Pharmacodynamics of Sishen decoction in relieving rheumatoid arthritis: Chemical composition, regulatory pathway and online prediction simulation.

As a commonly used traditional Chinese medicine formula for treating rheumatoid arthritis (RA), Sishen Decoction (SSD) has anti-inflammatory, analgesic and swelling relief effects. However, at present, the pharmacodynamic basis of SSD and its mechanism of treating RA have not been clarified, and further research is needed. Analyzing the pharmacological basis of SSD was the aim of our study and further elucidate its therapeutic mechanism and potential targets for treating RA. LC‒MS was used to identify the high content and characteristic chemical components of SSD. On this basis, a network of pharmacological analysis was established between the chemical structure and RA. According to the predicted possible pathways and targets, in vivo pharmacodynamic experiments and related pathway analysis were conducted. Finally, the possible targets and mechanisms of SSD in treating RA were analyzed. Identified 78 compounds from SSD by LC-MS, including 23 flavonoids, 19 phenolic acids, 9 monoterpenoids and 26 other compounds. Network pharmacological analysis based on pharmacodynamic substances revealed that the most likely interaction pathway between SSD and RA was the PI3K/AKT/mTOR pathway. Foot swelling and inflammatory factors (IL-6, IL-10, IL-18, TGF, TNF-α, VEGF) in model mice were shown to be significantly improved in vivo. WB and qPCR experiments proved that SSD could significantly regulate the pathway of PI3K/AKT/mTOR. The interaction between SSD and AKT target was further analyzed by multispectroscopy. This study revealed that SSD alleviates RA by regulating the pathway of PI3K/AKT/mTOR and preliminarily revealed the pharmacodynamic mechanism of SSD for the first time.

Analysis of Key Genes Related to Systemic Lupus Erythematosus and COVID-19.

BACKGROUND: Systemic Lupus Erythematosus (SLE) is a multifactorial and complex immune disease; however, the relevance of COVID-19 infection in SLE patients remains uncertain. AIM: This study aims to explore the key candidate genes and pathways in patients with SLE. It also seeks to employ bioinformatics analysis to unravel the molecular signatures inherent in both SLE and COVID-19 patients. The ultimate aim is to identify potential targets and markers specifically relevant to SLE patients who contract SARS-CoV-2. METHODS: Datasets (GSE12374, GSE20864, GSE61635, GSE81622, and GSE144390) from the Gene Expression Omnibus (GEO) database were analyzed using Robust Rank Aggregation (RRA) method to identify differential expression genes (DEGs) in SLE patients compared to healthy individuals. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, tissue-specific gene analysis, and Protein-protein interaction (PPI) network were performed. Finally, the Venn diagram was employed to identify the intersections of COVID-19 genes, serving as potential targets for SLE patients with COVID-19 infection. RESULTS: A total of 154 DEGs were discovered, with GO enrichment indicating a predominant involvement in the defense response against the virus (P<0.001). KEGG pathway analysis showed enrichment in the NOD-like receptor signaling pathway and coronavirus disease, specifically COVID-19 (P<0.001). Tissue-specific genes related to the hematological and immune systems were emphasized (74%). The PPI network highlighted 22 genes, and 5 key genes, namely, IFIT1, IFIT3, MX1, MX2, and OAS3, which were identified after intersecting with COVID-19 patients' data. CONCLUSION: IFIT1, IFIT3, MX1, MX2, and OAS3 exhibiting differential expression, as well as the pathways associated with COVID-19, could potentially function as biomarkers and therapeutic targets for individuals with SLE infected with COVID-19.

Network Pharmacology and Experimental Verification of Si Shen Decoction Regulating FABP4/PPARγ/NFκB Pathway in the Treatment of Collagen-induced Arthritis.

AIM: This study aimed to investigate the mechanism of SSD in rats with Collagen- Induced Arthritis (CIA). BACKGROUND: Rheumatoid arthritis (RA) is a complex immune disease characterized by bilateral symmetrical multi-joint pain and swelling. Si Shen Decoction (SSD) has shown good results in treating RA in clinical applications, but its mechanism of action remains unclear. OBJECTIVE: To investigate the mechanism of SSD in rats with Collagen-Induced Arthritis (CIA). METHODS: Bioinformatics and network pharmacology analyses were used to predict the possible treatment targets and signaling pathways. Elisa, Western blotting, and quantitative real-time polymerase chain reaction were used to verify the mechanism of SSD in the treatment of RA. RESULTS: FABP4, MMP9, and PTGS2 were the most common predicted therapeutic targets. SSD treatment significantly reduced synovitis, ankle swelling and bone erosion in CIA rats. The SSD group also significantly reduced the serum secretion of CRP, TNFα, and IL1ß, decreased mRNA levels of FABP4, IKKα, and p65 in the synovial membrane, but increased PPARγ. Western blot showed that SSD treatment could significantly reduce the expression of FABP4, IKKα, and phosphorylated p65 (p-p65) proteins in the synovium. SSD was found to inhibit the FABP4/PPARγ/NFκB signaling pathway and reduce the inflammatory response in CIA rats. The therapeutic effect of SSD was significant with the increase of dose. CONCLUSION: SSD can relieve joint symptoms in CIA rats and alleviate inflammation by inhibiting the FABP4/PPARγ/NFκB signaling pathway. The effect of high-dose SSD was more prominent.

