Anti-rheumatic Effects Research Articles

Synthesis, characterization, and anti-rheumatic potential of phthalazine-1,4-dione and its Cu(II) and Zn(II) complexes

Two new metal complexes derived from the reaction of 2-[(2-hydroxybenzoyl) 2,3,4a,5,10,10a-hexahydro-5,10[1′,2′]-benzenobenzo[g]phthalazine-1,4-dione] (HBPD) with Cu(II) and Zn(II) have been synthesized and characterized by using elemental analysis, spectral analysis (UV–Vis, IR, 1H NMR, 13C NMR), conductance, thermal analysis, and magnetic moments. The in vivo collagen-adjuvant arthritis model in rats revealed a significant antioxidant, analgesic, and anti-rheumatic effects for HBPD and its copper and zinc complexes in comparison with standard piroxicam. The results showed that, the investigated Cu and Zn complexes have higher anti-inflammatory activity than the free ligand.

Gaultheria: Phytochemical and pharmacological characteristics.

The genus Gaultheria, comprised of approximately 134 species, is mostly used in ethnic drugs to cure rheumatism and relieve pain. Phytochemical investigations of the genus Gaultheria have revealed the presence of methyl salicylate derivatives, C6-C3 constituents, organic acids, terpenoids, steroids, and other compounds. Methyl salicylate glycoside is considered as a characteristic ingredient in this genus, whose anti-rheumatic effects may have a new mechanism of action. In this review, comprehensive information on the phytochemistry, volatile components and the pharmacology of the genus Gaultheria is provided to explore its potential and advance research.

Bullatine A, a diterpenoid alkaloid of the genus Aconitum, could attenuate ATP-induced BV-2 microglia death/apoptosis via P2X receptor pathways

Bullatine A (BLA), a diterpenoid alkaloid of the genus Aconitum, possesses anti-rheumatic, anti-inflammatory and anti-nociceptive effects. The mechanism underlying the effects was examined in the present study. The effect of BLA on extracellular ATP induced cell death/apoptosis and pro-inflammatory cytokines release were investigated using BV-2 microglia cell line. The mediation/efficacy of inflammatory cytokines and P2X receptors was evaluated by detecting the mRNA levels of iNOS, IL-6, IL-1β and P2X receptors, respectively. The results demonstrated that BV-2 cells could be damaged after incubation with higher dose of ATP, leading to activation of pro-inflammatory cytokines, transcriptional activation of iNOS and overproduction of NO via activation of P2X receptor. The BLA (1-50μM) potently inhibits ATP-induced BV-2 cell death/apoptosis and P2X receptor-mediated inflammatory responses via selectively suppressing the up-regulation of P2X7 receptor mRNA. Since P2X7 receptors have an important role in immune and pain response, inflammation and inflammatory disease, this discovery of BLA as a potent P2X7 antagonist indicated that BLA may be a potential useful candidate for the treatment of neurodegenerative diseases such as arthritis.

THU0081 STAT3 Blockade Suppresses Autoimmune Arthritis in Mice Via the Reciprocal Regulation of Treg and Th17 Cells

BackgroundIL-6-mediated STAT3 signaling which is essential to Th17 differentiation plays the central role in the pathogenesis of rheumatoid arthritis.ObjectivesTo investigate the molecular mechanism underlying the anti-rheumatic effects and the T...

Harpagoside: from Kalahari Desert to pharmacy shelf

Harpagoside is an iridoid glycoside that was first isolated from Harpagophytum procumbens (devil's claw, Pedaliaceae), a medicinal plant in which it is the major constituent of the iridoid pool. Both the pure compound and devil's claw extracts have potent anti-rheumatic, anti-inflammatory and analgesic effects. According to the European Pharmacopoeia commercial devil's claw products should contain at least 1.2% harpagoside. However, the compound has also been isolated from several other plant species and in vitro plant culture systems. Recent advances in knowledge of harpagoside distribution, biosynthesis/accumulation and pharmacology are summarized in this review. We also discuss the possible synergism and/or antagonism between major constituents in harpagoside-containing phytopharmaceutical products. Finally, future perspectives for its potential application are highlighted.

