patients receiving sacroiliac joint puncture biopsy. Seven patients were diagnosed through blood culture or brucellosis agglutination test. Bone marrow edema and osteolytic lesions in magnetic resonance imaging (MRI) were more common in pyogenic or tuberculous sacroiliitis than in brucellosis infections. Conclusion Infectious sacroiliitis should be differentiated from spondyloarthritis, which develops more in female patients, with short disease duration and fever, mostlynegative HLA-B₂₇. The majority patients present unilateral sacroiliitis. Active inflammatory lesions are usually beyond sacroiliac joints with osteolytic changes in MRI examinations.

Objective: To analyze the clinical characteristics of patients with ankylosing spondylitis (AS) with inflammation bowel disease (IBD). Methods: AS patients fulfilling the 1984 modified New York diagnostic criteria were recruited in Chinese AS Prospective Imaging Cohort (CASPIC) consecutively from April 2016 to June 2017 in Chinese People′s Liberation Army General Hospital by using smart management system for spondyloarthritis (SpAMS). The diagnosis of IBD was confirmed by tissue pathology via ileocolonoscopy. Demographic, clinical and biochemical data were collected. Results: In total, 893 patients with AS were recruited with the mean age 30.8 years. The majority were men (739, 82.8%). There were 64 (7.2%) patients concomitant with IBD. The mean age [(34.5±7.5) years vs. (30.5±8.8) years, P<0.001] was older and the disease duration [(10.8±6.9) years vs. (8.1±5.9) years, P=0.001] was longer in patients with IBD than patients without. Compared with patients without IBD, patients with IBD had more frequent involvement of the cervical spine [(21.9% (14/64) vs. 10.5% (87/829), P=0.006) and thoracic spine [29.7% (19/64) vs. 12.3% (102/829), P<0.001]. Uveitis [28.1% (18/64) vs. 16.4% (136/829), P=0.017] and psoriasis [7.8% (5/64) vs. 2.3% (19/829), P=0.009] were also more common in patients concomitant with IBD. In addition, patients with IBD had significantly higher scores in BASDAI (3.3±2.1 vs. 2.4±1.8, P<0.001), BASFI [2.2 (1.0,3.3) vs. 1.1(0.2,2.4), P<0.001)] and ASAS HI (7.1±4.3 vs. 5.3±3.7, P= 0.001) than patients without IBD. Conclusions Compared with patients without IBD, AS patients concomitant with IBD have more severe disease activity and organ dysfunction. Furthermore, the uveitis and psoriasis are more frequently accompanied in AS patients with IBD.