Concurrent Session 5 - PAIN, CLINICAL AND PATHOPHYSIOLOGICAL ASPECTS <br />Friday 24 September 2010<br />Dietary Supplemen...
Dietary Supplements in OA: ‘Un Amour Impossible?’ <br />Management of OA primarily involves symptomatic pain relief<br />A...
Dietary Supplements in OA<br />Glucosamine and chondroitin sulfate<br />Vitamins (C, D, E and beta carotene)<br />Polyunsa...
Nutrigenomics<br />The study of the effects of foods and food constituents on gene expression<br />van Ommen (2004) Nutrit...
Nutrigenomics and Personalized Nutrition<br />Nutrigenomics is a form of personalized nutrition* that involves tailoring d...
Nutrigenomics and Systems Biology<br />Nutrigenomics and systems biology use the same models and tools to identify biomark...
What is the evidence linking nutrition and disease?<br />Malnutrition results in poor bone development<br />Evidence from ...
Obesity<br />Calories in = Calories consumed		Normal weight<br />Calories in > Calories consumed		Obese state<br />
Obesity and OA<br />Strong evidence supports a link between overweight, obesity and OA<br />Obesity: complex metabolic and...
Evidence for Nutritional Intervention from Studies on RA Patients<br />Dietary intervention clearly has a place in rheumat...
Evidence for Nutritional Intervention in OA<br />Controversial – there is a need for systematic scientific evaluation of t...
Phytalgic: a food supplement containing fish-oil, vitamin E and Urtica dioica<br />
NF-kB: a Therapeutic Target in OA<br />Nuclear factor-kappaB (NF-kB) - involved in the pathogenesis of OA and RA<br />Targ...
Curcumin - Diferuloylmethane<br />Curcumin is one of three curcuminoids obtained by solvent extraction from dried turmeric...
The Curcumin/AP-1/NF-kB Axis in Inflammatory Responses in Joint Cells<br />Naturally occurring plant-derived compounds suc...
Effects of Curcumin on TNF Signaling<br />Mobasheri, Aldinger and Shakibaei (2011) Role of Inflammation in Rheumatic Disea...
Clinical Trial of Curcumin in RA<br />Curcumin (Longvida™) - randomized, placebo-controlled, phase 0 clinical trial employ...
Curcumin inhibits GAG and PGE2 release from IL-1b stimulated cartilage explants <br />Clutterbuck, A (2010) PhD Thesis. Un...
Comparing the effects of curcumin and carprofen on GAG and PGE2 release from IL-1b stimulated cartilage explants<br />Clut...
Resveratrol - Trans-3,5,4'-trihydroxystilbene<br />Flavonol belonging to the group of flavonoids<br />Produced by plants a...
Scientific Basis for the Study of Resveratrol: Modulation of Sirtuins<br />Members of the sirtuin family regulate epigenet...
Biological Functions of SIRT1<br />
Sirtuins – Novel Therapeutic Targets to Treat Age-Associated Diseases<br />Lavu et al., (2008) Nature Reviews Drug Discove...
Activation of SIRT1 by Resveratrol, Calorie Restriction and Fasting<br />
SirT1 Activates IGFR Pathway and Suppresses Apoptosis in Chondrocytes<br />Gagarina et al., (2010) ARTHRITIS & RHEUMATISM<...
Effects of Resveratrol on Human Chondrocytes<br />Resveratrol inhibits <br />IL-1b–induced PGE2 and LTB4 <br />IL-1b–induc...
Resveratrol Suppresses IL-1b Signaling and Apoptosis in Chondrocytes<br />Resveratrol blocks IL-1b induced apoptosis in hu...
Curcumin and Resveratrol: Evidence for Synergistic Activity<br />
Curcumin Enhances Chondrogenesis of Mesenchymal Stem Cells in vitro<br />Insert copy of Arthritis Research and Therapy pap...
In vitro models of cartilage as biomimetic systems for high-throughput screening of nutrient-derived compounds and combina...
Explant Culture<br />Advantages: <br />Chondrocytes remain phenotypically stable in their native matrix<br />Ideal for stu...
Curcumin and Resveratrol Counteract GAG Release in LPS Treated Cartilage Explants<br />
High-Throuoghput Proteomic Study of the Cartilage Secretome<br />
Commonly Identified Proteins:Canine Cartilage Secretome<br />Poster 121<br />Hillier et al.,<br />OARSI 2010<br />Proteins...
