Collagen-induced Arthritis Rats Research Articles

Protective effect of lupeol on arthritis induced by type II collagen via the suppression of P13K/AKT signaling pathway in Sprague dawley rats

To explore the therapeutic value of lupeol on collagen-induced arthritis (CIA) in rats, a rheumatoid arthritis model. Lupeol is well known pentacyclic triterpene found in various plant sources, which possess anti-inflammatory and antioxidant actions. The current study was assessed the anti-arthritic potential of lupeol and its molecular mechanisms as compared with indomethacin (Indo) in collagen-induced arthritis CIA rats. The rats were randomly alienated into five groups: Control, CIA alone, CIA + lupeol (10mg/kg bw), CIA + Indomethacin (3mg/kg bw), and lupeol (10mg/kg bw) alone. The paw volume, biochemical, hematological parameters, inflammatory enzymes, and cytokines were measured. As well protein expression of apoptotic proteins, and histopathological of ankle joint were examined. Inflammatory markers, cytokines, histological changes, paw volume, and inflammation were intensely reduced and enhanced apoptosis by lupeol. Alterations in hematological parameters, rheumatoid factor, C-reactive protein, and ceruloplasmin in arthritis were reverted by lupeol. Protein expressions of Bcl-2, and P13K/Akt signaling were declined, whereas the Bax, caspssae-3, and caspase-9 were elevated. These results highlighted that lupeol suppresses P13K/Akt signaling and has a promising anti-arthritic potential for collagen-induced rheumatic arthritis treatment. Hence lupeol would be suggested as an alternative natural source with potent anti-inflammatory and apoptotic actions for chronic inflammatory disorders.

Dose-Dependent Efficacy of Umbelliferone and Gelatin-Coated ZnO/ZnS Core-Shell Nanoparticles: A Novel Arthritis Agent for Severe Knee Arthritis.

Rheumatoid arthritis (RA) is a well-known autoimmune disorder that affects 1% of the global population. Zinc (Zn) is crucial for bone homeostasis, when compared with normal human bone, Zn level found to be decreased in RA patients and collagen-induced arthritis (CIA) rats. Notably, Zn-based medicinal products play a prominent role in reducing disease symptoms and acute side effects of patients with bone-related diseases. In this study, we report the clinical efficiency of gelatin- (Gel-) coated ZnO-ZnS core-shell nanoparticles (CSNPs) with umbelliferon (Uf) drug (Uf-Gel-ZnO-ZnS CSNPs) on the normal and CIA-induced Wistar rats. The formed ZnO-ZnS CSNPs are spherical in shape, with an average particle diameter of 150 ± 7 nm. It showed strong cytocompatibility when tested on L929 and foreskin fibroblasts (BJ) cells by MTT assay. While comparing with free Uf, various doses (2.5 and 5 mg) of Uf-Gel-ZnO-ZnS CSNPs showed strong inhibition of CIA by attenuated proinflammatory cytokines such as interleukin-1β, IL-6, PEG2, and IL-17. The Uf-Gel-ZnO-ZnS CSNPs show more effectiveness in reducing joint swelling and also increase the level of antioxidant enzymes. In addition, CSNPs significantly reduced the infiltration of inflammatory cells in the knee joint. Thus, the current study concludes that Uf-Gel-ZnO-ZnS CSNPs feasibly reduce the incidence of arthritis in a dose-dependent manner by attenuation of inflammation.

Long Non-Coding RNA NR-133666 Promotes the Proliferation and Migration of Fibroblast-Like Synoviocytes Through Regulating the miR-133c/MAPK1 Axis.

