This articles expressed the significance of SOD in neutralizing the superoxide anion from ROS that plays a vital role in inflammation, especially in inflammatory joint diseases. Proinflammatory factors (cytokines, prostaglandins) are released at sites of inflammation with ROS and NO. These are associated with decreased SOD concentrations in joint fluid, which are important in the protection against the harmful effects of the superoxide anion, which damages cells and the extracellular matrix. Other antioxidants that play a role in protective role are glutathione peroxidase, catalase, and liposoluble antioxidants(e.g.vitamin E). SOD catalyses the superoxide anion to dioxygen and peroxide. The peroxide is eliminated by glutathione peroxidase or catalase.
There are three SOD's studied: SOD1 found in the cytoplasm, SOD2 found in the mitochondria, and SOD3 found in the ECM. The gene encoding regions for each are found on different chromosomes, which is not surprising seeing as how they have varied effects. SOD1 plays and important role in cell survival and growth; its transcription increases in resonse to heat shock, shear stress, and oxidative stress. Overproduction of TNF-alpha in inflammation is associated with increased oxidative stress and decreased SOD1 expression. SOD2 deficits can lead to increased risk factors for cardiomyopathies. However, proinflammatory cytokines such as TNF-alpha are SOD-2 activatiors. The SOD3 protects cells and the ECM against superoxide anion. Like SOD1, TNF-alpha is an inhibitor of SOD3. I found this very intriguing. Does anybody know why TNF-alpha would act as an SOD2 activator but inhibit the other two?? I did not see anything reguarding this in this article. TNF-alpha overproduction may be the main contributor to increased ROS release in patients with RA, so it is an extremely important part of the mechanisms involved in inflammatory joint diseases. Any insight on this would be great.
So SOD's are very important in inflammation and disease! SOD mimetics are available today. They may attenuate the inflammatory process by decreasing peroxynitrite formation leading to increased availability of NO, decrease the release of proinflammatory cytokines, and/or decrease influx of neutrophils at the sites of inflammation, thus providing a means of relief in several patients! If you have any questions, I'd be happy to answer them.
Happy spring break!!
13 March 2008
12 March 2008
The Many Roles of NO
In the review article “Molecular Aspects of Pathogenesis in Osteoarthritis: The Role of Inflammation” I found several tidbits interesting. In osteoarthritis , the inflammation factor is actually very low compared to other forms of arthritis however IL-1 and TNF-α have been found in the synovial fluid of osteoarthritis (OA) patients. While the cause of OA is unknown, one idea is that the loss (decreased synthesis) of proteoglycans (PG) leads to a decrease in water retention of the cartilage and consequently less fluidity and resilience of the cartilage.
In the article the relationship between Insulin-like Growth Factor-I and PG synthesis is explored. I found it interesting that IGF-I had a vast majority of roles and according to the article IGF-I was responsible for stimulating PG synthesis and that “particularly high levels of expression are shown by cells within areas of more advanced OA lesions”. This would make one wonder if the body is compensating by increasing IGF-I expression in affected areas why the disease was still having an effect. The paper presented the theory that IGF-I had a lessened effect on articular chrondocytes possibly due to an “upregulation of IGF-binding proteins” (Hedbom and Hauselmann 46).
A science article online shed further light on that theory. The presence of elevated levels of both IGF and IGF-binding proteins (IGF-BPs) in the synovial fluid of both RA and OA patients has inspired the hypothesis that an imbalance of these elements causes the insensitivity. IGF-BPs “act as transport proteins in plasma, prolong the half-life of IGF, provide a means of tissue localization for IGF, modulate interaction of IGF with its receptors, and, in some cases, have IGF-I independent effects on cells. Thus the maintenance of IGF actions on chrondocytes is complicated by regulation of and by IGFBPs and the proteases that degrade IGFBPs and therefore indirectly affect responses to IGF-I” (Studer, Levicoff, Georgescu et al.).
