Oral Intake of Lactobacillus delbrueckii subsp. bulgaricus OLL1073R-1 Prevents Collagen-Induced Arthritis in Mice

2002 ◽  
Vol 65 (1) ◽  
pp. 153-160 ◽  
Author(s):  
HIROSHI KANO ◽  
TSUTOMU KANEKO ◽  
SHUICHI KAMINOGAWA
Keyword(s):  
Oral Intake ◽  
Type Ii Collagen ◽  
Inhibitory Effect ◽  
Lactobacillus Delbrueckii ◽  
Broth Culture ◽  
Control Group ◽  
Collagen Induced Arthritis ◽  
Beneficial Effects ◽  
Ifn Γ ◽  
Lactobacillus Delbrueckii Subsp

Oral intake of some lactic acid bacteria can have beneficial effects on the host by activating immune responses and enhancing resistance to infection by pathogens. In this study, effects of Lactobacillus sp. on the development of autoimmune disease were examined in mice with collagen-induced arthritis (CIA). CIA, a model of some types of rheumatoid arthritis (RA), can be induced in DBA/1J mice by immunizing them with bovine type II collagen (bCII). Oral intake of skimmed milk (SM) fermented with Lactobacillus delbrueckii subsp. bulgaricus OLL1073R-1 (SM/OLL1073R-1) was found to markedly inhibit the development of CIA in these mice, compared with a control group fed the control foodstuff. The inhibitory effect of SM fermented with L. delbrueckii subsp. bulgaricus OLL1102 (SM/OLL1102) or fresh SM was weaker than that of SM/OLL1073R-1. A deMan Rogosa Sharpe (MRS) broth culture of OLL1073R-1 without any major components of SM had the same inhibitory effect as SM/OLL1073R-1, suggesting that the inhibitory effect of SM/OLL1073R-1 is attributable not only to SM components but also to OLL1073R-1 cells, their metabolites, or both. We found that SM/OLL1073R-1 and SM caused reduced secretion of the cytokine IFN-γ by lymph node cells (LNCs) in response to bCII. However, SM/OLL1102 did not affect the secretion of IFN-γ. A polysaccharide fraction secreted by OLL1073R-1 also exhibited the inhibitory effects on both development of CIA and secretion of IFN-γ.

scholarly journals Berberine Delays Onset of Collagen-Induced Arthritis through T Cell Suppression

2021 ◽  
Vol 22 (7) ◽  
pp. 3522
Author(s):  
Alexandra A. Vita ◽  
Hend Aljobaily ◽  
David O. Lyons ◽  
Nicholas A. Pullen
Keyword(s):  
T Cell ◽  
Type Ii Collagen ◽  
Control Group ◽  
Collagen Induced Arthritis ◽  
Preclinical Phase ◽  
T Cell Suppression ◽  
Cell Suppression ◽  
Freund’S Adjuvant ◽  
Freund's Adjuvant

There is evidence that berberine (BBR), a clinically relevant plant compound, ameliorates clinically apparent collagen-induced arthritis (CIA) in vivo. However, to date, there are no studies involving the use of BBR which explore its prophylactic potential in this model of rheumatoid arthritis (RA). The aim of this study was to determine if prophylactic BBR use during the preclinical phase of collagen-induced arthritis would delay arthritic symptom onset, and to characterize the cellular mechanism underlying such an effect. DBA/1J mice were injected with an emulsion of bovine type II collagen (CII) and complete Freund’s adjuvant (day 0) and a booster injection of CII in incomplete Freund’s adjuvant (day 18) to induce arthritis. Mice were then given i.p. injections of 1 mg/kg/day of BBR or PBS (vehicle with 0.01% DMSO) from days 0 to 28, were left untreated (CIA control), or were in a non-arthritic control group (n = 15 per group). Incidence of arthritis in BBR-treated mice was 50%, compared to 90% in both the CIA and PBS controls. Populations of B and T cells from the spleens and draining lymph nodes of mice were examined on day 14 (n = 5 per group) and day 28 (n = 10 per group). BBR-treated mice had significantly reduced populations of CD4+Th and CD4+CXCR5+ Tfh cells, and an increased proportion of Foxp3+ Treg at days 14 and 28, as well as reduced expression of co-stimulatory molecules CD28 and CD154 at both endpoints. The effect seen on T cell populations and co-stimulatory molecule expression in BBR-treated mice was not mirrored in CD19+ B cells. Additionally, BBR-treated mice experienced reduced anti-CII IgG2a and anti-CII total IgG serum concentrations. These results indicate a potential role for BBR as a prophylactic supplement for RA, and that its effect may be mediated specifically through T cell suppression. However, the cellular effector involved raises concern for BBR prophylactic use in the context of vaccine efficacy and other primary adaptive immune responses.

