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Inflamação nut desp 13_versão slide share
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Inflamação nut desp 13_versão slide share
Inflamação nut desp 13_versão slide share
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  • 1. INFLAMAÇÃO NO DESPORTONutrição no Exercício Físico e Desporto Pedro Carrera Bastos, 2013
  • 2. INFLAMAÇÃO AGUDA Perda deCalor Vermelhidão Inchaço Dor função Delves PJ, Roitt, IM. N Engl J Med. 2000 Jul 6;343(1):37-49.
  • 3. 24 The Underlying Principles of Human Metabolism Cells of tissue Erythrocytes Capillary O2 CO2 O2 Endothelial cells CO2 from Oxygen use cellular metabolism Extracellular fluid (in mitochondria) in the interstitial spaceFigure 1.12 Diffusion of chemical substances through the interstitial fluid. A typicaltissue is shown (schematically) in cross-section. The diffusion of oxygen from erythrocytes to cells in the Frayn KN. Metabolic Regulation. Blackwell Pub; 2010:384.tissue is shown as an example. Oxygen diffuses down a concentration gradient, from the erythrocytes,via the plasma and the interstitial fluid, into the cells, where its concentration is depleted as it is usedin mitochondrial oxidation. CO2 diffuses back to the plasma in the same way. The interstitial fluidoccupies the space between cells known as the extracellular space; this is not a true empty space, but
  • 4. Main function Monocytes Phagocytosis Macrophages Innate Neutrophils Granulocytes Basophils Exocytosis, Eosinophils NK lymphocytes Cytotoxicity T Cytotoxic T lymphocytes T Helper Modulation Adaptive (Th1, Th2) B lymphocytes Antibody productionFigure 10.1 Cellular components of Interventions for Arthritis and Related Inflammatory Diseases, 2013 Bioactive Food as Dietary the immune system and their main functions.
  • 5. Main function Monocytes Phagocytosis Macrophages Innate Neutrophils Granulocytes Basophils Exocytosis, Eosinophils NK lymphocytes Cytotoxicity T Cytotoxic T lymphocytes T Helper Modulation Adaptive (Th1, Th2) B lymphocytes Antibody productionFigure 10.1 Cellular components of Interventions for Arthritis and Related Inflammatory Diseases, 2013 Bioactive Food as Dietary the immune system and their main functions.
  • 6. Main function Monocytes Phagocytosis Macrophages Innate Neutrophils Granulocytes Basophils Exocytosis, Eosinophils NK lymphocytes Cytotoxicity T Cytotoxic T lymphocytes T Helper Modulation Adaptive (Th1, Th2) B lymphocytes Antibody productionFigure 10.1 Cellular components of Interventions for Arthritis and Related Inflammatory Diseases, 2013 Bioactive Food as Dietary the immune system and their main functions.
  • 7. 146 J. Romeo et al. Main function 146 J. Romeo etMonocytes al.146 J. Romeo et al. Main function Phagocytosis 146 J.Monocytes Macrophages Romeo et al. Main function Innate Monocytes Neutrophils Main function Phagocytosis Macrophages Monocytes 146 J. Romeo et al. J. Romeo et al. 146 Granulocytes Basophils Innate Neutrophils Phagocytosis Macrophages MainPhagocytosis function function Main Macrophages Exocytosis, Eosinophils Monocytes Innate Monocytes Neutrophils Basophils Granulocytes NK lymphocytes Cytotoxicity Innate Neutrophils Exocytosis, Basophils Eosinophils Granulocytes Cytotoxic Phagocytosis Phagocytosis T Macrophages Macrophages T lymphocytes NK lymphocytes Granulocytes Basophils Cytotoxicity T Helper Exocytosis, Innate Eosinophils Modulation Neutrophils Adaptive Innate (Th1, Th2) Neutrophils Exocytosis, T Cytotoxic Cytotoxicity Antibody Eosinophils NK B lymphocytes lymphocytes T lymphocytes production NK lymphocytes Cytotoxicity Basophils Granulocytes Granulocytes Basophils T Helper Modulation Figure 10.1 Cellular components ofTthe immune system and their main functions. Adaptive Cytotoxic (Th1, Th2) T lymphocytes T Cytotoxic Antibody Exocytosis, B lymphocytes immune response is required. This response is more complex and sophisticated production and its key Exocytosis, T Helper T lymphocytes Eosinophils Eosinophils Modulation Adaptive (Th1, Th2) feature is to be specifically effective forNK lymphocytes that triggered the response. The adap- Cytotoxicity Cytotoxicity those antigens T Helper Figure 10.1 Cellular components of the immune system and their main functions. NK lymphocytes Modulation Adaptive Antibody tive response is mainly mediated by lymphocytes and classified into two types: humoral and B lymphocytes (Th1, Th2) production cellular. immune response is required. This response is T Cytotoxic B lymphocytes whileand its key In general terms, the humoral response involves mainly B lymphocytesmore complex and sophisticated T Antibody T Cytotoxic Figure 10.1 in charge of the cell-mediated immune and their main functions. Both responses production cells arefeature iscomponents of theeffective for those antigens(Figure 10.1). the response. The adap- Cellular to be specifically immune system response T lymphocytes T lymphocytes triggered that are linked and togetherFigure mediated bycomponents T and classifiedsystem andtypes:main functions. tive response is mainly 10.1a Cellular effective antigen-driven Helper two their humoral and result in highly of the immune specific immune re- immune response is required. This response islymphocytesHelper sophisticated and its key Modulation Modulation Adaptive more complex and T into Adaptive response involves mainly B lymphocytes while T sponse. T helper In h) lymphocytes the characterized by(Th1, Th2) cellular. (T general terms, are humoral their capacity to produce cytokines triggered the(Th1, Th2) complex and feature is to be specifically effective for those antigens thatThis responseresponse. The adap- sophisticated and its key and participate inin charge of theresponse is required. immune response. Th1 cells pro- Antibody immune B lymphocytes B the is more the initiation and developmentimmune response (Figure 10.1). Both responses of lymphocytes Antibody tive response is are cells mainly mediated by lymphocytes and classified into two types: humoral and production cell-mediated feature is to be specifically effective humoral antigens that triggered the response. The adap- for those response. Several dis- production mote the cell-mediated response result in ha highly effective antigen-driven specific while T 2 stimulate the cellular. In general terms,togetherCellular components of themainly Bsystem and theirwhileimmune re- humoral and are linked and the humoral response involves mediated immune lymphocytes main into two T eases aresponse. T helpertivehresponse is mainlyor activityby lymphocytes and classified functions. types: Figure 10.1 Figure 10.1 Cellular components of the immune system and their main related to the inadequate activation characterized by their capacity to produce cytokines functions. (T ) lymphocytes are response (Figureimmune responses, and of the cells are in charge of the cellular. In general terms, the humoral response Both responses B lymphocytes while T cell-mediated immune 10.1). involves mainly they appear to be associatedinitiationisand developmenttowardsiseither Th1 or Th2hsophisticated and immune inwithchargeresponse antigen-driven more response (Figure 10.1). inappropriate bias of the re- are linkedand participate result are ainhighlyrequired. cell-mediated immunecomplex andcomplex and Bothits key and its key and together in the response effective This response immune response. T 1 cells pro- sophisticated specific immune re- mentioned that a genetic Th2 stimulate This response is more it cells immune of the is required. sponses.mote the be feature is to be specifically effective for thoseexists forthatresponse. Several dis- The adap- It must cell-mediated response while predispositionthe humoral triggered the response. antigens this bias, and responses sponse. T helper (Th) lymphocytes are characterizedresult in capacity to produceantigen-driven specific immune re- adap- are linked and together by their a highly for those antigens that triggered the response. The feature is to be specifically effective effective cytokines
  • 8. t al. Main function J. Romeo etMonocytes al. al. Main function Phagocytosis Monocytes Macrophages Main function nnate Monocytes Neutrophils Phagocytosis Macrophages Granulocytes Basophils Innate Neutrophils Phagocytosis Macrophages Exocytosis, Eosinophils ate Neutrophils Basophils Granulocytes 146 Cytotoxicity al. J. Romeo et NK lymphocytes Exocytosis, Basophils Eosinophils Granulocytes Cytotoxic Main function T T lymphocytes NK lymphocytes Cytotoxicity Monocytes 146 Exocytosis,al. J. Romeo et al. J. Romeo et 146 T Helper Modulation daptive Eosinophils (Th1, Th2) T Cytotoxic Cytotoxicity Antibody NK B lymphocytes lymphocytes MainPhagocytosis function function Main T lymphocytes production Macrophages T Helper Monocytes Monocytes 0.1 Cellular components ofTthe immune system and their main functions. Modulation Adaptive Cytotoxic (Th1, Th2) T lymphocytes Innate Neutrophils B lymphocytes Antibodye response is required. This response is more complex and sophisticated production T Helper Modulation and its key Phagocytosis Phagocytosis ptive (Th1, Th2) Macrophages Macrophages s to be specifically effective for those antigens that triggered the response. The adap- Figure 10.1 Cellular components of the immune system and their main functions. Granulocytes Basophils Antibody onse is mainly mediated by lymphocytes and classified into two types: humoral and B lymphocytes production In general terms, the humoral response involves mainly B lymphocytes while T Innate immune response is required. This response is more complex and sophisticated and its key Innate Neutrophils Neutrophils1 in charge of the cell-mediated immune and their main functions. Both responses Cellular components of the immune system response (Figure 10.1). Exocytosis, feature is to be specifically effective for those antigens that triggered the response. The adap- Eosinophils ed and together result mediated by lymphocytes and classifiedspecific immune re- lymphocytes tive response is mainly in a highly effective antigen-driven into two types: humoral Granulocytes Cytotoxicity esponse is required. This response is more complex and sophisticated and its key NK and Basophils Granulocytes Basophils T helper In h) lymphocytes the characterized by their capacity to produce cytokineswhile T cellular. (T general terms, are humoral response involves mainly B lymphocytes o be specifically effective for those antigens that triggered the response. The adap- cells mainly mediated by cell-mediated immune response (Figure Th1 cells pro- icipate in the initiation and development of the immune response. 10.1). Both nse is are in charge of thelymphocytes and classified into two types: humoral and responses T Cytotoxic Exocytosis, Exocytosis, e cell-mediated together result in ha highly effective antigen-driven specific immune re- are linked and response while T 2 stimulate the humoral response. Several dis- T lymphocytes Eosinophils Eosinophils n general terms, the humoral response involves mainly B lymphocytes while T Cytotoxicity Cytotoxicityesponse. T helper (Th) lymphocytes are or activity of by their capacity to produce cytokines NK lymphocytes related to the inadequate activation characterized the immune responses, NK and n charge of the cell-mediated immune response (Figure 10.1). Both responses lymphocytes Adaptive T Helper Modulation pearparticipate in the initiation and developmenttowardsimmuneTh1 or Th2h1 cells pro- and to be associated with inappropriate antigen-driveneither response. T re- bias of the (Th1, Th2) and together result in a highly effective specific immune re- Antibody It must mentioned that a genetic T exists for this bias, and it B lymphocytesT Cytotoxic T Cytotoxic mote the belymphocytesresponse while predispositionthe humoral response. Several dis- helper (Thcell-mediated are characterized h2 stimulate ) by their capacity to produce cytokines productionmonlyare related antigen-presentation sensitive genes. of the immune responses, and T lymphocytes eases linked to to the inadequate activation immune response. T 1 cells pro- lymphocytes T ipate in the initiation and development of the or activity Figure 10.1 Cellular components T Helper h of the immune system and their main functions. they appear to be associatedT 2 stimulate the humoraltowards either Thdis- Th2 re- Modulation cell-mediated response while with inappropriate bias response.Adaptive 1 or Several Adaptive (Th1, Th2) T Helper Modulation mune-Related Diseases h sponses. It must be mentioned that a activity of the immuneexists for response isand it (Th1, Th2) genetic predisposition immune this bias, required. This response is more complex and sophisticated and its key elated to the inadequate activation or responses, and Antibody Antibody to antigen-presentation sensitive disease, 1 or is to re- lymphocytesB lymphocytes is commonly linked with inappropriate the etiology ofeither T most conditions B h there are plenty of factors involved in bias towards genes. feature Th2 be specifically effective for those antigens that triggered the response. The adap-ear to be associated production production h t mustthe mentioned that athey frequently being infectious, this10.1 Cellularitcomponents of the by lymphocytesand their main functions. types: humoral and ed to be immune system, genetic predisposition exists for inflammatory, or Figure bias, Figure mainly mediated immune system and classified into two tive response is 10.1 Cellular components and 1.2 linked to antigen-presentation sensitive genes. viruses, bacteria, parasites, terms, the humoral of the immune system and their main functions.muneImmune-Related Diseases are caused byonly processes. Infectious diseases cellular. In general response involves mainly B lymphocytes while T Although there are plenty of factors involved in the etiology ofcellsimmune are in chargeresponsecell-mediated is more complex andcomplex and Bothits key and its key disease, immune of the is required. This response is more sophisticated and responses response is required. This response immune response (Figure 10.1). sophisticated most conditionsmune-Related Diseases system, they frequently being infectious, be specifically orresult in a highly for those triggered the response. The adap- re- are related to the immune feature is to inflammatory,effective for those antigens that antigens that triggered the response. The adap- feature is to be specifically effective effective antigen-driven specific immune are linked and together
  • 9. Exercise 24 hours after exercise 1 day to 2 weeks after exercise During exercise After exercise Recovery mechanical damage to muscle after exerciseinfiltration Exercise 24 hours • leukocyte • proliferation of satellite cells 1 day to 2 weeks after exercise tissue • inflammation • acquisition of protective effectDuring exercise After exercise Recoverymechanical damage to muscle • leukocyte infiltration • proliferation of satellite cells blood circulationtissue • inflammation • acquisition of protective effect priming adhesion molecules PMN monocytesblood circulation CK adhesion molecules endothelial cells priming MbPMN Inflammation and eccentric exercise • 77 monocytes CK CK cytokines Mb macrophages endothelial cells Mb chemoattractants cytokines Inflammation and eccentric exercise • 77 growth factorscytokines Mb ROS CK macrophages phagocytosis chemoattractants enzymescytokines growth phagocytosis factors damaged muscle tissue muscle tissue regenerated muscle fibres fragments ROS fragments phagocytosis satellite cells muscle fibres enzymes Figure 1 Exercise-induced muscle damage and subsequent muscle inflammation and regeneration process phagocytosis (PMN, polymorphonuclear leucocyte; Mb, myoglobin; CK, creatine kinase; ROS, reactive oxygen species) damaged muscle tissue muscle tissue regeneratedmuscle fibres fragments fragments satellite cells muscle fibres Figure 1 Exercise-induced muscle damage and subsequent muscle inflammation and regeneration process (PMN, polymorphonuclearJ, Nosaka K, Suzuki K. Exerc Immunol Rev. 2005;11:64-85 Peake leucocyte; Mb, myoglobin; CK, creatine kinase; ROS, reactive oxygen species)
  • 10. ac sa in ha op pa na co si R (C tio in th fo FIGURE 2. Diagrammatic representation of the movement of leukocytesthrough the endothelium and the subsequent generation of inflammatory anmediators. Calder PC. Am J Clin Nutr 2006;83(suppl):1505S–19S)   an
  • 11. The Chemistry of Food – and of Bodies 11 Cholesterol Aqueous (polar) environment molecules outside cell Non-polar (hydrophobic) region within membrane Phospholipid molecule Intrinsic protein Aqueous (polar) environment (e.g. sugar carrier, inside cell hormone receptor)Figure 1.5 Structure of biological membranes in mammalian cells. Cell membranesand intracellular membranes such as the endoplasmic reticulum are composed of bilayers of phos-pholipid molecules with their polar head-groups facing the aqueous environment on either side andtheir non-polar ‘tails’ facing inwards, forming a hydrophobic center to the membrane. The membranealso contains intrinsic proteins such as hormone receptors, ion channels, and sugar transporters, and Frayn KN. Metabolic Regulation. Blackwell Pub; 2010:384.molecules of cholesterol which reduce the ‘fluidity’ of the membrane. Modern views of cell mem-brane structure emphasize that there are domains, known as ‘rafts,’ in which functional proteinsco-locate, enabling interactions between them. These lipid rafts are characterized by high concentra-
  • 12. De Caterina R. N Engl J Med 2011
  • 13. AINES De Caterina R. N Engl J Med 2011
  • 14. Coxibs De Caterina R. N Engl J Med 2011
  • 15. Nonsteroidal Anti-Inflammatory Drugs 241 COX-1 COX-2 Coxibs AINES “Side pocket” NSAID binding space Intracellular membrane F S F Br CHCO2H SO2CH3 Bulky grouping CH3 COX-1 inhibitor COX-2 inhibitor Flurbiprofen DuP697Figure 18.2. Serhan CN, Ward PA, Gilroy DW, editors. Fundamentals of Inflammation. Cambridge Univ Pr; 2010: 234-243.
