stilbenes and Arthritis--Rheumatoid

Trans-resveratrol (t-Res) is a natural compound of a family of hydroxystilbenes found in a variety of spermatophyte plants. Because of its effects on lipids and arachidonic acid metabolisms, and its antioxidant activity, t-Res is considered as the major cardioprotective component of red wine, leading to the "French Paradox" health concept. In the past decade, research on the effects of resveratrol on human health has developed considerably in diverse fields such as cancer, neurodegenerative and cardiovascular diseases, and metabolic disorders. In the field of rheumatic disorders, in vitro evidence suggest anti-inflammatory, anti-catabolic, anti-apoptotic and anti-oxidative properties of t-Res in various articular cell types, including chondrocytes and synoviocytes, along with immunomodulation properties on T and B lymphocytes. In preclinical models of osteoarthritis and rheumatoid arthritis, resveratrol has shown joint protective effects, mainly mediated by decreased production of pro-inflammatory and pro-degradative soluble factors, and modulation of cellular and humoral responses. Herein, we comprehensively reviewed evidence supporting a potential therapeutic interest of t-Res in treating symptoms related to rheumatic disorders.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Arthritis, Rheumatoid; Biological Availability; Disease Models, Animal; Humans; Resveratrol; Stilbenes

Rheumatoid arthritis (RA) is a chronic debilitating disease of the joints. Both the innate and adaptive immune responses participate in the development and progression of RA. While several therapeutic reagents, such as TNF-α agonists, have been successfully developed for the clinical use in the treatment of RA, more than half of the patients do not respond to anti-TNF therapy. Therefore, new therapeutic reagents are needed. Recent studies have shown that sirtuin 1 (Sirt1), a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase, is a critical negative regulator of both the innate and adaptive immune response in mice, and its altered functions are likely to be involved in autoimmune diseases. Small molecules that modulate Sirt1 functions are potential therapeutic reagents for autoimmune inflammatory diseases. This review highlights the role of Sirt1 in immune regulation and RA.

Topics: Animals; Arthritis, Rheumatoid; Humans; Immune Tolerance; Macrophages; Resveratrol; Sirtuin 1; Stilbenes; T-Lymphocytes

Interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) are key cytokines that drive the production of inflammatory mediators and matrix-degrading enzymes in osteoarthritis (OA). These proinflammatory cytokines bind to their respective cell surface receptors and activate inflammatory signaling pathways culminating with the activation of nuclear factor κB (NF-κB), a transcription factor that can be triggered by a host of stress-related stimuli including, excessive mechanical stress and ECM degradation products. Once activated, NF-κB regulates the expression of many cytokines, chemokines, adhesion molecules, inflammatory mediators, and several matrix-degrading enzymes. Therefore, proinflammatory cytokines, their cell surface receptors, NF-κB and downstream signaling pathways are therapeutic targets in OA. This paper critically reviews the recent literature and outlines the potential prophylactic properties of plant-derived phytochemicals such as curcumin and resveratrol for targeting NF-κB signaling and inflammation in OA to determine whether these phytochemicals can be used as functional foods.

Topics: Angiogenesis Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Cartilage, Articular; Chondrocytes; Curcumin; Humans; Inflammation; Interleukin-1beta; Joints; Osteoarthritis; Phytochemicals; Phytotherapy; Resveratrol; Stilbenes; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Rheumatoid arthritis (RA) is a chronic inflammatory disease that mainly targets the synovial membrane, thus causing stiffness, deformity and dysfunction of joints. To date, no effective anti‑inflammatory treatments are available for RA. Piceatannol (PIC) is a natural derivative of resveratrol, which has been reported to attenuate the inflammatory response. To evaluate the effect of PIC on RA and to determine the underlying molecular target of PIC, both

Topics: Animals; Apoptosis; Arthritis, Rheumatoid; Cell Proliferation; Cells, Cultured; Fibroblasts; Humans; Inflammation; MAP Kinase Signaling System; NF-kappa B; Rats; Stilbenes; Synoviocytes

