To evaluate the efficacy and safety of Xinfeng capsule in patients suffering rheumatoid arthritis (RA). A multi-center parallel-group designed, double-blind, randomized, controlled trial was conducted. Totally 304 RA patients were assigned to two groups: one group was administered Xinfeng capsule (XFC) plus the placebo of leflunomide and the other given leflunomide (LEF) plus the placebo of XFC for twelve weeks. The clinical and laboratory parameters were compared at baseline and fourth, eighth, and twelfth weeks. After twelve-week treatment, patients in two groups all showed some trend of effectiveness when compared in terms of American Rheumatism Association (ACR) recommended 20%, 50%, 70% improvement criteria, but it was insignificant. The validity in ameliorate modified disease activity score (DAS28) and laboratory indexes as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF) were also found no difference. The score of health assessment questionnaire (HAQ), self-rating anxiety scale (SAS), self-rating depression scale (SDS) and quality of life questionnaire with rheumatoid arthritis (RAQOL) both lower than the first week and the changes showed no difference. However, the score of SDS dropped more in XFC group than in the other. A total of 147 adverse reaction cases were reported, which shows no difference between the two groups. The most common adverse reactions were hepatic impairment, anemia, leukocytopenia, epigastric discomfort and phalacrosis. XFC demonstrated better improvement in the scores of SDS and compared with those of LEF group.
Purpose: This study probed the mechanism of action of Xinfeng Capsule (XFC) in myocardial injury in rats with adjuvant arthritis (AA) via the growth arrest-specific transcript 5 (GAS5)/microRNA-21 (miR-21)/Toll-like receptor 4 (TLR4) axis. Methods: Rats were injected with Freund's complete adjuvant to establish a rat model of AA. Then, some modeled rats were given normal saline or drugs only, and some modeled rats were injected with adeno-associated viruses or necrosulfonamide (NSA; a pyroptosis inhibitor) before drug administration. Toe swelling and arthritis index (AI) were calculated. Pathological and morphological changes in synovial and myocardial tissues were analyzed with hematoxylin-eosin staining, and pyroptotic vesicles and the ultrastructural changes of myocardial tissues were observed with transmission electron microscopy. The serum levels of interleukin (IL)-1β, IL-18, IL-6, and tumor necrosis factor (TNF)-α were detected, and lactate dehydrogenase (LDH) release was measured in myocardial tissues, accompanied by the examination of GAS5, miR-21, TLR4, nuclear factor-kB (NF-κB) p65, nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), Caspase-1, and Gasdermin D (GSDMD) expression in myocardial tissues. Results: After AA modeling, rats presented with significantly increased toe swelling and AI scores, synovial and myocardial tissue damage, elevated pyroptotic vesicles, and markedly enhanced serum levels of IL-1β, IL-18, IL-6, and TNF-α, accompanied by significantly diminished GAS5 expression, substantially augmented miR-21, TLR4, NF-κB p65, NLRP3, Caspase-1, and GSDMD expression, greatly increased LDH release in myocardial tissues. XFC treatment significantly declined toe swelling, AI scores, synovial and myocardial tissue damage, and the serum levels of IL-1β, IL-18, IL-6, and TNF-α in AA rats. Additionally, XFC treatment markedly elevated GAS5 expression and substantially lowered LDH release and miR-21, TLR4, NF-κB p65, NLRP3, Caspase-1, and GSDMD expression in myocardial tissues of AA rats. Moreover, the above effects of XFC in AA rats were further promoted by GAS5 overexpression or NSA treatment. Conclusion: XFC alleviated myocardial injury in AA rats by regulating the GAS5/miR-21/TLR4 axis and inhibiting pyroptosis and pro-inflammatory cytokine secretion. Keywords: adjuvant arthritis, myocardial injury, GAS5/miR-21/TLR4 axis, pyroptosis, Xinfeng Capsule
Objective Autoimmune diseases (ADs) result from an aberrant immune response, in which the body mistakenly targets its own tissues. The association between TGF-β1 gene polymorphisms and risk of developing autoimmune diseases remains to be established. This meta-analysis aimed to reassess the relationship between TGF-β1 T869C gene polymorphisms and susceptibility to autoimmune diseases. Methods We conducted a comprehensive search of seven electronic databases for case-control studies investigating the TGF-β1 T869C polymorphism in relation to autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjögren’s syndrome, and juvenile idiopathic arthritis. The search encompassed publications published up to June 2024. Studies were categorized by ethnicity into three groups: Asian, Caucasian, and mixed-ethnicity groups. Five different genetic