Long non-coding RNA (lncRNA) is involved in the regulation of rheumatoid arthritis (RA) and many other diseases. In this study, a new lncRNA, NR-133666, was identified to be highly expressed in the adjuvant-induced arthritis rat model using the Agilent lncRNA microarray assay. qRT-PCR verified that NR-133666 was upregulated in fibroblast-like synoviocyte of a collagen-induced arthritis (CIA) rat model. Fluorescence in situ hybridization analysis showed that NR-133666 is mainly expressed in the cytoplasm of collagen-induced arthritis FLS. MTT assay and EdU staining results showed that the proliferation of CIA FLS was inhibited after NR-133666 was knocked down, and the wound healing assay showed that the migration of CIA FLS was also suppressed. Dual luciferase detection was used to confirm the relationship among NR-133666, miR-133c and MAPK1. MAPK1 is the target gene of miR-133c, where NR-133666 acts as a sponge of miR-133c to reduce the inhibitory effect of miR-133c on MAPK1. Overexpression of NR-133666 and MAPK1 can promote the proliferation and migration of CIA FLS, and overexpression of miR-133c can reverse this phenomenon. Western blot indicated that it may be related to the ERK/MAPK signaling pathway. Collectively, we identified that lncRNA NR-133666 acted as a miR-133c sponge that can promote the proliferation and migration of CIA FLS through regulating the miR-133c/MAPK1 axis.

Targeted co-delivery biomimetic nanoparticles reverse macrophage polarization for enhanced rheumatoid arthritis therapy

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease, which is characterized by synovial inflammation and autoimmunity. The main cause of the disease is the imbalance of the proportion of pro-inflammatory macrophages (M1-type) and anti-inflammatory macrophages (M2-type) in the synovial tissues of the joint. To restore this balance, in our study, the interleukin-10 encoding anti-inflammatory cytokines (IL-10 pDNA) and chemotherapeutic drug dexamethasone sodium phosphate (DSP) were co-loaded into human serum albumin (HSA) preparing pDNA/DSP-NPs to actively target macrophages in synovium tissue to promote M1-M2 polarization. Confocal laser scanning microscope and western blot were used to demonstrate the targeting ability of co-delivery nanoparticles. In vivo, the real-time fluorescence imaging system and HPLC were used to study the tissue distribution and pharmacokinetics of nanoparticles, and the results showed that the accumulation of nanoparticles in the inflammatory joint site was higher. Its pharmacodynamics were evaluated in collagen-induced arthritis (CIA) rat model, and it demonstrated that the pDNA/DSP-NPs significantly reduced the expression of serum inflammatory factors and alleviated joint swelling and bone erosion, suggesting the favorable therapeutic effect. The synergistic treatment effect of IL-10 pDNA and DSP in this system was achieved by reducing the secretion of pro-inflammatory factors (TNF-α, IL-1β) and increasing the expression of anti-inflammatory factors (IL-10) to promote the M1-M2 polarization of macrophages. Our strategy is promising for co-delivery of gene drugs and chemical drugs by biomimetic natural materials to promote macrophages polarization so that to achieve synergically treatment of inflammatory disease.

Novel Deep Eutectic Solvent-Hydrogel Systems for Synergistic Transdermal Delivery of Chinese Herb Medicine and Local Treatments for Rheumatoid Arthritis.

In this study, a novel hydrogel system incorporating an amino acid-based deep eutectic solvent (DES) was prepared, and the skin-permeation enhancement of traditional Chinese herb medicine was evaluated using "sanwujiaowan" extract as the model formula. Briefly, a DES-extract complex was constructed by co-heating the herb formula extracts with the amino acid as the hydrogen receptor and citric acid as the hydrogen donor. The DES-extract complex demonstrated excellent dissolution and skin permeability of the complicated ingredients in the extracts. Consequently, the DES-extract complex was introduced to a hydrogel system, which showed better mechanical properties and viscoelasticity performance. Using a collagen-induced arthritis rat model, the DES-hydrogels exerted an enhanced therapeutic effect that significantly reduced the inflammatory response with systemic toxicity of the extracts. Therefore, our work suggests a novel strategy for synergistic transdermal delivery of Chinese herb medicine and local treatments for rheumatoid arthritis.