Exploring the molecular mechanism of Sishen Decoction in the treatment of rheumatoid arthritis.

Background: To explore the potential targets and mechanism of action of Sishen Decoction in the treatment of rheumatoid arthritis (RA) using a network pharmacology approach. Methods: Firstly, we analyzed the differentially expressed genes in the Gene Expression Omnibus (GEO) database and constructed a protein-protein interaction (PPI) network using potential core target proteins determined by the STRING platform and Cytoscape software. We also performed gene ontology functional enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analysis, and gene set enrichment analysis (GSEA) on the potential targets, and then used the disease target database to download targets related to RA pathogenesis. The relevant targets were intersected with the action targets of Sishen Decoction to obtain the potential targets considered for the treatment of RA with Sishen Decoction. Results: The GSE55235 and GSE77298 datasets were downloaded from the GEO database for analysis, and 73 genes with abnormally high expression in RA and 26 genes with abnormally low expression in RA were obtained by taking the intersection of highly expressed genes and low expression genes in RA. The results of KEGG and Metascape showed that the differential genes were enriched in inflammation-related signaling pathways such as leukocyte migration, myeloid leukocyte-mediated immunity, and lymphocyte activation, as well as bone activation and bone development, which are closely related to RA. In the exploration of the drug targets of Sishen Decoction for the treatment of RA, it was found that Sishen Decoction may regulate the interleukin (IL)-17) signaling pathway, tumour necrosis factor (TNF) signaling pathway, and chemokine signaling pathway in RA by targeting MMP9 and CXCR4. Conclusions: This study explored the potential targets and signaling pathways of Sishen Decoction in the treatment of RA, which may help to illustrate the mechanisms involved in the action of Sishen Decoction and better understand its anti-RA role in the inhibition of angiogenesis, synovial proliferation, and bone destruction.

China rheumatoid arthritis registry of patients with Chinese medicine (CERTAIN): Rationale, design, and baseline characteristics of the first 11,764 enrollees.

BACKGROUND: Chinese medicine (CM) has become a popular interventional treatment for rheumatoid arthritis (RA). However, limited knowledge about general characteristics and long-term clinical outcomes hampers the development of CM for RA. PURPOSE: The main objectives of the China Rheumatoid Arthritis Registry of Patients with Chinese Medicine (CERTAIN) were to describe the population of RA patients receiving CM treatment in multiple centers in China using different variables and compare these findings with internationally reported data. STUDY DESIGN: The CERTAIN is a prospective, multicenter, observational disease registry. METHODS: Adult RA patients who fulfilled the 2010 American College of Rheumatology/ European League Against Rheumatism classification criteria for RA and received CM treatment were recruited into the CERTAIN by rheumatologists from 145 hospitals across 30 provinces in China. Data on demographics, disease characteristics, comorbidities, treatments, and adverse events, with a 2-year follow-up, were collected and documented using a predefined protocol. RESULTS: In the 2 years since the study began in September 2019, 11,764 patients have been enrolled (enrolment is ongoing), and 13.10% of participants have completed the 6-month follow-up. We present the baseline characteristics of the first 11,764 enrollees. CONCLUSIONS: The CERTAIN is the first nationwide registry to document comprehensive data on CM treatment in patients with RA. The development of the CERTAIN resource is a significant step forward for Chinese RA patients, herbal medicine users, and research communities and will deepen our understanding of CM for RA. REGISTRATION: The study was registered at ClinicalTrials.gov (NCT05219214).

The Impact of Traditional Chinese Medicine QingreHuoxue Treatment and the Combination of Methotrexate and Hydroxychloroquine on the Radiological Progression of Active Rheumatoid Arthritis: A 52-Week Follow-Up of a Randomized Controlled Clinical Study.