Commonly Identified Proteins:Equine Cartilage Secretome<br />Poster 503 Clutterbuck et al.,<br />OARSI 2010<br />Proteins ...
Western Blot Validation<br />Poster 503<br />Clutterbuck et al.,<br />OARSI 2010<br />
Heinegård D. (2009) Int J Exp Pathol. 90, 575-86<br />
Conclusions I<br />Whether supplements can be effectively and safely recommended to reduce NSAID usage is unclear and requ...
Conclusions II<br />There is potential for high quality basic research into gene nutrient interactions<br />However, subse...
A few words of caution…<br />
A few words of caution…<br />
Acknowledgements: Postgraduate Students and Funding<br />Abigail Clutterbuck<br />Adam Williams<br />Jasmine Penny<br />En...
Acknowledgements: Collaborators<br />Professor Alexandrina<br />Ferreira Mendes<br />Coimbra, Portugal<br />Professor Mehd...
Thank you for your attention<br />
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Oarsi 2010 Presentation A. Mobasheri

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Invited resentation given at the OARSI 2010 Congress - September 23-26 - Brussles, Belgium

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  • I would like to thank the organizers for givingme the opportunityto present at this year’s OARSI conference.I was very excited when I received the invitation letter from the Program Chair Professor Yves Henrotin.However, when I was told that the title of my talk was already selected by the organising committee and would be “Dietary Supplements in OA: Real Opportunity or Utopia?” my excitement rapidly turned into nervousness, fear and eventually panic. I broke into a cold sweat especially when I considered the meaning of the word “Utopia” and started to wonder if my Eurostar ticket was refundable!However, despite my initial fears and trepidations I am delighted to be here and believe that despite the controversial nature of this area there are excellent opportunities for hypothesis driven research in the area of dietary supplementation and nutrigenomics in OA.
  • Since we are in Belgium, the founding member of the European Union and the headquarters of the EU a more suitable title for my presentation could be Dietary Supplements in OA: ‘Un Amour Impossible?This alternative title may appeal to the French speaking Belgians in Brussels although I must apologize to the majority 60% of Belgians who speak Flemish but my knowledge of Flemish is virtually non-existent even though my wife’s family originally hail from Northern Belgium.Management of OA primarily involves symptomatic pain reliefAnalgesicsNon-steroidal anti-inflammatory drugs (NSAIDs)However, pharmacotherapy with conventional drugs does not influence disease progression and can be associated with significant side effectsTherefore, there is an acute need for alternative remedies for OANutritional supplements have been reported to improve symptoms and reduce NSAID usageBut there is no conclusive proof of efficacyAs many of you are well aware alternative and traditional medicine, nutraceuticals and nutritional supplementation can serve as useful adjuncts to OA therapy.A bewildering and mind-boggling variety of nutritional supplements are produced and consumed. Some of these have been reported to improve the symptoms of OA but no conclusive proof of efficacy for any nutritional supplement has emerged to date.This presentation will review some of the new and exciting recent research in this area. In the interests of time, I will focus mainly on the scientific basis and mechanistic mode of action of selected dietary supplements.
  • There are a variety of dietary and oral supplements for OA.The best known and studied supplements include:Glucosamine and chondroitin sulfate (these arethe best researched dietary supplements this area was discussed in detailat yesterday’s Rottapharm Sponsored Satellite Symposium)Vitamins (C, D, E and beta carotene)Polyunsaturated fatty acids (PUFAs) - omega-3 fatty acids (to be discussed by Dr. Moreau in the next presentation)Studies in humans and dogs suggest omega-3 fatty acids may reduce NSAID usageHerbal and botanical extracts – (i.e. Green tea catechins, phtochemicals, phytoestrogens and stilbenes)Phytoestrogens, sometimes called &quot;dietary estrogens&quot;, are a diverse group of naturally occurring nonsteroidal plant compounds that, because of their structural similarity with estradiol (17-β-estradiol), have the ability to cause estrogenic or/and antiestrogenic effects.Evidence is accruing that phytoestrogens may have protective action against diverse health disorders, such as prostate, breast, bowel, and other cancers, cardiovascular disease, brain function disorders and osteoporosis.However,there is no evidence to support the view that the administration of these supplements will be preventative
  • Health effects of food compounds start at the molecular level.Nutrigenomics is the study of the effects of foods and food constituents on gene expression.
  • Nutrigenomicsis a form of personalized nutrition and involves tailoring diets to an individual’s genetic makeup.The changes in gene expression translate to changes in the proteome and metabolome and consequently result in an altered metabolic state which may have beneficial health effects.