Effects of transcutaneous auricular vagus nerve stimulation on bone and cartilage destruction in rats with rheumatoid arthritis

To observe the alleviating effect of transcutaneous auricular vagus nerve stimulation (taVNS) on articular cartilage and bone destruction in rats with collagen-induced arthritis (CIA), and explore the cellular and molecular mechanisms of taVNS against rheumatoid arthritis (RA). The male SD rats were randomly divided into normal control group (n=12), model group (n=12), and taVNS group (n=12). The CIA rat model was established by multi-point injection of emulsion prepared from type Ⅱ bovine collagen and Freund's incomplete adjuvant into the root of rat tail. The rats in the taVNS group were treated with taVNS at bilateral auricular conchae, 30 min per time, once a day, for consecutive 28 d. The cartilage destruction of the ankle joint was observed by safranin O-fast green staining, the production of osteoclasts in the joint tissue by tartrate-resistant acid phosphatase (TRAP) staining, and the bone erosion by X-ray and Micro-CT imaging. The protein expression levels of matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, receptor activator of nuclear factor-κB ligand (RANKL), and osteoprotegerin (OPG) in the synovial tissues were detected by Western blot. Compared with the normal control group, the CIA rats presented with typical RA symptoms and elevated arthritis index (AI,P<0.05). After intervention with taVNS, the AI remarkably declined in comparison with that in the model group (P<0.05). Compared with the control group, the model group displayed loss of cartilage matrix in the ankle joint, thinned cartilage layer, obvious cartilage damage, and increased number of osteo-clasts in the joint (P<0.01); the imaging results showed bone loss and three-dimensional structural destruction of ankle joint and aggravated bone erosion (P<0.01); the expression levels of MMP-1, MMP-3 and MMP-13, and RANKL/OPG ratio were significantly elevated in the synovial tissue of ankle joint (P<0.01, P<0.05), while the expression level of OPG was decreased (P<0.05). Compared with the model group, taVNS resulted in relatively intact cartilage layer of ankle joint, alleviated cartilage destruction, decreased number of osteoclasts (P<0.01), improved bone erosion, loss, and three-dimensional structural destruction (P<0.01), and diminished MMP-1, MMP-3, and MMP-13 expression and RANKL/OPG ratio in the synovial tissue of ankle joint (P<0.05, P<0.01), while the expression level of OPG was increased (P<0.05). taVNS effectively relieves bone and cartilage destruction in CIA rats, which might be related to its efficacy in reducing the production of osteoclasts in joint tissues and down-regulating the expression levels of MMP-1, MMP-3 and MMP-13, and RANKL/OPG ratio.

Ebosin Attenuates the Inflammatory Responses Induced by TNF-α through Inhibiting NF-κB and MAPK Pathways in Rat Fibroblast-Like Synoviocytes.

Tumor necrosis factor-α (TNF-α) lies at the apex of signal transduction cascades that results in induced destruction of joints in rheumatoid arthritis. It is therefore of great medicinal interest to modulate the cellular responses to TNF-α. Ebosin, a novel exopolysaccharide derived from Streptomyces sp, has been demonstrated to have remarkable therapeutic actions on collagen-induced arthritis in rats, while it also suppressed the production of IL-1β, TNF-α, and IL-6 at both mRNA and protein levels in cultured fibroblast-like synoviocytes. In order to further understand the potential mechanisms involved in the anti-inflammatory effects of ebosin at molecular level, we investigated the impact of it on the activation of MAPK and NF-κB pathways following TNF-α induced in fibroblast-like synoviocytes (FLS). The results showed that the phosphorylation levels of TNF-α-induced p38, JNK1, JNK2, IKKα, IKKβ, and IκB, as well as NF-κB nuclear translocation, were reduced significantly in FLS cells in response to ebosin. Furthermore, we proved that ebosin decreased the level of NF-κB in the nucleus and blocked the DNA-binding ability of NF-κB using electrophoresis mobility gel shift assay. Besides, low levels of matrix metalloproteinases (MMP-1 and MMP-3) and chemokines (interleukin-8 and RANTES) were found in TNF-α-stimulated fibroblast-like synoviocytes treated with ebosin. These results indicate that ebosin can suppress a range of activities in both MAPK and NF-κB pathways induced by TNF-α in rat fibroblast-like synoviocytes, which provides a rationale for examining the use of ebosin as a potential therapeutic candidate for rheumatic arthritis.