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Cattle; Collagen; NF-kappa B; Phosphatidylinositol 3-Kinases; Physical Conditioning, Animal; Proto-Oncogene Proteins c-akt; Rats; Signal Transduction; Stilbenes

The roots of Caragana stenophylla have been used as folk medicine due to the functions of activating blood, diuresis, analgesic and tonicity, especially in treating rheumatoid arthritis and hypertension. However, the anti-rheumatoid arthritis mechanisms and bioactive ingredients have not previously been fully investigated.. The aim of this study was to assess the anti-rheumatoid arthritis effects of the roots of Caragana stenophylla ethanol extract (EC), elucidate its mechanism of action and identify its active substances.. Anti-rheumatoid arthritis activity of EC was assessed using type II-collagen induced arthritis in rats. Arthritis severity was evaluated by foot paw volume, arthritis index, joint swelling degree and histopathology. The serum inflammatory cytokines and matrix metalloproteinases (MMPs) were also detected by immunohistochemical analysis. In addition, the protein expression of IκB, p-IκB, iNOS and COX-2 was analyzed by western blot. RAW 264.7 macrophage cells were employed to assess the anti-inflammatory effects of fractions and compounds in vitro. UPLC-Q-TOF-MS was adopted to appraise the ingredients of the active fraction of the roots of C. stenophylla. Furthermore, various chromatographic techniques and spectroscopic methods were used for isolation and structure elucidation of compounds.. The results showed that EC could reduce type II collagen-induced rheumatoid arthritis model arthritic score and histopathology markedly at dose of 240 mg/kg. Besides, EC could suppress the levels of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, IL-17, and TNF-α) and matrix metalloproteinases (MMP-3, MMP-9), and the expression levels of COX-2, p-IκB and iNOS also were declined. While, the levels of IL-10 and IκB were increased. The ethyl acetate fraction exhibited potent inhibitory effects against nitric oxide production in RAW 264.7 macrophage cells. Eleven main components including 1 flavonoid and 10 oligostilbenes from active fraction were isolated by mass directed chromatographic techniques. Their structures were determined on the basis of various spectroscopic methods and by comparison with the published NMR data.. The roots of C. stenophylla attenuated arthritis severity, restored serum cytokine imbalances by regulating NF-κB signaling pathway in type II collagen-induced rheumatoid arthritis model. Oligostilbenes were essential ingredients in ethyl acetate extract of C. stenophylla roots. Stilbenes and flavonoids should be responsible for its anti-rheumatoid arthritis activities.

Topics: Animals; Anti-Inflammatory Agents; Antirheumatic Agents; Arthritis, Experimental; Arthritis, Rheumatoid; Caragana; Cytokines; Female; Male; Mice; Plant Extracts; Plant Roots; Rats; Rats, Sprague-Dawley; RAW 264.7 Cells; Stilbenes

Rheumatoid arthritis (RA) is a systematic, inflammatory, autoimmune disease, associated with a high number of disabilities. Increasing evidence has demonstrated that neutrophil extracellular trap (NET) formation plays a significant role in the pathogenesis and progression of RA. In this study, we have aimed to investigate the effects of polydatin (PD) on NET formation and its effects on disease activity in a collagen-induced arthritis (CIA) mouse model.. In the presence of PD or vehicle, neutrophils isolated from RA patients and mice were treated with phorbol 12-myristate 13-acetate (PMA) for 4 h, and NET formation investigated. For in vivo experiments, PD was administered intraperitoneally (45 mg/kg per day) to collagen-induced arthritis (CIA) mice. The incidence and severity of collagen-induced arthritis were assessed and NET deposition tested.. In vitro, PD significantly suppressed NET formation of neutrophils from RA patients. Consistently, decreased NETs were observed in PD treated bone marrow-derived neutrophils. In CIA mouse model, PD treatment delayed the onset of arthritis and attenuated arthritis severity. Compared with vehicle-treated CIA mice, the deposition of NETs in ankle joints was also reduced in PD-treated CIA mice.. In this study, we found that PD treatment markedly inhibited NET formation and protected CIA mice from the development of arthritis. These findings suggest that inhibition of NET formation by PD may serve as a novel mechanism for the treatment of RA.

