Capsaicin-Sensitive Peptidergic Sensory Nerves Are Anti-Inflammatory Gatekeepers in the Hyperacute Phase of a Mouse Rheumatoid Arthritis Model

Capsaicin-sensitive peptidergic sensory nerves play complex, mainly protective regulatory roles in the inflammatory cascade of the joints via neuropeptide mediators, but the mechanisms of the hyperacute arthritis phase has not been investigated. Therefore, we studied the involvement of these afferents in the early, “black box” period of a rheumatoid arthritis (RA) mouse model. Capsaicin-sensitive fibres were defunctionalized by pretreatment with the ultrapotent capsaicin analog resiniferatoxin and arthritis was induced by K/BxN arthritogenic serum. Disease severity was assessed by clinical scoring, reactive oxygen species (ROS) burst by chemiluminescent, vascular permeability by fluorescent in vivo imaging. Contrast-enhanced magnetic resonance imaging was used to correlate the functional and morphological changes. After sensory desensitization, both early phase ROS-burst and vascular leakage were significantly enhanced, which was later followed by the increased clinical severity scores. Furthermore, the early vascular leakage and ROS-burst were found to be good predictors of later arthritis severity. We conclude that the anti-inflammatory role of peptidergic afferents depends on their activity in the hyperacute phase, characterized by decreased cellular and vascular inflammatory components presumably via anti-inflammatory neuropeptide release. Therefore, these fibres might serve as important gatekeepers in RA.

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Platelets Disseminate Extracellular Vesicles in Lymph in Rheumatoid Arthritis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.119.313698 ◽

2020 ◽

Vol 40 (4) ◽

pp. 929-942 ◽

Cited By ~ 4

Author(s):

Nicolas Tessandier ◽

Imene Melki ◽

Nathalie Cloutier ◽

Isabelle Allaeys ◽

Adam Miszta ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Extracellular Vesicles ◽

Lymphatic System ◽

Circulatory System ◽

Donor Cell ◽

Vascular Leakage ◽

In Vivo Model ◽

Interstitial Tissue ◽

Tissue Fluid

Objective: The lymphatic system is a circulatory system that unidirectionally drains the interstitial tissue fluid back to blood circulation. Although lymph is utilized by leukocytes for immune surveillance, it remains inaccessible to platelets and erythrocytes. Activated cells release submicron extracellular vesicles (EV) that transport molecules from the donor cell. In rheumatoid arthritis, EV accumulate in the joint where they can interact with numerous cellular lineages. However, whether EV can exit the inflamed tissue to recirculate is unknown. Here, we investigated whether vascular leakage that occurs during inflammation could favor EV access to the lymphatic system. Approach and Results: Using an in vivo model of autoimmune inflammatory arthritis, we show that there is an influx of platelet EV, but not EV from erythrocytes or leukocytes, in joint-draining lymph. In contrast to blood platelet EV, lymph platelet EV lacked mitochondrial organelles and failed to promote coagulation. Platelet EV influx in lymph was consistent with joint vascular leakage and implicated the fibrinogen receptor α2bβ 3 and platelet-derived serotonin. Conclusions: These findings show that platelets can disseminate their EV in fluid that is inaccessible to platelets and beyond the joint in this disease.

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Effects of Muscone on Cartilage Morphology and Matrix Metalloproteinases-3 (MMP-3h) and Matrix Metalloproteinases-9 (MMP-9) Expression in Rheumatoid Arthritis Rat Models

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2022.2951 ◽

2022 ◽

Vol 12 (4) ◽

pp. 724-730

Author(s):

Xue Zhong ◽

Yuebo Jin ◽

Yufei Feng

Keyword(s):