Discovery of Serum Proteomic Biomarkers for Prediction of Response to Moxibustion Treatment in Rats with Collagen-Induced Arthritis: An Exploratory Analysis

2016 ◽  
Vol 34 (3) ◽  
pp. 184-193 ◽  
Author(s):  
Xiao Xu ◽  
Miao-Miao Wang ◽  
Zhi-ling Sun ◽  
Dan-ping Zhou ◽  
Ling Wang ◽  
...  
Keyword(s):  
Rat Model ◽  
Multiple Testing ◽  
Day Treatment ◽  
Expression Patterns ◽  
Control Group ◽  
Sprague Dawley ◽  
Collagen Induced Arthritis ◽  
Serum Samples ◽  
Beneficial Effects ◽  
Bovine Collagen

Objective To examine the possible impact of moxibustion on the serum proteome of the collagen-induced arthritis (CIA) rat model. Materials and Methods Thirty-six male Sprague-Dawley rats were included in this experiment. The CIA animal model was prepared by injection of type II bovine collagen in Freund's adjuvant on the first and seventh day. The 36 rats were randomly divided into two groups: the untreated CIA group (control), and the CIA plus treatment with moxibustion (CIA+moxi) group. Moxibustion was administered daily at ST36 and BL23 for 7, 14 or 21 days (n=12 rats each). Arthritis score was used to assess the severity of arthritis. At the end of each 7 day treatment, blood samples from the control group and the CIA+moxi group were collected. After removal of high abundance proteins from serum samples, two-dimensional gel combined with matrix-assisted laser desorption ionisation time-of-flight MS/MS (MALDI-TOF-MS/MS) techniques were performed to examine serum protein expression patterns of the CIA rat model with and without moxibustion treatment. In addition, the relevant proteins were further analysed with the use of bioinformatics analysis. Results Moxibustion significantly decreased arthritis severity in the rats in the CIA+moxi group, when compared with the rats in the CIA group 35 days after the first immunisation (p=0.001). Seventeen protein spots which changed >1.33 or <0.77 at p<0.05 using Bonferonni correction for multiple testing were found to be common to all three comparisons, and these proteins were used for classification of functions using the Gene Ontology method. Consequently, with the use of the Ingenuity Pathway Analysis, the top canonical pathways and a predicted proteomic network related to the moxibustion effect of CIA were established. Conclusions Using the proteomics technique, we have identified novel candidate proteins that may be involved in the mechanisms of action underlying the beneficial effects of moxibustion in rats with CIA. Our findings suggest that immune responses and metabolic processes may be involved in mediating the effects of moxibustion. Moreover, periodxiredoxin I (PRDX1) and inositol 1,4,5-triphosphate receptor (IP3R) may be potential targets.

scholarly journals Muscadine Grape and Wine Polyphenols Alleviated the Severity of Collagen Induced Arthritis in Mice

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 308-308
Author(s):  
Lindsey Christman ◽  
Taylor Washington ◽  
Liwei Gu
Keyword(s):  
Plasma Concentration ◽  
Type Ii Collagen ◽  
Intradermal Injection ◽  
Advisory Council ◽  
Control Group ◽  
Collagen Induced Arthritis ◽  
Matrix Metalloproteinase 3 ◽  
Arthritic Score ◽  
Wine Polyphenols ◽  
Muscadine Grape