Topics: Animals; Ankle Joint; Arthritis, Experimental; Arthritis, Rheumatoid; Autoantibodies; Extracellular Traps; Glucosides; Humans; Male; Mice, Inbred DBA; Neutrophils; Protective Agents; Stilbenes

The aim of the current study was to investigate the role and mechanism of sirtuin 1 (Sirt1) in the regulation of synovial cell invasion and joint destruction in rheumatoid arthritis (RA). The Sirt1 protein and mRNA levels in fibroblast‑like synoviocytes (FLS) isolated from RA synovial tissues were compared with normal tissues by western blot and reverse transcription‑polymerase chain reaction. RA FLS were then treated with the Sirt1 agonist resveratrol (1, 3 and 10 µg/ml) for 48 h, and their invasiveness and expression of matrix metalloproteinase (MMP) 1 and MMP13 protein and mRNA were measured. Furthermore, a collagen‑induced arthritis (CIA) rat model was established and the rats were divided into a model group, and low‑ and high‑dose resveratrol (2.5 and 10 mg/kg/day) groups to receive an intraperitoneal injection of resveratrol for 42 consecutive days. The joint morphology, arthritis index (AI), and MMP1 and MMP13 expression in synovial tissues was monitored. The Sirt1 protein and mRNA levels in RA FLS were significantly lower compared with normal FLS (P<0.01). The resveratrol treatment significantly inhibited the invasive ability of RA FLS (P<0.01) and reduced MMP1 and MMP13 expression (P<0.01). The AI in low‑ and high‑dose groups was significantly lower compared with the model group from day 28 (P<0.01). Resveratrol also reduced the swelling and damage and decreased MMP1 and MMP13 expression levels in CIA rats (P<0.01). The resveratrol‑induced upregulation of Sirt1 in RA FLS may significantly inhibit the invasion of these cells and reduce the degree of joint damage, which may be mediated through the inhibition of MMP1 and MMP13 expression. The present results suggested a regulatory role for Sirt1 in RA pathogenesis, and demonstrated the beneficial effects of resveratrol, which may have potential as an alternative therapeutic strategy for the treatment of patients with RA.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Arthritis, Rheumatoid; Disease Models, Animal; Gene Expression; Joints; Matrix Metalloproteinases; Rats; Resveratrol; RNA, Messenger; Sirtuin 1; Stilbenes; Synoviocytes

The aim of this study was to investigate the effects of resveratrol (Res) on hydrogen peroxide (H₂O₂)-treated fibroblast-like synoviocytes (FLSs) in vitro. We studied the phosphoinositide 3-kinase (PI3K)-Akt pathway inhibition-mediated effects of Res on forkhead box O (FoXO) mRNA expression levels. FLS viability was determined by Cell Counting Kit-8 (CCK-8) assay, and FLS apoptosis was measured by terminal deoxyribo nucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining and flow cytometry. FoXO1, FoXO3 and FoXO4 mRNA expression levels in FLSs were determined by RT-PCR, and p-Akt, Akt, p-FoXO1, FoXO1, p-FoXO3, FoXO3, Bcl-2 and Bax protein expression levels were determined by western blotting. Our results showed that low H₂O₂ concentrations (20 μM) can promote FLS growth and that Res significantly inhibited FLS activity. Moreover, Res significantly increased the number of apoptotic cells and the ratio of Bax/Bcl-2 protein expression in the group treated with Res compared with the group treated with H₂O₂ and LY294002, a PI3K inhibitor. Res also decreased FoXO1, FoXO3 and FoXO4 mRNA expression levels and p-Akt/Akt, p-FoXO1/FoXO1, p-FoXO3/FoXO3 protein expression levels. Taken together, these findings indicate that Res can induce apoptosis in H₂O₂-treated FLSs in part by inhibiting the PI3K-Akt signaling pathway.