  • We often overlook the fact that nutrigenomics and systems biology apply the same set of tools and technologies.The nutrigenomics approach extracts relevant differences, which become leads for further hypothesis driven and mechanistic research. The application of systems biology approaches in nutritional research aim to describe the physiological responses of culture models, experimental animals and human subject by exploiting the datasets, focusing on biochemical pathways, molecular targets for therapy and potential biomarkers.
  • The Dutch famine, or Hungerwinter, started in November 1944 carried on until liberation in May 1945. During this period rations were as low as 400-800 calories a day; less than a quarter of the recommended adult caloric intake.The Dutch Famine Birth Cohort Study is an ongoing study investigating the effects of exposure to the 1944-1945 famine in utero on health in adulthood. The study has shown that the offspring of mothers who were pregnant during the famine have more diabetes.  People exposed to famine during mid gestation develop more obstructive pulmonary disease and microalbuminuria. Those who were exposed early gestation have more atherogenic lipid profile, altered clotting, more obesity, and a 3-fold increase in cardiovascular disease. 
  • This is a very simplistic overview of the problem of obesity.When calories in equals calories consumed Normal weightBut when calories in exceed calories consumed Obese state
  • There is strong evidence to support a link between overweight, obesity and OA.Obesity is one of the main risk factors for osteoarthritis (OA). For many years the association of obesity and OA has been simply attributed to the effects of overload on weight-bearing joints, and epidemiological surveys have shown a strict correlation between an increased body mass index and the severity of knee or hip OA, as well as some relief of pain and disability following weight loss.There is now a growing body of evidence that obesity is a complex metabolic and inflammatory syndrome in which an abnormal activation of neuroendocrine and pro-inflammatory pathways leads to an altered control of food intake, fat expansion and metabolic changes. Activated white adipose tissue increases the synthesis of pro-inflammatory cytokines, such as IL-6, IL-1, IL-8, TNFalpha, IL-18, while regulatory cytokines, such as IL-10, are decreased.Adipocytes also produce peculiar cytokines, namely adipokines, that exert multiple effects, being capable of promoting synovial inflammation, cartilage degrading enzymes, and bone matrix remodeling. Furthermore, pro-inflammatory cytokines stimulate adipocytes to synthesize neuropeptides, such as substance P and nerve growth factor, that have been shown to be critical in regulating both the appetite and cartilage homeostasis. In this scenario, where the influence of obesity on OA stems from a complex interaction of genetic, metabolic, neuroendocrine, and biomechanical factors, there may be various different potential targets for OA therapy.Adipokines like leptin, resistin, adiponectin and visfatin, seems to play a pro-inflammatory role in arthritis. Studying the role of obesity in OA could be more complex than expected. The link between OA and obesity may not simply be due to high mechanical stresses applied on the tissues, but soluble mediators may play an important role in the onset of OA in obese patients.Weight loss, calorie restriction and moderate non-ballistic exercise are sensible lifestyle changes for OA patients.
  • Research in rheumatoid arthritis clearly suggests that dietary intervention has a place in rheumatology and allows patients to have some control over their disease.Inflammatory fare-ups in many RA patients have been linked to certain foods.30-40% of rheumatoid arthritis patients benefit from excluding foods individually identified during the reintroduction phase of an elimination diet.The elimination diet involves gradual re-introduction of specific food types in the diet of the patient until an inflammatory flare-up reoccurs. This approach allows the offending foods to be avoided by the patient in the future.
  • Controversial – there is a need for systematic scientific evaluation of the claims made for dietary supplementsComplicated by occasional reports of toxicity from contaminantsLack of research on intestinal absorption, bioavailability and clearance of dietary supplementsCombinations of dietary supplements with with NSAIDs have shown beneficial trendsSome studies suggest that he trends are not significantOthers suggest that some dietary supplements can reduce NSAID usage in patientsArthritis Res Ther. 2006;8(4):R127.Osteoarthritis and nutrition. From nutraceuticals to functional foods: a systematic review of the scientific evidence.Ameye LG, Chee WS.