models were assessed, and the quality of the included studies was evaluated using the Newcastle-Ottawa Scale (NOS). Statistical analyses were performed using Stata 14.0, by calculating the odds ratio (OR) and 95% confidence interval (CI). Results A total of 32 case-control studies (31 articles), comprising 4,304 cases and 4,664 controls, were included in this meta-analysis. The overall analysis indicated no significant association between TGF-β1 T869C gene polymorphism and susceptibility to autoimmune diseases. However, subgroup analyses based on race and disease status revealed significant associations. Ethnic subgroup analysis showed that the TGF-β1 T869C allele model (T vs C: OR = 1.422, 95% CI = 1.109–1.824, P = 0.006), homozygous model (TT vs CC: OR = 1.923, 95% CI = 1.232–3.004, P = 0.004), and dominant model (TT + TC vs CC: OR = 1.599, 95% CI = 1.164–2.196, P = 0.004) were associated with autoimmune disease susceptibility in Asians. In the disease subgroup analysis, the results showed that the TGF-β1 T869C allele model (T vs C: OR = 1.468, 95% CI = 1.210–1.781, P = 0.000), recessive model (TT vs TC + CC: OR = 1.418, 95% CI = 1.097–1.832, P = 0.008), dominant model (TT + TC vs CC: OR = 1.747, 95% CI = 1.330–2.295, P = 0.000), homozygous model (TT vs CC: OR = 1.937, 95% CI = 1.373–2.734, P = 0.000), and heterozygous model (TC vs CC: OR = 1.555, 95% CI = 1.199–2.016, P = 0.001) were associated with rheumatoid arthritis susceptibility. Conclusion The findings of this meta-analysis suggest that carrying the T allele of the TGF-β1 T869C polymorphism increases the risk of autoimmune diseases in Asian populations. Moreover, individuals carrying the T allele are at higher risk of developing rheumatoid arthritis.
Objective To investigate the effect of serum containing Xinfeng capsule (XFC) on the angiogenesis of human umbilical vein endothelial cells (HUVEC) induced by rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) and its mechanism of action. Methods An in vitro co-culture model of RA-FLS and HUVEC was established. Serum containing XFC was prepared by oral gavage of SD rats. CCK-8 was used to screen the optimal co-culture ratio and XFC serum concentration. The lncRNA HOTAIR overexpression plasmid (pcDNA3.1-lncRNA HOTAIR), along with the negative control group, were constructed and transfected into RA-FLS. The experiments were done in HUVEC control group, model group (co-culture of HUVEC and RA-FLS), XFC group (co-culture of RA-FLS treated with 200 mL/L XFC), HOTAIR negative control group (co-culture of RA-FLS transfected with pcDNA3.1-NC), HOTAIR overexpression group (co-culture of RA-FLS transfected with pcDNA3.1-lncRNA HOTAIR), and XFC-treated HOTAIR overexpression group (co-culture of RA-FLS transfected with pcDNA3.1-lncRNA HOTAIR and treated with 200 mL/L XFC). The proliferation ability of HUVEC was detected by CCK-8 method. The migration ability of HUVEC was detected by Transwell
To investigate the effects of Xinfeng Capsule (XFC) on pulmonary function and related mechanism in adjuvant-induced arthritis (AA) rats.The rats were randomly divided into five groups: normal control (NC), model control (MC) groups, methotrexate (MTX), tripterygium glycosides tablet (TPT) and Xinfeng capsule (XFC) treatment groups. The adjuvant-induced arthritis model was established by intracutaneous injection of 0.1 mL Freund ' s complete adjuvant in the right paw of rats; the drugs were given 19 d after model establishment. The toe swelling degree (E), arthritis index (AI), pulmonary function, peripheral blood Treg levels, pathological changes of lung tissue and expression of Foxp3, TGF-β1, Smad3, Smad7 proteins in lung tissue were measured 30 d after drug administration.Compared to NC group, the levels of E, AI, alveolitis score, TGF-β1 and Smad3 were significantly increased (P <0.05 or P <0.01); maximum expiratory flow 25% of vital capacity (FEF25),50% maximal expiratory vital capacity flow (FEF50), maximum expiratory flow at 75% of vital capacity (FEF75), maximum mid-expiratory flow (MMF), force peak expiratory flow (PEF), CD4+ CD25+ Treg, Foxp3 and Smad7 were significantly decreased in MC group (P <0.05 or P < 0.01). Compared to MC group,the expression of E, AI, TGF-β1 and Smad3 were reduced, while FEF50, FEF75, MMF, PEF, Treg, Foxp3 and Smad7 were elevated in XFC group (P <0.05 or P <0.01). Compared to XFC group, the level of body mass,FEF25,FEF50, FEF75, MMF and Treg were lower in MTX and TPT groups (P <0.05 or P <0.01).There are inflamed joints and reduced pulmonary function in rats of adjuvant-induced arthritis. XFC can inhibit paw edema degrees, reduce arthritis response, and improve pulmonary function, which is associated with up-regulating expression of Treg and Foxp3, down-regulating the expression of TGF-β1 and adjusting TGF-β1/Smads signal pathway.