Topics: Antioxidants; Apoptosis; Arthritis, Rheumatoid; Cells, Cultured; Forkhead Transcription Factors; Humans; Hydrogen Peroxide; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Resveratrol; Signal Transduction; Stilbenes; Synoviocytes

Polydatin is a natural extract used in traditional Chinese medicine, which leads to a marked improvement in the microcirculation perfusion and enhances the animal myocardial contraction force. The present study aimed to determine whether an effective treatment of polydatin ameliorates the symptoms of collagen‑induced arthritis (CIA), and also to explore the potential mechanism. Male DBA/1J mice were induced into CIA model mice. The administration of polydatin effectively suppressed CIA in mice. The serum levels of malondialdehyde (MDA), superoxide dismutase (SOD), tumor necrosis factor‑α (TNF‑α) and interleukin 1β (IL‑1β) were effectively increased following the induction of CIA in the model mice compared with the control group. The elevated serum levels of MDA, SOD, TNF‑α and IL‑1β were markedly suppressed by the effective treatment of polydatin in CIA mice, compared with the CIA model group. However, an increase in the level of matrix metalloproteinase‑9 (MMP‑9) was markedly induced in the CIA mice compared with the control group. As compared with the CIA group, the expression of MMP‑9 was substantially reduced by the effective treatment of polydatin. Taken together, the effective treatment of polydatin ameliorated the symptoms of CIA through an exertion of its antioxidative and anti‑inflammatory effects, and also via activation of the expression of matrix metalloproteinase-9 (MMP-9) in mice.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Arthritis, Experimental; Arthritis, Rheumatoid; bcl-2-Associated X Protein; Biomarkers; Caspase 3; Caspase 9; Disease Models, Animal; Glucosides; Glutathione; Male; Malondialdehyde; Matrix Metalloproteinase 9; Mice; Oxidative Stress; Proto-Oncogene Proteins c-bcl-2; Stilbenes; Superoxide Dismutase

In RA, synoviocytes cause increased oxidative stress, leading to mitochondrial alterations that may participate in the pathogenesis of RA. Here we investigated whether mitochondrial dysfunction induces inflammatory responses in cultured normal human synoviocytes, a hallmark of RA.. Mitochondrial dysfunction was induced with the inhibitor oligomycin. The effects of mitochondrial dysfunction on cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) and IL-8 expression; cellular and mitochondrial reactive oxygen species (ROS) production; nuclear factor-κB (NF-κB) activation and p65 translocation were studied. ROS scavengers (N-acetylcysteine and mitoTEMPO) and an NF-κB inhibitor (BAY-117085) were used to investigate the pathways involved. The natural anti-inflammatory antioxidant resveratrol was also tested.. Mitochondrial dysfunction per se significantly stimulated mitochondrial ROS production as well as low-grade expressions of COX-2, PGE2 and IL-8. Interestingly, mitochondrial dysfunction induced by pretreatment of synoviocytes with oligomycin synergized with IL-1β to increase the expression of these inflammatory mediators. The inflammatory effects of mitochondrial damage appeared to be dependent on ROS production and NF-κB activation since the inflammatory response was counteracted by both N-acetylcysteine and mitoTEMPO and it was also reduced by BAY-117085. Antimycin A and paraquat (inhibitors of mitochondrial function) also induced inflammatory responses. Furthermore, resveratrol significantly reduced the inflammatory response by decreasing ROS production and NF-κB activation.. These data suggest that mitochondrial dysfunction could induce an inflammatory response in normal human synoviocytes and sensitize these cells, causing a significant amplification of the inflammatory response induced by IL-1β. Resveratrol may represent a promising strategy in controlling the synovial inflammatory response.