Abstract Objectives The aim of this study was to investigate the effect of concentrated muscadine grape polyphenols (MGP) and muscadine wine polyphenols (MWP) on the onset and progression of collagen induced arthritis (CIA) in mice. Methods MGP and MWP were concentrated using Amberlite XAD16N resin. Polyphenol composition was determined on HPLC. Male DBA/1 mice were divided into four treatment groups as (1) healthy control, (2) CIA control, (3) CIA + MWP, and (4) CIA + MGP. Arthritis was induced by intradermal injection of type II collagen on days 0 and day 21. Mice in groups 3 and 4 were gavaged with MWP and MGP using a dose of 400 mg/kg body weight for a total of 21 days. Severity of CIA was evaluated using clinical arthritic score and inflammation in the hind-paws. Plasma levels of cytokines, proteases, and anti-collagen antibody were measured using ELISA. Results MGP and MWP contained anthocyanin 3, 5-diglucosides, flavonols, and ellagic acid. Mice in the CIA control group had an onset of arthritis on day 18, which was delayed to day 22 and 24 by MWP and MGP, respectively (P &lt; 0.05). Severity of arthritis was much lower in mice gavaged with muscadine polyphenols after the onset. On day 42, the average arthritic score of mice in the CIA control group progressed to 7.75 on a scale of 0–16, while MGP and MWP significantly reduced this score to 3.75 and 4.00, respectively (P &lt; 0.01). In addition, MGP and MWP significantly reduced the plasma concentration of TNF-α, IL-6, anti-collagen antibodies, and matrix metalloproteinase-3 in CIA mice but not to the same level of healthy mice. The plasma concentration of IL-17 was drastically elevated in CIA mice, but it was not affected by MWP or MGP like other cytokines. This suggested that muscadine polyphenols had limited impact on the Th17 cells in the immune system. Mice gavaged with MPG and MWP had comparable plasma cytokine content, suggesting similar anti-inflammation activity. Conclusions Muscadine grape and wine polyphenols blunt the development of arthritis in mice by reducing the levels of key inflammatory cytokines, antibodies, and proteases, and may offer a promising dietary approach to manage arthritic symptoms. Funding Sources Florida Department of Agriculture and Consumer Service and Florida Viticulture Advisory Council.

scholarly journals IL-38 restrains inflammatory response of collagen-induced arthritis in rats via SIRT1/HIF-1α signaling pathway

2020 ◽  
Vol 40 (5) ◽  
Author(s):  
Bing Pei ◽  
Keyan Chen ◽  
Shenglai Zhou ◽  
Dongyu Min ◽  
Weiguo Xiao
Keyword(s):  
Inflammatory Response ◽  
Signaling Pathway ◽  
Joint Damage ◽  
Inhibitory Effect ◽  
Angiogenic Factor ◽  
Inflammatory Factors ◽  
Control Group ◽  
Collagen Induced Arthritis ◽  
Related Proteins

Abstract Objective: To observe the restraining effect of IL-38 on inflammatory response in collagen-induced arthritis rats (CIA), and to explore the regulatory mechanism of SIRT1/HIF-1α signaling pathway. Methods: 40 SD rats were randomly divided into Control group, CIA group, CLL group and CLH group, with 10 rats in each group; CIA rat model was established. The effects of IL-38 on arthritis index, inflammatory response, osteogenic factor and angiogenic factor were observed by methods including HE staining, ELISA, immunohistochemical and immunofluorescence. Human synoviocytes were cultured in vitro, and SIRT1 inhibitors were added to detect the expression for relating factors of SIRT1/HIF-1α signaling pathway by Western blot. Results: IL-38 could alleviate CIA joint damage and restrain inflammatory response, could up-regulate the expression of OPG in CIA rats and could down-regulate the expression of RANKL and RANK. IL-38 could restrain the expression of VEGF, VEGFR1, VEGFR2 and HIF. Moreover, we found that IL-38 could up-regulate the SIRT1 expression and down-regulate the HIF-1α, TLR4 and NF-KB p65 expression in CLL and CLH groups. From the treatment of synoviocytes to simulate the CIA model and the treatment of SIRT1 inhibitors, we demonstrated that the inhibitory effect of IL-38 on inflammatory factors and regulation of SIRT1/HIF-1α signaling pathway-related proteins were inhibited. Conclusion: IL-38 can restrain the inflammatory response of CIA rats, can promote the expression of osteogenic factors, can inhibit neovascularization, and can alleviate joint damage in rats. The mechanism may be related to the regulation of SIRT1/HIF-1α signaling pathway.