Tubastatin, a selective histone deacetylase 6 inhibitor shows anti-inflammatory and anti-rheumatic effects

Epigenetic modifications represent a promising new approach to modulate cell functions as observed in autoimmune diseases. Emerging evidence suggests the utility of HDAC inhibitors in the treatment of chronic immune and inflammatory disorders. However, class and isoform selective inhibition of HDAC is currently favored as it limits the toxicity that has been observed with pan-HDAC inhibitors. HDAC6, a member of the HDAC family, whose major substrate is α-tubulin, is being increasingly implicated in the pathogenesis of inflammatory disorders. The present study was carried out to study the potential anti-inflammatory and anti-rheumatic effects of HDAC6 selective inhibitor Tubastatin. Tubastatin, a potent human HDAC6 inhibitor with an IC50 of 11 nM showed significant inhibition of TNF-α and IL-6 in LPS stimulated human THP-1 macrophages with an IC50 of 272 nM and 712 nM respectively. Additionally, Tubastatin inhibited nitric oxide (NO) secretion in murine Raw 264.7 macrophages dose dependently with an IC50 of 4.2 μM and induced α-tubulin hyperacetylation corresponding to HDAC6 inhibition in THP-1 cells without affecting the cell viability. Tubastatin showed significant inhibition of paw volume at 30 mg/kg i.p. in a Freund's complete adjuvant (FCA) induced animal model of inflammation. The disease modifying activity of Tubastatin was also evident in collagen induced arthritis DBA1 mouse model at 30 mg/kg i.p. The significant attenuation of clinical scores (~70%) by Tubastatin was confirmed histopathologically and was found comparable to dexamethasone (~90% inhibition of clinical scores). Tubastatin showed significant inhibition of IL-6 in paw tissues of arthritic mice. The present work has demonstrated anti-inflammatory and antirheumatic effects of a selective HDAC6 inhibitor Tubastatin.

A Single Nucleotide Polymorphism of Reduced Folate Carrier 1 Predicts Methotrexate Efficacy in Japanese Patients with Rheumatoid Arthritis

Methotrexate (MTX) exhibits large inter-individual and inter-ethnic differences in the dose required for its anti-rheumatic effect. To maintain low disease activity, patients may require increased MTX doses or co-administration of biologic disease-modifying anti-rheumatic drugs (bDMARDs). The availability of a marker predicting the effect of MTX will make it possible to increase the MTX dose and prescribe bDMARDs to patients at an early stage. To establish individualized medication for rheumatoid arthritis (RA), we investigated genetic polymorphisms of the folate pathway in Japanese RA patients. Eighty-nine patients were treated with MTX alone (MTX group). MTX and bDMARDs were co-administered to 81 patients because of insufficient MTX efficacy (MTX + bDMARDs group); an equally stable therapeutic effect was achieved in both groups. Polymorphism analyses using bDMARD co-treatment as the objective variable revealed a significant association between age and the G80A polymorphism of the reduced folate carrier 1 gene (RFC1) as an explanatory variable. Compared to patients with the A allele, patients with the G allele may have less intracellular MTX uptake and, therefore, poor efficacy; a greater number of them were found to be bDMARD concomitant cases. The results of this study suggest that the RFC1 G80A polymorphism may be a useful marker for predicting MTX efficacy in Japanese patients with RA.

Bioinformatics Analysis for the Antirheumatic Effects of Huang-Lian-Jie-Du-Tang from a Network Perspective

Huang-Lian-Jie-Du-Tang (HLJDT) is a classic TCM formula to clear “heat” and “poison” that exhibits antirheumatic activity. Here we investigated the therapeutic mechanisms of HLJDT at protein network level using bioinformatics approach. It was found that HLJDT shares 5 target proteins with 3 types of anti-RA drugs, and several pathways in immune system and bone formation are significantly regulated by HLJDT's components, suggesting the therapeutic effect of HLJDT on RA. By defining an antirheumatic effect score to quantitatively measure the therapeutic effect, we found that the score of each HLJDT's component is very low, while the whole HLJDT achieves a much higher effect score, suggesting a synergistic effect of HLJDT achieved by its multiple components acting on multiple targets. At last, topological analysis on the RA-associated PPI network was conducted to illustrate key roles of HLJDT's target proteins on this network. Integrating our findings with TCM theory suggests that HLJDT targets on hub nodes and main pathway in the Hot ZENG network, and thus it could be applied as adjuvant treatment for Hot-ZENG-related RA. This study may facilitate our understanding of antirheumatic effect of HLJDT and it may suggest new approach for the study of TCM pharmacology.