  • Signaling transduction: target in osteoarthritis.Berenbaum F.Curr Opin Rheumatol. 2004 Sep;16(5):616-22. Review.Transcriptional regulation of collagenase (MMP-1, MMP-13) genes in arthritis: integration of complex signaling pathways for the recruitment of gene-specific transcription factors.Vincenti MP, Brinckerhoff CE.Arthritis Res. 2002;4(3):157-64. Epub 2001 Nov 23. Review.NF-kappaB signaling: multiple angles to target OA.Marcu KB, Otero M, Olivotto E, Borzi RM, Goldring MB.Curr Drug Targets. 2010 May;11(5):599-613. Review.Inflammatory signaling in cartilage: MAPK and NF-kappaB pathways in chondrocytes and the use of inhibitors for research into pathogenesis and therapy of osteoarthritis.Saklatvala J.Curr Drug Targets. 2007 Feb;8(2):305-13. Review.
  • The curcumin/AP-1/NF-kB axis in inflammatory cell signalling responses in joint cells. This schematic illustrates the potential sites of action of curcumin in the NF-kB signalling pathway in a typical joint cell. Curcumin (C) can prevent IkBa phosphorylation, as well as preventing the translocation of active NF-kB into the nucleus, thereby preventing it from activating gene expression of MMPs, stimulators of MMP synthesis (cytokines), inflammatory mediators (cytokines and COX-2) and apoptotic executioners (caspase-3).
  • Curcumin in Rheumatoid ArthritisPurposeCurcuma longa or turmeric is a tropical plant native to south and southeast tropical Asia. Perhaps the most active component in turmeric is curcumin which may make up 2-5% of the total spice in turmeric. The study drug being tested in this study is curcumin. This study is called a cross-over study because all subjects will receive the study drug for a certain amount of time and then switch to placebo (an inactive substance) for a certain time or vice versa. The subject&apos;s participation may last up to 8 months. The subject will be randomized (by chance; like flipping a coin) to receive either the study drug, curcumin, or placebo for 4 months. After 4 months, if the subject was takingcurcumin they will stop taking it and begin to take placebo and if the subject was taking placebo they will stop taking it and begin taking curcumin for the remaining 4 months. By completion of the study, all 40 subjects will have taken curcumin and placebo for 4 months each. Curcumin/placebo will be provided in capsule form and the subject will take it by mouth. The dose dose will be increased every week for up to a total of 4 grams per day. Subjects will have blood tests, complete questionnaires, and be seen by the study doctor.Intervention Details:Drug: Curcumin (Longvida™)Curcumin (Longvida™) or matching placebo. They will begin by taking 4 capsules (approximately 2 grams) once a day for 2 weeks and then the dose will be increased to 4 capsules twice a day (4 gram per day) beginning at week 3. Subjects will remain at this dose for an additional 13 weeks for a total 16 weeks. After 16 weeks, the same procedures will be repeated for another 16 weeks.EligibilityAges Eligible for Study: 18 Years and olderGenders Eligible for Study: BothAccepts Healthy Volunteers: NoCriteriaInclusion Criteria:1. Age ≥ 18 years; read and understand English2. Stable dose of non-steroidal anti-inflammatory agents (NSAID) for ≥ 2weeks.3. Oral prednisone or equivalent ≤ 10 mg daily and stable dose for ≥ 2weeks(and must be kept stable throughout the duration of the protocol).ESR &gt; 20 mm/hr, or CRP &gt; 0.8 mg/dl4. May be using any of the following DMARDs: methotrexate, sulfasalazine,hydroxychloroquine or leflunomide. If using any of these DMARDs mustbe using them for ≥ 12 weeks and stable dose for ≥ 4 weeks. If usingother DMARD, or DMARD combinations, these additional or otherDMARDs must be stopped for ≥ 4 weeks before baseline visit. May alsoparticipate if patient not on DMARD,5. Subjects must be diagnosed with rheumatoid arthritis based on therevised American College of Rheumatology criteria:Presence of &gt;swollen and &gt; 6 tender joint count (28 joint count), and either ESR &gt; 20mm/hr or CRP &gt; 0.8 mg/dlExclusion Criteria:1. Acute medical conditions deemed as inappropriate by the investigators(acute heart failure, uncontrolled diabetes mellitus, uncontrolledhypertension)2. AST/ALT &gt; 1.5 upper limit of normal (ULN)3. Serum creatinine &gt; 1.6 mg/dl4. Hemoglobin/Hematocrit &lt; 10.0 gram/dl/ 30.05. Platelet count &lt; 100,0006. Current use of warfarin (as there is a drug interaction between curcuminand warfarin).7. Currently on biologic therapy (must have stopped etanercept for ≥ 4weeks or adalimumab or infliximab for ≥ 8 weeks at time of Time 1 visit),8. Women who are pregnant,9. Subjects who are taking digoxin, warfarin and/or heparin,10. Subjects with a history of antiphospholipid syndrome and otherthrombophilic states,11. Subjects who have an INR &gt;= 1.5 at baseline,12. Subjects with acute episode(s) of cholecystitis within the last 6 months,13. Subjects with active peptic ulcer disease within the last 6 weeks
  • Sirtuins post-translationally modulate the function of many cellular proteins that undergo reversible acetylation–deacetylation cycles, affecting physiological responses that have implications for treating diseases of ageing. Potent small-molecule modulators of sirtuins have shown efficacy in preclinical models of metabolic, neurodegenerative and inflammatory diseases, and so hold promise for drug discovery efforts in multiple therapeutic areas.