Traditional Chinese medicine (TCM) has been used successfully to treat rheumatoid arthritis (RA). QingreHuoxue treatment (QingreHuoxue decoction [QRHXD]/QingreHuoxue external preparation [QRHXEP]) is a Chinese medicine treatment for RA. To date, very few studies have compared the long-term effects of QRHXD with those of conventional disease-modifying antirheumatic drugs on RA disease activity and radiological progression. QRHXD delayed the radiological progression and showed long-term clinical efficacy of RA. In clinical experiments, the clinical evidence of delaying the radiological progression of RA patients was obtained. A portion of the patients who participated in the "Traditional Chinese Medicine QingreHuoxue Treatment vs. the Combination of Methotrexate and Hydroxychloroquine for Active Rheumatoid Arthritis" study were followed up for 52 weeks, and intention-to-treat (ITT) and compliance protocol (PP) analyses were used to collect and compare the clinical indicators and imaging data between baseline and week 52. Two radiologists who were blind to treatment scored the images independently. Of the 468 subjects, 141 completed the 52-week follow-up. There were no significant differences among the three groups: the traditional Chinese medicine comprehensive treatment group, the Western medicine treatment group, and the integrated traditional Chinese and Western medicine treatment group. There were no differences in the total Sharp score, joint space stenosis score, and joint erosion score at baseline or 52 weeks. In the comparison of the estimated annual radiographic progression (EARP) and the actual annual Sharp total score changes among the three groups, the actual changes were much lower than the EARP at baseline. The radiological progress in all three groups was well controlled. Results of the ITT and PP data sets showed that the disease activity score 28 level of the three groups at 52 weeks was significantly lower than that at baseline. During the 52-week treatment period, the clearance of heat and promotion of blood circulation controlled disease activity and delayed the radiological progress of active RA.

The method of Yiqi Yangyin Tongluo can attenuate the pyroptosis of rheumatoid arthritis chondrocytes through the ASIC1a/NLRP3 signaling pathway.

Background: Based on the ASIC1a/NLRP3 signaling pathway, we explored the specific molecular mechanism of the pyroptosis of rheumatoid arthritis (RA) chondrocytes by the method of nourishing qi, nourishing yin, and dredging collaterals to provide new ideas for the treatment of this disease. Methods: A total of 50 rats were divided into a normal group, model group, methotrexate group, Yiqi Yangyin Tongluo group, and combined group. Except for the normal control group, the other groups used Freund's complete adjuvant (FCA) to make RA rat model. The arthritis index and ankle joint swelling of rats in each group were recorded. HE staining and ELISA were used to assess the pathology of the ankle joint of each group of rats and the content of IL-1ß and IL-18 in rat serum. Furthermore, immunofluorescence and qPCR methods were used to detect the protein and mRNA expression levels of NLRP3, caspase 1, ACS, and ASIC1a in the cartilage tissue of each group of rats. Results: Compared with the normal group, the right hind foot joint of the model group was significantly swollen, the levels of IL-18 and IL-1ß in the serum of rats increased significantly, and the mRNA and protein levels of NLRP3, caspase 1, ACS, and ASIC1a in the chondrocytes also increased significantly. Compared with the model group, the degree of ankle joint swelling and IL-18 and IL-1ß content in rat serum in each medication group was significantly reduced, and the combined group showed the greatest reduction compared with the other groups. After 8 weeks of treatment, compared with the model group, the mRNA and protein levels of NLRP3, caspase 1, ACS, and ASIC1a in the chondrocytes of each medication group were down-regulated. HE staining found that there were large numbers of infiltrating inflammatory cells and pannus in the joint tissue of the model group, while only a small amount of inflammatory cell infiltration and pannus was seen in the joint tissue of the rats in each treatment group. Conclusions: The method of Yiqi Yangyin Tongluo can attenuate the pyroptosis of RA chondrocytes through the ASIC1a/NLRP3 signaling pathway.

Traditional Chinese Medicine Qingre Huoxue Treatment vs. the Combination of Methotrexate and Hydroxychloroquine for Active Rheumatoid Arthritis: A Multicenter, Double-Blind, Randomized Controlled Trial.