  • 16. 52 • Exercise-induced muscle damage and inflammation 10 Change in force-generating capacity (%) 0 -10 -20 -30 -40 -50 Mild damage Moderate damage Severe damage -60 -24 0 24 48 72 96 120 144 168 Time (hours after exercise)Figure 2. Recovery of the force-generating capacity of subjects that have performed heavyresistance exercise or G, Mikkelsen UR, Raastad T, Peake JM. Exerc(subjects from several studies are com- Paulsen maximal eccentric exercise Immunol Rev. 2012;18:42-97bined: (230,248-251), as well as unpublished data). The subjects are organized so thatthose who recover their force-generating capacity within 48 hours are represented as mild
  • 17. Lesão c/ contracçõesexcêntricas em Coelhos 2xdia Durante 6 dias
  • 18. Lesão c/ contracçõesexcêntricas em Coelhos 2xdia Durante 6 dias
  • 19. Lesão c/ contracçõesexcêntricas em Coelhos 2xdia Durante 6 dias
  • 20. ü Células em cultura durante 96 horasü Inibição selectiva da COX-2 diminui proliferação de células satéliteü Inibição de COX-1 e COX-2 reduz diferenciação e fusão de células satélite Muscle Nerve 30: 497–500, 2004
  • 21. MODULATING SKELETAL MUSCLE REPAIR BY MUSCLE DERIVED STEM CELLS AND ANTIFIBROTIC AGENTS 83 Mio D – factor de transcrição responsável pela activação das células satélite e subsequente proliferação dos mioblastosFigure 1. Generalized scheme of myogenic differentiation. Other markers are used by different investigators. (Adapted from Deasyet al., 2001, Blood Cells Mol Dis, 27, 924–933) Gharaibeh B, et al. Birth Defects Res C Embryo Today. 2012 Mar;96(1):82-94.fibers, as previously mentioned. genetic disease (such as Duch- skeletal muscle is limited and veryThese cells have also been used enne muscular dystrophy [DMD]), often, fibrotic tissue forms, delay-
  • 22. J Appl Physiol 103: 425–431, 2007ü 14 atletasü Corrida de 36 Kmü Indometacina (100 mg) vs Placeboü  Ingestão: durante 4 dias antes da corrida até à data da última biópsia RESULTADOS:
  • 23. J Appl Physiol 103: 425–431, 2007 Células Satélite23
  • 24. J Appl Physiol 103: 425–431, 2007 Células Satélite24
  • 25. J Appl Physiol 103: 425–431, 2007 Células Satélite25
  • 26. J Appl Physiol 107: 1600–1611, 2009 Células satélite200 contrações excêntricas26NSAID numa perna (antes, durante e até 4,5 h depois) e a outra como controlo
  • 27. Exercise-Induced Muscle Damage TABLE 1. Summary of human studies investigating the effect of NSAID consumption on satellite cell activity.* Study Subjects NSAID/dosage Results Bondesen et al. (16) Rodents SC-560/3 mgÁkg21Ád21 Significant blunting of satellite cell SC-236 /6 mgÁkg21Ád21 activity in NSAID compared with placebo Bondesen et al. (17) Rodents SC-236 /6 mgÁkg21Ád21 Significant blunting of satellite cell activity in NSAID compared with placebo Mackey et al. (91) Humans Indomethacin/100 mg Significant blunting of satellite cell activity in NSAID compared with placebo Mikkelsen et al. (100) Humans Indomethacin/45 mg Significant blunting of satellite cell activity in NSAID compared with placebo Paulsen et al. (117) Humans Celcoxib/400 mg No significant differences in satellite cell activity between groups *NSAIDs = nonsteroidal anti-inflammatory drugs.protein accretion seen in eccentric protocols. Other studies, generally less compared with those performed concentri-however, seem to refute whether a reversal of the size cally. This paradox was demonstrated by Grabiner et al. (55),principle actually does occur. An extensive review of the who found that the maximum EMG of the vastus lateralis Schoenfeld BJ. J Strength Cond Res. 2012 eccentric knee extension was only 84 6 41% of thatliterature by Chalmers (26) concluded that the preponder- during May;26(5):1441-53.ance of evidence does not support selective recruitment of obtained concentrically. Hence, although the potential tofast-twitch fibers during eccentric contractions. These results exert peak force is greater with eccentric exercise, most find itheld constant in 9 out of 10 studies deemed suitable to extremely difficult to achieve the maximum force during
  • 28. Am J Physiol Cell Physiol 287: C475–C483, 2004Lesão induzida pelo frio Inibidor de COX-2
  • 29. INIBIDOR DA COX-2 EM RATOS APÓS ESTÍMULO MUSCULAR:ü  Reduziu Inflamaçãoü  Atenuou o crescimento das miofibrilhasü  Reduziu a activação e proliferação das células satélite
  • 30. Shen W. Am J Pathol 2005; 167:1105–1117
  • 31. J. Clin. Endocrinol. Metab. 2001 86: 5067-5070ACETAM IBUPROF PLACEBO
  • 32. Inibidor da COX-2
  • 33. Am J Physiol Endocrinol Metab 2002; 282: E551–E556ü 24 adultos masculinosü RCT com Placeboü 10-14 series de 10 rep excéntricas RM DIMINUIÇÃO (24h): Fractional synthesis rate Sem efeitos na dor comparado com placebo
  • 34. Am J Physiol Endocrinol Metab 2002; 282: E551–E556 Fractional Synthesis Rate34
  • 35. 35 Am J Physiol Regul Integr Comp Physiol 296: R1132–R1139, 2009.
  • 36. Exercise 24 hours after exercise 1 day to 2 weeks after exercise During exercise After exercise Recovery mechanical damage to muscle after exerciseinfiltration Exercise 24 hours • leukocyte • proliferation of satellite cells 1 day to 2 weeks after exercise tissue • inflammation • acquisition of protective effectDuring exercise After exercise Recoverymechanical damage to muscle • leukocyte infiltration • proliferation of satellite cells blood circulationtissue • inflammation • acquisition of protective effect priming adhesion molecules PMN monocytesblood circulation CK adhesion molecules endothelial cells priming MbPMN Inflammation and eccentric exercise • 77 monocytes CK CK cytokines Mb macrophages endothelial cells Mb chemoattractants cytokines Inflammation and eccentric exercise • 77 growth factorscytokines Mb ROS CK macrophages phagocytosis chemoattractants enzymescytokines growth phagocytosis factors damaged muscle tissue muscle tissue regenerated muscle fibres fragments ROS fragments phagocytosis satellite cells muscle fibres enzymes Figure 1 Exercise-induced muscle damage and subsequent muscle inflammation and regeneration process phagocytosis (PMN, polymorphonuclear leucocyte; Mb, myoglobin; CK, creatine kinase; ROS, reactive oxygen species) damaged muscle tissue muscle tissue regeneratedmuscle fibres fragments fragments satellite cells muscle fibres Figure 1 Exercise-induced muscle damage and subsequent muscle inflammation and regeneration process (PMN, polymorphonuclearJ, Nosaka K, Suzuki K. Exerc Immunol Rev. 2005;11:64-85 Peake leucocyte; Mb, myoglobin; CK, creatine kinase; ROS, reactive oxygen species)
  • 37. Exercise 24 hours after exercise 1 day to 2 weeks after exercise During exercise After exercise Recovery mechanical damage to muscle after exerciseinfiltration Exercise 24 hours • leukocyte • proliferation of satellite cells 1 day to 2 weeks after exercise tissue • inflammation • acquisition of protective effectDuring exercise After exercise Recoverymechanical damage to muscle • leukocyte infiltration • proliferation of satellite cells blood circulationtissue • inflammation • acquisition of protective effect priming adhesion molecules PMN monocytesblood circulation CK adhesion molecules endothelial cells priming MbPMN Inflammation and eccentric exercise • 77 monocytes CK CK cytokines Mb macrophages endothelial cells Mb chemoattractants cytokines Inflammation and eccentric exercise • 77 growth factorscytokines Mb ROS CK macrophages phagocytosis chemoattractants enzymescytokines growth phagocytosis factors damaged muscle tissue muscle tissue regenerated muscle fibres fragments ROS fragments phagocytosis satellite cells muscle fibres enzymes Figure 1 Exercise-induced muscle damage and subsequent muscle inflammation and regeneration process phagocytosis (PMN, polymorphonuclear leucocyte; Mb, myoglobin; CK, creatine kinase; ROS, reactive oxygen species) damaged muscle tissue muscle tissue regeneratedmuscle fibres fragments fragments satellite cells muscle fibres Figure 1 Exercise-induced muscle damage and subsequent muscle inflammation and regeneration process (PMN, polymorphonuclearJ, Nosaka K, Suzuki K. Exerc Immunol Rev. 2005;11:64-85 Peake leucocyte; Mb, myoglobin; CK, creatine kinase; ROS, reactive oxygen species)
  • 38. Basic & Clinical Pharmacology & Toxicology 2007; 102: 10–14
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  • 44. EPA/DHA E AACalder PC. Am J Clin Nutr 2006;83(suppl):1505S–19S.
  • 45. Time course relativo à incorporação de EPA e DHA INCORPORAÇÃO DE EPA Y DHA NOS em fosfolipídios de membrana de células mononucleares FOSFOLÍPIDOS DE CÉLULAS MONONUCLEARES DHA in mononuclear cell PL (%) EPA in mononuclear cell PL (%) 4 4 3 3 2 1 2 0 1 0 4 8 12 20 0 4 8 12 20 Time (weeks) Time (weeks) Indivíduos saudáveis: 2,1 g EPA + 1,1 g DHA/dia/12 semanas Eur. J. Clin. Invest. 30, 260-274, 2000Eur. J. Clin. Invest. 30, 260-274, 2000
  • 46. DHA    Calder PC. Am J Clin Nutr 2006;83(suppl):1505S–19S)
  • 47. DHA    Calder PC. Am J Clin Nutr 2006;83(suppl):1505S–19S)
  • 48. RESOLUÇÃO DA INFLAMAÇÃO Gilroy DW. 2010
  • 49. SeráadequadoBloquear? Serhan CN, Chiang N. Rheum Dis Clin N Am 30 (2004) 69–95
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  • 51. RESOLUÇÃO DA INFLAMAÇÃO1578 SerhanAJP October 2010, Vol. 177, No. 4 Lipoxinas! Serhan CN. Am J Pathol. 2010 Oct;177(4):1576-91!
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  • 56. DOSES BAIXAS DE ASPIRINAChiang N et al. Aspirin triggers antiinflammatory 15-epi-lipoxin A4 and inhibits thromboxane in a randomized human trial. PNAS 2004. 101; 42
  • 57. De Caterina R. N Engl J Med 2011
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  • 59. NF-kB e Lesão MuscularTidball JG, Villalta SA. Am J Physiol Regul Integr Comp Physiol 2010; 298: R1173–R1187
  • 60. EPA  &  DHA  Calder PC. Biochimie. 2009 Feb 3. [Epub ahead of print]
  • 61. ÓMEGA-3 E INFLAMAÇÃOü  17 meta-análises de RCTs testando os efeitos de Ómega-3 na ARü  3-4 meses: redução da dor articular, minutos de rigidez matutina, número de articulações com dor e menor uso de AINES Goldberg RJ, Katz J. Pain 129 (2007)
  • 62. EPA & DHA por cada 100g peixeFedacko. n−3 PUFAs—From dietary supplements to medicines. Pathophysiology 14 (2007) 127–132
  • 63. CONCENTRAÇÕES DE MERCÚRIO Concentração Peixe Mercúrio (ppm) Peixe-espada 0,97 Arenque 0,35 Atum 0,12 Bacalhau 0,11 Salmão 0,01 Adaptado: FDA (EUA) 66
  • 64. BETA-OXIDAÇÃOACTIVIDADE LIMITADA ACTIVIDAD E LIMITADA
  • 65. VEGANS TÊM NÍVEIS BAIXOS DE AA E DHAFokkema et al. Polyunsaturated fatty acid status of Dutch vegans and omnivores. Prostaglandins, Leukotrienes and Essential FattyAcids (2000)
  • 66. 9 vegans saudáveis suplementados com:ü A: 2.01 g ALA (4 ml óleo de linhaça)ü B: 1.17 g GLA (6 ml óleo borragem)ü A+B
  • 67. ESSENTIAL FATTY ACID INTAKE IN T FIGUR supply fr indicated FIGURE 4. Regression Blasbalg TL, et for the availability of linoleic acid (LA) analysis al. Am J Clin Nutr. 2011 line, and nbetween 1909 and 1999. The linear relation [LA percentage of energy line. 190(en%) = 2115.4221 + 0.0617 · x] was significant at P , 0.000001 with data are
  • 68. TABLE 12 Sources of docosahexaeno Food category Poultry Shellfish Eggs Finfish Beef Game Total 1 NA, not applicable. lipids (37), presumab dietary intakes of LA account for the poten However, because LA effects may be nonlin A randomized trial t with high LA (6.7% of Blasbalg TL, et al. Am J Clin Nutr. 2011 FIGURE 8. Omega-3 tissue highly unsaturated fatty acid (HUFA)predictions over the 20th century. Solid arrows indicate the percentage of
  • 69. DIET AND RED BLOOD CELL n–6 AND n–3 FATTY ACIDS LA diminui DHA na membrana dos eritrócitos N= 105 Mulheres (Canadá) Grávidas (com 36semanas de LA diminui gestação) EPA na membrana dos eritrócitos Friesen RW, Innis SM. Am J Clin Nutr. 2010 Jan;91(1):23-31.