Topics: Aged; Arthritis, Rheumatoid; Cells, Cultured; Cyclooxygenase 2; Dinoprostone; Enzyme Inhibitors; Humans; Inflammation; Interleukin-1beta; Interleukin-8; Middle Aged; Mitochondria; NF-kappa B; Oligomycins; Oxidative Stress; Reactive Oxygen Species; Resveratrol; Stilbenes; Synovial Membrane

Rheumatoid arthritis (RA) is a chronic inflammatory disease with unknown etiology. The present study investigated the anti-inflammatory effect of resveratrol on rats with adjuvant arthritis (AA) with abnormal immunological function via the reduction of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2). AA model rats were established by injection of complete Freund's adjuvant and alterations in the rats secondary paw swelling and the polyarthritic scores were observed. Pathological examination of joint tissues was observed by hematoxylin and eosin staining. The proliferation of spleen cells was examined using a 3-(4,5-dimethylthiazol-2‑yl)-2,5-diphenyltetrazolium bromide assay in vitro. The protein expression of COX-2 in the synovial tissues was detected by western blotting. The level of PGE2 in the serum was assayed using an ELISA kit. The results demonstrated that resveratrol (10 or 50 mg/kg) was able to significantly reduce paw swelling and decrease the arthritis scores. Compared with the AA model rats, a significant reduction in the proliferation of concanavalin A-stimulated spleen cells was observed, articular cartilage degeneration with synovial hyperplasia and inflammatory cell infiltration was suppressed and the production of COX-2 and PGE2 in AA rats was reduced by treatment with resveratrol. These results suggest that resveratrol has significant anti-inflammatory effects on AA rats, which may be associated with the reduction of COX-2 and PGE2 inflammatory mediators.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Arthritis, Rheumatoid; Cyclooxygenase 2; Dinoprostone; Lymphocyte Activation; Lymphocytes; Male; Rats; Resveratrol; Stilbenes; Synovial Membrane

Topics: Adult; Aged; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Humans; Leukocytes, Mononuclear; Middle Aged; Resveratrol; Sirtuin 1; Stilbenes

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease that primarily attacks joints and is therefore a common cause of chronic disability and articular destruction. The hyperplastic growth of RA-fibroblast-like synoviocytes (FLSs) and their resistance against apoptosis are considered pathological hallmarks of RA. The natural antioxidant resveratrol is known for its antiproliferative and pro-apoptotic properties. This study investigated the effect of resveratrol on RA-FLS. RA-FLS were isolated from the synovium of 10 RA patients undergoing synovectomy or joint replacement surgery. RA-FLS were first stressed by pre-incubation with interleukin 1beta (IL-1β) and then treated with 100 μM resveratrol for 24h. In order to evaluate the influence of resveratrol on the transcription of genes, a Gene Chip Human Gene 1.0 ST Array was applied. In addition, the effect of dexamethasone on proliferation and apoptosis of RA-FLS was compared with that of resveratrol. Gene array analysis showed highly significant effects of resveratrol on the expression of genes involved in mitosis, cell cycle, chromosome segregation and apoptosis. qRT-PCR, caspase-3/7 and proliferation assays confirmed the results of gene array analysis. In comparison, dexamethasone showed little to no effect on reducing cell proliferation and apoptosis. Our in vitro findings point towards resveratrol as a promising new therapeutic approach for local intra-articular application against RA, and further clinical studies will be necessary.