Inhibition of Listeria innocua in Milk by Bacteriocin-Producing Enterococcus faecium 7C5

1995 ◽  
Vol 58 (6) ◽  
pp. 621-623 ◽  
Author(s):  
GIORGIO GIRAFFA ◽  
DOMENICO CARMINATI ◽  
GIOVANNA TORRI TARELLI
Keyword(s):  
Enterococcus Faecium ◽  
Streptococcus Thermophilus ◽  
Inhibitory Effect ◽  
Bacteriocin Production ◽  
Listeria Innocua ◽  
Lactobacillus Delbrueckii ◽  
Bacteriostatic Effect ◽  
Soft Cheese ◽  
Ph Decrease ◽  
Lactobacillus Delbrueckii Subsp

Enterococcus faecium 7C5 produces a bacteriocin active against Listeria monocytogenes and Listeria innocua. In co-cultures of the strain 7C5 with a thermophilic starter, which was composed of Streptococcus thermophilus and Lactobacillus delbrueckii subsp. bulgaricus, the acidifying activity of the latter was not affected. In contrast, the rate of bacteriocin production was lower when compared with the pure culture of strain 7C5. In co-cultures of L. innocua CNRZ LIN 11 with the thermophilic starter or with strain 7C5, a bacteriostatic effect on Listeria growth was observed. In the co-culture of L. innocua with both strain 7C5 and the thermophilic starter, a complete listerial inhibition occurred. The combined inhibitory effect of the pH decrease and bacteriocin production, which were shown to be synergistic, was demonstrated both at 37°C and under temperature conditions reproducing the first 24 h of a soft-cheese technology. This data substantially supported the potential of using bacteriocin-producing strains as a culture adjunct to inhibit Listeria during cheese manufacturing.

scholarly journals Effects of the Cathepsin K Inhibitor ONO-5334 and Concomitant Use of ONO-5334 with Methotrexate on Collagen-Induced Arthritis in Cynomolgus Monkeys

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Hiroyuki Yamada ◽  
Hiroshi Mori ◽  
Yasutomo Nakanishi ◽  
Satoshi Nishikawa ◽  
Yasuaki Hashimoto ◽  
...  
Keyword(s):  
Joint Destruction ◽  
Cathepsin K ◽  
Type Ii Collagen ◽  
Control Group ◽  
Type I ◽  
Type Ii ◽  
Collagen Induced Arthritis ◽  
Cynomolgus Monkeys ◽  
X Ray ◽  
Cathepsin K Inhibitor

We examined whether the cathepsin K inhibitor, ONO-5334, administered alone or in combination with methotrexate (MTX), could ameliorate joint destruction evoked by collagen-induced arthritis (CIA) in female cynomolgus monkeys. CIA was induced by immunizing with bovine type II collagen. ONO-5334 (30 mg/kg/day) was orally administered once daily and MTX (10 mg/body/day) twice weekly for 9 weeks. X-ray (evaluation of joint destruction) and swelling (inflammatory) scores of proximal interphalangeal (PIP), distal interphalangeal (DIP), and metacarpophalangeal (MP) joints were evaluated. Urinary concentrations of C-terminal telopeptide of type I collagen (CTX-I) and type II collagen (CTX-II) were measured. Arthritis, accompanied by bone and cartilage destruction, was successfully induced in this collagen-induced arthritis monkey model. ONO-5334 showed no suppressive effect on joint swelling, while the joint swelling scores in the MTX and combination (ONO-5334 + MTX) groups were less than 50% compared with the control group. ONO-5334 decreased X-ray score by a mean of 64% (p<0.05 vs the control group), and MTX also decreased in X-ray score by a mean of 46% but with no statistical significance. Combination of ONO-5334 and MTX further decreased the X-ray score by 28% over MTX group (74% reduction vs the control group, p<0.01). Maximum increase in CTX-I (10-fold) and CTX-II (7-fold) compared to baseline was observed at 7 and 3 weeks after the first sensitization, respectively. After treatment with ONO-5334 alone or in combination with MTX, concentrations were maintained near baseline for both markers. In conclusion, ONO-5334 prevented joint destruction but not joint inflammation in this monkey CIA model. Concomitant use of ONO-5334 with MTX reduced architectural joint destruction compared to MTX alone; therefore, ONO-5334 may help to prevent joint destruction in combination with MTX for the treatment of rheumatoid arthritis.