Lactiplantibacillus plantarum HG20 attenuates II type collagen-induced rheumatoid arthritis in rats via anti-inflammatory and inhibition of apoptosis.

This study aimed to explore the therapeutic effects of Lactiplantibacillus plantarum HG20 (HG20) on collagen-induced arthritis (CIA) rats and its mechanism. CIA rats were established by injecting bovine type II collagen for 7days, and treated by intragastric administration HG20 for 21days. The foot palm temperature and arthritis score were measured once a week. The pathological changes in the knee joint were observed by hematoxylin and eosin staining. The levels of cytokines were detected by enzyme linked immunosorbent assay, and the effects of HG20 on inflammatory and apoptosis pathway of spleen cells were detected by western blot analysis. The results indicated that HG20 reduced the joint swelling degree and foot palm temperature, inhibited the development of joint histopathology, decreased the levels of pro-inflammatory cytokines, down-regulate the expression of pro-inflammatory cytokines by nuclear factor kappa-B pathway, and inhibited the apoptosis of spleen cells by inhibiting phosphatidylinositol 3-kinase/protein kinase B pathway and regulating apoptosis pathways. HG20 had an adjuvant therapeutic effect on arthritis in CIA rats, and its mechanism might be related to the inflammatory and apoptosis pathway. These results revealed that HG20 could be used as a functional probiotic in the field of food and medical, and which played a potential role in the prevention and treatment of arthritis.

CD81 inhibition with the cytoplasmic RNA vector producing anti-CD81 antibodies suppresses arthritis in a rat CIA model

ObjectiveCluster of differentiation 81 (CD81) is a tetraspanin membrane protein consisting of 4 transmembrane domains and 2 outer membrane loops. CD81 inhibition is a potential treatment for rheumatoid arthritis (RA). Here, we investigated the therapeutic effects of the cytoplasmic RNA vector expressing anti-CD81 antibodies (the anti-CD81 vector) on the ankle joint synovium in collagen-induced arthritis (CIA) rats. MethodsBody weight, paw volume, and clinical scores were measured on days 0, 7, and 10 and daily thereafter. On day 28, the ankle joints of the rats were removed and stained with haematoxylin, eosin, and Safranin O. Arthritic changes such as inflammatory cell infiltration, synovial proliferation, articular cartilage destruction, and bone erosion were evaluated by histological scoring. ResultsSymptom onset was delayed in the right lower limbs of the rats administered the cytoplasmic RNA vector (CIA + anti-CD81) compared with that in the control group (CIA + control). The CIA + anti-CD81 rats were heavier than the CIA + control rats. The paw volume and clinical scores were significantly lower in the CIA + anti-CD81 than in the CIA + control. The histological scores indicated significantly milder manifestations of RA in the CIA + anti-CD81 than in the CIA + control. ConclusionsAdministration of the cytoplasmic RNA vector expressing anti-CD81 antibodies suppressed arthritis and joint destruction in CIA rats. Our findings suggest that the cytoplasmic RNA vector can be used to treat RA.

The inhibitory effect of tocilizumab on systemic bone loss and tendon inflammation in a juvenile Collagen-Induced arthritis rat model