Another part of the article addressed the role of NO in arthritis not only as an element responsible for cartilage damage via inflammation and inhibition of PG and collagen synthesis in conjunction with IL-1 and other cytokines but also as one of the responsible parties for “cartilage insentivity to IGF-I.” (Studer, Levicoff, Georgescu et al.) The role of NO was suggested by an experiment with arthritis induced mice in which wild-type mice showed the expected IGF-I insensitivity but the second group had iNOS (the enzyme responsible for the production o f NO) knocked out and that showed an ability to increase PG in response to IGF-I. That led to the experiment design in the paper:
“The current studies were designed to 1) determine whether chondrocyte insensitivity to IGF-I could be observed in an in vitro system, and if so, 2) utilize cartilage and chondrocytes in culture to begin an analysis of the mechanisms by which NO causes unresponsiveness to IGF-I. We used lapine cartilage and chondrocytes in organ and monolayer culture and found that exposure to NO inhibits the IGF-I-stimulated increase in proteoglycan synthesis. This is seen with NO produced exogenously from the NO donors S-nitroso-N-acetylpenicillamine (SNAP) and (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate] (DETA NONOate) or endogenously following IL-1 stimulation or adenoviral transfer of iNOS (Ad-iNOS) into chondrocytes. This effect of NO is reversible. Relevance to human disease is implied, as inhibition of NO synthesis with NG-monomethyl-L-arginine (L-NMA) during in vitro organ culture of human articular cartilage recovered from OA joints restores a brisk anabolic response to IGF-I. IGF-I-stimulated tyrosine phosphorylation of the IGF-I receptor is decreased by prior exposure of chondrocytes to NO, suggesting that chondrocyte insensitivity to IGF-I in the presence of NO is due at least in part to an action of NO on this step in the signal transduction pathway” (Studer, Levicoff, Georgescu et al.).
In conclusion the paper described how NO was partially responsible for chondrocyte insentivity to IGF-I due to the inhibition of receptor autophosphorylation, which is an integral part of IGF-I receptor (Tyrosine Kinase) functionality. Therefore the disruption of this mechanism is one hypothesis to explain the insensitivity of arthritic cartilage to IGF-I.
Nitric oxide inhibits chondrocyte response to IGF-I: inhibition of IGF-IRβ tyrosine phosphorylation
R. K. Studer, E. Levicoff, H. Georgescu, L. Miller, D. Jaffurs, and C. H. Evans
http://ajpcell.physiology.org/cgi/content/full/279/4/C961
In the article the relationship between Insulin-like Growth Factor-I and PG synthesis is explored. I found it interesting that IGF-I had a vast majority of roles and according to the article IGF-I was responsible for stimulating PG synthesis and that “particularly high levels of expression are shown by cells within areas of more advanced OA lesions”. This would make one wonder if the body is compensating by increasing IGF-I expression in affected areas why the disease was still having an effect. The paper presented the theory that IGF-I had a lessened effect on articular chrondocytes possibly due to an “upregulation of IGF-binding proteins” (Hedbom and Hauselmann 46).
A science article online shed further light on that theory. The presence of elevated levels of both IGF and IGF-binding proteins (IGF-BPs) in the synovial fluid of both RA and OA patients has inspired the hypothesis that an imbalance of these elements causes the insensitivity. IGF-BPs “act as transport proteins in plasma, prolong the half-life of IGF, provide a means of tissue localization for IGF, modulate interaction of IGF with its receptors, and, in some cases, have IGF-I independent effects on cells. Thus the maintenance of IGF actions on chrondocytes is complicated by regulation of and by IGFBPs and the proteases that degrade IGFBPs and therefore indirectly affect responses to IGF-I” (Studer, Levicoff, Georgescu et al.).