Topics: Aged; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Arthritis, Rheumatoid; Caspase 3; Caspase 7; Cell Movement; Cell Proliferation; Cells, Cultured; Dexamethasone; Drug Evaluation, Preclinical; Female; Gene Expression Profiling; Humans; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Phenotype; Phytotherapy; Real-Time Polymerase Chain Reaction; Resveratrol; Stilbenes

Resveratrol (trans-3,4'-trihydroxystilbene), a natural phytoalexin, possesses anti-inflammatory, anti-proliferative, and immunomodulatory properties and has the potential for treating inflammatory disorders. The present study was designed to investigate the effects of resveratrol on TNF-α-induced inflammatory cytokines production of IL-1β and MMP3 in Rheumatoid arthritis (RA) Fibroblast-like synoviocytes (FLS) and further to explore the role of PI3K/Akt signaling pathway by which resveratrol modulates those cytokines production. The levels of IL-1β, MMP-3 in cultural supernatants among groups were measured by enzyme-linked immunosorbent assay. Messenger RNA expression of IL-1β and MMP-3 in RA FLS was analyzed using a reverse transcription-polymerase chain reaction. Western blot analysis was used to detect proteins expression in RA FLS intervened by resveratrol. Resveratrol inhibited both mRNA and proteins expressions of IL-1β and MMP-3 on RA FLS in a dose-dependent manner. Resveratrol also decreased significantly the expression of phosphorylated Akt dose dependently. Activation of PI3K/Akt signaling pathway exists in TNF-α-induced production of IL-1β and MMP3 on RA FLS, which is hampered by PI3K inhibitor LY294002. Immunofluorescence staining showed that TNF-α alone increased the production of P-Akt, whereas LY294002 and 50 μM resveratrol suppressed the TNF-α-stimulated expression of P-Akt. Resveratrol attenuates TNF-α-induced production of IL-1β and MMP-3 via inhibition of PI3K-Akt signaling pathway in RA FLS, suggesting that resveratrol plays an anti-inflammatory role and might have beneficial effects in preventing and treating RA.

Topics: Aged; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Enzyme Activation; Female; Fibroblasts; Gene Expression Regulation; Humans; Interleukin-1beta; Male; Matrix Metalloproteinase 3; Middle Aged; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Resveratrol; RNA, Messenger; Signal Transduction; Stilbenes; Synovial Membrane; Tumor Necrosis Factor-alpha

Resveratrol, a phytoalexin, reduced the viability of MH7A cells, a human rheumatoid arthritis synovial cell line. In the apoptosis assay, resveratrol increased TUNEL-positive cells and stimulated H2A.X phosphorylation. Resveratrol disrupted mitochondrial membrane potentials in MH7A cells and stimulated cytochrome c release from the mitochondria to the cytosol. Resveratrol activated caspase-3 and caspase-9 but not caspase-8 in MH7A cells. Resveratrol upregulated the expression of the NAD-dependent deacetylase sirtuin 1 mRNA and downregulated the expression of the Bcl-X(L) mRNA, and resveratrol-induced MH7A cell death, mitochondrial damage, and caspase-3/-9 activation were prevented by sirtinol, an inhibitor of sirtuin 1. The results of the present study show that resveratrol induces MH7A cell apoptosis by activating caspase-9 and the effector caspase-3 along mitochondrial disruption as a result of reduced Bcl-X(L) expression, allowing cytochrome c release from the mitochondria into the cytosol, in a sirtuin 1-dependent manner. This suggests that resveratrol could suppress hyperplasia of synovial cells, a critical factor of rheumatoid arthritis.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Arthritis, Rheumatoid; bcl-X Protein; Benzamides; Caspase 3; Caspase 9; Cell Line; Cytochromes c; Humans; Mitochondria; Naphthols; Resveratrol; Sirtuin 1; Stilbenes; Synovial Membrane; Up-Regulation

To observe the effect of resveratrol (Res) on in vitro proliferation and apoptosis of TNF-alpha induced rheumatoid arthritis fibroblast-like synoviocytes (RA FLS), and further to investigate the PI3 K/Akt/BAD signal mechanism.. The inhibition rate of RA FLS was examined by MTT assay. Cell cycle and the amount of apoptotic cells was measured by flow cytometry. PI3K/Akt/BAD signal transduction proteins expression was measured by western blot.. The living cells measured by MTT dose and time-dependently reduced in Res groups. In Res groups, the fraction of living cells in the S-phase and G2/M-phase decreased respectively, while that in G1-phase increased, the difference was statistically significant compared with the TNF-alpha group (P < 0.05). Flow cytometry demonstrated that the apoptosis rate increased with increased Res concentration. Res inhibited TNF-alpha induced phosphorylation of Akt and BAD in RA FLS.. Res can inhibit RA FLS proliferation and induce apoptosis through inhibition of PI3K/Akt/BAD signalling pathway. Res may provide a new therapeutic approach in treatment of RA.