Objective: to observe the effects of Xinfeng Capsule on adjuvant arthritis rat model of pulmonary function, B, T cell immunity. Methods 40 rats were randomly divided into normal, model, Tripterygium Glycosides tablet and XFC group. Except the normal group, the other rat’s right rear paw intradermal injection of Freund’s complete adjuvant induced arthritis in 0.1 mL. Inflammation induced 19 d after administration, the normal group, the model groups were given physiological saline, rats in the treatment group were given of Xinfeng Capsule (2.4 g/kg), Tripterygium Glycosides tablet (10 mg/kg), once a day, continuous administration of 30D. Joint inflammation in rats was observed performance, flow cytometry detection of peripheral blood B, T lymphocyte attenuator (BTLA), regulatory T cells (Treg) and surface markers of forkhead transcription factor (FoxP3) expression was detected by Western blotting, synovial membrane, lung tissue BTLA, FoxP3. Results compared with the normal group, model group of rat paw swelling degree, arthritis index increased; pulmonary function, reduce the expression levels of peripheral blood BTLA, Tregs and BTLA in pulmonary tissue, synovium, FoxP3 (P <0.05 or P <0.01). While the XFC group rat paw swelling and arthritis index lower than the model group, pulmonary function, BTLA, Tregs and FoxP3 increased (P <0.05 or P <0.01); Xinfeng capsule group is better than control group (P <0.05) medicine Tripterygium wilfordii. Conclusion of Xinfeng capsule may be through upregulation of BTLA, Tregs, and FoxP3 expression, reduce the stimulation of inflammatory mediators in the lung tissue and improve the lung function of rats with adjuvant arthritis.
Objective To explore the regulatory axis of circular RNA Cbl proto-oncogene B (circCBLB)/miR-486-5p on the proliferation, apoptosis, and inflammatory cytokines of fibroblast-like synoviocytes in rheumatoid arthritis (RA-FLS). Methods Human RA-FLS were stimulated with 100 μL of 10 ng/mL of tumor necrosis factor-alpha (TNF-α) to establish the model. The binding relationship of circCBLB/miR-486-5p was validated by a dual-luciferase reporter gene assay. pcDNA3.1/siRNA-circCBLB, negative control (pcDNA3.1-NC/si-NC), and miR-486-5p-mimics were created and transfected into RA-FLS, respectively. The experiment was divided into seven groups: control, TNF-α-treated RA-FLS, pcDNA3.1-circCBLB, pcDNA3.1-NC, si-circCBLB, si-NC, and pcDNA3.1-circCBLB combined with miR-486-5p-mimics. Cell viability was assessed by a CCK-8 assay; cell cycle and apoptosis by flow cytometry; colony formation ability by a colony formation assay; and the expression levels of circCBLB and miR-486-5p by real-time quantitative PCR. The levels of interleukin 4 (IL-4), IL-10, IL-6 and TNF-α were measured by ELISA. Results The dual-luciferase reporter gene assay showed that circCBLB bound to the 3' untranslated region (3'UTR) of miR-486-5p. Compared with the model group at the same time point, the cell viability of the overexpression group was lower, while that of the interference group was higher. Compared with the model group, the overexpression group had a higher apoptosis rate, a higher proportion in S and G2 phases, a lower colony formation rate, a lower miR-486-5p expression level, higher IL-4 and IL-10 levels, and lower IL-6 and TNF-α levels. The interference group had a lower apoptosis rate, a lower proportion in S and G2 phases, a higher colony formation rate, a higher miR-486-5p expression level, and a higher TNF-α level. The pcDNA3.1-circCBLB combined with miR-486-5p-mimics group reversed the effects of circCBLB on cell viability, apoptosis rate, cell cycle, colony formation ability, antiinflammatory cytokines, and proinflammatory cytokines. Conclusion circCBLB inhibits the viability of RA-FLS, increases apoptosis rate, prolongs the cell cycle, reduces colony formation ability, increases antiinflammatory cytokines, and decreases proinflammatory cytokines. In contrast, miR-486-5p has opposite regulatory effects on circCBLB and can partially reverse and offset the effects of circCBLB.