Evaluation of anti-inflammatory activities of ethanolic extract of Annona muricata leaves

Traditionally, the leaves of Annona muricata L., Annonaceae, are used to treat headaches, fever, toothache, cough and asthma. The decoction of the leaves has parasiticide, antirheumatic and antineuralgic effects when used internally, while the cooked leaves, applied topically, fight rheumatism and abscesses. The aim of this study was to investigate acute and chronic anti-inflammatory potential of an ethanolic leaf extract of A. muricata (AML) in animal models. The ethanolic extract of A. muricata leaf extract was prepared and administered orally to experimental animals used. The anti-inflammatory activity was determined by xylene-induced ear edema in mice and Complete Freund's adjuvant (CFA)-induced arthritis in rats. The results demonstrated that AML is effective for both acute and chronic inflammation. It also significantly attenuated both TNF-α and IL-1β levels in CFA-induced arthritis model. Thus, these results have suggested that AML possesses both anti-inflammatory and anti-arthritic activities. The findings also suggest that AML presents notable anti-arthritic activity that may be mediated by suppressing pro-inflammatory cytokines.

Anti-arthritic activity of the Indian leafy vegetable Cardiospermum halicacabum in Wistar rats and UPLC–QTOF–MS/MS identification of the putative active phenolic components

The present work was carried out to investigate the free radical scavenging activity of the ethanol extract of C. halicacabum leaves (EECH), to study its antioxidant properties and anti-rheumatic effects in Wistar rats with CFA-induced arthritis, and to profile the phenolic components thereof by LC-MS/MS. The free radical scavenging activities of the extract was evaluated by NO and superoxide anion scavenging assays. Arthritis was induced to the albino Wistar rats by CFA. Fifteen days after CFA induction, arthritic rats received EECH orally at the doses of 250 and 500mg/kg daily for 20days. Diclofenac sodium was used as reference standard. EECH is subjected to LC-MS/MS analysis for the identification of phenolic compounds. The IC(50) value of the EECH to scavenge the NO and superoxide radicals are 83 and 60μg/ml respectively. Ultrasonography and histology images of hind limb in EECH treated groups confirmed the complete cartilage regeneration. The LC/MS/MS analysis indicated the presence of anti-inflammatory compounds luteolin-7-O-glucuronide, apigenin-7-O-glucuronide and chrysoeriol. These findings lend pharmacological support to the reported folkloric use of C. halicacabum in the treatment and management of painful, arthritic inflammatory conditions.

Serum Pharmacological Effect of Chinese Herbal Pill Yi Shen Juan Bi (YJB) on Cultured Macrophages and Synoviocytes

The patent herbal compound drug, Yi Shen Juan Bi (YJB), has been found to be effective for the treatment of rheumatoid arthritis (RA), and our previous studies revealed that it has potent anti rheumatic effects [1, 2, 3]. We have conducted further investigations into the anti arthritic activity of YJB using macrophage and synoviocytes cells in an ex-vivo serum pharmacology assay. For that purpose, we used mouse serum containing YJB and analyzed the macrophage derived cytokine tumor necrosis factor alpha (TNF-á) and interleukin-1 (IL-1) using ELISA kits, nitric oxide (NO) by Griess reaction and the proliferation of rats synoviocytes stimulated by TNF-á by MTT reduction assay in vitro. In addition, we analyzed the cytotoxicity concentrations of YJB by MTT reduction assay. This study confirmed the anti-rheumatic effects of YJB correlated with a significant decrease of TNF-á, IL-1 and NO production by macrophages and also with significant decrease in the proliferation of synoviocytes in vitro. A subsequent cytotoxicity assay also revealed no significant difference in cell viability. Our results suggest that YJB is a potential anti-rheumatic agent targeting the inflammatory and immunomodulatory response of macrophages and synoviocyte cells.