Topics: Aged; Apoptosis; Arthritis, Rheumatoid; Cell Cycle; Cell Proliferation; Cells, Cultured; Female; Fibroblasts; Humans; Male; Middle Aged; Resveratrol; Stilbenes; Synovial Membrane; Tumor Necrosis Factor-alpha

Resveratrol is a naturally occurring polyphenol, which possesses chemotherapeutic potential through its ability to trigger apoptosis. The objective of this study was to investigate the major determinant for the apoptotic cell death induction by resveratrol in fibroblast-like synoviocytes (FLS) derived from patients with RA.. The effect of resveratrol on apoptotic cell death was quantified in a population of subG1 in RA FLS by flow cytometry. The underlying signalling mechanism for apoptotic death was examined by analysing mitochondrial membrane potential, activation of the caspase cascade and translocation of Bid.. We show that activation of caspase-8 is essential for triggering resveratrol-induced apoptotic signalling via the involvement of the mitochondrial pathway in RA FLS. Our findings also suggest that this enhanced apoptosis caused by resveratrol occurred in RA FLS irrespective of p53 status. Exposure to resveratrol caused extensive apoptotic cell death, along with a caspase-dependent (activation of caspase-9 and -3, poly ADPribose polymerase (PARP) cleavage and mitochondrial cytochrome c release) or caspase-independent [translocation of apoptosis-inducing factor (AIF) to the nucleus] signalling pathway. Analysis of upstream signalling events affected by resveratrol revealed that the activated caspase-8 triggered mitochondrial apoptotic events by inducing Bid cleavage without any alteration in the levels of Bax, Bcl-xL or Bcl2. The caspase-8 inhibitor or over-expression of crmA abrogated cell death induced by resveratrol and prevented processing of the downstream cascade.. The results suggest that resveratrol causes activation of caspase-8, which in turn results in modulation of mitochondrial apoptotic machinery to promote apoptosis of RA FLS.

Topics: Apoptosis; Apoptosis Inducing Factor; Arthritis, Rheumatoid; Caspase 8; Cells, Cultured; Fibroblasts; Fluorescent Antibody Technique; Humans; Membrane Potentials; Mitochondria; Probability; Resveratrol; Sensitivity and Specificity; Stilbenes; Synovial Membrane

Nuclear factor kappa B (NF-kappaB), is a pivotal transcription factor involved in the activation of the TNF-alpha and IL-1beta genes. Activation of NF-kappaB in synovial cells is a feature seen in arthritis patients. Resveratrol, a polyphenolic, natural phytoalexin found with particularly high levels in grape skin and red wine is potent and specific inhibitor of TNF-alpha and IL-1beta induced NF-kappaB activation. We aimed to determine the in vivo effects of intra-articular injections of resveratrol on cartilage and synovium in an experimental rabbit inflammatory arthritis model.. Arthritis was induced by intra-articular injection of three times of 50 mug lipopolysaccharide (LPS) at day 0, 4 and 8 at 4-day intervals into the knee joints of rabbits. To the test group, 10 muMol/kg resveratrol in the DMSO was injected in the knees at day 0 and then it was continued once daily for 2 weeks. To the control group the same time and amount of DMSO was injected the knees of rabbits. All rabbits were killed 1 week after the last injection and cartilage tissue and synovium were evaluated with semiquantitative scoring histologically.. According to control group in the resveratrol group, significantly decreased cartilage destruction was determined by H&E staining (p = 0.04). Loss of matrix proteoglycan content in the cartilage was much lower, as determined by safranin O staining (p = 0.03). We also observed marked synovial inflammation after intra-articular injection to control knees, but not in the resveratrol treated group knees (p = 0.01).. This study suggests that intra-articular injection of resveratrol may protect cartilage against the development of experimentally induced IA.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Arthritis, Rheumatoid; Cartilage; Female; Injections, Intra-Articular; Knee Joint; Lipopolysaccharides; Proteoglycans; Rabbits; Resveratrol; Stilbenes; Synovial Membrane