Another part of the article addressed the role of NO in arthritis not only as an element responsible for cartilage damage via inflammation and inhibition of PG and collagen synthesis in conjunction with IL-1 and other cytokines but also as one of the responsible parties for “cartilage insentivity to IGF-I.” (Studer, Levicoff, Georgescu et al.) The role of NO was suggested by an experiment with arthritis induced mice in which wild-type mice showed the expected IGF-I insensitivity but the second group had iNOS (the enzyme responsible for the production o f NO) knocked out and that showed an ability to increase PG in response to IGF-I. That led to the experiment design in the paper:
“The current studies were designed to 1) determine whether chondrocyte insensitivity to IGF-I could be observed in an in vitro system, and if so, 2) utilize cartilage and chondrocytes in culture to begin an analysis of the mechanisms by which NO causes unresponsiveness to IGF-I. We used lapine cartilage and chondrocytes in organ and monolayer culture and found that exposure to NO inhibits the IGF-I-stimulated increase in proteoglycan synthesis. This is seen with NO produced exogenously from the NO donors S-nitroso-N-acetylpenicillamine (SNAP) and (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate] (DETA NONOate) or endogenously following IL-1 stimulation or adenoviral transfer of iNOS (Ad-iNOS) into chondrocytes. This effect of NO is reversible. Relevance to human disease is implied, as inhibition of NO synthesis with NG-monomethyl-L-arginine (L-NMA) during in vitro organ culture of human articular cartilage recovered from OA joints restores a brisk anabolic response to IGF-I. IGF-I-stimulated tyrosine phosphorylation of the IGF-I receptor is decreased by prior exposure of chondrocytes to NO, suggesting that chondrocyte insensitivity to IGF-I in the presence of NO is due at least in part to an action of NO on this step in the signal transduction pathway” (Studer, Levicoff, Georgescu et al.).
In conclusion the paper described how NO was partially responsible for chondrocyte insentivity to IGF-I due to the inhibition of receptor autophosphorylation, which is an integral part of IGF-I receptor (Tyrosine Kinase) functionality. Therefore the disruption of this mechanism is one hypothesis to explain the insensitivity of arthritic cartilage to IGF-I.
Nitric oxide inhibits chondrocyte response to IGF-I: inhibition of IGF-IRβ tyrosine phosphorylation
R. K. Studer, E. Levicoff, H. Georgescu, L. Miller, D. Jaffurs, and C. H. Evans
http://ajpcell.physiology.org/cgi/content/full/279/4/C961
Phytonutrient Flavenoids
In the article "Can Diet or Supplements Relieve Your Arthritis Aches and Inflammation?" The phrase phytonutrients like flavonoids caught my attention as I’d never heard of flavonoids before. Phytonutrients are simply components thought to promote human health that are derived from plants. Some commonly known phytonutrients are carotenoids such as alpha and beta carotene. Flavonoids are compounds also found in natural substances, but they are thought to have specifically have anti-oxidant properties. Antioxidants are compounds that protect against reactive oxygen species (ROS) “such as singlet oxygen, superoxide, peroxyl radicals, hydroxyl radicals and peroxynitrite” (LPI). In the article, a recent study indicated that flavonoids may have anti-oxidative properties equal to that of vitamin E (a recognized anti-oxidant) due to similarities in structure. This is important as it correlates with the Environmental Nutrition's’ article position that an intake of a diet rich in these flavonoids would be beneficial.
Reference Links
Phytonutrients
http://www.ars.usda.gov/Aboutus/docs.htm?docid=4142#what_are
Flavonoids
http://lpi.oregonstate.edu/f-w00/flavonoid.html
Reference Links
Phytonutrients
http://www.ars.usda.gov/Aboutus/docs.htm?docid=4142#what_are
Flavonoids
http://lpi.oregonstate.edu/f-w00/flavonoid.html
11 March 2008
Supplements Help Arthritis Symptoms: Fact or Fiction?
The article "Can Diet or Supplements Relieve Your Arthritis Aches and Inflammation" in Environmental Nutrition addressed the issue of the increased use of dietary supplements among suffers of arthritis. While many companies advertise the benefits of their product, there are many doubts as to their effectiveness within the scientific community. While some products may offer some relief from symptoms or progression of arthritis, others may simply be feeding off of the placebo effect.
Products that have shown significant reductions in arthritis symptoms include Omega-3 fatty acids and s-adenosylmethionine. In the article "Collateral Benefits of Fish Oil Therapy for Rheumatoid Arthritis" from The Journal of Rheumatology, Dr. Chak Sing Lau discusses how there is growing evidence that a diet that includes fish oils may improve the symptoms associated with rheumatoid arthritis.