  • SirT1, an NAD-dependent histone deacetylase. SirT1 has been shown to be responsible for lifespan extension during caloric restriction in a variety of organisms.Additionally, SirT1 can enhance cell survival and affect differentiation and proliferation.SirT1 can positively regulate expression of a number of cartilage-specific ECM genes, such as type II collagen, type IX collagen, aggrecan, and cartilage oligomeric matrix protein.SirT1 protein levels are reduced in chondrocytes derived from OA cartilage compared with those derived from normal cartilage.SirT1 mediates activation of the insulin-like growth factor receptor (IGFR) pathway and suppresses apoptosis in human chondrocytes. The pathway illustrates the fact that the proteins are affected by increased expression of SirT1 in chondrocytes. A direct reduction in protein tyrosine phosphatase 1B (PTP1B) levels by SirT1 led to activation of IGFR along with the attendant kinases phosphatidylinositol 3-kinase (PI 3K), phosphoinositide-dependent protein kinase 1 (PDK-1), and Akt. Activation of mTOR is thought to occur via receptor tyrosine kinases through unknown intermediaries. Phosphorylated Akt also functions to activate mTOR by phosphorylation, leading to increased phosphorylation of pAkt (on residue Ser473). SirT1 also functions to directly block p53 by deacetylation.
  • It has been demonstrated that resveratrol, a natural product known to activate a number of cellular proteins including SirT1, can enhance chondrocyte survival.In this study we established an in vitro model of joint inflammation mimicking the events that occur in osteoarthritis (OA) and osteochondritis dissecans (OCD) to investigate whether curcumin and resveratrol can counteract lipopolysaccharide (LPS) induced glycosaminoglycan (GAG) release. Cartilage was obtained from canine stifle and porcine hock joints. Explants were incubated in serum-free culture medium and challenged with LPS (0.25µg/ml) to mimic joint inflammation. LPS-stimulated samples and controls were co-treated with either curcumin or resveratrol, both at 2.5µM for 5 days. Tissue culture media and the papain digested cartilage explants were analyzed for GAG content in order to asses the anti-catabolic potential of curcumin and resveratrol using the dimethylmethylene blue (DMMB) assay. There was a significant increase in GAG release from LPS-stimulated canine and porcine samples when compared to controls (P&lt;0.001). Co-treatment with curcumin and resveratrol antagonized the degradative effects of LPS and inhibited GAG release from the explants. There was a marked decrease in GAG release from LPS-stimulated canine and porcine samples with 2.5μM resveratrol and this difference was found to be statistically significant in the canine explants (P&lt;0.05). Differences were also noted between LPS stimulated samples with and without 2.5μM curcumin but these did not reach statistical significance. Curcumin and resveratrol antagonized the catabolic and degradative effects of LPS in explant cultures. However, resveratrol had a more significant anti-catabolic effect on canine explants. These plant-derived compounds may have potential as novel anti-inflammatory nutraceuticals.LPS was used experimentally to activate Toll-like receptor/NF-κB mediated catabolic signaling pathways in explant cultures of equine cartilage.Curcumin and resveratrol antagonized one of the catabolic and degradative effects of LPS, namely GAG release.Resveratrol appeared to have a more significant anti-catabolic effect on canine explants treated with LPS. Modulation of NF-κB signaling using dietary phytochemicals and phytoalexin stilbenes may be a realistic therapeutic strategy in the treatment of inflammatory arthritis. Curcumin and resveratrol may have potential as naturally-occurring plant-derived anti-inflammatory agents for joint inflammation.Carney SL, Billingham ME, Caterson B, Ratcliffe A, Bayliss MT, Hardingham TE, Muir H. (1992). Matrix. 12: 137-47. Takafuji VA, McIlwraith CW, Howard RD. (2002) Am. J. Vet. Res. 63: 551-8.Clutterbuck AL, Mobasheri A, Shakibaei M, Allaway D, Harris P. (2009) Ann. N. Y. Acad. Sci. 1171: 428-35.