To investigate the effect of resveratrol on the proliferation and apoptosis of synoviocytes in patients with rheumatoid arthritis (RA) in vitro and explore its mechanism.. The levels of cell proliferation of synoviocytes in RA after 24 h treated with different concentrations of resveratrol were measured by monotetrazolium colourmetric assay method. The percentages of synoviocytes apoptosis in RA after 24 h treated with different concentrations of resveratrol were tested by TUNEL and flow cytometry. The relative activities of caspase-3 were determined by colorimetric assay after 4, 8, 12, 18, and 24 h treated with resveratrol (200 micromol/L) and 12 h treated with different concentrations of resveratrol. The cleavages of pro-caspase-3 were analyzed by Western blot after 24 h treated with different concentrations of resveratrol.. The levels of cell proliferation of synoviocytes with RA after 24 h treated with different concentrations of resveratrol were significantly decreased compared with the control group (P<0.01). The percentages of the apoptotic cells were increased of resveratrol-treated after 24 h, the apoptosis rates between the treated groups and the control group were significantly different (P<0.01). When the synoviocytes in RA were treated with 200 micromol/L resveratrol for different time respectively, the caspase-3 activity began to rise significantly at 4h, reaching the peak at 12 h, and was still much higher than that of the control group at 24 h (P<0.01). After the cells were treated with different concentrations of resveratrol for 12 h, caspase-3 activity increased in a concentration-dependent manner. After synoviocytes in RA were treated with different concentrations of resveratrol for 24 h, the expressions of pro-caspase-3 decreased as the concentration increased, the caspase-3 active fragment P11 (11 kD) appeared at 100 micromol/L and was increased at 400 micromol/L.. Resveratrol inhibits the proliferation of synoviocytes and induces cell apoptosis in rheumatoid arthritis in vitro, which may relate to the activation of caspase-3.

Topics: Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Cell Proliferation; Cells, Cultured; Depression, Chemical; Female; Humans; Male; Middle Aged; Resveratrol; Stilbenes; Synovial Membrane

The cytokine macrophage migration inhibitory factor (MIF) has recently emerged as a crucial factor in the pathogenesis of rheumatoid arthritis (RA). It is debated whether the MIF mediated tautomeric conversion of either phenylpyruvate or of its other phenolic substrates is implicated in the pro-inflammatory action of this cytokine. Traditional herbal remedies have been used for centuries to alleviate inflammatory ailments of many kinds including arthritis. Several of their active ingredients identified are mono- or poly-phenol derivatives. In the present study the effect of some anti-inflammatory plant phenols on MIF mediated tautomerism of phenylpyruvate was investigated. Curcumin and caffeic acid were found to be the most potent inhibitors, exhibiting IC(50) values in the submicromolar range in the ketonase assay. Resveratrol and umbelliferon were almost as potent inhibitors as the antipyretic-analgetic drug acetaminophen. Our results reveal MIF as a possible target for the herbal anti-rheumatic agents.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Caffeic Acids; Cattle; Curcumin; Enzyme Inhibitors; Humans; In Vitro Techniques; Intramolecular Oxidoreductases; Kidney; Macrophage Migration-Inhibitory Factors; Phenols; Phenylpyruvic Acids; Phloretin; Phytotherapy; Plants, Medicinal; Resveratrol; Stilbenes