  • 70. RÁCIO ÓMEGA 6/ÓMEGA 3 DE ALGUNS ALIMENTOS Alimento Rácio ω6/ω3 Ovo convencional 19,4 Ovo de Creta 1,3 Carne (músculo) bovina 5,19 alimentada com cereais Carne (músculo) bovina 2,2 alimentada a pasto Simopoulos AP. J Nutr. 2001 Nov;131(11 Suppl):3065S-73S. Review Cordain L et al. European Journal of Clinical Nutrition 2002; 56:181 – 191.
  • 71. Original ResearchSaraswathi Viswanathan PhD, Bruce D. Hammock 2C9 in Mediating thePhD, Purushothaman Meerarani PhD, Involvement of CYP PhD, John W. Newman, Proinflammatory Effects of Linoleic Acid in VascularMichal Toborek MD, PhD, and Bernhard Hennig PhD, FACN Endothelial CellsMolecular and Cell Nutrition Laboratory, College of AgricultureJournal ofP.M., B.H.), Department of Surgery 502–510 (2003) (S.V., the American College of Nutrition, Vol. 22, No. 6, (M.T.), University ofKentucky, Lexington, KY, 40546-0215, and PhD, Bruce D. Hammock Entomology and UC CancerMeerarani PhD, Saraswathi Viswanathan Department of PhD, John W. Newman, PhD, Purushothaman Center (B.D.H., J.W.N.), University ofCalifornia, Davis, CA, USA.Michal Toborek MD, PhD, and Bernhard Hennig PhD, FACN Molecular and Cell Nutrition Laboratory, College of Agriculture (S.V., P.M., B.H.), Department of Surgery (M.T.), University ofKey words: linoleic acid, CYP 2C9, leukotoxin, leukotoxin diol, oxidative stress Kentucky, Lexington, KY, 40546-0215, and Department of Entomology and UC Cancer Center (B.D.H., J.W.N.), University of California, Davis, CA, USA. Key words: linoleic acid, CYP 2C9, leukotoxin, leukotoxin diol, oxidative stress Objective: Polyunsaturated Polyunsaturated fattysuchsuch aslinoleic are well are well lipids that may be Objective: fatty acids acids as linoleic acid acid known dietary known dietary lipids that may be atherogenic by activating vascular endothelial cells. In the liver, fatty acids can be metabolized by cytochrome atherogenic by activating vascular endothelial cells. In of theseliver, fatty acids can be metabolized by cytochrome P450 (CYP) enzymes, but little is known about the role the enzymes in the vascular endothelium. CYP 2C9 P450 (CYP) enzymes, butinvolved inis knownepoxygenation, androle of product ofenzymesisin the vascular endothelium. CYP 2C9 is little linoleic acid about the the major these this reaction leukotoxin (LTX). We investigated the role of CYP-mediated mechanisms of linoleic acid metabolism in endothelial cell activation by is involved in linoleic acid epoxygenation, and oxidizedmajor product of leukotoxin diol (LTD). is leukotoxin (LTX). We examining the effects of linoleic acid or its the metabolites such as LTX and this reaction Methods: The effect of linoleic acid on CYP 2C9 gene expression was studied by RT-PCR. Oxidative stress investigated the role of CYP-mediated mechanismsand intracellular glutathione levels, and electrophoretic mobility was monitored by measuring DCF fluorescence of linoleic acid metabolism in endothelial cell activation by examining the effects of linoleicwas carriedto studyliquid chromatography/massstress sensitive transcription factors. and leukotoxin diol (LTD). shift assay was carried out oxidized lipids acid or its the activation of oxidative spectrometry. as LTX Analysis of out by oxidized metabolites such Methods: The effect of linoleic acid on CYP 2C9increased the expression of CYP 2C9studied by RT-PCR. Oxidative stress Results: Linoleic acid treatment for six hours gene expression was in endothelial cells. Linoleic acid-mediated increase in oxidative stress and activation of AP-1 were blocked by sulfaphenazole, a was monitored by measuring inhibitor of CYP 2C9. The linoleic acid metabolites LTX and LTD increased oxidative stress and electrophoretic mobility specific DCF fluorescence and intracellular glutathione levels, and activation of transcription factors only at high concentrations. shift assay was carried out to study the show that CYP 2C9 plays a key role in linoleic acid-induced oxidative stress and Conclusion: Our data activation of oxidative stress sensitive transcription factors. Analysis of subsequent proinflammatory events in vascular endothelial cells by possibly causing superoxide generation oxidized lipids was carried out by liquid chromatography/mass spectrometry. through uncoupling processes. Results: Linoleic acid treatment for six hours increased the expression of CYP 2C9 in endothelial cells. INTRODUCTION Linoleic acid-mediated increase in oxidative stress and activation of AP-1 were blockedlipids play an in sub-endothelial regions. These biologically active by sulfaphenazole, a important role in the development of atherosclerosis. Polyunsatu- specific inhibitor of CYPis 2C9. The a chronic inflammatory Atherosclerosis believed to be linoleic acid metabolites LTX and LTD increased oxidative stress and rated fatty acids and/or their metabolites can have potent biolog- disease, and the earliest event of coronary atherosclerosis is activation of characterized by endothelial activation at high concentrations.Evidence suggeststypes by functioning as signaling mol- transcription factors only and dysfunction [1]. ical effects in various cell ecules. that linoleic acid, a major dietary Conclusion: Our data show Several factors are implicated that CYP 2C9 plays a key role inacid in the American diet, has proinflammatory in the initiation of endothelial unsaturated fatty linoleic acid-induced oxidative stress and dysfunction of which the formation of reactive oxygen species and proatherogenic effects by causing endothelial cell activation subsequent proinflammatory events in this process [2,3]. is believed to play a critical role during vascular endothelial cells by possibly causingis superoxide generation [4]. Linoleic acid-induced endothelial activation considered to Endothelial cells are continuously exposed to circulating through uncoupling processes. be mediated through oxidative stress [4,5]. However, the precise lipids (e.g., dietary fatty acids) and to lipids that have accumulated mechanism involved in linoleic acid-induced oxidative stress andINTRODUCTION in sub-endothelial regions. These biologically active lipids play an Address reprint requests to: Bernhard Hennig, PhD, RD, FACN, Molecular and Cell Nutrition Laboratory, College of Agriculture, 213 Garrigus Building, University of Kentucky, Lexington, KY 40546-0215. E-mail: bhennig@uky.edu
  • 72. tabolites. Cells were; upper trace) for 24ed epoxides and diolsy. These metabolites without supplemen- arachidonates werea not shown). Results aliquots analyzed by fatty acids may beTo examine if the Fig. 8. Proposedthe American College of mechanism of linoleic (2003) (LA)- Journal of model for the Nutrition, Vol. 22, No. 6, 502–510 acido oxidative stress, mediated endothelial cell activation. LA treatment results in CYP 2C9
  • 73. Exercício ã Número de Neutrófilos circulantes Físico Fagocitose dos Migração para resíduos celulares local da lesão Libertação de lisoenzimas e radicais de oxigénioApós o exercício excêntrico são observados maiores ã nos neutrófilos do que após o exercício concêntrico CANNON JG. ORENCOLE SF. FIELDING RA. et al. Am J Physiol, 259(6 Pt 2): R1214-9, 1990. SMITH JK. GRISHAM MB. GRANGER DN. KORTHUIS RJ. Am J Physiol, 256(3 Pt 2): H789-93, 1989.
  • 74. 488 Howatson & van Someren VITAMINA CTable I. Studies reporting effects of antioxidant supplementation on markers of exercise-induced muscle damageStudy Supplementation Exercise protocol Effects post-exercise (compared with control group)Bryer and Goldfarb[70] Vit C (3000 mg/d) for 14 d prior and 70 elbow flexor eccentric ↓ CK 4 d post-exercise contractions ↓ DOMS ↓ Glutathione ratio ↔ Muscle force ↔ ROMKaminsky and Boal[71] Vit C (3000 mg/d) for 3 d prior and 15 min cyclic plantar flexion and ↓ DOMS 4 d post-exercise extensionThompson et al.[72] Vit C (400 mg/d) for 12 d prior 90 min intermittent shuttle ↔ CK, Mb running ↔ MDA ↔ Muscle force ↓ DOMS ↓ IL-6 ↔ CRPConnolly et al.[73] Vit C (3000 mg/d) for 3 d prior and 40 elbow flexor eccentric ↔ DOMS 5 d post-exercise contractions ↔ Muscle force ↔ ROMChilds et al.[74] Vit C (12.5 mg/kg/d) and NAC 30 elbow flexor eccentric ↑ CK (10 mg/kg/d) for 7 d post-exercise contractions ↑ LDH ↔ DOMS ↔ ROM ↔ IL-6Close et al.[75] Vit C (1000 mg/d) 2 h prior and 14 d 30 min downhill running ↓ MDA post-exercise ↓ Muscle force ↔ DOMSSacheck et al.[76] Vit E (1000 IU/d) for 12 wk prior 45 min downhill running ↓ CK in younger men Howatson G, van Someren KA. Sports Med. 2008;38(6):483-503. ↓ iPF(2α) in older menMcBride et al.[77] Vit E (1200 IU/d) for 14 d prior Whole-body resistance exercise ↓ CK ↔ MDA
  • 75. ↓ DOMS ↓ IL-6 ↔ CRPConnolly et al.[73] 5 d post-exercise VITAMINA E eccentric Vit C (3000 mg/d) for 3 d prior and 40 elbow flexor contractions ↔ DOMS ↔ Muscle force ↔ ROM488 Howatson & van SomerenChilds et al.[74] Vit C (12.5 mg/kg/d) and NAC 30 elbow flexor eccentric ↑ CK (10 mg/kg/d) for 7 d post-exercise contractions ↑ LDH ↔ DOMS ↔ ROMTable I. Studies reporting effects of antioxidant supplementation on markers of exercise-induced muscle ↔ IL-6 damageClose et al.[75] Vit C (1000 mg/d) 2 h prior and 14 d 30 min downhill running ↓ MDAStudy Supplementation Exercise protocol Effects post-exercise post-exercise ↓ Muscle force (compared with control group) ↔ DOMSBryer and Goldfarb[70] Vit C (3000 mg/d) for 14 d prior and 70 elbow flexor eccentric ↓ CKSacheck et al.[76] 4 d E (1000 IU/d) for 12 wk prior Vit post-exercise 45 min downhill running contractions ↓ CK ↓ DOMSin younger men ↓ iPF(2α) in older ↓ Glutathione ratio menMcBride et al.[77] Vit E (1200 IU/d) for 14 d prior Whole-body resistance exercise ↔↓ CK force Muscle ↔↔ MDA ROMKaminsky and Boal[71] Vit C (3000 mg/d) for 3 d prior and ↔ DOMS 15 min cyclic plantar flexion and ↓ DOMSBeaton et al.[78] 4 d E (1200 IU/d) for 30 d prior exerciseextension flexor and extensor Vit post-exercise 240 knee ↔ CKThompson et al.[72] Vit C (400 mg/d) for 12 d prior 90 min intermittent shuttle eccentric contractions ↔↔ Muscle force CK, Mb running ↔↔ Z-band disruption MDA ↔↔ DOMS Muscle force ↓ DOMSShafat et al.[79] Vit C (500 mg/d) and vit E (1200 IU/d) 300 knee extensor eccentric ↓ Decline in torque during ↓ IL-6 for 30 d prior and 7 d post-exercise contractions exercise ↔ CRP ↑ Muscle forceConnolly et al.[73] Vit C (3000 mg/d) for 3 d prior and 40 elbow flexor eccentric ↔↔ DOMS DOMS 5 d post-exercise contractions ↔ Muscle forceGoldfarb et al.[80] Vit C (1000 mg/d) and vit E (400 IU/d) 48 elbow flexor eccentric ↔↓ MDA ROM for 14 d prior and 2 d post-exercise contractions ↓ Plasma protein carbonylsChilds et al.[74] Vit C (12.5 mg/kg/d) and NAC 30 elbow flexor eccentric ↑ CK ↔ Glutathione status (10 mg/kg/d) for 7 d post-exercise contractions ↑ LDHMastaloudis et al.[81] Vit C (1000 mg/d) and vit E (300 mg/d) 50 km ultramarathon run ↔↔ CK DOMS for 6 wk prior ↔↔ LDH ROM Howatson G, van Someren KA. Sports Med. 2008;38(6):483-503. ↔ Muscle force ↔ IL-6Petersen al.[75] [82]Close et et al. Vit C (1000 mg/d) and prior and 14 d Vit C (500 mg/d) 2 h vit E (400 mg/d) 30 min downhill running 90 min downhill running ↔ IL-6 ↓ MDA post-exercise and 7 d post-exercise for 14 d prior ↓ Muscle force ↔ CK
  • 76. post-exercise ↓ Muscle force ↔ DOMSSacheck et al.[76] Vit E (1000 IU/d) for 12 wk prior 45 min downhill running ↓ CK in younger men488McBride et al.[77] VITAMINAS C +resistance exercise Vit E (1200 IU/d) for 14 d prior Whole-body E ↓ iPF(2α) in older men Someren ↓ CK Howatson & van ↔ MDA ↔ DOMSBeaton et al.[78] Vit E (1200 IU/d) for 30 d prior exercise 240 knee flexor and extensor ↔ CKTable I. Studies reporting effects of antioxidant supplementation on markers of exercise-induced muscle damage eccentric contractions ↔ Muscle forceStudy Supplementation Exercise protocol Effects post-exercise ↔ Z-band disruption (compared with control group) ↔ DOMSShafatandal.[79]Bryer et Goldfarb [70] Vit C (3000mg/d) and 14 d prior and Vit C (500 mg/d) for vit E (1200 IU/d) 70 elbow flexor eccentric 300 knee extensor eccentric ↓↓CK Decline in torque during 4 d 30 d prior and 7 d post-exercise for post-exercise contractions contractions ↓exercise DOMS ↓↑Glutathione ratio Muscle force ↔ Muscle force ↔ DOMS ↔ ROMGoldfarb et al.[80] [71] Vit C (1000 mg/d) and vit E (400 IU/d) 48 elbow flexor eccentric ↓ MDAKaminsky and Boal Vit C (3000 mg/d) for 3 d prior and 15 min cyclic plantar flexion and ↓ DOMS for 14 d prior and 2 d post-exercise contractions ↓ Plasma protein carbonyls 4 d post-exercise extension ↔ Glutathione statusThompson et al.[72] Vit C (400 mg/d) for 12 d prior 90 min intermittent shuttle ↔ CK, MbMastaloudis et al.[81] Vit C (1000 mg/d) and vit E (300 mg/d) 50 km ultramarathon run ↔ CK running ↔ MDA for 6 wk prior ↔ LDH ↔ Muscle force ↔ Muscle force ↓ DOMSPetersen et al.[82] Vit C (500 mg/d) and vit E (400 mg/d) 90 min downhill running ↓↔ IL-6 IL-6 for 14 d prior and 7 d post-exercise ↔ CK ↔ CRPConnolly et al.[73] Vit C (3000 mg/d) for 3 d prior and 40 elbow flexor eccentric ↔ Lymphocytes (CD4+, CD8+, ↔ DOMS 5 d post-exercise contractions NK) ↔ Muscle forceJakeman and Maxwell[83] Vit C (400 mg/d) or vit E (400 mg/d) 60 min box stepping ↔ ROM LFF, ↔ muscle force Vit C: ↓Childs et al.[74] Vit C (12.5 mg/kg/d) d post-exercise for 21 d prior and 7 and NAC 30 elbow flexor eccentric ↑Vit E: ↔ LFF, ↔ muscle force CKCK = creatine kinase; CRP = C-reactive protein; post-exercise ↑ LDH (10 mg/kg/d) for 7 d DOMS = delayed-onset muscle soreness; IL-6 = interleukin-6; iPF(2α) = iso-prostaglandin contractions ↔ DOMS2α; LDH = lactate dehydrogenase; LFF = low frequency fatigue; Mb = myoglobin; MDA = malondialdehyde; NAC = N-acetyl-cysteine; NK = ↔ ROMnatural killer cells; ROM = range of motion; vit C = vitamin C (ascorbic acid); vit E = vitamin E (tocopherol); ↓ indicates decrease;↑ indicates increase; ↔ indicates no change. ↔ IL-6Close et al.[75] Vit C (1000 mg/d) 2 h prior and 14 d 30 min downhill running ↓ MDA post-exercise ↓ Muscle force Howatson G, van Someren KA. Sports Med. 2008;38(6):483-503. ↔ DOMS© 2008 Adis Data Information BV. All rights reserved. Sports Med 2008; 38 (6)Sacheck et al. [76] Vit E (1000 IU/d) for 12 wk prior 45 min downhill running ↓ CK in younger men ↓ iPF(2α) in older men
  • 77. t 16 MULHERES 14 HOMENS f D o t D t D B a ( • FIGURE 2 anos Idade: 21-24 Effect of the BCAA supplement on DOMS induced by msquat exercise.séries females; (B) males. min de intervalomeans 6 SEM for •  Sessão de 7 (A) de 20 Agachamentos c/ 3 Values are entre séries •  Solução Placebo vs Solução c/ BCAA 15 min antes da sessão t16 •  females mg/Kg 14 males. *P , (Homens) the corresponding placebo Dose: 92 and (Mulheres); 77 mg/Kg 0.05 to Ttrial (Wilcoxon signed-rank test). •  Cross-over p sthis study were as follows: a BCAA solution (150 mL) con- Shimomura Y, et al. J Nutr. 2006 Feb;136(2):529S-532S. mtaining 5 g of a BCAA mixture (Ile:Leu:Val 5 1:2.3:1.2), 1 g b
  • 78. a prolonged ride of “easy- lactate analyzer (YSI 2300 STAT). Samples to be analyzedjects, this self-selected watt- for plasma CPK were obtained immediately before and d that was• consistently be- 12–15 h after the first prolonged exercise bout. CPK was 15 ciclistas Sexo Masculinoized excessive test duration vs determined from 1,8 ml/Kg a cada 15 Vitro DT60II (John- •  Bebida c/ CHO CHO + P (4/1): blood plasma using a mintandardized protocols.c/ CHO vs son and P (4/1): 10Before CPK analysis, the Vitro DT60II •  Bebida Self- CHO + Johnson). ml/Kg após exercíciod from 60 to Bebidawith a •  150 W c/ CHO: 26 g CHO por 355 ml a reconstituted lyophilized calibration was calibrated using de água Workload was uniformly + P (4/1): [26 g CHO + 6,5 g P] por 355 ml de água •  Bebida CHO standard purchased from the manufacturer. Concentrationsrotocol.can College of Sports Medicine http://www.acsm-msse.org Saunders MJ, Kane MD, Todd MK. Med Sci Sports Exerc. 2004 Jul;36(7):1233-8.