Objective To observe the effect of Xinfeng Capsule (XFC) on Notch/Jagged-HES of type II alveolar epithelial cells (AECII). Methods Rats were divided for four groups: normal control (NC) group, model control (MC) group, leflunomide (LEF) group, XFC group, with 10 rats in each group. Complete Freund's adjuvant (CFA) was injected in the right foot plantar skin of each rat except for the NC group. After adjuvant arthritis was successfully induced, LEF group was given LEF (0.5 mg/100 g), and XFC group was treated with XFC (0.034 g/100 g), once a day from the 13th day to the 42th day. The NC and MC groups were given normal saline instead. Swelling degree (SD), arthritis index (AI) and pulmonary function were observed. AECII was observed by transmission electron microscopy (TEM). The expressions of transforming growth factor β1 (TGF-β1), Notch1, Notch3, Jagged1 and HES1 proteins in AECII were detected by Western blotting. Results The pulmonary function parameters such as forced expiratory volume in 1 second (FEV1), maximum expiratory flow rate at 50% FVC (FEF50), instantaneous flow at 75% of expired volume (FEF75), peak expiratory flow (PEF) in the MC group were significantly lower than those in the NC group, and the expressions of TGF-β1, Notch1, Notch3, Jagged1 and HES1 in AECII increased. The ultrastructure of AECII was damaged. Compared with the MC group, FEV1, FEF50, FEF75 and PEF increased, and TGF-β1, Notch1, Notch3, Jagged1 and HES1 decreased in the XFC group. Compared with LEF group, the lung function was better in XFC group. Conclusion XFC can inhibit pulmonary fibrosis and improve pulmonary function by down-regulating TGF-β1, Notch1, Notch3, Jagged1 and HES1 in rats with adjuvant arthritis.
To observe the relationship between reduced pulmonary function and regulatory T cells (Tregs) and helper T cells (Th)1/Th2 drift in a rat model of adjuvant arthritis (AA), and to study the impact of Xinfeng capsule (XFC) on pulmonary function and investigate the mechanism of action.Forty rats were randomly divided into normal control group (NC), model control group (MC), Tripterygium glycosides tablet group (TPT), and XFC group, with 10 in each. Except for the NC group, AA was induced in all rats by intracutaneous injection of 0.1 mL Freund's complete adjuvant in the right paw. On the 19th day after modeling, the NC and MC groups were given physiological saline (0.9%), while the TPT and XFC groups were given TPT (10 mg/kg) and XFC (2.4 g/kg), once daily, respectively. Thirty days after administration, changes in paw swelling, arthritis index (AI), pulmonary function, levels of serum gamma-interferon (IFN-gamma) and interleukin (IL)-4, Tregs in peripheral blood, and IFN-gamma, IL-4, Forkhead box transcription factor 3 (FoxP3) in lung tissue were observed by enzyme-linked immunosorbent assay, flow cytometry, polymerase chain reaction, and western blot.Compared with the NC group, paw swelling, AI, IFN-gamma, and Th1/Th2 were increased, and pulmonary function parameters, IL-4, FoxP3 were decreased significantly in the MC group (P < 0.05 or P < 0.01). Pulmonary function parameters, Treg, IL-4, FoxP3 (and mRNA) were higher, and paw swelling, AI, and IFN-gamma (and mRNA) were lower in the XFC group than those in the MC group. The XFC group was also much better than the TPT group in improving pulmonary function, FoxP3 mRNA, IFN-gamma, IL-4, Th1/Th2, and IL-10 (P < 0.05 or P < 0.01).Xinfeng capsule can improve pulmonary function by regulating the levels of Tregs, inhibiting the activation of Th1 to Th2 cells, inducing drift, maintaining cell immune suppression, correcting the imbalance of Th1/Th2, and reducing inflammatory mediators.
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