  • Many of the proteins we have identified are arranged into large multi-molecular assemblies in articular cartilage.
  • Whether supplements can be effectively and safely recommended to reduce NSAID usage is unclear and requires more high-quality researchThis area will remain controversial if there is substantial commercial involvement in research and in influencing publicationsAmbiguous results or failure of clinical trials can make matters worse
  • There is potential for high quality basic research into gene nutrient interactionsHowever, subsequent clinical studies will need to select more homogeneous populationsThe marriage between dietary supplements and OA therapy can be a viable one as long as the relationship involves hypothesis driven basic research followed by well-designed, rigorous and unbiased clinical trialsL&apos;amour est possible mais très difficile…
  • If I was obese or had some form of post-traumatic OA (and my diet consisted mainly of these items), I don’t think there would be any dietary supplement that would help me.
  • I’m not even sure if dietary supplements would help me if I had a balanced diet consisting of the items pictured here.
  • Oarsi 2010 Presentation A. Mobasheri

    1. 1. Concurrent Session 5 - PAIN, CLINICAL AND PATHOPHYSIOLOGICAL ASPECTS <br />Friday 24 September 2010<br />Dietary Supplements in OA: Real Opportunity or Utopia?<br />Ali Mobasheri, D.Phil.<br />Musculoskeletal Research Group<br />School of Veterinary Medicine and Science<br />Faculty of Medicine and Health Sciences<br />
    2. 2. Dietary Supplements in OA: ‘Un Amour Impossible?’ <br />Management of OA primarily involves symptomatic pain relief<br />Analgesics<br />Non-steroidal anti-inflammatory drugs (NSAIDs)<br />However, pharmacotherapy with conventional drugs does not influence disease progression and can be associated with significant side effects<br />Therefore, there is an acute need for alternative remedies for OA<br />Nutritional supplements have been reported to improve symptoms and reduce NSAID usage<br />But there is no conclusive proof of efficacy<br />
    3. 3. Dietary Supplements in OA<br />Glucosamine and chondroitin sulfate<br />Vitamins (C, D, E and beta carotene)<br />Polyunsaturated fatty acids (PUFAs) <br />Omega-3 fatty acids<br />Herbal and botanical extracts<br />Polyphenols, phytochemicals and phytoestrogens<br />Green tea catechins<br />Curcumin<br />Resveratrol<br />
    4. 4. Nutrigenomics<br />The study of the effects of foods and food constituents on gene expression<br />van Ommen (2004) Nutrition 20, 4-8 <br />
    5. 5. Nutrigenomics and Personalized Nutrition<br />Nutrigenomics is a form of personalized nutrition* that involves tailoring diets to an individual’s genetic makeup, considering genetic variation, allergies and intolerances<br />An important aim of nutrigenomic research is defining the relationship between genes and nutrients from basic biology to clinical states<br />*International Society of Nutrigenetics/Nutrigenomics (ISNN)<br />http://www.isnn.info/<br />
    6. 6. Nutrigenomics and Systems Biology<br />Nutrigenomics and systems biology use the same models and tools to identify biomarkers and therapeutic targets<br />van Ommen (2004) Nutrition 20, 4-8 <br />
    7. 7. What is the evidence linking nutrition and disease?<br />Malnutrition results in poor bone development<br />Evidence from Dutch famine cohort study and subsequent research suggests that:<br />we are what we eat<br />we are what our mothers ate<br />
    8. 8. Obesity<br />Calories in = Calories consumed Normal weight<br />Calories in > Calories consumed Obese state<br />
    9. 9. Obesity and OA<br />Strong evidence supports a link between overweight, obesity and OA<br />Obesity: complex metabolic and inflammatory syndrome <br />Adipokines, (adipocytokines) play important roles in the onset of disease<br />Lifestyle changes for OA patients<br />Weight loss, calorie restriction and moderate (non-ballistic) exercise<br />Gabay, Hall, Berenbaum, Henrotin and Sanchez (2008) Joint Bone Spine 75, 675-9.<br />Abramson and Attur (2009) Arthritis Res Ther 11, 227.<br />Iannone and Lapadula (2010) Curr Drug Targets 11, 586-98.<br />
    10. 10. Evidence for Nutritional Intervention from Studies on RA Patients<br />Dietary intervention clearly has a place in rheumatology and allows patients some control over their own disease<br />30-40% of rheumatoid arthritis patients benefit from excluding foods individually identified during the reintroduction phase of an elimination diet<br />Rayman and Pattison (2008) Best Pract Res Clin Rheumatol 22, 535-561.<br />
    11. 11. Evidence for Nutritional Intervention in OA<br />Controversial – there is a need for systematic scientific evaluation of the claims made for dietary supplements<br />Complicated by occasional reports of toxicity from contaminants<br />Lack of research on intestinal absorption, bioavailability and clearance of dietary supplements<br />Combinations of dietary supplements with NSAIDs have shown beneficial trends<br />Some studies suggest that the trends are not significant<br />Others suggest that some dietary supplements can reduce NSAID usage in patients<br />McAlindon and Biggee (2005) Curr Opin Rheumatol. 17, 647-52.<br />Ameye and Chee (2006) Arthritis Res Ther. 8, R127.<br />
    12. 12. Phytalgic: a food supplement containing fish-oil, vitamin E and Urtica dioica<br />
    13. 13.