  • 79. TABLE 2. Physiologic Performance Glucose (mg⅐dL Ride 1 (75% Ride 2 (85% Lactate (mmol⅐L Ride 1 (75% Ride 2 (85% Ventilation (L⅐m Ride 1 (75% Ride 2 (85% ˙ VO2 (L⅐minϪ1) Ride 1 (75% Ride 2 (85% RPE Ride 1 (75% Ride 2 (85% Heart rate (bpm Ride 1 (75% Ride 2 (85% ride. None ofFIGURE 2—Time to exhaustion during performance rides. *Signifi-cantly greater (P < 0.05) than CHO ride. different (P Ͻ Saunders MJ, Kane MD, Todd MK. Med Sci Sports Exerc. 2004 Jul;36(7):1233-8. DISCUSSIOlower (P Ͻ 0.05) after the CHOϩP trial (with additional
  • 80. availabilit have cont the effect subjects i diet befor dietary re verified th caloric co One of whether a mance du than a CH age, subj ˙ VO2peak 2 CHO bev pared CH that simul varying inFIGURE 3—Change in CPK levels. *Significantly lower (P < 0.05) tained exethan CHO Saunders MJ, Kane MD, Todd MK. Med Sci Sports Exerc. 2004 Jul;36(7):1233-8. ride. a CHO tri1236 Official Journal of the American College of Sports Medicine
  • 81. ü  N: 387 recrutas ü  Duração: 54 dias ü  Metodologia: Imediatamente após o treino: ü  Grupo Prot: 8 grs de HC + 10 grs de P + 3 g de L ü  Grupo HC: 8 grs de HC + 0 grs de P + 3 g de L ü  Grupo Placebo: 0 grs de HC + 0 grs de P + 0 g de LFlakoll  PJ,  et  al..  J  Appl  Physiol.  2004  Mar;96(3):951-­‐6    
  • 82. Alterações   34º  dia  vs   início   Alterações   úlLmo  dia  vs   início  Flakoll  PJ,  et  al..  J  Appl  Physiol.  2004  Mar;96(3):951-­‐6    
  • 83. NF-KB E DOENÇAS DA CIVILIZAÇÃO •  DCV •  Hipertensão •  Síndrome Metabólica •  Sarcopenia •  Osteoporose •  Depressão •  Cancro Ahn KS, Aggarwal BB. Ann N Y Acad Sci. 2005 Nov;1056:218-33
  • 84. Informação para o resto do organismoStraub, R.H. et al., 2010. Journal of Internal Medicine
  • 85. GASTO ENERGÉTICOStraub, R.H. et al., 2010. Journal of Internal Medicine
  • 86. SISTEMA IMUNOLÓGICO Consumo de 2000 kJ/dia: 477,6 Kcal/dia ü Activação≈ 25-30% ü En repouso: 1600 kJ ü 381 Kcal/dia70%: glucose e glutamina Straub, R.H. et al., 2010. Journal of Internal Medicine
  • 87. information).Based on Gould and Holman (1993); Joost et al . (2002); Thorens (1996); Wallner et al . u LUTS G(2001); Wright (1993). For recent updates see Sch¨rmann and Manolescu et al ., FurtherReading. 250 Km = 20 mmol/l Rate (% of that at 5 mmol/l) [Hígado, Riñon, Intestino, Células beta (GLUT-2)] 200 [Eritrocitos, feto, placenta (GLUT-1)] Km = 5 mmol/l 150 [Musculo, Adipocito (GLUT-4)] 100 Km = 1.6 mmol/l [Cerebro (GLUT-3)] 50 Physiological range 0 0 5 10 15 20 Glucose concentration (mmol/l)Figure 2.2.1 Frayn KN. Metabolic Regulation. Blackwell Pub; 2010:384. The term Km (Michaelis–Menten constant) is often used in this context, bor-rowed from enzyme kinetics. Think of Km as follows. Imagine that at a very high
  • 88. ATP-sensitive K+ channel + + + K+ + K+ K+ GLUT2 GK Glycolysis Glucose Glucose G6P ATP Glucose oxidation Mem b ra n e d e p o l a r i z a t Insulin Voltage-sensitive Ca2+ channel Se Ca2+ cr io n et or y Ca2+ ve sic esl InsulinFigure 6.4 Glucose stimulation Frayn KN. Metabolic Regulation. Blackwell Pub; 2010:384.pancreatic β-cell. Glucose of insulin secretion in theenters the cell via the transporter GLUT2 (but see below) and is phosphorylated by glucokinase (GK)
  • 89. Metabolic Regulation Brought About by the Characteristics of Tissues 37 GLUT-4 Insulin Glucose GLUT4 at the cell membrane Insulin receptor Cell membr ane Fusion with cell membrane Internalization at end of insulin signal Insulin signalling via PI3 kinase etc Intracellular pool of GLUT4Figure 2.3 GLUT4 recruitment to the cell membrane. There is an intracellular pool ofGLUT4 in membranous vesicles thatKN. Metabolic Regulation. Blackwell to 2010:384.cell membrane when insulin binds to Frayn can translocate Pub; theits receptor. When the insulin signal is withdrawn, the GLUT4 proteins return to their intracellularpool. Based loosely on Shepherd and Kahn (1999). A similar mechanism may operate for GLUT2
  • 90. IR
  • 91. IR
  • 92. IR
  • 93. IR
  • 94. GLICEMIA E INSULINEMIALast  AR,  Wilson  SA.  Low-­‐Carbohydrate  Diet.  Am  Fam  Physician  2006;73:1942-­‐8    
  • 95. ORIGINAL ARTICLEEffects of dietary carbohydrate on delayed onset musclesoreness and reactive oxygen species after contractioninduced muscle damageG L Close, T Ashton, T Cable, D Doran, C Noyes, F McArdle, D P M MacLaren............................................................................................................................... Br J Sports Med 2005;39:948–953. doi: 10.1136/bjsm.2005.019844 Background: Delayed onset muscle soreness (DOMS) occurs after unaccustomed exercise and has been suggested to be attributable to reactive oxygen species (ROS). Previous studies have shown increased ROS after lengthening contractions, attributable to invading phagocytes. Plasma glucose is a vital fuel for phagocytes, therefore carbohydrate (CHO) status before exercise may influence ROS production and DOMS Objective: To examine the effect of pre-exercise CHO status on DOMS, ROS production, and muscle function after contraction induced muscle damage. Method: Twelve subjects performed two downhill runs, one after a high CHO diet and one after a low CHO diet. Blood samples were drawn for analysis of malondialdehyde, total glutathione, creatine kinase, non-esterified fatty acids, lactate, glucose, and leucocytes. DOMS and muscle function were assessedSee end of article forauthors’ affiliations daily........................ Results: The high CHO diet resulted in higher respiratory exchange ratio and lactate concentrations than the low CHO diet before exercise. The low CHO diet resulted in higher non-esterified fatty acidCorrespondence to:Dr Close, Clinical Sciences, concentrations before exercise. DOMS developed after exercise and remained for up to 96 hours, afterUniversity of Liverpool, both diets. A biphasic response in creatine kinase occurred after both diets at 24 and 96 hours afterLiverpool L69 3GA, UK; exercise. Malondialdehyde had increased 72 hours after exercise after both diets, and muscle functiongclose@liv.ac.uk was attenuated up to this time.Accepted 17 May 2005 Conclusions: Downhill running resulted in increased ROS production and ratings of DOMS and secondary....................... increases in muscle damage. CHO status before exercise had no effect.D elayed onset muscle soreness (DOMS) is a symptom of during exercise, resulting in a greater stress response and an a type I muscle strain injury that presents as tender or associated immunosuppression. aching muscles, usually felt during palpation or move- The contribution of phagocytes to ROS production afterment and can affect any skeletal muscle.1 It is associated with exercise and the role of ROS in the aetiology of DOMS andunaccustomed exercise, particularly if the exercise involves loss of muscle function are unclear. Likewise, despite thelengthening contractions.2 Although there have been many popular practice by athletes of altering their CHO statusproposed mechanisms to account for DOMS, its exact before exercise to maximise performance, the effect of suchaetiology remains unresolved. The most recent suggestion is dietary manipulations on DOMS, muscle function, and ROSthat reactive oxygen species (ROS) may be responsible, production has not been reported. Therefore the main aims ofalthough this remains questionable. We have recently shown, this study were to: (1) investigate the effects of alterations inusing electron spin resonance spectroscopy, that 48–72 hours CHO status before exercise on phagocyte derived ROSafter downhill running there is a significant increase in ROS production; (2) clarify the effects of dietary CHO manipula-production, which is likely to be from invading phagocytes.3 tion on DOMS and muscle function.This finding is similar to those of a previous study whichreported increased ROS using indirect measures 96 hoursafter downhill running.4 The 48–96 hour delay in the METHODSproduction of ROS in these studies suggests that the likely Subjectssource is invading phagocytes. However, the exact role of this Twelve physically active male subjects of mean (SEM) ageincreased ROS production in the aetiology of DOMS is not 23.3 (0.98) years, height 175 (1.56) cm, body mass 76.7fully established. (1.73) kg, maximal oxygen uptake (VO2MAX) 4.2 (0.14) litres/ ˙
  • 96. INFLAMAÇÃO E OSSO!ü Substratos importantes na Inflamação: Cálcio e Fósforo!ü Aportados pelo osso se estiver próximo do local de Inflamação! ü TNF-a! ü IL-6! ü IL-1-b! ü PTH! Straub, R.H. et al., 2010. Journal of Internal Medicine, 267(6), pp.543-560.!