Rheumatoid Arthritis ◽

Matrix Metalloproteinases ◽

Morphological Changes ◽

Cartilage Tissue ◽

Model Group ◽

Rt Pcr ◽

Rat Models ◽

Matrix Metalloproteinases 9 ◽

Masson Staining

Aim: To discuss Muscone treatment in Rheumatoid Arthritis Rat Models and relative mechanisms. Materials and methods: Dividing 36 rats as 4 groups as Normal, Model, DMSO and Muscone groups (n = 9). Rats of Model, DMSO and Muscone groups were made Rheumatoid Arthritis model. Muscone group were treated with 2 mg/kg Muscone after modeling. HE staining and Masson staining were used to observe the morphological changes of cartilage tissue, measuring MMP-3 and MMP-9 expression by RT-PCR, Western Blotting (WB) and Immunohistochemistry (IHC). Results: Compared with Model group, the pathological changes of Muscone group was significantly improved and average optical density of collagen fibers was significantly depressed (P < 0.001, respectively) via MMP-3 and MMP-9 proteins significantly depressing (P < 0.001, respectively). Conclusion: Muscone improved Rheumatoid Arthritis by depressing MMP-3 and MMP-9 proteins in vivo study.

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Comparison of the Therapeutic Effects of Gold Nanoclusters and Gold Nanoparticles on Rheumatoid Arthritis

Journal of Biomedical Nanotechnology ◽

10.1166/jbn.2019.2848 ◽

2019 ◽

Vol 15 (11) ◽

pp. 2281-2290 ◽

Cited By ~ 3

Author(s):

Yao Zhao ◽

Zhesheng He ◽

Ruoping Wang ◽

Pengju Cai ◽

Xiangchun Zhang ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Au Nanoparticles ◽

Type Ii Collagen ◽

Therapeutic Effects ◽

Type Ii ◽

Au Clusters ◽

Anti Inflammatory ◽

Inflammatory Effect

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and progressive cartilage and bone damage. In our previous studies, we found that Au clusters using glutathione as a template (GACs) produced profound anti-inflammatory effects in vitro on lipopolysaccharide (LPS)-induced inflammation in mouse macrophage RAW 264.7 cells and type II collagen-induced rat RA in vivo. In this study, we examined whether the template for Au clusters synthesis has an effect on its anti-inflammatory effect and whether Au nanoparticles with larger particle diameter produce the same anti-inflammatory effect. We synthesized Au clusters with bovine serum albumin (BSA) as a template (BACs), Au clusters with glutathione (GSH) as a template (GACs), and Au nanoparticles with glutathione as a template (GANs) and compared their anti-inflammatory effects in vitro and in vivo. These three Au nanomaterials can inhibit the production of lipopolysaccharide (LPS)-induced proinflammatory mediators and ameliorate type II collagen-induced rat RA. However, although the three Au nanomaterials produced similar anti-inflammatory effects, the GANs with larger particle sizes were less stable in vivo and accumulated in the peritoneum after intraperitoneal injection, resulting in poor absorption in vivo. The BACs showed relatively high liver accumulation due to the larger molecular weight of the outer shell. Therefore, we believe that the GACs are potential reliable nanodrugs for the treatment of RA.

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Effects of lysosomal collagenolytic enzymes, anti-inflammatory drugs and other substances on some properties of insoluble collagen

Biochemical Journal ◽

10.1042/bj1130457 ◽

1969 ◽

Vol 113 (3) ◽

pp. 457-463 ◽

Cited By ~ 47

Author(s):

A. J. Anderson

Keyword(s):