ABSTRACT Purpose of the study Reduced Bone Mineral Density (BMD) is a prevalent comorbidity in Juvenile Idiopathic Arthritis (JIA). Enthesitis and other tendon abnormalities, such as tenosynovitis, tendinitis and tendon ruptures are, also, common extra-articular manifestations of the disease. The aim of the present study was to investigate the effect of tocilizumab, an antibody that binds the Interleukin-6 (IL-6) Receptor, on inflammation-related bone loss and tendon inflammation in an animal model of JIA. Materials and Methods The Collagen-Induced Arthritis (CIA) model was induced in male rats followed by intraperitoneal administration of tocilizumab for 8 weeks. Methotrexate, the most widely used Disease-Modifying Antirheumatic Drug in the management of JIA, was, also, administered, either as a monotherapy or as an add-on therapy to tocilizumab. BMD was evaluated with Micro-Computed Tomography (Micro-CT) and histopathological examination. Tendon damage was, also, assessed histologically. Finally, two pro-inflammatory cytokines, Tumor Necrosis Factor-alpha (TNF-a) and Interleukin-23 (IL-23) were quantified in tendon tissues by ELISA analysis. Results Tocilizumab-treated animals exhibited a significantly improved trabecular microarchitecture on micro-CT analysis and histological examination. Tendon morphology was also improved. Anti-IL-6 treatment led to a significant decrease in TNF-a and IL-23 expression in tendon tissue. Conclusions The results of the present study provide evidence that tocilizumab reduces inflammation-related bone loss and suppresses tendon inflammation in a juvenile CIA rat model. These findings offer perspectives for the management of osteoporosis and enthesitis in JIA.

Traditional Tibetan Medicine Twenty-Five Wei'er Tea Pills Ameliorate Rheumatoid Arthritis Based on Chemical Crosstalk Between Gut Microbiota and the Host.

Twenty-Five Wei’er Tea Pills (TFP), a traditional Tibetan medicine, has shown to have a promising therapeutic effect in patients with Rheumatoid arthritis (RA), as well as being safe. Nonetheless, there have been limited pharmacological studies that have explored this therapeutic option. As gut microbiota has been proven to have a critical role in the pathogenesis of RA, this study aims to explore and reveal relevant ways by which TFP interacts with the chemical crosstalk between the gut microbiome and its host. 16S rRNA sequencing, combined with un-targeted metabolomics, were conducted on collagen-induced arthritis (CIA) rats. CIA model rats treated with TFP showed significant improvement in weight gain, pathological phenomena in joints, as well as decreased serum levels of TNF-α, IL-6 and increased level of IL-4 and IL-10. Significant dysfunction in the gut microbiome and alteration in serum metabolites were observed in CIA model rats, which were restored by TFP treatment. Coherence analysis indicated that TFP modulated the pathways of histidine metabolism, phenylalanine metabolism, alanine, aspartate, glutamate metabolism, amino sugar and nucleotide sugar metabolism owing to the abundances of Lactobacillus, Bacteroides, Prevotellaceae_UCG-001 and Christensenellaceae_R-7_group in the gut microflora. The corresponding metabolites involved L-histidine, histamine, phenylethylamine, asparagine, L-aspartic acid, D-fructose 1-phosphate, D-Mannose 6-phosphate, D-Glucose 6-phosphate, and Glucose 1-phosphate. In conclusion, this study reveals the ameliorative effects of TFP on RA through the chemical crosstalk that exists between the gut microbiota and its host, and also further enriches our understandings of the pathogenesis of RA.

Yunnan Baiyao Ameliorates Rheumatoid Arthritis in Rats by Shifting the Th17/Treg Cell Balance and Preventing Osteoclast Differentiation.

Yunnan Baiyao (YNB) is a traditional Chinese medicine that possesses anti-inflammatory effects. Previously, we have demonstrated the effects of YNB in rheumatoid arthritis (RA) animal models; however, the underlying mechanisms are unclear. In the present study, we aimed to investigate the effects of YNB on the T-helper (Th)17/T-regulatory (Treg) cell balance in a collagen-induced arthritis rat model orally administrated YNB or methotrexate, a widely used therapeutic agent for treating RA. Our results showed that YNB treatment significantly decreased the voix pedis thickness and joint functionality scores and alleviated joint histopathology in these rats. These YNB-induced effects were achieved by decreasing the number of Th17 cells and increasing that of Treg cells in the spleen. Moreover, the interleukin- (IL-) 17 level considerably decreased in the serum of YNB-treated rats, whereas the IL-10 level significantly increased. Furthermore, YNB could inhibit RANKL-induced osteoclast formation by regulating the tumor necrosis factor receptor-associated factor 6/NF-κB/nuclear factor of the activated T-cell pathway. In summary, our study shows that YNB exhibits antiarthritic activity by decreasing the ratio of Th17/Treg cells, regulating the cytokine balance, and inhibiting osteoclast activation, providing an experimental basis that supports the use of this traditional Chinese medicine for the clinical treatment of RA.