  • 97. Nakase et al 1997; Gilbert et al 2000, 2002). Furthermore, bone damage in vivo (Joosten et al 1999; Kong et al 1999; TNF TNF + + Bone erosion Osteoclast Osteoclast precursor and bone loss RANK OPG RANKL + TNF TNF Osteoblast + or = Secre t ion OPGFigure 1 Increasing the balance of receptor activator of nuclear factor κB ligand (RANKL)-receptor activator of nuclear factor κB (RANK) induced by tumor necrosis factoralpha (TNFα).Abbreviations: OPG, osteoprotegerin; +, stimulation; O, inhibition. Biologics: Targets & Therapy 2008:2(4) 663–669!664 Biologics: Targets & Therapy 2008:2(4)
  • 98. Sleep Medicine Reviews 16 (2012) 137e149 Contents lists available at ScienceDirect Sleep Medicine Reviews journal homepage: www.elsevier.com/locate/smrvCLINICAL REVIEWImmune, inflammatory and cardiovascular consequences of sleep restrictionand recoveryBrice Faraut a, b, c, Karim Zouaoui Boudjeltia b, Luc Vanhamme d, Myriam Kerkhofs a, b, *a Sleep Laboratory, CHU de Charleroi, A. Vésale Hospital, Montigny-le-Tilleul, Université Libre de Bruxelles, Belgiumb Laboratory of Experimental Medicine (ULB 222 Unit), CHU de Charleroi, A. Vésale Hospital, Montigny-le-Tilleul, Université Libre de Bruxelles, Belgiumc Université Paris Descartes, APHP, Hôtel Dieu, Centre du Sommeil et de la Vigilance, Paris, Franced Laboratory of Molecular Parasitology, Institute for Molecular Biology and Medicine, Université Libre de Bruxelles, Gosselies, Belgiuma r t i c l e i n f o s u m m a r yArticle history: In addition to its effects on cognitive function, compelling evidence links sleep loss to alterations in theReceived 2 February 2011 neuroendocrine, immune and inflammatory systems with potential negative public-health ramifications.Received in revised form The evidence to suggest that shorter sleep is associated with detrimental health outcomes comes from4 May 2011 both epidemiological and experimental sleep deprivation studies. This review will focus on the post-Accepted 4 May 2011Available online 10 August 2011 sleep deprivation and recovery changes in immune and inflammatory functions in well-controlled sleep restriction laboratory studies. The data obtained indicate non-specific activation of leukocyte populations and a state of low-level systemic inflammation after sleep loss. Furthermore, one night ofKeywords:
  • 99. most common complaints by individuals who experience situation of extended work shifts experienced by health workersTable 2Consequences of sleep restriction on immune and inflammatory changes and effects of recovery and sleep countermeasures. “After 8-h recovery sleep” indicates changes fromsimilar time points measured following the sleep restriction intervention. “Sleep countermeasures” indicates the napping period during the day following the sleep restrictionintervention. Abbreviations: C-reactive protein (CRP), interleukin-1 b (IL-1b); interleukin-6 (IL-6), interleukin-17 (IL-17); myeloperoxidase-modified low-density lipoprotein(Mox-LDL); peripheral blood mononuclear cell (PBMC); tumor necrosis factor-alpha (TNF-a). Sleep restriction (SR) Immune changes Inflammatory changes After 8 h-recovery sleep Sleep countermeasures 38 Vgontzas, 2004; 7 nights of 6 h-sleep IL-6, TNF-a only in _ ? (22:30e04:30 h), n ¼ 25 _ 34 IL-6, TNF-a gene expression Irwin, 2006, 2010; 1 night of 4 h-sleep and protein by in vitro-stimulated Not reported ? (03:00e07:00 h), n ¼ 30 _ monocytes 39 Haack, 2007; 10 nights of 4 h-sleep IL-6, unchanged CRP Not reported ? (23:00e03:00 h), n ¼ 18 _ 21 Kerkhofs, 2007; 3 nights of 4 h-sleep Leukocyte and Not reported ? (01:00e05:00 h), n ¼ 10 monocyte counts 32 Meier-Ewert; 2007; 10 nights of 4,2 h-sleep CRP Not reported ? (01:00e05:00 h), n ¼ 10 _ 20 Boudjeltia, 2008; 3 nights of 4 h-sleep Leukocyte and Not reported ? (01:00e05:00 h), n ¼ 8 _ neutrophil counts 40 CRP, IL-6, IL-17 and IL-1b van Leeuwen, 2009; 5 nights of 4 h-sleep gene expression CRP and IL-17 > baseline ? (03:00e07:00 h), n ¼ 13 _ by in vitro-stimulated PBMC 35 Greater IL-6, TNF-a by in Irwin, 2010; 1 night of 4 h-sleep vitro-stimulated monocytes Not reported ? (03:00e07:00 h), n ¼ 26 _ in than in _ 19 Faraut, 2011; 1 night of 2 h-sleep Leukocyte and Myeloperoxidase Leukocyte and neutrophil À30 min nap (02:00e04:00 h), n ¼ 12 _ neutrophil counts counts > baseline (13:00e13:30 h) post-SR: Leukocyte, neutrophil counts; cortisole10 h extended recovery sleep (21:00e07:00 h): Leukocyte, neutrophil counts Zouaoui-Boudjeltia, submitted; 5 nights of 5 h-sleep Mox-LDL Myeloperoxidase ? (01:00e06:00 h), n ¼ 9 _
  • 100. 142 B. Faraut et al. / Sleep Medicine Reviews 16 (2012) 137e149Fig. 1. Potential pathway(s) by which sleep restriction and insufficient recovery sleep lead to cardiovascular pathologies. Sleep restriction coupled to insufficient recovery sleepenhance the activity of the autonomic and stress systems. Vascular shear stress exacerbated by increased blood pressure leads to inflammation in the vascular wall potentially
  • 101. LIGANDOS DOS TLRS
  • 102. ivalis and Helicobacter pyroli (7–9). These LPS structurally range of microbial products through functional cooperr from the typical LPS of Gram-negative bacteria recog- with several proteins that are either structurally related by TLR4 in the number of acyl chains in the lipid A unrelated. Bactérias Bactérias Gram Positivas Gram Negativas Vírus Takeda K, Akira S. Int Immunol. 2005 Jan;17(1):1-14.1. TLRs and their ligands. TLR2 is essential in the recognition of microbial lipopeptides. TLR1 and TLR6 cooperate with TLR2 to discrime differences between triacyl and diacyl lipopeptides, respectively. TLR4 is the receptor for LPS. TLR9 is essential in CpG DNA recogn
  • 103. CitoquinasInflamatórias
  • 104. Resposta Inflamatória Recrutamento de células imunológicas Calor “Calor” Rubor “Enrojecimiento” “Hinchazon” Inchaço “dor” DorPodolsky. Inflammatory Bowel Disease. N Engl J Med. 2002 Aug 8;347(6):417-29
  • 105. VIAS ENTRADA LPS NA CIRCULAÇÃO Caesar R, et al. Journal of Internal Medicine 2010
  • 106. Viswanathan VK, Hodges K, Hecht G. Nat Rev Microbiol. 2009 Feb;7(2):110-9
  • 107. VIAS ENTRADA LPS NA CIRCULAÇÃO Caesar R, et al. Journal of Internal Medicine 2010
  • 108. X3 +90 g Gordura e/ou
  • 109. Orange Juice on Inflammation, EndotoC l li in i icca l l C a rree//EEd uucca t t i o n / N u t r i t oo Expression e of cToll-Like ReceptC n a Ca d a andu the nn / P s y c h o s o c aa l R R s s e a r h h ion/N tritii /Psychosoci i l e ear c O R I I G I I N A LL O R G N A and Suppressor of Cytokine Signaling- A R TT I I CC L L EE A R RUPALI DEOPURKAR, PHD PRIYA MOHANTY, MD vital to the protection froDifferential Effects of Cream, Glucose, andDifferential Effects of Cream, Glucose, andHUSAM GHANIM, PHD JAY FRIEDMAN, PHD PRABHAKAR VISWANATHAN, PHD AJAY CHAUDHURI, MD ins and immunological commensal and pathoOrange Juice on Inflammation, Endotoxin,Orange Juice on Inflammation, Endotoxin, SANAA ABUAYSHEH, BSC PARESH DANDONA, MD, PHD bacteria. CHANG LING SIA, BSC In this context, we w which macronutrient waand the Expression of Toll-Like Receptor-4and the Expression of Toll-Like Receptor-4 the induction of oxidati OBJECTIVE — We have recently shown that a high-fat high-carbohydrate (HFHC) meal flammation, on the one hand Suppressor of Cytokine Signaling-3and Suppressor of Cytokine Signaling-3 induces an increase in plasma concentrations of endotoxin (lipopolysaccharide [LPS]) and the crease in LPS concent expression of Toll-like receptor-4 (TLR-4) and suppresser of cytokine signaling-3 (SOCS3) in mononuclear cells (MNCs) in addition to oxidative stress and cellular inflammation. Saturated expression of TLR-4 and fat and carbohydrates, components of the HFHC meal, known to induce oxidative stress and tokine signaling (SOCS)RUPALI DEOPURKAR, ,PHD RUPALI DEOPURKAR PHD PPRIYA induce an , MD in LPS, TLR-4, and SOCS3. toto the protection from To elucidate this, we inv inflammation, alsoMOHANTYMD RIYA MOHANTY, increase vital the protection from bacterial tox- vital bacterial tox-HUSAM GHANIM, ,PHD HUSAM GHANIM PHD PPRABHAKAR VISWANATHANPHD RABHAKAR VISWANATHAN, , PHD ins and immunological responses glucose, fect ofto the the most ins and immunological responses to theJJAYFRIEDMAN, ,PHD AY FRIEDMAN PHD RESEARCH DESIGN AND METHODS — Fasting normal subjects were given 300- hydrate, cream, a sat AAJAY CHAUDHURIMD JAY CHAUDHURI, , MD commensal and pathogenic intestinal commensal and pathogenic intestinalSANAA ABUAYSHEH, ,BSC SANAA ABUAYSHEH BSC calorie drinks of either glucose, saturated fat as cream, orange juice, or only water to ingest. Blood orange juice, a carbohy PPARESH DANDONAMD, PHD ARESH DANDONA, , MD, PHD bacteria.CHANG LING SSIA,BSC bacteria. food product, which do CHANG LING IA, BSC samples were obtained at 0, 1, 3, and 5 h for analysis. InIn this context, we wanted to analyzestress or in this context, we wanted to analyze ther oxidative which macronutrient was responsible for is a protein RESULTS — Indexes of inflammation including nuclear factor-␬B (NF-␬B) binding, andwas responsible for which macronutrient the SOCS3 the induction ofof in MNCs, stress and in- expression of SOCS3, tumor necrosis factor-␣ (TNF-␣), and interleukin (IL)-1␤ oxidative the induction oxidative stress and in- shown to interfere with iOBJECTIVE — We have recently shown thatsignificantly high-carbohydrate (HFHC) meal TLR-4 expressionon the one LPS signal transduction (2– OBJECTIVE — We have recently shown thata ahigh-fat after glucose and cream intake, but flammation, and plasma hand, and the in- increased high-fat high-carbohydrate (HFHC) meal flammation, on the one hand, and the in-induces an increase in plasma concentrations of endotoxin (lipopolysaccharide intake. The intake of orangein LPS water did not work has shown that SO concentrations increased only after cream [LPS]) and the induces an increase in plasma concentrations of endotoxin (lipopolysaccharide [LPS]) and the crease juice LPS concentrations and theexpression of Toll-like receptor-4 (TLR-4) andany change inof cytokineindexes measured. crease in or concentrations and the induce suppresser of of the signaling-3 (SOCS3) in expression of Toll-like receptor-4 (TLR-4) and suppresser anycytokine signaling-3 (SOCS3) in expression of TLR-4 and suppresser of cy-mononuclear cells (MNCs) in addition to oxidative stress and cellular inflammation. Saturated expression of TLR-4 and suppressercirculating mo mononuclear cells (MNCs) in addition to oxidative stress and cellular inflammation. Saturated tokine signaling (SOCS)-3 on the other. obese hu in the of cy- (MNCs) of thefat and carbohydrates, components of the HFHC meal, known toto induce oxidative stress and tokine signalingand an in- on the other. fat and carbohydrates, components of CONCLUSIONSknown induce oxidative stress and induce NF-␬B binding (SOCS)-3 increased when compar the HFHC meal, — Although both glucose and cream To elucidate this, we investigated the ef- inflammation, also induce an increase in LPS, the expression of SOCS3, TNF-␣, and IL-1␤ in MNCs, onlyelucidate this, increase normalthe ef-inflammation, also induce an increase in LPS, inTLR-4, and SOCS3. crease TLR-4, and SOCS3. To cream caused an we investigated subjects fectorange juice or watermost important carbo- (6). I in LPS concentration and TLR-4 expression. Equicaloric amounts of ofof glucose, the did not work carbo- fect glucose, the most important demonstrated that hydrate, cream, a a saturated fat, and hydrate, cream, saturated fat, andRESEARCH DESIGN AND METHODS — Fasting normal subjects were given 300-are relevant to the pathogenesis of sion in MNCs is inverse induce a change in any of these indexes. These changes RESEARCH DESIGN AND METHODS — Fasting normal subjects were given 300- orange juice, a carbohydrate-containingcalorie drinks of either glucose, saturatedatherosclerosisorange juice,resistance. water to ingest. Blood orange juice, a carbohydrate-containing fat as cream, and insulin or only water to ingest. Blood calorie drinks of either glucose, saturated fat as cream, orange juice, or only tyrosine phosphorylatiosamples were obtained at 0, 1, 3, and 55 h for analysis. samples were obtained at 0, 1, 3, and h for analysis. food product, which does not induce and directly rel product, which does receptor ei- foodCare 33:991–997, 2010 not induce ei- Diabetes ther oxidative stress oror inflammation. ther oxidative stress inflammation.insulin resistance (home O SOCS3 is is a protein that has beenRESULTS — Indexes of inflammation including nuclear factor-␬Bshown thatbinding, and the because the content of LPS sessment of a protein that has been insulin res ur recent work has (NF-␬B) binding, and the shown to interfere with insulin and leptin RESULTS — Indexes of inflammation including nuclear factor-␬B (NF-␬B) a great interest SOCS3expression of SOCS3, tumor necrosis factor-␣ (TNF-␣), and interleukin (IL)-1␤ ininthese meals is not to interfere with insulin and leptin MNCs, IR]), consistent with expression of SOCS3, tumor necrosis factor-␣ (TNF-␣), and interleukin (IL)-1␤ in MNCs, shown significantly differ- high-fat high-cholesterol (HFHC)increased significantly after glucose and cream intake, but TLR-4 expression and plasma LPS signal transduction (2–5). Our recent of insulin r increased significantly after glucose and cream intake, butoxidative and inflam- plasma LPS signal transduction (2–5). Our recent pathogenesis meal induces TLR-4 expression and ent, and, thus, it would appear that theconcentrations increased only after cream intake. The intake ofof orange juice or water did not work has shown that SOCS3 resistance in human obe concentrations increased only after cream intake. The intake orange juice oran inflammatory work has shownmay lead water did not expression matory stress in addition to inducing nature of the meal that SOCS3 expressioninduce any change in any of the indexes measured. inability of leptin to ca
  • 110. (R01-D Differential Effects of Cream, Gluco the Am Orange Juice on Inflammation,The da End and we and the Expression of Toll-Likepretatio Rec and Suppressor of Cytokine Signal investig vestiga RUPALI DEOPURKAR, PHD PRIYA MOHANTY, MD vitalfor the to the pro HUSAM GHANIM, PHD PRABHAKAR VISWANATHAN, PHD ins and immu JAY FRIEDMAN, PHD AJAY CHAUDHURI, MD commensal p No a SANAA ABUAYSHEH, BSC PARESH DANDONA, MD, PHD bacteria. art this CHANG LING SIA, BSC In this con Nata which macron the induction OBJECTIVE — We have recently shown that a high-fat high-carbohydrate (HFHC) meal flammation, on induces an increase in plasma concentrations of endotoxin (lipopolysaccharide [LPS]) and the Referen crease in LPS expressionGh 1. of T expression of Toll-like receptor-4 (TLR-4) and suppresser of cytokine signaling-3 (SOCS3) in mononuclear cells (MNCs) in addition to oxidative stress and cellular inflammation. Saturated fat and carbohydrates, components of the HFHC meal, known to induce oxidative stress and tokine signalin nie inflammation, also induce an increase in LPS, TLR-4, and SOCS3. To elucidate th JM fect of glucose, RESEARCH DESIGN AND METHODS — Fasting normal subjects were given 300- tox hydrate, crea calorie drinks of either glucose, saturated fat as cream, orange juice, or only water to ingest. Blood orange juice, samples were obtained at 0, 1, 3, and 5 h for analysis. Sumo de of food product, Laranja cyt ther oxidative RESULTS — Indexes of inflammation including nuclear factor-␬B (NF-␬B) binding, and the SOCS3 is expression of SOCS3, tumor necrosis factor-␣ (TNF-␣), and interleukin (IL)-1␤ in MNCs, fol shown to inter increased significantly after glucose and cream intake, but TLR-4 expression and plasma LPS me signal transdu concentrations increased only after cream intake. The intake of orange juice or water did not work has show induce any change in any of the indexes measured. Dia in the circul (MNCs) ofRu 2. the CONCLUSIONS — Although both glucose and cream induce NF-␬B binding and an in- increased whe crease in the expression of SOCS3, TNF-␣, and IL-1␤ in MNCs, only cream caused an increase normal subje Wh in LPS concentration and TLR-4 expression. Equicaloric amounts of orange juice or water did not work demonstsul induce a change in any of these indexes. These changes are relevant to the pathogenesis of sion in MNCs atherosclerosis and insulin resistance. degFigure 3—Change in NF␬B binding activity in MNC (A) and plasma endotoxin concentrations tyrosine phosp Diabetes Care juice (OJ, ‚), Ch receptor and d(B) in normal subjects after a 300-calorie drink of cream (E), glucose (Œ), orange 33:991–997, 2010 3. Sen insulin resistan and ؉, P Ͻ 0.05 with a great interest because the content of LPSor water (F). Data are means Ϯ SEM. *ur recent work has shown thatRMANOVA comparing changes in sessment of in TA IR]), consisterelation to baseline after cream and glucose challenges; # andin $, P meals 0.05 significantly differ- high-fat high-cholesterol (HFHC) these Ͻ is not with two-way