Other supplements such as selenium, vitamin A and vitamin C are advertised to the consumer as decreasing the oxidative effects of arthritis. However, in another article published in The Journal of Rheumatology, titled "The antioxidant vitamins A, C, E and selenium in the treatment of arthritis: a systematic review of randomized clinical trials", showed that there is no convincing evidence indicating that these supplements offer any relief for arthritis and should not be considered an arthritis treatment.
The Environmental Nutrition journal concludes that while many of the supplement's benefits are uncertain, eating a well balanced diet reduced in fat and high in fruits and vegetables with regular exercise will help manage arthritis pain. ... hmmmm, seems to be a trend :)
Collateral Benefits of Fish Oil... article:
http://www.jrheum.com.ezproxy2.library.arizona.edu/subscribers/06/10/1931.html
The antioxidant vitamins A, C, E and selenium... article: http://www.ncbi.nlm.nih.gov.ezproxy2.library.arizona.edu/sites/entrez
Products that have shown significant reductions in arthritis symptoms include Omega-3 fatty acids and s-adenosylmethionine. In the article "Collateral Benefits of Fish Oil Therapy for Rheumatoid Arthritis" from The Journal of Rheumatology, Dr. Chak Sing Lau discusses how there is growing evidence that a diet that includes fish oils may improve the symptoms associated with rheumatoid arthritis.
Other supplements such as selenium, vitamin A and vitamin C are advertised to the consumer as decreasing the oxidative effects of arthritis. However, in another article published in The Journal of Rheumatology, titled "The antioxidant vitamins A, C, E and selenium in the treatment of arthritis: a systematic review of randomized clinical trials", showed that there is no convincing evidence indicating that these supplements offer any relief for arthritis and should not be considered an arthritis treatment.
The Environmental Nutrition journal concludes that while many of the supplement's benefits are uncertain, eating a well balanced diet reduced in fat and high in fruits and vegetables with regular exercise will help manage arthritis pain. ... hmmmm, seems to be a trend :)
Collateral Benefits of Fish Oil... article:
http://www.jrheum.com.ezproxy2.library.arizona.edu/subscribers/06/10/1931.html
The antioxidant vitamins A, C, E and selenium... article: http://www.ncbi.nlm.nih.gov.ezproxy2.library.arizona.edu/sites/entrez
Dietary supplements and Arthritis
I was just reading the article "Can Diet or Supplements relieve your Arthritis aches and Inflammation" assigned for this week. It talks about the various dietary supplements that Arthritis patients take in order to ease some of the symptoms of Arthritis: pain, aches, stiffness and swelling around the joints. Arthritis patients have an overactive immune system which leads to the breakdown of the tissues (commonly around the joints) causing pain and swelling and there are many forms of Arthritis; the two most common ones are osteoarthritis (OA) and rheumatoid arthritis (RA). It is due to the influence of the immune system that people are looking at dietary supplements as a way of relieving arthritis symptoms. Vitamins, minerals and omega-3 FA from fish oils are some of the supplements taken by arthritis sufferers. While some of these supplements offer some benefits, others have no effect at all.
Supplements containing high quantity of copper, zinc or alfalfa and low-fat/low-calorie/low-protein diets are not recommended by the Arthritis Foundation as an alternative way of relieving the symptoms because it cuts out an entire food group that helps maintain a healthy weight, which is an important part of managing arthritis. One study have found that allergy to shellfish can trigger an RA-like symptoms in some people (I went on the Mayo clinic website and found that Glucosamine, commonly used by OA patients, are found in the covering of shellfish and it doesn't appear to cause an allergic reaction to some people allergic to shellfish. It looks like an effective way of relieving arthritis but more studies still need to be done in order to determine whether it is safe or not for arthritis patients who are allergic to shellfish). Low intake of Vit. D is also associated to both OA and RA. According to Dr. Louise Gagne at the University of Saskatchewan, OA sufferers intake of Vit. D is only 20% of the Recommended Dietary Allowance for older people (51-70 y.o.).
There seem to be conflicting evidence (or not enough studies) to support the effectiveness of some of these supplements/diets. But it looks like having a well-balanced diet, eating right and maintaining a healthy weight is one way of reducing arthritis symptoms (such is recommended by the Arthritis Foundation and EN).