Rheumatoid Arthritis ◽

Electrostatic Interactions ◽

Enzyme System ◽

Maximum Activity ◽

Thiol Compounds ◽

Insoluble Collagen ◽

Other Substances ◽

Inflammatory Drugs ◽

Anti Inflammatory

1. An enzyme system present in a rat liver lysosome-rich fraction was found to liberate soluble hydroxyproline-containing products from insoluble collagen, with maximum activity at pH3·45. It was concluded that a form of cathepsin D was involved since synthetic substrates specific for trypsin were not hydrolysed. Collagenolysis was enhanced by thiol compounds and inhibited by Cu2+ ions and the anti-inflammatory drugs phenylbutazone and ibufenac. 2. The possibility that behaviour of collagen and collagenolysis were modified by various substances, either by destruction of intramolecular and intermolecular bonds in tropocollagen or by electrostatic interactions, is discussed. Insoluble collagen was found to bind electrostatically to chondromucoprotein. This interaction was inhibited by some anti-inflammatory drugs. 3. Possible roles of the lysosomal collagenolytic enzyme system in experimental lathyrism in rats given penicillamine, and in erosion of cartilage in rheumatoid arthritis, are considered. 4. Collagenolysis in vivo, which may depend on complex interrelationships between collagen, chondromucoprotein and metal ions, is discussed in relation to possible effects, both harmful and beneficial, of anti-inflammatory drugs used in rheumatoid arthritis.

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The Anti-Inflammatory Fungal Compound (S)-Curvularin Reduces Proinflammatory Gene Expression in an In Vivo Model of Rheumatoid Arthritis

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.112.192047 ◽

2012 ◽

Vol 343 (1) ◽

pp. 106-114 ◽

Cited By ~ 18

Author(s):

Nadine Schmidt ◽

Julia Art ◽

Ingrid Forsch ◽

Anke Werner ◽

Gerhard Erkel ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Gene Expression ◽

In Vivo Model ◽

Proinflammatory Gene ◽

Anti Inflammatory ◽

Proinflammatory Gene Expression

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The Immunomodulatory and Anti-Inflammatory Effect of Curcumin on Immune Cell Populations, Cytokines, and In Vivo Models of Rheumatoid Arthritis

Pharmaceuticals ◽

10.3390/ph14040309 ◽

2021 ◽

Vol 14 (4) ◽

pp. 309

Author(s):

Sebastian Makuch ◽

Kamil Więcek ◽

Marta Woźniak

Keyword(s):

Rheumatoid Arthritis ◽

Immune Cells ◽

Immune Cell ◽

Autoimmune Disorder ◽

Lymphoid Cells ◽

In Vivo Models ◽

Rheumatoid Arthritis Development ◽

Bone Degradation ◽

Anti Inflammatory

Rheumatoid arthritis (RA) is a widespread chronic autoimmune disorder affecting the joints, causing irreversible cartilage, synovium, and bone degradation. During the course of the disease, many immune and joint cells are activated, causing inflammation. Immune cells including macrophages, lymphocytes, neutrophils, mast cells, natural killer cells, innate lymphoid cells, as well as synovial tissue cells, like fibroblast-like synoviocytes, chondrocytes, and osteoclasts secrete different proinflammatory factors, including many cytokines, angiogenesis-stimulating molecules and others. Recent studies reveal that curcumin, a natural dietary anti-inflammatory compound, can modulate the response of the cells engaging in RA course. This review comprises detailed data about the pathogenesis and inflammation process in rheumatoid arthritis and demonstrates scientific investigations about the molecular interactions between curcumin and immune cells responsible for rheumatoid arthritis development to discuss this herbal drug’s immunoregulatory role in RA treatment.

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Hei-Gu-Teng Zhuifenghuoluo Granule Modulates IL-12 Signal Pathway to Inhibit the Inflammatory Response in Rheumatoid Arthritis

Journal of Immunology Research ◽

10.1155/2018/8474867 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 6

Author(s):

Kang Zheng ◽

Zexu Chen ◽

Wen Sun ◽

Bin Liu ◽

Danping Fan ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Signaling Pathway ◽