Traditional Chinese medicine (TCM) has been used successfully to treat rheumatoid arthritis (RA). Qingre Huoxue treatment (Qingre Huoxue decoction (QRHXD)/Qingre Huoxue external preparation (QRHXEP)) is a therapeutic scheme of TCM for RA. To date, there have been few studies comparing the efficacy and safety of QRHXD and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for the treatment of active RA. This was investigated in a multicenter, double-blind, randomized controlled trial involving 468 Chinese patients with active RA [disease activity score (DAS)-28 > 3.2] treated with QRHXD/QRHXEP (TCM group), methotrexate plus hydroxychloroquine [Western medicine (WM) group], or both [integrative medicine (IM) group]. Patients were followed up for 24 weeks. The primary outcome measure was the change in DAS-28 from baseline to 24 weeks. The secondary outcome measures were treatment response rate according to American College of Rheumatology 20, 50, and 70% improvement criteria (ACR-20/50/70) and the rate of treatment-related adverse events (TRAEs). The trial was registered at ClinicalTrials.gov (NCT02551575). DAS-28 decreased in all three groups after treatment (p < 0.0001); the score was lowest in the TCM group (p < 0.05), while no difference was observed between the WM and IM groups (p > 0.05). At week 24, ACR-20 response was 73.04% with TCM, 80.17% with WM, and 73.95% with IM (based on the full analysis set [FAS], p > 0.05); ACR-50 responses were 40.87, 47.93, and 51.26%, respectively, (FAS, p > 0.05); and ACR-70 responses were 20.87, 22.31, and 25.21%, respectively, (FAS, p > 0.05). Thus, treatment efficacy was similar across groups based on ACR criteria. On the other hand, the rate of TRAEs was significantly lower in the TCM group compared to the other groups (p < 0.05). Thus, QRHXD/QRHXEP was effective in alleviating the symptoms of active RA-albeit to a lesser degree than csDMARDs-with fewer side effects. Importantly, combination with QRHXD enhanced the efficacy of csDMARDs. These results provide evidence that QRHXD can be used as an adjunct to csDMARDs for the management of RA, especially in patients who experience TRAEs with standard drugs. Clinical Trial Registration: ClinicalTrials.gov, identifier NCTNCT025515.

A multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of Tong Luo Hua Shi capsule, a modernized Tibetan medicine, in patients with rheumatoid arthritis.

BACKGROUND: Tong Luo Hua Shi (TLHS) is a new formulation of the traditional Tibetan medicine Wu-wei-gan-lu that has been used for the treatment of rheumatoid arthritis (RA) for hundreds of years in China. This study aimed to evaluate the efficacy and safety of TLHS in patients with RA. METHODS: This was a randomized, double-blind, placebo-controlled, dose-finding study performed in patients with active RA from five medical centers. Patients received three doses (4.8, 3.6, or 2.4 g/day po) of TLHS or placebo (tid po) for 8 weeks. Blood sampling, physical examination, and assessment of the American College of Rheumatology (ACR) 20 % improvement (ACR20) criteria were performed before and every 2 weeks after starting treatment. The primary endpoint was the ACR20. The secondary endpoints included safety. RESULTS: A total of 240 participants were screened and 236 patients were randomized (n = 59/group); 20 dropped out. After 8 weeks, ACR20 improvements in the TLHS 4.8 g and 3.6 g groups were significantly higher than in the placebo group (P < 0.01 and P < 0.05, respectively). ACR50 improvement in the TLHS 4.8 g group was significantly higher compared with the placebo group (P < 0.01). Symptoms of RA were significantly relieved in the TLHS groups. In the TLHS groups, insomnia (n = 1), gastroenteric reactions (n = 2), arrhythmia (n = 1), and minor hepatic lesion (n = 1) were reported; in the placebo group, hepatic dysfunction (n = 1) was reported (P = 0.878). CONCLUSIONS: TLHS improved the symptoms of patients with RA according to the ACR20. Moreover, TLHS was safe. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR-TRC-12003871 . Registered on 1 January 2012.

[Clinical effect analysis of ankylosing spondylitis treated by Chinese medical syndrome differentiation].

OBJECTIVE: To evaluate the curative effect and safety of Bushen Qiangji Decoction (BQD) and Qingre Qiangji Decoction (QQD) in treating ankylosing spondylitis (AS) patients, and to verify the clinical utility of AS syndrome differentiation and treatment scheme [Shen-deficiency induced stasis obstruction syndrome (SDISOS) and dampness-heat obstruction syndrome (DHOS) being two basic syndrome types, Shen invigorating blood activating method (SIBAM) and heat clearing dampness resolving method (HCDRM) being two basic treatment methods]. METHODS: Totally 354 AS patients of SDISOS and DHOS were randomly assigned to the treatment group and the control group using a multi-center randomized, positive drug parallel-controlled clinical trail. Patients in treatment group were treated by BQD or QQD according to syndrome typing, while those in the control group took Sulfasalazine enteric-coated tablet (SECT), 24 weeks as one therapeutic course. After treatment, the clinical efficacy was evaluated by using ASAS20 standard (set by Asessment in Ankylosing Spondylitis working group), Chinese medical efficacy evaluation standards, and BASDAI, BASFI, BASMI, night-pain index, spinal pain index, PGA, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). RESULTS: After 24 weeks of treatment by BQD or QQD, ASAS20 standard rate was 86.75% in the treatment group, and the total effective rate of Chinese medical syndrome was 85.47%. They could significantly reduce patients' integrals of Chinese medical syndrome, BASDAI, BASFI, BASMI, night-pain index, spinal pain index, and PGA (all P < 0.01). CONCLUSIONS: QQD and BQD got confirmable clinical effects in treating AS, providing strong evidence of evidence-based medicine for syndrome differentiation and treatment of AS.