4-Hydroxy-2-methyl-N-(2-thiazole)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (EX15) and its Cu(II) Complex as New Oxicam Selective Cyclooxygenase-2 Inhibitors

4-Hydroxy-2-methyl-N-(2-thiazole)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (EX15) as nonsteroidal antiinflammatory drug (NSAIDs) of oxicam family has been synthesized bearing high selectivity for cyclooxygenase-2 (COX-2) inhibition and high ability to chelate with Cu(II) ions. The EX15Cu(II) complex, and [Cu(EX15)(OAc)(H2O)2], were synthesized and characterized by using elemental analysis, spectral (UV-Vis, IR), conductance, thermal and magnetic studies. Two equations were predicted using quantitative structure activity relationship (QSAR) and regression analysis for the COX-2 and COX-1 selectivity (microsomal assay) with a regression correlation (R) close to unity. Two techniques were used to investigate the validity of these equations; macrophage cell line (in vitro) selectivity and collagenadjuvant arthritis model in rats (in vivo) which showed a significant antioxidant, analgesic and antirheumatic effect for 4-hydroxy-2-methyl-N-(2-thiazole)-2H-1,2-benzothiazine-3-carboxamide-1,1dioxide and its Cu(II) complex, [Cu(EX15)(OAc)(H2O)2]. (doi: 10.5562/cca1802)

Anti-rheumatic effect of JAK-inhibitors

Treatment of rheumatoid arthritis (RA) has dramatically developed with the use of biologics targeting inflammatory cytokines. However, expense and parenteral use can cause issues in the initiation and continuation of the treatment. Therefore a new orally available anti-rheumatic drug has been long-awaited. Recently, small-molecule compounds targeting Janus kinase (JAK) has shown clinical efficacy similar to biologics in clinical trials for active RA. Among the JAK-inhibitors, new drug application for tofacitinib is concurrently under review in western and asian countries and is highly expected to become a new anti-rheumatic drug in the near future. In order to evaluate the mode of action, we utilized peripheral blood and synovium from RA patients. Proliferation and cytokine production of CD4+ T cell was prominently reduced and subsequently inhibited cartilage destruction by the synovium. Our result is in line with the inhibitory effect of tofacitinib on joint destruction in RA patients those who were treated with tofacitinib. Therefore, further clinical efficacy is expected in the in the long-term treatment with tofacitinib.

Recent findings on phosphoinositide-3 kinase in rheumatic diseases

Rheumatic diseases are chronic inflammatory disorders, and many of them are autoimmune diseases. Class I phosphatidylinositol-3 kinases (PI3Ks) are enzymes that phosphorylate phosphoinositides in response to extracellular stimuli and regulates cellular activation, proliferation, and migration, in a variety of cell types, suggesting that they play critical roles in the development of inflammation. In patients with rheumatic diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), recent reports have shown convincing pathogenic evidence for the involvement of PI3K/Akt signaling pathways in chronic inflammation. Moreover, selective inhibition of PI3K γ reduced incidence and severity of the renal disease. More recently, the kinome array analysis revealed particular up-regulation of PI3K in B cells from patients with SLE in comparison with matched controls. Up-regulation of PI3K in T cells was also reported in patients with SLE. Further, we have demonstrated anti-rheumatic effects of a novel PI3K-specific inhibitor, ZSTK474, in mouse collagen-induced arthritis (CIA). Administration of ZSTK474, even if started after the development of arthritis, ameliorated CIA with no apparent adverse effect. Proliferation of B lymphocytes and synovial fibroblasts were inhibited by ZSTK474 in vitro. ZSTK474 suppressed osteoclast formation in vitro and also in the joints of CIA mice. These findings indicate that PI3K might be a potential therapeutic target of rheumatic diseases.

