Mirac Inhibits the Activation of Nuclear Factor-kappa B 65 which causes Arthritis. Arthritis, Rheumatoid and Osteo, are caused by the induction of InterLeukin-8 and monocyte chemoattractant protein-1 expression by tumor necrosis factor alpha. Mirac inhibits the activation of Nuclear Factor-kappa B 65 which causes these chain reactions through H2O2 mediated responses. (J. Rheumatol. 1997 Sep;24(9):1680-4. "... a bioflavonoid, inhibits the induction of interleukin 8 and monocyte chemoattractant protein-1 expression by tumor necrosis factor-alpha in cultured human synovial cells." Sato M, Miyazaki T, Kambe F, Maeda K, Seo H.Department of Endocrinology and Metabolism, Nagoya University, Japan.)

    Rheumatoid Arthritis (RA)

	What is it?
	What are the symptoms?
	What causes it?
	What are the effects?
	How is it diagnosed?
	Who is at risk?
	Other information

What is it?

Rheumatoid arthritis (rue-ma-TOYD arth-write-tis) involves inflammation in the lining of the joints and/or other internal organs. RA typically affects many different joints. It can be chronic, which means it lasts a long time, and can be a disease of flares (active) and remissions (little to no activity).

RA is a systemic disease that affects the entire body and is one of the most common forms of arthritis. It is characterized by the inflammation of the membrane lining the joint, which causes pain, stiffness, warmth, redness and swelling. The inflamed joint lining, the synovium, can invade and damage bone and cartilage. Inflammatory cells release enzymes that may digest bone and cartilage. The involved joint can lose its shape and alignment, resulting in pain and loss of movement.

What are the symptoms?

Symptoms include inflammation of joints, swelling, difficulty moving and pain. Other symptoms include: Loss of appetite, Fever, Loss of energy, Anemia, Sometimes rheumatoid nodules (lumps of tissue under the skin) Can affect other parts of the body.

What causes it?

RA is an autoimmune disease. The body's natural immune system does not operate as it should, resulting in the immune system attacking healthy joint tissue and causing inflammation and subsequent joint damage.

Researchers suspect that agent-like viruses may trigger RA in some people who have an inherited tendency for the disease. Many people with RA have a certain genetic marker called HLA-DR4. Researchers know that there are other genes that influence the development of RA.

What are the effects?

Early in the disease, people may notice general fatigue, soreness, stiffness and aching. Pain and swelling may occur in the same joints on both sides of the body and will usually start in the hands or feet. RA affects the wrist and many of the hand joints, but usually not the joints that are closest to the fingernails (except the thumb). RA also can affect elbows, shoulders, neck, knees, hips and ankles. It tends to persist over prolonged periods of time, and over time, inflamed joints may become damaged. Other features include lumps, called rheumatoid nodules, under the skin in areas that receive pressure, such as the back of the elbows.

How is it diagnosed?

It is important to diagnose RA early in the course of the disease, because with the use of disease-modifying drugs, the condition can be controlled in many cases. Physicians diagnose RA based on the overall pattern of symptoms, medical history, physical exam, X-rays and lab tests including a test for rheumatoid factor. Rheumatoid factor is an antibody found in the blood of about 80 percent of adults with RA. However, the presence or absence of rheumatoid factor does not indicate that one has RA.

Who Is At Risk?

Rheumatoid arthritis affects 2.1 million Americans, mostly women Onset is usually in middle-age, but often occurs in the 20s and 30s. 1.5 million women have rheumatoid arthritis compared to 600,000 men.

Other information

Musculoskeletal conditions such as rheumatoid arthritis cost the U.S. economy nearly $65 billion per year in medical care and indirect expenses such as lost wages and production.