    14. 14. NF-kB: a Therapeutic Target in OA<br />Nuclear factor-kappaB (NF-kB) - involved in the pathogenesis of OA and RA<br />Targeting the NF-kB signaling pathway:<br />New therapeutic strategies for developing new arthritis drugs<br />Must target cartilage and synovium to avoid adverse systemic effects<br />Vincenti and Brinckerhoff (2002) Arthritis Res 4, 157-64.<br />Berenbaum (2004) Curr Opin Rheumatol 16, 616-22.<br />Roman-Blas and Jimenez SA (2006) Osteoarthritis Cartilage 14, 839-48. <br />Saklatvala (2007) Curr Drug Targets 8, 305-13.<br />Marcu, Otero, Olivotto, Borzi and Goldring (2010) Curr Drug Targets 11, 599-613.<br />
    15. 15. Curcumin - Diferuloylmethane<br />Curcumin is one of three curcuminoids obtained by solvent extraction from dried turmeric roots<br />Used globally for food coloring. It has potent antioxidant, anti-inflammatory, antiviral and antifungal properties<br />It exerts anti-inflammatory activity by inhibition of a number of different molecules and pathways that play an important role in inflammation (i.e. NF-kB)<br />
    16. 16. The Curcumin/AP-1/NF-kB Axis in Inflammatory Responses in Joint Cells<br />Naturally occurring plant-derived compounds such as curcumin can modulate NF-kB activity without undesired systemic effects<br />Henrotin et al., (2010) Osteoarthritis Cartilage 18, 141-9.<br />
    17. 17. Effects of Curcumin on TNF Signaling<br />Mobasheri, Aldinger and Shakibaei (2011) Role of Inflammation in Rheumatic Diseases<br />In: Inflammation, Life Style and Chronic Diseases: The Silent Link. CRC Press<br />ISBN: 978-1-4398398-9-8<br />
    18. 18. Clinical Trial of Curcumin in RA<br />Curcumin (Longvida™) - randomized, placebo-controlled, phase 0 clinical trial employing 40 subjects<br />Cross-over design lasting up to 8 months<br />Start Date: January 2010, Completion Date: January 2011<br />Location: University of California, Los Angeles<br />ClinicalTrials.gov Identifier: NCT00752154<br />Source: http://clinicaltrials.gov/<br />
    19. 19. Curcumin inhibits GAG and PGE2 release from IL-1b stimulated cartilage explants <br />Clutterbuck, A (2010) PhD Thesis. University of Nottingham<br />Clutterbuck et al., (unpublished observations)<br />
    20. 20. Comparing the effects of curcumin and carprofen on GAG and PGE2 release from IL-1b stimulated cartilage explants<br />Clutterbuck, A (2010) PhD Thesis. University of Nottingham<br />Clutterbuck et al., (unpublished observations)<br />
    21. 21. Resveratrol - Trans-3,5,4'-trihydroxystilbene<br />Flavonol belonging to the group of flavonoids<br />Produced by plants as a defence against fungal disease<br />Antioxidant but weaker that quercetin and epicatechin<br />Present in many plants and fruits, including red grapes (and red wine), eucalyptus, spruce, blueberries, mulberries, peanuts, giant Japanese knotweed<br />
    22. 22. Scientific Basis for the Study of Resveratrol: Modulation of Sirtuins<br />Members of the sirtuin family regulate epigenetic gene silencing<br />Sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity<br />In human cells resveratrol increases cell survival by stimulating SIRT1-dependent deacetylation of p53<br />In yeast cells resveratrol stimulates Sir2, increasing DNA stability and extending lifespan by up to 70% <br />Howitz et al., (2003) Nature 425, 191-196<br />
    23. 23. Biological Functions of SIRT1<br />
    24. 24. Sirtuins – Novel Therapeutic Targets to Treat Age-Associated Diseases<br />Lavu et al., (2008) Nature Reviews Drug Discovery 7, 841-853<br />
    25. 25. Activation of SIRT1 by Resveratrol, Calorie Restriction and Fasting<br />