Supplements containing high quantity of copper, zinc or alfalfa and low-fat/low-calorie/low-protein diets are not recommended by the Arthritis Foundation as an alternative way of relieving the symptoms because it cuts out an entire food group that helps maintain a healthy weight, which is an important part of managing arthritis. One study have found that allergy to shellfish can trigger an RA-like symptoms in some people (I went on the Mayo clinic website and found that Glucosamine, commonly used by OA patients, are found in the covering of shellfish and it doesn't appear to cause an allergic reaction to some people allergic to shellfish. It looks like an effective way of relieving arthritis but more studies still need to be done in order to determine whether it is safe or not for arthritis patients who are allergic to shellfish). Low intake of Vit. D is also associated to both OA and RA. According to Dr. Louise Gagne at the University of Saskatchewan, OA sufferers intake of Vit. D is only 20% of the Recommended Dietary Allowance for older people (51-70 y.o.).
There seem to be conflicting evidence (or not enough studies) to support the effectiveness of some of these supplements/diets. But it looks like having a well-balanced diet, eating right and maintaining a healthy weight is one way of reducing arthritis symptoms (such is recommended by the Arthritis Foundation and EN).
p38 and arthritic symptoms
Hello everyone,
I was reading the articles this week and there was one I found particularly interesting. I liked the article CNS Can Control Arthritic Joint Inflammation and Destruction. Researchers at the University of California, San Diego tried a new approach to treating arthritic joint inflammation and destruction. The researchers believed the CNS is a controlling influence for the body and can regulate peripheral inflammation and immune responses. They used a very small amount of p38 inhibitor and administered it through a catheter implanted in the rats' spinal cord. The results showed a significantly decrease in inflammation in the joints when the enzyme was exclusively blocked in a highly restricted site and not in the whole body. TNF-alpha was also examined because it is thought to continue activating spinal p38 causing ongoing symptoms and destruction. When TNF-alpha was also inhibited symptoms of arthritis decreased. I found these results to be interesting. This might lead to some new treatments, or at least a new way of thinking. I went on the web and found a few clinical trials that have been performed and ones looking for participants. So it looks like they are moving forward.
I was reading the articles this week and there was one I found particularly interesting. I liked the article CNS Can Control Arthritic Joint Inflammation and Destruction. Researchers at the University of California, San Diego tried a new approach to treating arthritic joint inflammation and destruction. The researchers believed the CNS is a controlling influence for the body and can regulate peripheral inflammation and immune responses. They used a very small amount of p38 inhibitor and administered it through a catheter implanted in the rats' spinal cord. The results showed a significantly decrease in inflammation in the joints when the enzyme was exclusively blocked in a highly restricted site and not in the whole body. TNF-alpha was also examined because it is thought to continue activating spinal p38 causing ongoing symptoms and destruction. When TNF-alpha was also inhibited symptoms of arthritis decreased. I found these results to be interesting. This might lead to some new treatments, or at least a new way of thinking. I went on the web and found a few clinical trials that have been performed and ones looking for participants. So it looks like they are moving forward.
10 March 2008
Dietary Intervention Case Study
I came across this very interesting case study and wanted to share it with all.
Parenteral nutrition (intravenous feeding) and enteral nutrition (tube feeding) with an elemental diet have been proven to control CD activity. This treatment is not widely used because it is expensive and has side effects. However, in this particular case study total disease remission was induced with non-elemental formula diet of known composition (Ensure Plus).
A 35-year-old patient was diagnosed with CD at the age of 20 (1974) after a year of diarrhea, cramps, and weight loss. He was anemic and his x-ray revealed a diformed & narrowed ileum . He was treated with sulfasalazine and prednisone (20mg/day) from 1974-1980. When he attempted to discontinue the corticosteroid he had reocurrence of cramps and anemia. From 1980-1982 his disease became more progressively active; prednisone (10-40 mg/day) was required to control his symptoms which at that time included an aphthous ulceration in the mouth and tongue. In June 1982 he had a sudden onset of gross hematochezia in the RLQ (here is a site to view images of hematochezia: http://images.google.com/images?um=1&hl=en&q=hematochezia&btnG=Search+Images). At this time prednisone was increased from 10 to 16 mg/day. An examination revealed a fistula from the ileum to the sigmoid colon with two areas of ileal stenosis; he later underwent surgery. The patient did well for about a year but later had gradual reocurrence of cramps, diarrhea, and weight loss. He was placed on prednisone again (10-30mg) for about 3-years. Everytime he attempted to reduce the prednisone dose, cramps would increase. So to make this short, his condition worsen, he had a recurrence in CD; prednisone dose was again increase to 60mg/day.