Bioinformatics Analysis ◽

Cell Model ◽

Mice Model ◽

Sinomenium Acutum ◽

Systemic Inflammatory Disease ◽

Anti Inflammatory

Rheumatoid arthritis (RA) is a type of chronic systemic inflammatory disease; it has a very complicated pathogenesis, and multiple pathological changes are implicated. Traditional Chinese medicine (TCM) like Tripterygium wilfordii Hook. F. or Sinomenium acutum (Thunb.) Rehd et Wils. has been extensively used for centuries in the treatment of arthritic diseases and been reported effective for relieving the severity of RA. Hei-Gu-Teng Zhuifenghuoluo granule (HGT) which contains Periploca forrestii Schltr., Sinomenium acutum (Thunb.) Rehd et Wils., and Lysimachia paridiformis Franch. var. stenophylla Franch. was a representative natural rattan herb formula for the treatment of RA in China, but the mechanism has not been elucidated. This study aimed at exploring the mechanism of HGT on RA using the bioinformatics analysis with in vivo and in vitro experiment validation. The potential action mechanism was first investigated by bioinformatics analysis via Ingenuity Pathway Analysis (IPA) software. After that, we use experimental validation such as collagen-induced arthritis (CIA) mice model in vivo and U937 cell model in vitro. The bioinformatics results suggested that HGT may have anti-inflammatory characteristic on RA and IL-12 signaling pathway could be the potential key trigger. In vivo experiments demonstrated that HGT ameliorated the symptoms in CIA mice and decreased the production of inflammatory cytokines in both mice ankle joints and serum. Furthermore, HGT effectively inhibited the activation of IL-12R and STAT4 on IL-12 signaling pathway. In vitro experiments showed that HGT inhibited the production of IL-12R and STAT4 induced by IL-12 in lipopolysaccharide- (LPS-) stimulated U937 cells. Moreover, IL-12R knockdown was able to interfere with the inhibition effects of HGT on the production of these cytokines. Our results confirmed the anti-inflammatory property of HGT, which was attributed to its inhibition on IL-12 signaling pathway.

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Validating potent anti-inflammatory and anti-rheumatoid properties of Drynaria quercifolia rhizome methanolic extract through in vitro, in vivo, in silico and GC-MS-based profiling

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-021-03265-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Debabrata Modak ◽

Subhashis Paul ◽

Sourav Sarkar ◽

Subarna Thakur ◽

Soumen Bhattacharjee

Keyword(s):

Rheumatoid Arthritis ◽

In Silico ◽

Methanolic Extract ◽

Paw Edema ◽

Active Components ◽

Tnf Α ◽

Cox 2 ◽

Anti Inflammatory

Abstract Background The fronds of Drynaria quercifolia have traditionally been used in rheumatic pain management. The goal of the present study was to validate the potent anti-inflammatory and anti-rheumatoid properties of the methanolic-extract of its rhizome using in vitro, in vivo and in silico strategies. Methods The plant was collected and the methanolic extract was prepared from its rhizome. Protein denaturation test, hypotonicity and heat-induced haemolysis assays were performed in vitro. The in vivo anti-rheumatoid potential was assessed in Freund’s complete adjuvant (FCA)-induced Wistar rat model through inflammatory paw-edema, haematological, biochemical, radiological and histopathological measurements. Moreover, metabolites of methanolic extract were screened by gas chromatography-mass spectrometry (GC-MS) and 3D molecular structures of active components were utilized for in silico docking study using AutoDock. Results In vitro results evinced a significant (p < 0.05) anti-inflammatory activity of the rhizome methanolic extract in a dose-linear response. Further, Drynaria quercifolia rhizome methanolic extract (DME) significantly ameliorated rheumatoid arthritis as indicated by the inhibition of arthritic paw-edema (in millimeter) in the rat rheumatoid arthritis models in both the low (57.71 ± 0.99, p < 0.01) and high dose groups (54.45 ± 1.30, p < 0.001) when compared to arthritic control. Treatment with DME also normalized the haematological (RBC, WBC, platelet counts and hemoglobin contents) and biochemical parameters (total protein, albumin, creatinine and ceruloplasmin) significantly (p < 0.05), which were further supported by histopathological and radiological analyses. Furthermore, GC-MS analysis of DME demonstrated the presence of 47 phytochemical compounds. Compounds like Squalene, Gamma Tocopherol, n-Hexadecanoic acid showed potent inhibition of cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF-α), and interleukin (IL-6) in the docking analysis. Conclusion Results from in vivo and in vitro studies indicated that DME possesses a potent anti-inflammatory and anti-arthritic activity. In silico studies delineated the emergent potent inhibitory effects of several bio-active components on the target inflammatory markers (COX-2, TNF-α and IL-6).

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