Integrating 16S sequencing and metabolomics study on anti-rheumatic mechanisms against collagen-induced arthritis of Wantong Jingu Tablet.

Wantong Jingu Tablet (WJT), a mixture of traditional Chinese medicine, was reported to relieve the symptoms of rheumatoid arthritis (RA), but its pharmacological mechanism was not completely understood. The aim of this study was to investigate the therapeutic mechanisms of WJT for RA in vivo. The effects of WJT on joint pathology, as well as the levels of Bax, Bcl-2, caspase-3, cleaved-caspase-3, ERK1/2, pERK1/2, TNF-α, IL-1β, and IL-6 were measured using collagen-induced arthritis (CIA) rats. The intestinal flora composition and the metabolites alteration were analyzed by 16S rDNA sequencing and metabolomics method, respectively. We found that WJT ameliorated the severity of the CIA rats which might be mediated by inducing apoptosis, inactivating the MEK/ERK signals and reducing the production of pro-inflammatory cytokines. WJT, in part, relieved the gut microbiota dysbiosis, especially bacterial phylum Bacteroidetes, Tenericutes and Deferribacteres, as well as bacterial genus Vibrio, Macrococcus and Vagococcus. 3'-N-debenzoyl-2'-deoxytaxol, tubulysin B, and magnoline were significantly associated with the specific genera. We identified serotonin, glutathione disulfide, N-acetylneuraminic acid, naphthalene and thromboxane B2 as targeted molecules via metabolomics. Our findings contributed to the understanding of RA pathogenesis, and WJT played essential roles in gut microbiota health and metabolite modulation in the CIA rats.

Network Pharmacology and Molecular Docking Study of the Chinese Miao Medicine Sidaxue in the Treatment of Rheumatoid Arthritis.

PurposeThis study aimed to investigate the molecular mechanisms of Compound Sidaxue (SX), a prescription of Chinese Miao medicine, in treating rheumatoid arthritis (RA) using network pharmacology and in vivo experimental approaches.MethodsNetwork pharmacology was adopted to detect the active components of four Traditional Chinese herbal medicine (TCM) of SX, and the key targets and signaling pathways in the treatment of RA were predicted, and the key components and targets were screened for molecular docking. The predicted targets and pathways were validated in bovine type II collagen and incomplete Freund’s adjuvant emulsifier-induced rat RA model.ResultsIn this study, we identified 33 active components from SX, predicted to act on 44 RA-associated targets by network pharmacology. PPI network demonstrated that TNF-α, VEGF-A, IL-2, IL-6, AKT, PI3K, STAT1 may serve as the key targets of SX for the treatment of RA. The main functional pathways involving these key targets include PI3K-AKT signaling pathway, TNF signaling pathway, NF-κB signaling pathway. Molecular docking analysis found that the active components β-amyrin, cajanin, eleutheroside A have high affinity for TNF-α, VEGFA, IL-2, AKT, and PI3K, etc. SX can improve joint swelling in Collagen-induced arthritis (CIA) rats, reduce inflammatory cell infiltration and angiogenesis in joint synovial tissue, and down-regulate IL-2, IL-6, TNF-α, VEGF, PI3K, AKT, p-AKT, NF-κBp65, the expression of p-NF-κBp65, STAT1, and PTGS2 are used to control the exacerbation of inflammation and alleviate the proliferation of synovial pannus, and at the same time play the role of cartilage protection to achieve the effect of treating RA.ConclusionThrough a network pharmacology approach and animal study, we predicted and validated the active compounds of SX and their potential targets for RA treatment. The results suggest that SX can markedly alleviate CIA rat by modulating the VEGF/PI3K/AKT signaling pathway, TNF-α signaling pathway, IL/NF-κB signaling pathway.