scholarly journals IL-6 Promotes Islet β-Cell Dysfunction in Rat Collagen-Induced Arthritis

2016 ◽  
Vol 2016 ◽  
pp. 1-6 ◽  
Author(s):  
Huan Jin ◽  
Yaogui Ning ◽  
Haotong Zhou ◽  
Youlian Wang
Keyword(s):  
Glucose Metabolism ◽  
Caspase 3 ◽  
Islet Cells ◽  
Type Ii Collagen ◽  
Intradermal Injection ◽  
Control Group ◽  
Collagen Induced Arthritis ◽  
Abnormal Glucose Metabolism ◽  
Pancreas Islet ◽  
Related Enzyme

The aim of this study was to explore the possible mechanism of rheumatoid arthritis- (RA-) related abnormal glucose metabolism. The model of collagen-induced arthritis (CIA) was established by intradermal injection of type II collagen into Wistar rats; complete Freund’s adjuvant injections were used as the control group. Fasting plasma glucose (FBG) was measured by the glucose oxidase method. Fasting insulin (FIns) and the expressions of IL-6 were detected by ELISA. Islet caspase-3 was examined by immunohistochemistry. On day 17 after immunization, FBG of the CIA group showed an elevated FBG value compared with the control group. Meanwhile, the FIns of group CIA was lower when compared with the control group. Interestingly, the inflammatory cytokine IL-6 expression was significantly increased when compared with the control group. As expected, the abnormal glucose metabolism was accompanied by the increased IL-6 expression. Furthermore, in line with the upregulated IL-6 expression, the apoptosis related enzyme caspase-3 was also markedly increased. These data showed that the elevated FBG in CIA may be associated with the reduced FIns level secondary to the overapoptosis of pancreas islet cells induced by IL-6.

scholarly journals Comparative Evaluation of 68Ga-Citrate PET/CT and 18F-FDG PET/CT in the Diagnosis of Type II Collagen-Induced Arthritis in Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Zi Wang ◽  
Liang Cai ◽  
Tingting Xu ◽  
Dan Tang ◽  
Lin Liu ◽  
...  
Keyword(s):  
Fdg Pet ◽  
Type Ii Collagen ◽  
Thigh Muscle ◽  
Control Group ◽  
Late Time ◽  
Type Ii ◽  
Collagen Induced Arthritis ◽  
Pet Ct ◽  
Fdg Pet Ct

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic, symmetrical, and erosive synovitis. RA is one of the most common disabling diseases in the clinic. The main clinical intervention strategies are early diagnosis and early treatment. This study aims to predict the diagnostic value of 68Ga-citrate and 18F-FDG PET/CT in RA by comparing and analyzing the value of 68Ga-citrate and 18F-FDG PET/CT for diagnosing type II collagen-induced arthritis (CIA) in rats. Some CIA models were established. Normal rats were selected as the control group, and 23 days and 40 days were selected as the early and late time points of arthritis, respectively. The semiquantitative analysis of CIA rats was carried out with 68Ga-citrate PET/CT and 18F-FDG PET/CT, and the ratio of the maximum standardized uptake (SUVmax) values in the regions of interest (ROIs) of the hind foot ankle joint and thigh muscle was calculated and statistically analyzed. The distribution of CIA rats in vivo at the 68Ga-citrate 90 min time point was studied, and the ankle tissues were evaluated with hematoxylin and eosin (HE) staining. 68Ga-citrate PET/CT is obviously superior to 18F-FDG PET/CT for CIA imaging, and the statistical results show that the difference between the two examination methods is statistically significant (P<0.001). The uptake of these two radiopharmaceuticals showed the same trend in arthritis rats with different scores. The distribution of 68Ga-citrate at 90 min is consistent with the trend shown by 68Ga-citrate PET/CT. 68Ga-citrate PET/CT can reflect the inflammatory activity of affected joints in CIA rats earlier and more sensitively than 18F-FDG PET/CT, and this imaging advantage continues until the later stage of inflammation. Therefore, 68Ga-citrate PET/CT is worthy of further promotion and application in the clinical diagnosis of RA.