  • 111. Macronutrients, oxidative stress, and inflammation Differential Effects of Cream, Gluco Orange Juice on Inflammation, Endcytok and the Expression of Toll-Like Rec know and Suppressor of Cytokine Signal anim RUPALI DEOPURKAR, PHD PRIYA MOHANTY, MD but vital to the pro HUSAM GHANIM, PHD JAY FRIEDMAN, PHD PRABHAKAR VISWANATHAN, PHD AJAY CHAUDHURI, MD creas ins and immu commensal a SANAA ABUAYSHEH, BSC CHANG LING SIA, BSC PARESH DANDONA, MD, PHD and bacteria. In this con creas which macron Nata SOC the induction OBJECTIVE — We have recently shown that a high-fat high-carbohydrate (HFHC) meal flammation, on induces an increase in plasma concentrations of endotoxin (lipopolysaccharide [LPS]) and the expression of Toll-like receptor-4 (TLR-4) and suppresser of cytokine signaling-3 (SOCS3) in of in crease in LPS Glucose expression of T mononuclear cells (MNCs) in addition to oxidative stress and cellular inflammation. Saturated fat and carbohydrates, components of the HFHC meal, known to induce oxidative stress and juice tokine signalin inflammation, also induce an increase in LPS, TLR-4, and SOCS3. stres To elucidate th fect of glucose, RESEARCH DESIGN AND METHODS — Fasting normal subjects were given 300- Sumo de an in hydrate, crea orange juice, calorie drinks of either glucose, saturated fat as cream, orange juice, or only water to ingest. Blood samples were obtained at 0, 1, 3, and 5 h for analysis. Laranja food product, ther oxidative RESULTS — Indexes of inflammation including nuclear factor-␬B (NF-␬B) binding, and the SOCS3 is expression of SOCS3, tumor necrosis factor-␣ (TNF-␣), and interleukin (IL)-1␤ in MNCs, Ackn shown to inter increased significantly after glucose and cream intake, but TLR-4 expression and plasma LPS signal transdu concentrations increased only after cream intake. The intake of orange juice or water did not porte work has show induce any change in any of the indexes measured. Flori in the circul (MNCs) of the CONCLUSIONS — Although both glucose and cream induce NF-␬B binding and an in- supp increased whe crease in the expression of SOCS3, TNF-␣, and IL-1␤ in MNCs, only cream caused an increase in LPS concentration and TLR-4 expression. Equicaloric amounts of orange juice or water did not (R01 normal subje work demonst induce a change in any of these indexes. These changes are relevant to the pathogenesis of atherosclerosis and insulin resistance. the A sion in MNCs tyrosine phosp The receptor and d Diabetes Care 33:991–997, 2010 and w insulin resistan sessment of in ur recent work has shown that a great interest because the content of LPS preta IR]), consiste high-fat high-cholesterol (HFHC) in these meals is not significantly differ-
  • 112. Differential Effects of Cream, GlucoOrange Juice on Inflammation, End dand the Expression of Toll-Like Reccand Suppressor of Cytokine Signalo Glucose sRUPALI DEOPURKAR, PHD PRIYA MOHANTY, MD vital to the proHUSAM GHANIM, PHD PRABHAKAR VISWANATHAN, PHD ins and immu dJAY FRIEDMAN, PHD AJAY CHAUDHURI, MD commensal aSANAA ABUAYSHEH, BSC PARESH DANDONA, MD, PHD bacteria.CHANG LING SIA, BSC a In this con which macronOBJECTIVE — We have recently shown that a high-fat high-carbohydrate (HFHC) meal the inductionk flammation, oninduces an increase in plasma concentrations of endotoxin (lipopolysaccharide [LPS]) and the Nataexpression of Toll-like receptor-4 (TLR-4) and suppresser of cytokine signaling-3 (SOCS3) in crease in LPSimononuclear cells (MNCs) in addition to oxidative stress and cellular inflammation. Saturatedfat and carbohydrates, components of the HFHC meal, known to induce oxidative stress and m expression of T tokine signalininflammation, also induce an increase in LPS, TLR-4, and SOCS3. d To elucidate th fect of glucose,RESEARCH DESIGN AND METHODS — Fasting normal subjects were given 300- hydrate, creal orange juice, Sumo decalorie drinks of either glucose, saturated fat as cream, orange juice, or only water to ingest. Blood food product,dsamples were obtained at 0, 1, 3, and 5 h for analysis. Laranja ther oxidativeRESULTS — Indexes of inflammation including nuclear factor-␬B (NF-␬B) binding, and the SOCS3 isiexpression of SOCS3, tumor necrosis factor-␣ (TNF-␣), and interleukin (IL)-1␤ in MNCs, shown to interincreased significantly after glucose and cream intake, but TLR-4 expression and plasma LPS signal transduconcentrations increased only after cream intake. The intake of orange juice or water did notinduce any change in any of the indexes measured. work has show in the circul n (MNCs) of thecCONCLUSIONS — Although both glucose and cream induce NF-␬B binding and an in- increased whecrease in the expression of SOCS3, TNF-␣, and IL-1␤ in MNCs, only cream caused an increase normal subje rin LPS concentration and TLR-4 expression. Equicaloric amounts of orange juice or water did not work demonstinduce a change in any of these indexes. These changes are relevant to the pathogenesis of sion in MNCs patherosclerosis and insulin resistance. d tyrosine phosp receptor and d Diabetes Care 33:991–997, 2010 ( insulin resistan sessment of in ur recent work has shown that a great interest because the content of LPS m IR]), consiste
  • 113. 24 PorcosEx vivo mucosal to serosal endotoxin LPS no plasmatransport permeability (Papp) Mani V, Hollis JH, Gabler NK. Nutr Metab (Lond). 2013 Jan 10;10(1):6. [Epub ahead of print]
  • 114. 24 PorcosEx vivo mucosal to serosal endotoxin LPS no plasmatransport permeability (Papp) Mani V, Hollis JH, Gabler NK. Nutr Metab (Lond). 2013 Jan 10;10(1):6. [Epub ahead of print]
  • 115. INTRODUCTION Health, Buffalo, NY (CLS, MU, KHusam Ghanim, Chang and Sia, Mannish Upadhyay,that high-fat,75 g (300 kcal) University, Seoul, Koreaplasm Background: The intakeWe a glucose or a the intake of high-carbohydrate atherogenesis Ling haveof chronically elevated food intake (23). (PD). previously showed Kelly Korzeniewski, Prabhakar Viswanathan, Sanaa imm 2Priya Mohanty, and Paresh not glucose induced an acuteinduces reactiveincrease in inflam-by a grant from the Dandona (HFHC) meal,neutralizes (ROS) proinflammatory effect ana in an increaseinterference factorincrease in oxygen species Supported Furthermore, but Orange juice inflammatory juice,orange factors contribute to in grant R01DK069805-02 (to clon the generation and inflammation as reflected high-fat, of PD) from grant 08-CR-13 (to PD) from the AABSTRACTand oxidative stress prevents endotoxinand an increaseand cells (MNCs) mationinsulin signal transductionfactor jB insulin resistance. responsecorrespondencesubu and in circulating mononuclear growth 3 Address factor-1 expres nuclear transcription with and (NF-jB)binding,aearly in of Western NY, State University Da high-carbohydrate meal the expression of inhibitory jB-a, increase in inhibitory binding, decrease flammto P of Toll-like receptor subjects.1–3 in of normal-weight expression increaseperipheral blood mononuclear cellsmatrix metalloproteinase (MMP)-2 aBackground: The intake of glucose or a high-fat, high-carbohydrate jB kinases plasma (MNCs) (1, Buffalo, NY 14209. E-mail: pdando(HFHC) meal, but Changorange juice, induces an increase inbinding is associated with anAbuaysheh, intake (3). In 27, 2009. Accep not Ling Sia, Mannish 2). An Kelly Korzeniewski, Prabhakar Viswanathan, Sanaa increase in NF-jB inflam- factor after glucose Received August terms of a gen higmationPriya Mohanty, andWe Dandona Objective: stress investigatednecrosis factor-a (TNF-a) expression, activator protein-1 a HFHC online intake and oxidative Paresh in circulating mononucleareffect of orange juice on similar response follow in tumor the Husam Ghanim, Upadhyay, First published March 3, 2 cells (MNCs) flammatory stress,of normal-weight subjects. brid meal–induced inflammation and binding, early growth response and the expression ABSTRACT 940 oxidative stress a factor-1 expression andClin Nutr 2010;91:940–9. Printedmeal (4 high-fat, high-carbohydrate (HFHC) in USA. Ó Am J binding, (totalObjective: We The intake of glucose or a high-fat, high-carbohydrate juice on HFHC Background: investigated the effect of orange plasma matrix metalloproteinase (MMP)-2 orange juice containing sucrose, gluc intake of and -9, and tissue pho of plasma endotoxinoxidativeToll-like expression response follows the intake of inflammation and and stress and SUBJECTS AND METHODS the factorreceptors (3). In terms of oxidative and in- after glucose intake (TLRs).meal–inducedoxidative stress in circulating mononuclear cells (MNCs) flammatory stress, a similar(total sugar content: 75 g = 300 kcal) does RO (HFHC) meal, but not orange juice, induces an increase in inflam- in not Downloaded from www.ajcn.org at Lund University Libraries on August 20, 2010of plasma endotoxin and Toll-like receptors (TLRs). high-fat, high-carbohydratein ROS generation or NF-jB binding (5).Bio mation and Design: WeThree(10effectoforange in healthy, normal-weight men of the women and ad investigated thegroups juice on HFHC of normal-weight subjects. Three groupssubjects Objective: of (10 subjects normal,each sucrose, glucose, andand 10 expression (total of intake of orange juice containing group) a in (HFHC) meal (4). In contrast,Design:Threegroups and oxidative stress and theeach group) sugar content: 75 g = 300 kcal) does not cause an2 major flavonoids that are co fructosenormal, In n meal–induced inflammationhealthy subjects were askedwere(TLRs). and naringenin, increase healthyThree groups (10 subjects indrinkasked to]:kcal glucosemajor flavonoids thatbut containedhesperetin acid,were to juice, wer (body in combination towater[in900-kcal HFHC20–25; oror orrange:in20–40.50% are able suppres mass index eacha300 kcal of or 300drink water juice,(5).are addition, inglucose(5). Toll-like(Pie subjects kg/m2 in ROS generation age by 300In kcal orange y) or water of plasma endotoxin and Toll-like receptors Design: group) normal, NF-jB binding not ascorbic and naringenin, 2orangehealthy subjects were asked to drinkwith or orangejuiceobtainedinwith a 900-kcalstudy. Blood juice,meal.900-kcal able to suppress ROS generation the in- by M juice orange before and 3, and 5 glucose or a Blood presentedmeal. juicefor combinationh All thebut notvitro andacid, are Toll-like receptorvitro 2bythe Blood withMNCs in ascorbic.50% (5). HFHC (TLR) issamples were in combination this 1,HFHC meal. after subjects specific receptor for lipopeptides and pept recruited before and 1, 3, and 5 h after the drinks and specific receptor for lipopeptides and peptidoglycans from drinks by MNCs for recep samples were obtained by samples were obtained before and 1, 3,bacteria, and TLR4 after the drinks and is speci with gram-positive and 5gram-positive receptor for and TLR4 h is the specific bacteria,meal combinations were consumed. meal combinations were consumed. the spe vestigation p38ofmitogen-activated protein kinase, and lipopolysaccharide to the Clinical (LPS) or endotoxin from after an overnight fast (LPS) lipopolysaccharide ResearchResults: Protein expression of the oxidase subunit p47 , subunit p47phox, or endotoxin from gram-negative Results: Protein expression the NADPH NADPH oxidase phox valu meal combinationsTLR2 and TLR4 messenger bacteria pathogenesis was atherosclerosis play an7).diet-induced was also shown gram phosphorylated and total were consumed. (6, 7). TLR4 of also shown to (8–11),important rolephosphorylated and total p38 mitogen-activated protein kinase, and Center,cytokine expression; mRNA expression of New Yorkrelated insulin resistance (12, 13),TLR4 in the to play State signaling-3; University matrix in the and the at Buffalo. Subjects suppressor of cytokine signaling-3;suppressor(mRNA)Protein expressionofofofthe NADPH oxidasepathogenesisp47phox, bacteria (6, Results: RNA of and(MMP)-9 in MNCs; and plasmaTLR2 and TLR4 messenger protein obesity, in the subunit whereas TLR2 was shown to be involved in ischemia-reperfusion– of atherosclerosis (8–1 3 endotoxin and MMP-9the meal butsignificantlya glucosewaswater induced of matrixinjury obesity,recent study (15) (Glucola; lipop metalloproteinase groups ingested orangemRNA con- increased after concentrationsRNA (mRNA) and protein expression;300-kcal drink of 75 g aglucoserelated insulin resistance ( or expression and the wemetalloproteinase (MMP)-9 in of reactive oxygen plasma concentrationswas a significant protein kinase, and phosphorylated and total p38 mitogen-activated Inincrease in plasma concen- be involved in Tot myocardial (14). were consumed with not when juice Fisher theScientific, significantly juice trations of endotoxinafter anTLR2ofinwas and (“Not From bacte sumed with meal. The generation MNCs; and species by showed that there ofendotoxin and MMP-9 wascytokinewhen orange after glucoseinor water the intake juice meal. This polymorphonuclear cells increased lower Pittsburgh,pression MNCs and increase an HFHC TLR2 ex- PA), orange TLR4 shown to ische suppressormeal than when water or glucose was added to the of significantly signaling-3; TLR2 and TLR4 messenger In inrecen induced myocardial injury (14). a Florida Orange Juice;mRNA human thatrodents (16–18). a significant poly Concentrate” and protein the HFHC confirmed in previous reports inexpression was matrix increaseth was added to thewere consumed with the meal but not when orangeincrease of endotoxemia induced by a fatty meal was also of Cit- juice was con- Florida Department RNA induced oxidative and inflammatory stress andand increase inoxygen species contribute to and prolong thethere of and an increaseobesi meal. (mRNA) expression; showed and insumedConclusions: The combination generationocidentais: couldby Alimentos or an with the meal. The of glucose or water reactive This increase ofpolymorphonuclear cells endotoxin concentrations. In contrast,when orangefollows the a 900-kcal HFHC meal rus, expression and plasma was (MMP)-9 in MNCs; and plasma concentrations of ofinan T Lakeland, FL), water along with intake of such aof endotoxin the intake TLR