After two weeks, prednisone dosage was reduced to 40mg/day and they began a diet of solely Ensure (only caloric intake). For 10-weeks the patient only consumed Ensure and water and by the week-8, the prednisone was tapered out and discontinued for the first time in 3-years. The patient became asymptomatic. They gradually started to introduce food (chicken, beef, grean beans, etc) to the Ensure Plus Diet. He did well until he was introduced with milk, he had severe cramping and diarrhea for a week.
The patient was instructed to take Ensure Plus eat the foods he previously tolerated. His symptoms improved within a week without prednisone. The patient has remained in total remission.
I thought the case report was intriguing because they were able to induce total remission with a form of palatable enteral therapy (with Ensure Plus) in a patient with history of long-standing CD with steroid dependency. The authors claim this is the only case reported of total remission; however, they did cite another case similar to the one discussed here where milk was the food that triggered CD symptoms.
Case Report side: http://www.springerlink.com/content/v757h63674365281/fulltext.pdf
Note: I could not open this site at home, only at the UA.
Parenteral nutrition (intravenous feeding) and enteral nutrition (tube feeding) with an elemental diet have been proven to control CD activity. This treatment is not widely used because it is expensive and has side effects. However, in this particular case study total disease remission was induced with non-elemental formula diet of known composition (Ensure Plus).
A 35-year-old patient was diagnosed with CD at the age of 20 (1974) after a year of diarrhea, cramps, and weight loss. He was anemic and his x-ray revealed a diformed & narrowed ileum . He was treated with sulfasalazine and prednisone (20mg/day) from 1974-1980. When he attempted to discontinue the corticosteroid he had reocurrence of cramps and anemia. From 1980-1982 his disease became more progressively active; prednisone (10-40 mg/day) was required to control his symptoms which at that time included an aphthous ulceration in the mouth and tongue. In June 1982 he had a sudden onset of gross hematochezia in the RLQ (here is a site to view images of hematochezia: http://images.google.com/images?um=1&hl=en&q=hematochezia&btnG=Search+Images). At this time prednisone was increased from 10 to 16 mg/day. An examination revealed a fistula from the ileum to the sigmoid colon with two areas of ileal stenosis; he later underwent surgery. The patient did well for about a year but later had gradual reocurrence of cramps, diarrhea, and weight loss. He was placed on prednisone again (10-30mg) for about 3-years. Everytime he attempted to reduce the prednisone dose, cramps would increase. So to make this short, his condition worsen, he had a recurrence in CD; prednisone dose was again increase to 60mg/day.
After two weeks, prednisone dosage was reduced to 40mg/day and they began a diet of solely Ensure (only caloric intake). For 10-weeks the patient only consumed Ensure and water and by the week-8, the prednisone was tapered out and discontinued for the first time in 3-years. The patient became asymptomatic. They gradually started to introduce food (chicken, beef, grean beans, etc) to the Ensure Plus Diet. He did well until he was introduced with milk, he had severe cramping and diarrhea for a week.
The patient was instructed to take Ensure Plus eat the foods he previously tolerated. His symptoms improved within a week without prednisone. The patient has remained in total remission.
I thought the case report was intriguing because they were able to induce total remission with a form of palatable enteral therapy (with Ensure Plus) in a patient with history of long-standing CD with steroid dependency. The authors claim this is the only case reported of total remission; however, they did cite another case similar to the one discussed here where milk was the food that triggered CD symptoms.
Case Report side: http://www.springerlink.com/content/v757h63674365281/fulltext.pdf
Note: I could not open this site at home, only at the UA.
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