Wu-Teng-Gao External Treatment Improves Th17/Treg Balance in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) represents the consequence of an immune response of the body's immune system attacking healthy cells. This chronic inflammatory disorder has complicated pathogenesis. Traditional Chinese medicine (TCM) is well recognized as an effective therapy in treating RA and has been widely applied for centuries. Wu-Teng-Gao (WTG) is used as a representative natural herb formula in RA treatment in China, while its mechanisms are to be fully clarified. The present study attempted to explore mechanisms of WTG on RA treatment in a network pharmacological approach and verified using experiments in vitro. Following the establishment of a rat model of collagen-induced arthritis (CIA), WTG was applied externally on the metapedes of rats. HE staining was subsequently performed to visualize the pathological changes of synovium and bone. Simultaneously, flow cytometry was conducted to detect the cell ratio of T helper 17 (Th17) and Regulatory T cells (Treg) in splenic lymphocytes. Additionally, ELISA, qRT-PCR, and Western blot assays were adopted to determine expressions of RA-related factors in joints and serum. Results of network pharmacological analysis suggested that Th17 cell differentiation might serve as a potential signaling pathway of WTG therapy for RA. Animal experiments demonstrated that WTG ameliorated the articular inflammation and effectively inhibited the destruction of articular cartilage, and decreased Th17 and Treg cell ratios in CIA rats. Furthermore, WTG also greatly suppressed relevant levels of inflammatory cytokines (IL-17, TNF-α, IL-1, and IL-6) and RNAKL, whereas it elevated expressions of anti-inflammatory cytokines IL-10 and TGF-β. Our results confirmed that WTG might improve the imbalance of Th17/Treg cells in CIA animals through differentiation regulation, thus alleviating joint inflammation and bone destruction.

Metabolic Enzyme Triosephosphate Isomerase 1 and Nicotinamide Phosphoribosyltransferase, Two Independent Inflammatory Indicators in Rheumatoid Arthritis: Evidences From Collagen-Induced Arthritis and Clinical Samples.

Metabolic intervention is a novel anti-rheumatic approach. The glycolytic regulator NAMPT has been identified as a therapeutic target of rheumatoid arthritis (RA), while other metabolic regulators coordinating NAMPT to perpetuate inflammation are yet to be investigated. We continuously monitored and validated expression changes of Nampt and inflammatory indicators in peripheral while blood cells from rats with collagen-induced arthritis (CIA). Gene transcriptional profiles of Nampt + and Nampt ++ samples from identical CIA rats were compared by RNA-sequencing. Observed gene expression changes were validated in another batch of CIA rats, and typical metabolic regulators with persistent changes during inflammatory courses were further investigated in human subjects. According to expression differences of identified genes, RA patients were assigned into different subsets. Clinical manifestation and cytokine profiles among them were compared afterwards. Nampt overexpression typically occurred in CIA rats during early stages, when iNos and Il-1β started to be up-regulated. Among differentially expressed genes between Nampt + and Nampt ++ CIA rat samples, changes of Tpi1, the only glycolytic enzyme identified were sustained in the aftermath of acute inflammation. Similar to NAMPT, TPI1 expression in RA patients was higher than general population, which was synchronized with increase in RFn as well as inflammatory monocytes-related cytokines like Eotaxin. Meanwhile, RANTES levels were relatively low when NAMPT and TPI1 were overexpressed. Reciprocal interactions between TPI1 and HIF-1α were observed. HIF-1α promoted TPI1 expression, while TPI1 co-localized with HIF-1α in nucleus of inflammatory monocytes. In short, although NAMPT and TPI1 dominate different stages of CIA, they similarly provoke monocyte-mediated inflammation.