Further studies on membrane stabilizing, anti-inflammatory and FCA induced arthritic activity of various fractions of bark of Machilus macrantha in rats

Machilus macrantha Nees, Lauraceae, bark is traditionally used in the treatment of asthma, tuberculosis and rheumatoid arthritis. In order to validate, mechanism based anti-inflammatory activity of fractions M. macrantha bark are investigated for first time. Test materials viz. petroleum ether (PE), alkaloidal fraction (CH), acetone extracts (TAN) and mucilage (MM) (250 and 500 mg/kg, p.o.) obtained from M. macrantha bark were tested for membrane stabilizing, anti-nociceptive; anti inflammatory and Freund's complete adjuvant (FCA) induced arthritis activity. Diclofenac sodium and morphine were used as the reference standards in pharmacological assay. Test materials have significantly (p<0.01) inhibited paw edema after Carrageenan and histamine induction at higher doses. Administration of test materials of M. macrantha (250 and 500 mg/kg b.w.) significantly reduced abdominal writhing, formalin nociception, cotton pellet granuloma and vascular permeability in experimental animal. In addition to this, bark of M. macrantha showed chronic anti-rheumatic effect by suppressing the swelling volume, arthritis index, hematological and biochemical parameters (ESR, RA factor, CRP, liver transferase enzyme) in FCA-induced arthritis. It also significantly inhibited protein denaturation, heat-induced haemolysis of RBC and reduction in total leukocyte migration. Bioassay guided fractionation of the pet. ether extract of bark of M. macrantha led to isolation and characterization of β-sitosterol and stigma sterol confirmed by its HPLC, NMR and GC-MS study. In conclusion, extracts of M. macrantha bark can be explored as a therapeutic agent for the treatment of acute and chronic arthritis.

The analgesic and anti-rheumatic effects of Thladiantha dubia fruit crude polysaccharide fraction in mice and rats

Ethnopharmacological relevanceThe fruit of Thladiantha dubia has been used in Chinese manchu nationality folk medicine for treatment of various pains, such as rheumatic pain, lumbocrural pain, and dysmenorrhea. The aim of the present study was to evaluate the anti-rheumatic effect of Thladiantha dubia fruit crude polysaccharide (TF-P) fraction in rats. Materials and methodsTF-P was evaluated in mice for analgesic activity using acetic acid-induced abdominal contractions test and for anti-inflammatory activity using xylene-induced ear oedema model. Moreover, rheumatoid arthritis (RA) was induced by injection of CFA into the subplantar surface of the hind paw of the male Wistar rats. Joint swelling was measured. In order to evaluate the effect of TF-P on disease progression, proinflammatory mediators (TNF-α and IL-2), and antioxidant indicators (SOD, MDA, and NO) were determined in rats induced by CFA. Pathologic changes of RA in rats were also observed under light microscope. Results and conclusionsIn the present study, TF-P at the dose of 200mg/kg (according to the clinical traditional dosage) significantly reduced writhings and stretchings induced by the acetic acid in mice. TF-P significantly inhibited xylene-induced ear oedema in mice, compared with control group. TF-P significantly inhibited inoculated and non-inoculated joint swellings in rats induced by CFA. TF-P had no effect of body weight in rats. The histopathological analysis suggested that TF-P obviously alleviated the degree of RA rats. TF-P treated rats preserved a nearly normal histological architecture of the joint.Results of the present study confirm the use of Thladiantha dubia traditionally for the treatment of painful and inflammatory conditions. Those results suggest TF-P has protective and therapeutic effects on RA rats induced by CFA.

Total and free-plasma tryptophan concentrations in rheumatoid disease.

Abstract It has been proposed (McArthur, Dawkins &amp; others, 1971) that human connective tissue diseases may arise from modifications in the binding characteristics of the plasma proteins. McArthur, Smith &amp; Freeman (1972) presented evidence that human serum contains a substance that possesses anti-inflammatory activity and is bound to circulating proteins. Furthermore, it has been suggested that, in patients with active rheumatoid arthritis, the anti-inflammatory substance is bound to an abnormal extent to the plasma proteins and that the clinically useful antirheumatic drugs act by re-establishing the bound: free ratio to that in the normal subject (Smith &amp; Dawkins, 1971). There is evidence that the behaviour of L-tryptophan mimics that of the hypothetical substance which protects susceptible tissues against chronic inflammatory insults. All the clinically useful antirheumatic agents were found to displace L-tryptophan from human plasma in vitro (McArthur, Dawkins &amp; Smith, 1971) but not so other drugs which bind to plasma proteins to an equivalent extent but have no demonstrable antirheumatic effects (Smith, Dawkins &amp; McArthur, 1971). In patients with rheumatoid arthritis receiving drug therapy the percentage of L-tryptophan bound to plasma proteins is significantly reduced but increases when drug administration is stopped (McArthur, Dawkins &amp; others, 1971).

