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      Salvianolic Acid B Suppresses Inflammatory Mediator Levels by Downregulating NF-κB in a Rat Model of Rheumatoid Arthritis

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          Abstract

          Background

          Salvianolic acid B (SB) is a major active phyto-component of the plant Radix Salvia miltiorrhiza, which is traditionally used to treat joint pain and arthritis. The present study examined the anti-rheumatoid arthritis efficacy of SB on collagen-induced rheumatoid arthritis (CIA) in a rat model.

          Material/Methods

          Forty-eight rats were divided into 4 groups: Control rats treated with saline (Group I), rats subjected to CIA induction by intradermal injection of bovine collagen II type at the tail (Group II), and rats subjected to CIA and supplemented with either 20 or 40 mg/kg of SB for 28 days (group III or IV).

          Results

          Paw swelling, edema, arthritis score, thymus and spleen indexes, and neutrophil infiltration were significantly decreased ( p<0.01) by treatment with 20 or 40 mg/kg of SB. The levels of inflammatory cytokines (interleukin-1β, -6, and -17, and TNF-α) and anti-collagen II-specific immunoglobulins (IgG 1 and IgG 2a) were markedly decreased ( p<0.01), and those of antioxidant enzymes (SOD, CAT, and GSH) were significantly increased ( p<0.01) in SB-treated rats. Administration with SB (20 or 40 mg/kg) resulted in lower phosphorylated IκB-α and NF-κB p65 protein levels and markedly downregulated IκB-α expression. Furthermore, CIA rats revealed the presence of highly diffused polymorphonuclear cells (PMNs) infiltration with eroded cartilage; however, these phenomena were considerably ameliorated by SB.

          Conclusions

          SB alleviates oxidative stress and inflammation in CIA rats, thus verifying its anti-rheumatoid arthritis property.

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          Most cited references37

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          Transcriptional regulation via the NF-kappaB signaling module.

          Stimulus-induced nuclear factor-kappaB (NF-kappaB) activity, the central mediator of inflammatory responses and immune function, comprises a family of dimeric transcription factors that regulate diverse gene expression programs consisting of hundreds of genes. A family of inhibitor of kappaB (IkappaB) proteins controls NF-kappaB DNA-binding activity and nuclear localization. IkappaB protein metabolism is intricately regulated through stimulus-induced degradation and feedback re-synthesis, which allows for dynamic control of NF-kappaB activity. This network of interactions has been termed the NF-kappaB signaling module. Here, we summarize the current understanding of the molecular structures and biochemical mechanisms that determine NF-kappaB dimer formation and the signal-processing characteristics of the signaling module. We identify NF-kappaB-kappaB site interaction specificities and dynamic control of NF-kappaB activity as mechanisms that generate specificity in transcriptional regulation. We discuss examples of gene regulation that illustrate how these mechanisms may interface with other transcription regulators and promoter-associated events, and how these mechanisms suggest regulatory principles for NF-kappaB-mediated gene activation.
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            Increased Reactive Oxygen Species Formation and Oxidative Stress in Rheumatoid Arthritis

            Background Rheumatoid arthritis (RA) is an autoimmune inflammatory disorder. Highly reactive oxygen free radicals are believed to be involved in the pathogenesis of the disease. In this study, RA patients were sub-grouped depending upon the presence or absence of rheumatoid factor, disease activity score and disease duration. RA Patients (120) and healthy controls (53) were evaluated for the oxidant—antioxidant status by monitoring ROS production, biomarkers of lipid peroxidation, protein oxidation and DNA damage. The level of various enzymatic and non-enzymatic antioxidants was also monitored. Correlation analysis was also performed for analysing the association between ROS and various other parameters. Methods Intracellular ROS formation, lipid peroxidation (MDA level), protein oxidation (carbonyl level and thiol level) and DNA damage were detected in the blood of RA patients. Antioxidant status was evaluated by FRAP assay, DPPH reduction assay and enzymatic (SOD, catalase, GST, GR) and non-enzymatic (vitamin C and GSH) antioxidants. Results RA patients showed a higher ROS production, increased lipid peroxidation, protein oxidation and DNA damage. A significant decline in the ferric reducing ability, DPPH radical quenching ability and the levels of antioxidants has also been observed. Significant correlation has been found between ROS and various other parameters studied. Conclusion RA patients showed a marked increase in ROS formation, lipid peroxidation, protein oxidation, DNA damage and decrease in the activity of antioxidant defence system leading to oxidative stress which may contribute to tissue damage and hence to the chronicity of the disease.
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              Myeloperoxidase and oxidative stress in rheumatoid arthritis.

              To determine whether MPO contributes to oxidative stress and disease activity in RA and whether it produces hypochlorous acid in SF. Plasma and where possible SF were collected from 77 RA patients while 120 healthy controls supplied plasma only. MPO and protein carbonyls were measured by ELISAs. 3-Chlorotyrosine in proteins and allantoin in plasma were measured by mass spectrometry. Plasma MPO concentrations were significantly higher in patients with RA compared with healthy controls [10.8 ng/ml, inter-quartile range (IQR): 7.2-14.2; P 3.2) and those with low disease activity (LDA; DAS-28 ≤ 3.2) (HDA 27.9 ng/ml, 20.2-34.1 vs LDA 22.1 ng/ml, 16.9-34.9; P>0.05). There was a significant relationship between plasma MPO and DAS-28 (r=0.35; P=0.005). Plasma protein carbonyls and allantoin were significantly higher in patients with RA compared with the healthy controls. MPO protein was significantly higher in SF compared with plasma (median 624.0 ng/ml, IQR 258.4-2433.0 vs 30.2 ng/ml, IQR 25.1-50.9; P<0.0001). The MPO present in SF was mostly active. 3-Chlorotyrosine, a specific biomarker of hypochlorous acid, was present in proteins from SF and related to the concentration of MPO (r=0.69; P=0.001). Protein carbonyls in SF were associated with MPO protein concentration (r=0.40; P=0.019) and 3-chlorotyrosine (r=0.66; P=0.003). MPO is elevated in patients with RA and promotes oxidative stress through the production of hypochlorous acid.
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                Author and article information

                Journal
                Med Sci Monit
                Med. Sci. Monit
                Medical Science Monitor
                Medical Science Monitor : International Medical Journal of Experimental and Clinical Research
                International Scientific Literature, Inc.
                1234-1010
                1643-3750
                2018
                25 April 2018
                : 24
                : 2524-2532
                Affiliations
                Department of Orthopaedics, The First People’s Hospital of Huzhou, Huzhou, Zhejiang, P.R. China
                Author notes
                Corresponding Author: Ji-Kang Min, e-mail: mbelvatime@ 123456yahoo.com
                [A]

                Study Design

                [B]

                Data Collection

                [C]

                Statistical Analysis

                [D]

                Data Interpretation

                [E]

                Manuscript Preparation

                [F]

                Literature Search

                [G]

                Funds Collection

                Article
                907084
                10.12659/MSM.907084
                5939601
                29691361
                ee57c42f-ee11-4c1a-af7f-54bd6769be2e
                © Med Sci Monit, 2018

                This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International ( CC BY-NC-ND 4.0)

                History
                : 12 September 2017
                : 05 October 2017
                Categories
                Animal Study

                arthritis, juvenile,immunoglobulins,inflammation,oxidative stress

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