    26. 26. SirT1 Activates IGFR Pathway and Suppresses Apoptosis in Chondrocytes<br />Gagarina et al., (2010) ARTHRITIS & RHEUMATISM<br />Vol. 62, No. 5, May 2010, pp 1383–1392<br />
    27. 27. Effects of Resveratrol on Human Chondrocytes<br />Resveratrol inhibits <br />IL-1b–induced PGE2 and LTB4 <br />IL-1b–induced induction of the apoptotic markers cytochrome C and annexin V<br />Mitochondrial membrane depolarization, loss of mitochondrial biomass, and IL-1b–induced ATP depletion<br />
    28. 28. Resveratrol Suppresses IL-1b Signaling and Apoptosis in Chondrocytes<br />Resveratrol blocks IL-1b induced apoptosis in human chondrocytes<br />
    29. 29. Curcumin and Resveratrol: Evidence for Synergistic Activity<br />
    30. 30. Curcumin Enhances Chondrogenesis of Mesenchymal Stem Cells in vitro<br />Insert copy of Arthritis Research and Therapy paper<br />
    31. 31. In vitro models of cartilage as biomimetic systems for high-throughput screening of nutrient-derived compounds and combinations of herbal extracts<br />
    32. 32. Explant Culture<br />Advantages: <br />Chondrocytes remain phenotypically stable in their native matrix<br />Ideal for studies of extracellular matrix synthesis and degradation<br />GAG and collagen assays <br />Suitable for proteomic work and studying anti-inflammatory drugs and plant derived compounds<br />
    33. 33. Curcumin and Resveratrol Counteract GAG Release in LPS Treated Cartilage Explants<br />
    34. 34. High-Throuoghput Proteomic Study of the Cartilage Secretome<br />
    35. 35. Commonly Identified Proteins:Canine Cartilage Secretome<br />Poster 121<br />Hillier et al.,<br />OARSI 2010<br />Proteins identified using the SwissProt 51.6 database <br />
    36. 36. Commonly Identified Proteins:Equine Cartilage Secretome<br />Poster 503 Clutterbuck et al.,<br />OARSI 2010<br />Proteins identified using the SwissProt 51.6 database <br />
    37. 37. Western Blot Validation<br />Poster 503<br />Clutterbuck et al.,<br />OARSI 2010<br />
    38. 38. Heinegård D. (2009) Int J Exp Pathol. 90, 575-86<br />
    39. 39. Conclusions I<br />Whether supplements can be effectively and safely recommended to reduce NSAID usage is unclear and requires more high-quality research<br />This area will remain controversial if there is substantial commercial involvement in research and in influencing publications<br />Ambiguous results or failure of clinical trials can make matters worse<br />
    40. 40. Conclusions II<br />There is potential for high quality basic research into gene nutrient interactions<br />However, subsequent clinical studies will need to select more homogeneous patient populations<br />The marriage between dietary supplements and OA therapy can be a viable one as long as the relationship involves hypothesis driven basic research followed by well-designed, rigorous and unbiased clinical trials<br />L'amour est possible mais très difficile…<br />
    41. 41. A few words of caution…<br />
    42. 42. A few words of caution…<br />
    43. 43. Acknowledgements: Postgraduate Students and Funding<br />Abigail Clutterbuck<br />Adam Williams<br />Jasmine Penny<br />EnricoGlaab<br />
    44. 44. Acknowledgements: Collaborators<br />Professor Alexandrina<br />Ferreira Mendes<br />Coimbra, Portugal<br />Professor Mehdi Shakibaei<br />LMU Munich, Germany<br />Professor Yves Henrotin<br />University of Liège, Belgium<br />Dr. Susan Liddell<br />Dr. Jaume Bacardit<br />Professor Sean May<br />Professor Kevin Shakesheff<br />Dr. Julia Smith<br />Dr. John Kelly<br />Dr. Pat Harris<br />Dr. David Allaway<br />
    45. 45. Thank you for your attention<br />
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