Anti-inflammatory Effect of Bee Venom on Type II Collagen-Induced Arthritis

2004 ◽  
Vol 32 (03) ◽  
pp. 361-367 ◽  
Author(s):  
Jae-Dong Lee ◽  
Su-Young Kim ◽  
Tae-Woo Kim ◽  
Sang-Hoon Lee ◽  
Hyung-In Yang ◽  
...  
Keyword(s):  
Acupuncture Therapy ◽  
Acupuncture Point ◽  
Type Ii Collagen ◽  
Bee Venom ◽  
Control Group ◽  
Type Ii ◽  
Collagen Induced Arthritis ◽  
Collagen Injection ◽  
Tnf Α ◽  
Anti Inflammatory

Bee venom (BV) has been used to relieve pain and reduce inflammation in traditional Oriental medicine, especially in chronic inflammatory diseases such as rheumatoid arthritis (RA). We previously reported that the BV injection into a traditional acupuncture point (Zusanli) reduced arthritis-associated edema and nociceptive responses in Freund's adjuvant-induced arthritis in rats (Kwon et al., 2001). This study was designed to evaluate the anti-inflammatory and anti-cytokine effect of BV on a murine type-II collagen-induced arthritis (CIA) model. Male mice were immunized by spontaneous injection of 100 μg of an emulsion of bovine type-II collagen and complete Freund's adjuvant (CFA), with a booster injection after 2 weeks. In the experimental group, 0.1 ml BV was injected at acupuncture point (Zusanli) near both knees twice a week for a total of 5 times. In the control group, normal saline was injected at the same frequencies. These injections began 5 weeks after the first collagen injection. Starting the 3rd week after the first collagen injection, we examined limb swelling and severity of arthritis twice a week. At 8 weeks, mice were sacrificed and synovial tissue was examined with the light microscope and serum cytokines (IL-1β and TNF-α) were measured by ELISA. The incidence of arthritis, the mean arthritis index and the number of arthritic limbs were significantly lower in the treatment compared to the control group (63% versus 75%, 3.4% versus 8.5%, 23% versus 75%, respectively). Among the serum proinflammatory cytokines, the production of TNF-α in the BV group was suppressed compared to the control group (59+/-4.5 versus 99.5+/-6.5, p <0.05), but IL-1β was not suppressed. The examination of the histopathology of the joints of murine CIA showed decreased inflammation signs and less lymphocyte infiltration after BV acupuncture therapy. Acupuncture therapy with BV suppressed the development of arthritis and caused inhibition of the immune responses in type-II collagen-induced arthritis.

scholarly journals Tomatidine Suppresses the Destructive Behaviors of Fibroblast-Like Synoviocytes and Ameliorates Type II Collagen-Induced Arthritis in Rats

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaolu Yu ◽  
Junnan Zhou ◽  
Fuli Zhao ◽  
Xuan Liu ◽  
Yuhang Mao ◽  
...  
Keyword(s):  
Joint Destruction ◽  
Type Ii Collagen ◽  
Inhibitory Effect ◽  
Collagen Induced Arthritis ◽  
Alternative Agent ◽  
And Migration ◽  
Solanaceae Family ◽  
Fibroblast Like Synoviocytes

Fibroblast-like synoviocytes (FLSs) are the prominent non-immune cells in synovium and play a pivotal role in rheumatoid arthritis (RA) pathogenesis. Searching for natural compounds that may suppress the pathological phenotypes of FLSs is important for the development of RA treatment. Tomatidine (Td), a steroidal alkaloid derived from the solanaceae family, has been reported to have anti-inflammatory, anti-tumor and immunomodulatory effects. However, its effect on RA remains unknown. Here, we examined the inhibitory effect of Td on TNFα-induced arthritic FLSs, and subsequently investigated its therapeutic effect on collagen-induced arthritis (CIA) rats. Our results revealed that Td significantly inhibited TNFα-induced proliferation and migration of arthritic FLSs. In addition, we found that Td treatment could efficaciously ameliorate synovial inflammation and joint destruction of rats with CIA. Both in vitro and in vivo studies showed that Td significantly suppressed the production of pro-inflammatory cytokines including IL-1β, IL-6 and TNFα, and downregulated the expression of MMP-9 and RANKL. Further molecular mechanism studies revealed that the inhibitory effect of Td on RA might attribute to the decreased activations of MAPKs (ERK and JNK) and NF-κB. These findings provide evidence that Td has the potential to be developed into a complementary or alternative agent for RA therapy.

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