Inflammation-Triggered Supramolecular Nanoplatform for Local Dynamic Dependent Imaging-Guided Therapy of Rheumatoid Arthritis.

The aging of population has resulted in a significant increase in the prevalence of rheumatoid arthritis (RA), which is a persistent and recurrent synovial inflammation caused by abnormal immune activation. Herein, the authors designed an inflammation‐triggered disassembly (ITD) nanoplatform by a supramolecular assembly method, which controls the decomposition and drug release through changes in cytokine concentrations and redox potentials during the onset of arthritis, and its dual‐targeted synergistic effect on collagen‐induced arthritis (CIA) rats resulted in higher cell death rate and immunosuppressive rate. Meanwhile, they propose the local dynamic dependent imaging (LDDI) technology to diagnose the disease status, which may produce corresponding changes with the fluctuation of inflammatory activity and improve the accuracy of dual‐target therapy by monitoring the synovial changes through in situ photoactivation of the second near infrared light (NIR‐II). Very importantly, histological analysis shows that ITD strategy relieved joint destruction and cartilage degeneration and its clinical score is similar to that of the healthy group. Their work provides an effective strategy for the early diagnosis and treatment of acute and chronic inflammation diseases, which can interfere to abnormal immune activation, rather than affecting the normal function of immune system.

Cell-free DNA depletion via cell-penetrating poly(disulfide)s for rheumatoid arthritis therapy

Cell-free DNA (cfDNA)-induced inflammation is linked to various autoimmune diseases, though cfDNA scavenging for cationic polymers has been regarded as an efficient therapeutic pathway. However, most existing cfDNA scavengers have significant cytotoxicity and weakly binds to cfDNA. Here, an advanced cfDNA scavenging strategy via assembly of cfDNA is reported for rheumatoid arthritis (RA) therapy. In this study, we developed a pH-responsive calcium carbonate nanoplatform loaded with low-toxicity guanidinium-containing cell-penetrating poly(disulfide)s (CPDs, LA). The LA could strongly adhere to nucleic acid (NA) and further self-assemble into NA nanospheres. Importantly, the NA nanospheres could be directly delivered into the cell through thiol-mediated uptake, which avoided the activation of the endosomal toll-like receptors (TLRs), thereby inhibited CpG-activated inflammation. As a result, LA@CaCO3 effectively decreased the cfDNA level and alleviated the joint swelling and bone erosion on a collagen-induced arthritis (CIA) rat model of RA. Accordingly, the study proposes an advanced approach to deplete NA for autoimmune disease treatment.

Therapeutic effects of benzoylaconitine and paeoniflorin in rats with collagen-induced arthritis

To explore the effects and mechanisms of benzoylaconitine and paeoniflorin on collagen-induced arthritis (CIA) rats. Weight, paw swelling, arthritis index and joint pathologic changes were examined in each group after CIA induction. PGE2, IL-1β, IL-6, IL-10, TNF-α, VEGF, MMP-3, IgG and anti-CII Ab were assessed by ELISA; STAT1 and STAT3 expressions were analyzed immunohistochemically, and the ultrastructure of synovial cells was observed by transmission electron microscopy. Therapeutic effects were determined in CIA rats via injecting benzoylaconitine and paeoniflorin, which could alleviate the degree of swelling and arthritis index (AI) and pathological lesions of the sacroiliac gland; decrease the levels of PGE2, IL-1β, TNF-α, VEGF and IgG in serum; reduce STAT1 and STAT3 expression in the membrane tissue; and inhibit the secretion and proliferation of synovial cells. These results showed that benzoylaconitine and paeoniflorin could significantly palliate the arthritic symptoms of CIA rats, and better therapeutic effects could be achieved if the two components were used in combination.

A Combination of Docosahexaenoic Acid and Anti-TNF Therapy Against Functional and Metabolic Alterations During Collagen-Induced Arthritis in Rats

A Combination of Docosahexaenoic Acid and Anti-TNF Therapy Against Functional and Metabolic Alterations During Collagen-Induced Arthritis in Rats