inflammatory trations meal. Whether this meal significantly lower response that juice metalloproteinase meal prevented meal-induced increase of endotoxemia is due to the lipidin MNCs after TLRwas added to the meal than when water or glucose was added absorption into the circulation with the fat con- pression solubility of endo- TLR2 H toxin and its to the orange juice intake with the HFHC endotoxin and andincluding theincreased inflammation of the intestinalafter glucoseitor reports in humanchai (egg-muffin MMP-9 increase in endo- significantlyincrease of endotoxemia induced by a fatty sausage-muffin sandwiches and 2 hash-brownmeal. toxin and TLR expression. These observations may help explain the tained in the meal or is secondary to other factors such as the water oxidative and inflammatory stress, potatoes that containedmeal g carbohydrates, increase clear. If was con- gand prolong combination of glucose 81Am and the other factors, mechanisms underlying postprandial oxidative stress and inflamma- 51 g could contribute to induc confirmed not previous epithelium is inConclusions: The of insulin resistance, and atherosclerosis. water secondary to HFHC the potential antiinflammatory effect were consumed with the tion, pathogenesis or but not when orange juice This fat, and 32is The andTLR expression To meal. The generationdifference inNY (HG Metabolism, State the intake of showmeal induced oxidative and inflammatory stress and an increase in J Clin Nutr 2010;91:940–9. protein).andthecompensate for theInthecontrast,atEndocrinology, Diabetes,volume between such(mR sumed with plasma endotoxin concentrations. of of York Buffalo, Buffalo, of endotoxemia is due to the lipid m 1 From response that follows New reactive oxygen species by Division of and a drinks, subjects 75 gwas significantly(PD). KK, extraits absorption into the tratio University and PD); Kaleida thejuice intakeshowed that the intake of meal(300 kcal) Health, Buffalo, NY (CLS,lower whenand Kyung Hee juice circulationso prevented meal-induced MU, increaseorangeINTRODUCTION with the HFHCwere asked to drink an PV, SA, and PM);350 mL water polymorphonuclearin cellsoxygen species University, Seoul, aKorea toxin and orange We previously meroxidative and inflammatory stress, including the increase inbyendo-from the Florida Department of Citrus (to PD), with generation and inflammation as reflected in an All helpR01DK069805-02were thegiven 10–15ismin to to press 2 glucose induced an acute increase reactive Supported granttoxin and TLR expression. Thesedrink.increase in subjects the (ROS) the glucose tained in Institutesmeal or secondary National the of Health, and other fa was added to the meal than when water or glucose was added to the observations may grant explain (to PD) from grant 08-CR-13 (to PD) from the American Diabetes Association. mel
  • 116. T and B lymphocytes contained in the MNC fraction are known to ibraries on August 20, 2010 ry for theprotein (A fat, high-), glucoseand C areANOVA)] OJ+meal, betweeny. P forifferences 0.044 for= 10 each. ranja Sumo de Laafter theenic and hyper-mediated FIGURE 8. Mean (6SE) change in plasma endotoxin concentrations
  • 117. servation. It is possible that incretin mechanisms are involved in the genesis of this phenomenon. Downloaded from www.ajcn.org at Lund University Libraries on August 20, 2010 Sumo de Laranja Mean (6SE) change in matrix metalloproteinase (MMP)-9 A (mRNA) expression in mononuclear cells (MNC) (A) and ntration (B) after intake of a 900-kcal high-fat, high- meal and a 300-kcal drink of orange juice (OJ+meal), meal), or water (W+meal) in normal subjects. *,**P , 0.05 sures ANOVA (RMANOVA)] compared with baseline values Glu+meal, or OJ+meal, respectively; ^P , 0.05 (2-factor or comparisons between W+meal and Glu+meal; +,$P , 0.05ANOVA) for comparison between W+meal or Glu+meal and ments, respectively. P for interaction (treatment · time) =MP-9 mRNA with differences between the groups at 1 anderaction (treatment · time) = 0.028 for plasma MMP-9 with ween the groups at 3 h. n = 10 each.atory effects of these flavonoids in the human in uired. Sumo de Laranja surprised to find no increase in glucose concen- h after the orange juice intake. Indeed, even whene was taken with the fast-food meal, there was no ucose concentrations. Although we do not have any FIGURE 5. Mean (6SE) change in Toll-like receptor (TLR) 2 expression d glucose concentrations between 0 and 60 min, and (A) and TLR4 messenger RNA (mRNA) expression (B) in mononucleare that there may have been a peak of glucose during cells (MNC) after intake of a 900-kcal high-fat, high-carbohydrate meal
  • 118. TRANSPORTE TRANS E PARA CELULAR ü  3mm de epitélio ü  Moléculas <100 Da passam por difusão: Na+ ou Cl- ü  Se aumenta a permeabilidade passam moléculas de >100-150 Da ü  Outras barreiras: muco, peristaltismo, junções estreitas, enzimas, secreções ácidas, IgA, etcThe Institute for Functional Medicine. CLINICAL NUTRITION. A Functional Approach. Second Edition. 2004
  • 119. CAUSAS DA HIPERPERMEABILIDADE INTESTINAL!
  • 120. DIETA RICA EM GORDURA Y ANTIBIÓTICOS Cani PD, et al. Diabetes 2008;57(6):1470–81.
  • 121. DIETA RICA EM GORDURA Y ANTIBIÓTICOS Cani PD, et al. Diabetes 2008;57(6):1470–81.
  • 122. FÁRMACOS ü AINES ü AntiácidosCordain  L,  et  al.  Br  J  Nutr.  2000  Mar;83(3):207-­‐17  
  • 123. CAUSAS DIETÉTICASü Pimentosü Álcool Jensen-Jarolim E, et al. J Nutr. 1998 Mar;128(3):577-81 Tsukura Y, et al. Biol Pharm Bull. 2007 Oct;30(10):1982-6 Purohit V, et al. Alcohol. 2008 Aug;42(5):349-61
  • 124. Yan AW et al .  Microbiome  in  alcoholic  liver  disease A B Alcohol Bacteria Bacteria Mucin Mucin Anti- microbial Anti- molecules microbial molecules Bacterial translocationFigure 1 Intestinal changes following alcohol administration. A: In health, antimicrobial molecules as part of the innate immune response are secreted by intes-tinal epithelial cells and kill enteric bacteria. B: Alcohol suppresses the expression of these molecules resulting in intestinal bacterial overgrowth and dysbiosis. Thismight  contribute  to  bacterial  translocation  observed  after  alcohol.  Alcohol  might  also  exert  a  direct  effect  on  the  intestinal  microflora.
  • 125. DISBIOSE / SIBO Bacterias Intestinales Linfocitos TCordain L, et al. Br J Nutr. 2000 Mar;83(3):207-17
  • 126. Visser J et al. Tight Junctions, Intestinal Permeability, and Autoimmunity. Ann. N.Y. Acad. Sci. 1165: 195–205 (2009).
  • 127. Cani  PD,  et  al.  Diabetologia  2007  
  • 128. with the presence of SIBO. idiopathic constipation that stool fre- is observed in IBS patients.18 The im-Figure 1. Distribution of Intestinal Bacterial Flora in Normal Gut and in Small Intestinal Bacterial Overgrowth A Normal Distribution of Intestinal Bacterial Flora Duodenum Jejunum Ileum Colon Easily Digestible Digestion Starch (eg, Rice) and Absorption Major Region of Complete Fermentation and Gas Production Poorly Digestible Bacterial Concentration, Starch (eg, Beans) organisms/mL 100 B Small Intestinal Bacterial Overgrowth 103 Duodenum Jejunum Ileum Colon 106 1011 Easily Digestible Starch (eg, Rice) Major Region of Fermentation and Gas Production Poorly Digestible Starch (eg, Beans)A, In the normal gut, easily digestible starch undergoes complete digestion and absorption within the proximal small intestine and is not available for fermentation inthe distal ileum and colon where bacterial colonization is the greatest.29-31 In contrast, gas production results from bacterial fermentation of poorly digestible starch thatis not assimilated by the proximal gut. B, In small intestinal bacterial overgrowth, the concentration of bacterial flora increases proximally allowing fermentation of botheasily digestible and poorly digestible starches. Lind HC. JAMA. 2004;292(7):852-858854 JAMA, August 18, 2004—Vol 292, No. 7 (Reprinted) ©2004 American Medical Association. All rights reserved.
  • 129. ever, 2 observations point away from number (58%) had an abnormal lac- elevation of corticotropin-releasingrapid transit as the primary explana- tose breath test result and there was a factor (CRF) concentration, 86 andtion for the findings by Pimentel et significant correlation between lactu- change in neurotransmitter levels,87al.34,35 First, the time-to-rise of breath lose (SIBO) and lactose breath test such altered brain-gut interactions mayhydrogen normalized with successful result.38 be a part of the systemic response to aFigure 2. Regions of Intestine Accessible by Various Diagnostic Methods to Detect Small Intestinal Bacterial Overgrowth (SIBO) Duodenum Jejunum Ileum Colon Ligament of Treitz Detection Method Direct Aspiration Bacterial Concentration, and Culture organisms/mL Absorption Complete 100 Glucose Breath Test Major Region of Fermentation and Gas Production Glucose 1011 Lactulose Breath Test LactuloseDetection of SIBO depends on location of and access to bacterial flora. SIBO by culture is defined by bacterial concentration proximal to the distal ileum Ͼ10 5 organ-isms per mL. In this example of SIBO, the concentration of bacterial flora in the distal jejunum and ileum has increased to that typically present in the normal colon (1011organisms per mL). Culture of intestinal flora sampled by direct aspiration, which commonly is able to access the duodenum, would not detect the region of increasedbacterial flora in this example. Similarly, a breath test using glucose as the fermentable substrate would only detect bacterial flora in the duodenum and proximaljejunum because glucose is rapidly absorbed. In contrast, a breath test using lactulose, which is not absorbed by the intestine, would be able to detect bacterial floraanywhere along the gut.856 JAMA, August 18, 2004—Vol 292, No. 7 (Reprinted) ©2004 American Medical Association. All rights reserved. Downloaded from www.jama.com at Capes Consortia on June 29, 2009 Lind HC. JAMA. 2004;292(7):852-858
  • 130. GOLD STANDARD: LACTULOSE BREATH TEST Bures J, et al. WJG. 2010 vol. 16 (24) pp. 2978-90
  • 131. CEREAIS ! PROLAMINAS! GLÚTEN GLUTENINAS!Kagnoff  MF.  Celiac  disease:  pathogenesis  of  a  model  immunogeneNc  disease.  J  Clin  Invest.  2007  Jan;117(1):41-­‐9    
  • 132. PROLAMINASü Hordeina – Cevadaü Secalina - Centeioü Gliadina – Trigo Drago S, et al. Scand J Gastroenterol. 2006 Apr;41(4):408-19. Lammers KM, et al. Gastroenterology. 2008 Jul;135(1):194-204.e3.
  • 133. ORIGINAL ARTICLE: GASTROENTEROLOGY J  Pediatr  Gastroenterol  Nutr.  2010  Oct;51(4):418-­‐24.  Alterations of the Intestinal Barrier in Patients With Autism Spectrum Disorders and in Their First-degree Relatives Laura de Magistris, ÃValeria Familiari, y#Antonio Pascotto, ÃAnna Sapone, Ã JPGN Volume Frolli, Number 4, zOctober 2010 De Rosa, ô y Alessandro 51, §Patrizia Iardino, Maria Carteni, zMario Alterations Ruggiero Francavilla, ÃGabriele Riegler, yRoberto Militerni, and jjCarmela BravaccioABSTRACT TABLE 3. FC inObjectives: Intestinal permeability (IPT) was investigated in patients withautism as well as in their first-degree relatives to investigate leaky guthypothesis. Faecal calprotectin (FC) was also measured in patients with I t was hypothesised that primary gastrointestinal (GI) pathologies and intestinal barrier defects could play an important role in the triggering and clinical expression of some childhood developmental relativesautism, either with or without gastrointestinal symptoms, and in their first- disorders, including autism (1–4). Autism is a complex spectrum ofdegree relatives. clinically heterogeneous neurodevelopmental disorders now com-Patients and Methods: IPT results, assessed by means of the lactulose/ monly known as autism spectrum disorders (ASD). This disabilitymannitol test, were compared with adult and child controls and with FC has a variable phenotype, each probably involving different aetio-values. pathogenetic aspects. A variety of GI dysfunctions and symptomsResults: A high percentage of abnormal IPT values were found amongpatients with autism (36.7%) and their relatives (21.2%) compared with AuLstas  creported frequently in children with ASD. A recent have been on  normal subjects (4.8%). Patients with autism on a reported gluten-casein–free diet had significantly lower IPT values compared with those who were dieta  sconference report (5) states that more(eg, the existence of consensus in   to establish the prevalence of GI abnormalities studies are requiredon an unrestricted diet and controls. Gastrointestinal symptoms were present gluten   specific GI disturbances such as abnormal GI permeability) inin 46.7% of children with autism: constipation (45.5%), diarrhoea (34.1%), subjects with ASD. GI symptoms (6,7) have been reported in Patients withand others (alternating diarrhoea/constipation, abdominal pain, etc: 15.9%). children with ASD and in adults with other psychiatric diseases,FC was elevated in 24.4% of patients with autism and in 11.6% of their such as schizophrenia (8,9). ASD (N ¼ 90)relatives; it was not, however, correlated with abnormal IPT values. Ileocolonic lymphoid nodular hyperplasia and mild acute andConclusions: The results obtained support the leaky gut hypothesis andindicate that measuring IPT could help to identify a subgroup of patients chronic inflammation of the colon-rectum, small bowel, and Relatives (N ¼ 146 stomach have been reported in children with ASD. Although somewith autism who could benefit from a gluten-free diet. The IPT alterations of the reported findings are still controversial (3,10–12), it isfound in first-degree relatives suggest the presence of an intestinal (tight-junction linked) hereditary factor in the families of subjects with autism. generally assumed that it is a common finding (13). Increased intestinal permeability (IPT) has also been reported (14) as repre- Mean Æ SD of pathKey Words: autism, calprotectin, first-degree relatives, gastrointestinal senting a possible link in the chain of the so-called leaky gut hypothesis (4). second column. ASDsymptoms, intestinal permeability Although the possible mechanisms are unknown, it has long GCFD ¼ gluten-casei been suggested that some intestinal lesions that increase IPT to(JPGN 2010;51: 418–424) exogenous peptides of dietary origin may lead to the disruption of neuroregulatory mechanisms and normal brain development (enter- ocolonic encephalopathy) (15). Previously, Wakefield et al (10) found that ileocolonic (ileum more predominant) lymphoid nodularReceived November 11, 2009; accepted March 9, 2010. hyperplasia was highly prevalent among children with ASD com-From the ÃDepartment Magrassi-Lanzara, Gastroenterology, the pared with controls; however, this endoscopic finding was not First-degree FIGURE 2. Small intestine barrier function is more deregu- yDepartment of Psychiatry, Neuropsychiatry, Dermatovenereology, accompanied by inflammation histologically. the zDepartment of Experimental Medicine, the §Department of Labora- tory Medicine, Second University of Naples, the jjDepartment of Pae- The question then arises as to whether it is possible to screened for the pr lated in the children with autism spectrum disorders with diatrics, Federico II University of Naples, the ôClinica Pediatrica ‘‘B identify subgroups—that is, either gut inflammation or abnormal
  • 134. LECTINAS!1.  Sjolander A et all. Int Arch Allergy Appl Immunol 1984; 75, 230–236.!!2.  Greer F, et al. Digestion 1985; 32, 42–46.!3.  Pellegrina CD et al. Toxicol Appl Pharmacol 2005;207:170-78!