Gemmotherapy-complementary treatment in juvenile rheumatoid arthritis

Rheumatoid arthritis is a chronic disease that damagesandeventually destroys the joints of the body. Juvenile rheumatoid arthritis (JRA) is not a single disease, but a group of diseases with symptoms and signs developed in children younger than 16 years. There are three major forms: pauciarticular disease, poliarticular disease, and systemic disease. The aim of treatment is to stop or slow down the progress of inflammation, improving function, and preventing joint damage. The most usefull drugs are: 1) nonsteroidal anti-inflammatorydrugs (NSAIDs) reduce inflammation, swelling, and pain, 2) disease-modifying antirheumatic drugs (DMARDs), in children Methotrexat is the most used drug, it interferes in the immune processes that cause inflammation and JRA. 3) Biologic response modifiers are a newer, specialized type of immunosuppressive drugs, carefully designed to block the actions of natural substances that are part of the immune response, such as tumor necrosis factor. A variety of complementary approaches can be very effective in relieving pain and improving the outcome of the disease. One of these complementary therapy is gemmoterapy, a scientific use of a special glycerin extracts from plant buds. In our study,19 pacients with diagnosed JRA (15 with pauciarticular disease and 4 with poliarticular form) was treated with specific antirheumatic drugs associating gemmotherapy. It has been used three types of bud extracts (Ribes nigrum, Buxus sempervirens, Vitis vinifera) with proved antirheumatic effects, during a period of 3 months. In all the pacients we observed a clinical amelioration, permitting a slight reduction of the dose of the NSAIDs and the DMARDs.

LC–MS Qualitative Analysis and Simultaneous Determination of Six Filipendula Salicylates with Two Standards

Salicylate containing herbs, such as Salix alba (white willow) and Filipendula ulmaria (meadowsweet) are commonly used, because of their antipyretic, analgesic and antirheumatic effect. In this work six salicylates were identified and/or structurally characterized in the methanolic extract of F. ulmaria and were simultaneously determined using salicylic acid and salicin as external standards. Analysis occured by an LC-DAD-MS–MS triple quadrupole system, determination was accomplished in SIM mode. Linearity, inter- and intra-day precision (highest RSD % 9.85), accuracy and recovery were all within acceptable ranges, except recovery for salicin standard (51.76%). LLOQ for salicylic acid was 150 ng mL−1, for salicin 24 ng mL−1. Estimative contents of salicylates were calculated with both standard calibrations, results and their error were compared. This is the first study to provide detailed quantitative data on Filipendula salicylates.

Effects of total flavonoids of Chrysanthemum indicum on free radical in adjuvant arthritic rats

To investigate the effects of total flavonoids of Chrysanthemum indicum (TFC) on metabolism of free radical and immunoregulatory effects in adjuvant arthritis (AA) rats. AA rats were induced by Freunds complete adjuvant. Secondary paw swelling of AA rats was measured with volume meter to observe the antirheumatic effect of TFC. The levels of SOD, MDA and NO in serum and supernatant of peritoneal macrophage were measured by commercial assay kits. ConA-induced splenocyte proliferation and IL-2 level produced by splenocyte were detected by MTT method. TFC could decrease the levels of MDA and NO, as well as increase the activity of SOD in serum and supernatant of peritoneal macrophage compared with AA model group. Meanwhile, the suppressed lymphocyte proliferation and IL-2 production of splenic lymphocytes in AA rats were reversed by treatment with TFC. TFC showed significant therapeutical effect on adjuvant arthritis and its mechanism was at least in part related to the antioxidant and immunoregulatory effects.