OBJECTIVE: Tumor necrosis factor (TNF)-alpha is present in synovial fluid of patients with rheumatoid arthritis. It induces the expression of proinflammatory cytokines in synovial cells. Based on our recent finding that reactive oxygen intermediates play important roles in mediating TNF-alpha action, we examined the effect of an antioxidant bioflavonoid, quercetin, on TNF-alpha induced expression of interleukin 8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) in cultured human synovial cells. METHODS: The amounts of mRNA for IL-8 and MCP-1 were determined by Northern blot analysis. Electrophoretic mobility shift assays (EMSA) were performed for the detection of a transcription factor, nuclear factor-kappa B (NF-kappa B). RESULTS: Addition of quercetin suppressed TNF-alpha induced increase in the mRNA for IL-8 and MCP-1 in a dose dependent manner. Quercetin did not affect the stability of these mRNA. H2O2 mediated induction of IL-8 and MCP-1 genes was also inhibited by quercetin. EMSA revealed that quercetin inhibited the activation of NF-kappa B by TNF-alpha. CONCLUSION: Quercetin suppresses TNF-alpha mediated stimulation of IL-8 and MCP-1 expression, at least in part, by inhibiting the activation of NF-kappa B.

Osteoarthritis

A degenerative joint disease characterized by the breakdown of the joint's cartilage, Osteoarthritis affects hands and weight-bearing joints such as knees, hips, feet and the back mostly in middle-aged and older adults.

1. Isr Med Assoc J. 2003 May;5(5):361-4. Potential Applications of Matrix Metalloproteinase Inhibitors in Geriatric Practice. Marder G, Greenwald RA. Department of Rheumatology, Long Island Jewish Medical Center, NewYork, NY, USA. Matrix metalloproteinases are a family of enzymes that degrade different components of extracellular matrix. They play an important role in normal physiologic processes of maintaining tissue integrity and remodeling, as in wound healing, processes of development, and regeneration. However, excessive expression of MMP has been observed in many disease states, including rheumatoid arthritis and osteoarthritis, vascular remodeling in atherosclerosis and aortic aneurysm formation, neoplastic processes, macular degeneration and many others.

2. Biochem Biophys Res Commun. 2003 Feb 21;301(4):1069-78. Quercetin exerts multiple inhibitory effects on vascular smooth muscle cells: role of ERK1/2, cell-cycle regulation, and matrix metalloproteinase-9. Moon SK, Cho GO, Jung SY, Gal SW, Kwon TK, Lee YC, Madamanchi NR, Kim CH. National Research Laboratory for Glycobiology, Korean Ministry of Science and Technology, Kyungju, 780-714, Kyungbuk, Republic of Korea.

The French paradox has been attributed to the antioxidant properties of flavonoids present in the red wine. Quercetin, a bioflanoid present in the human diet, is known to inhibit angiotensin II-induced hypertrophy and serum-induced smooth muscle cell proliferation. However, it is not known whether quercetin exerts similar cardioprotective effects in cells treated with TNF-alpha. In this study, we investigated whether quercetin exerts the multiple suppressive effects on cytokine TNF-alpha-induced human aortic smooth muscle cells (HASMC). Treatment of quercetin showed potent inhibitory effects on the DNA synthesis of cultured HASMC in the presence of TNF-alpha. These inhibitory effects were associated with reduced extracellular signal-regulated kinase (ERK)1/2 activity and G1 cell-cycle arrest. Treatment of quercetin, which induced a cell-cycle block in G1-phase, induced down-regulation of cyclins and CDKs and up-regulation of the CDK inhibitor p21 expression, whereas up-regulation of p27 or p53 by quercetin was not observed. Because anti-atherogenic effects need not be limited to antiproliferation, we decided to examine whether quercetin exerted inhibitory effects on matrix metalloproteinase-9 (MMP-9) activity in TNF-alpha-induced HASMC. Quercetin inhibited TNF-alpha-induced MMP-9 secretion on HASMC in a dose-dependent manner. This inhibition was characterized by down-regulation of MMP-9, which was transcriptionally regulated at NF-kappaB site and activation protein-1 (AP-1) site in the MMP-9 promoter. These findings indicate the efficacy of quercetin in inhibiting cell proliferation, G1- to S-phase cell-cycle progress, and MMP-9 expression through the transcription factors NF-kappaB and AP-1 on TNF-alpha-induced HASMC.