  • 135. LECTINAS QUE PODEM LIGAR-SE A CÉLULAS INTESTINAIS Gérmen de Trigo: 300 – 350 mg/kg WGA (1) Farinha de trigo integral: 30-50 mg/kg WGA (2) Farinha de trigo refinado: 4.4 mg/kg WGA (2) Feijão: 1,000-10,000 mg/kg PHA (3) Soja: 200 – 2,000 mg/kg SBA (3) Tomate: 10 mg/kg TL (3) Amendoim: 110 mg/kg PNA (1) 1. Vincenzi S, et al. J Agric Food Chem. 2002 Oct 23;50(22):6266-70. 2. Matucci A et al. Food Control 2004;15: 391-95 3. Peumans WJ, Van Damme EJM. Trends Food Sci Technol 1996;7:132-39
  • 136. Adaptado de Cordain L, 2009 (con autorização) Vilosidades LÚMEN WGA/PHA Enterócitos Tight Junction Integridade Hiperpermeabilidade1. Sjolander A et al. The effect of concanavalin A and wheat germ agglutinin on the ultrastructureand permeability of rat intestine. Int Arch Allergy Appl Immunol 1984; 75, 230–236.2. Greer F Pusztai A (1985) Toxicity of kidney bean (Phaseolus vulgaris) in rats: changes in intestinalpermeability. Digestion32, 42–46.3. Pellegrina CD et al. Plant lectins as carriers for oral drugs: Is wheat germ agglutinin a suitablecandidate? Toxicol Appl Pharmacol 2005;207:170-78
  • 137. SAPONINAS Leguminosas ü  Glicosídeos Esteróides (Glicoalcalóides) ou Glicosídeos Triterpenóides ü  Função Principal: Proteger aSolanáceas planta do ataque de insectos e de microrganismos ü  Em mamíferos aumenta permeabilidade intestinal e causa hemólise de eritrócitos Francis G et al. Brit J Nutr 2002;88:587-605
  • 138. Adaptado de Cordain L, 2009 (com permissão) BATATA INGLESA O PIOR!! Total saponinas: α-solanina + α-chaconina (mg/kg) Casca de Batata 1. Casca Frita 1450 Frita 2. Batata Frita com Casca 720 3. Chips (EUA) 180 4. Batata Assada Congelada 123 5. Casca de batata congelada 121 6. Batata Assada 113 7. Farinha de Batata desidratada 75 8. Batata Cozida sem casca 42 9. Batata com casca enlatada 34 10. Batata Frita Congelada 31 11. Batata Frita (McDonald’s) 8 12. Puré de Batata Congelado 5 13. Batata sem casca enlatada 2Smith DB, Roddick JG, Jones JL. Trends in Food Sci Technol 1996;7:126-131.
  • 139. Adaptado de Cordain L, 2009 (con autorização) α-Tomatina (mg/kg) TOMATE 1. Tomates verdes pequenos 548 2. Tomates verdes médios 169 3. Tomates verdes em escabeche (Marca A) 71.5 4. Tomates verdes não maduros escabeche 28 O pior!! 5. Tomates verdes em escabeche (Marca B) 28 6. Molho tomate verde 27.5 7. Tomate vermelho secado ao sol 21 8. Verde grande não maduro 16 9. Verde grande não maduro tipo 210 10. Tomate cherry sungold 11 11. Tomate verde frito 11 12. Tomate verde no microondas 11 13. Tomate cherry amarelo 9.7 14. Ketchup 8.6 15. Molho tomate vermelho 5.7 16. Tomate cherry pera amarelo 4.5 17. Sumo de tomate 2.8 18. Tomate cherry vermelho 2.7 19. Caldo concentrado de tomate 2.2 20. Tomate cherry pera vermelho 1.3 21. Tomate amarelo médio 1.3 22. Tomate amarelo grande 1.1 23. Tomate estufado em lata 1.1 24. Tomate maduro vermelho para carne 0.9 25. Tomate green zebra 0.6 26. Roma 0.4 27. Tomate vermelho maduro normal 0.3 Friedman M, Levin CE. J Agric Food Chem 1995;43:1507-1511
  • 140. Adaptado de Cordain L, 2009 (com permissão) SOJA Total de Saponinas da Soja (mg/kg)O PIOR!! 1. Isolado de Proteína de Soja 10600 2. Feijão de Soja 4040 4. Farinha de Soja 3310 5. Tempeh 1530 6. Tofu 590 7. Leite de Soja 470 Tempeh Tofu Ju J, Lee S, Hendrich S, Murphy PA. J Agric Food Chem 2002;50:2587-94
  • 141. Adaptado de Cordain L, 2009 LEGUMINOSAS (mg/kg)1. Feijão haricot 41002. Fríjoles (P. vulgaris) 38003. Feijão Vermelho (P. vulgaris) 35004. Judías negras 34005. Fava (Vicia faba) 31006. Grão 23007. Ervilha 18008. Rebenmtos de Feijão 11009. Lentilhas 110010. Chícharo 110011. Feijão Manteiga 100012.  Feijão cozido em lata 110013.  Feijão verde (P. vulgaris) 100014. Amendoim 100 Shi J. J Med Food. 2004 Spring;7(1):67-78 Price KR, et al. J Sci Food Agric 1986;37:1185-91 Sparg SG, et al. J Ethnopharmacol. 2004 Oct;94(2-3):219-43
  • 142. Adaptado de Cordain L, 2009 (com permissão) OUTROS ALIMENTOS Total saponinas: (mg/kg) 1. Rebentos de Alfalfa 8000 2. Amaranto 7900 3.  Quinoa 5930 4. Extracto de Quillaja 100Quinoa Amaranto Alfalfa Oda K, et al. Biol Chem. 2000 Jan;381(1):67-74
  • 143. Adaptado de Cordain L, 2009 (com permissão) COMO AS SAPONINAS CAUSAM HIPERPERMEABILIDADE INTESTINAL Saponina ColesterolSaponinas ligam-se a moléculas de colesterolna membrana pela afinidade do componente Aglicónico pelo esterol de membrana Keukens EA et al. Biochim Biophys Acta 1995;1240: 216-228.
  • 144. SAPONINAS QUE DEMONSTRARAM AUMENTAR PERMEABILIDADE INTESTINALSaponina Alimento Referênciaα-Tomatina Tomate Johnson IT et al. J Nutr 1986;116:2270-77α-Solanina, Keukens EA et al. Biochimica et Biopysica Actaα-chaconina Batata Inglesa 1995;1240:216-228Saponina daSoja Soja Alvarez JR et al. Pediatr Res 1982;16:728-31.Saponina da Extracto deQuillaja Quillaja Chao AC et al. J Pharm Sci 1998;87:1395-99.Saponina daQuinoa Quinoa Gee JM et al. J Sci Food Agric 1993;63:201-09Saponina da Rebentos deAlfalfa Alfalfa Story JA et al. Am J Clin Nutr 1984;39:917-29 To  
  • 145. Adaptado de Cordain L, 2009 (com permissão) (SAPONINA + LECTINA) tem efeito sinérgico sobre permeabilidade intestinal:Saponina Lectina AlimentoSaponina da Soja SBA Soja Tofu Alvarez JR et al. Pediatr Res 1982;16:728-31.
  • 146. Adaptado de Cordain L, 2009 (com autorização) PHA   o WGA   Lumen intestinal EGF Receptor EGF Receptor Para LinfaHormi K et al. Cell Tissue Res 1994;278:439-50Rebbaa A et al. J Neurochem 1996;67:2265-2272 Para CirculaçãoLochner N, et al. Pharm Res. 2003 May;20(5):833-9.
  • 147. Cordain  L.  PotenNal  TherapeuNc  CharacterisNcs  of  Pre-­‐agricultural  Diets  in   the  PrevenNon  and  Treatment  of  MulNple  Sclerosis.  Direct  MS  (MulNple   Sclerosis)  of  Canada  Conference.  Calgary,  Canada,  Outubro  de  2007   B/A   B/A   WGA   Bacteria/Péptidos dietéticosLectina B/A   WGA   Lumen intestinal Receptor EGF Receptor EGF Para Linfa B/A   WGA   Para Activa Células T Circulação
  • 148. Food and Chemical Toxicology 49 (2011) 1464–1467 Contents lists available at ScienceDirect Food and Chemical Toxicology journal homepage: www.elsevier.com/locate/foodchemtoxBrief communicationStimulants of Toll-like receptor (TLR)-2 and TLR-4 are abundant in certainminimally-processed vegetablesClett Erridge ⇑Department of Cardiovascular Sciences, Glenfield General Hospital, University of Leicester, Leicester LE3 9QP, UKa r t i c l e i n f o a b s t r a c tArticle history: Stimulants of the innate immune receptors Toll-like receptor (TLR)-2 and TLR4 have been shown to pro-Received 27 October 2010 mote insulin resistance and atherosclerosis in animal models of these diseases. As minimally processedAccepted 25 February 2011 vegetables (MPV) can contain a relatively large bacterial load compared to other foodstuffs, we aimed toAvailable online 3 March 2011 quantify the abundance of stimulants of TLR2 and TLR4 in MPV using a transfection-based bioassay cal- ibrated with Escherichia coli LPS and the synthetic lipopeptide Pam3CSK4. Of 5 classes of MPV and 3 clas-Keywords: ses of related vegetable products considered to be likely to contain a high microbial load, diced onion andToll-like receptors bean sprouts contained the highest levels of stimulants of TLR2 (up to 18.5 lg Pam3CSK4-equivalents perMinimally processed vegetablesInsulin resistance g) and TLR4 (up to 11.4 lg LPS-equivalents per g). By contrast, the majority of fresh whole vegetablesAtherosclerosis examined reproducibly contained minimal or undetectable levels of TLR2- or TLR4-stimulants. The accu-
  • 149. ESTIMULANTES TLRS EM VERDURAS E FRUTAS PROCESSADAS MINIMAMENTEü  Inicialmente só em algumas carnes e lácteosü  Analisados: cenoura ralada, cebola cortada, maçã em rodelas, folhas verdes de salada, espinafres, grelos e rebentos de leguminosasü  Armazenados a 5ºCErridge, C., 2011. Stimulants of Toll-like receptor (TLR)-2 and TLR-4 are abundant in certain minimally-processed vegetables. Food and Chemical Toxicology, 49(6), pp.1464-1467.
  • 150. ESTIMULANTES DE TLRS TLR4 TLR2ü  Agrião em salada ü  Agriãoü  Vegetais verdes em ü  Agrião em salada saladas ü  Vegetais verdes emü  Espinafres saladasü  Cenoura ralada ü  Espinafresü  Cebola cortada +++ ü  Cenoura raladaü  Rebentos de feijão +++ ü  Cebola cortada +++ ü  Rebentos de feijão +++ Erridge, C., 2011. Stimulants of Toll-like receptor (TLR)-2 and TLR-4 are abundant in certain minimally-processed vegetables. Food and Chemical Toxicology, 49(6), pp.1464-1467.
  • 151. QUANTIDADE ü Concentrações mais altas que as que estão no intestino delgado ü LPS: 100 ng/ml vs 11 g/g ü BLP: 1000 ng/ml vs 18 g/gErridge, C., 2011. Diet, commensals and the intestine as sources of pathogen-associated molecular patterns in atherosclerosis, type 2 diabetes and non-alcoholic fatty liver disease. Atherosclerosis, 216(1), pp.1-6.
  • 152. MESMO QUANDO SÃO FERVIDOS DURANTE 10 MIN
  • 153. MAS NÃO EM VERDURAS NÃO PROCESSADAS E DESCASCADAS ü Cenoura ü Cebola ü Batata ü Brócolo ü Pimento ü Abóbora ü Grão Erridge, C., 2011. Stimulants of Toll-like receptor (TLR)-2 and TLR-4 are abundant in certain minimally-processed vegetables. Food and Chemical Toxicology, 49(6), pp.1464-1467.
  • 154. EFEITO ARMAZENAMENTO A 5ºC C. Erridge / Food and Chemical Toxicology 49 (2011) 1464–1467Erridge, C., 2011. Stimulants of Toll-like receptor (TLR)-2 and TLR-4 are abundant in certain minimally-processed vegetables. Food and Chemical Toxicology, 49(6), pp.1464-1467.
  • 155. SUFICIENTE PARA ACTIVAR SIST IMUNOLÓGICO? Se humanos absorvessem 0.1% de LPS ü 5 µg/kg de LPS oral seria suficiente ü Possível dieta ocidentalErridge, C., 2011. Diet, commensals and the intestine as sources of pathogen-associated molecular patterns in atherosclerosis, type 2 diabetes and non-alcoholic fatty liver disease. Atherosclerosis, 216(1), pp.1-6.
  • 156. ÓMEGA-3 E INFLAMAÇÃO ü Inibição TLR4 ü Inibição TLR2 ü Inibe transcrição NFk-B através de PPARWendel M and Heller PAR. Lipoproteins in inflammation and sepsis. II. Clinical aspects. Intensive Care Med (2007) 33:25–35
  • 157. CURCUMINAhZp://www.curcuminresearch.org  
  • 158. hZp://www.curcuminresearch.org  
  • 159. hZp://www.curcuminresearch.org  
  • 160. OBRIGADO 
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