Unité de Nutrition Humaine

The production of ROS (reactive oxygen species) by mammalian mitochondria is important because it underlies oxidative damage in many pathologies and contributes to retrograde redox signalling from the organelle to the cytosol and nucleus. Superoxide (O2(*-)) is the proximal mitochondrial ROS, and in the present review I outline the principles that govern O2(*-) production within the matrix of mammalian mitochondria. The flux of O2(*-) is related to the concentration of potential electron donors, the local concentration of O2 and the second-order rate constants for the reactions between them. Two modes of operation by isolated mitochondria result in significant O2(*-) production, predominantly from complex I: (i) when the mitochondria are not making ATP and consequently have a high Deltap (protonmotive force) and a reduced CoQ (coenzyme Q) pool; and (ii) when there is a high NADH/NAD+ ratio in the mitochondrial matrix. For mitochondria that are actively making ATP, and consequently have a lower Deltap and NADH/NAD+ ratio, the extent of O2(*-) production is far lower. The generation of O2(*-) within the mitochondrial matrix depends critically on Deltap, the NADH/NAD+ and CoQH2/CoQ ratios and the local O2 concentration, which are all highly variable and difficult to measure in vivo. Consequently, it is not possible to estimate O2(*-) generation by mitochondria in vivo from O2(*-)-production rates by isolated mitochondria, and such extrapolations in the literature are misleading. Even so, the description outlined here facilitates the understanding of factors that favour mitochondrial ROS production. There is a clear need to develop better methods to measure mitochondrial O2(*-) and H2O2 formation in vivo, as uncertainty about these values hampers studies on the role of mitochondrial ROS in pathological oxidative damage and redox signalling.

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The Human Metabolome Database or HMDB (www.hmdb.ca) is a web-enabled metabolomic database containing comprehensive information about human metabolites along with their biological roles, physiological concentrations, disease associations, chemical reactions, metabolic pathways, and reference spectra. First described in 2007, the HMDB is now considered the standard metabolomic resource for human metabolic studies. Over the past decade the HMDB has continued to grow and evolve in response to emerging needs for metabolomics researchers and continuing changes in web standards. This year's update, HMDB 4.0, represents the most significant upgrade to the database in its history. For instance, the number of fully annotated metabolites has increased by nearly threefold, the number of experimental spectra has grown by almost fourfold and the number of illustrated metabolic pathways has grown by a factor of almost 60. Significant improvements have also been made to the HMDB's chemical taxonomy, chemical ontology, spectral viewing, and spectral/text searching tools. A great deal of brand new data has also been added to HMDB 4.0. This includes large quantities of predicted MS/MS and GC-MS reference spectral data as well as predicted (physiologically feasible) metabolite structures to facilitate novel metabolite identification. Additional information on metabolite-SNP interactions and the influence of drugs on metabolite levels (pharmacometabolomics) has also been added. Many other important improvements in the content, the interface, and the performance of the HMDB website have been made and these should greatly enhance its ease of use and its potential applications in nutrition, biochemistry, clinical chemistry, clinical genetics, medicine, and metabolomics science.

Evidence for the occurrence of microbial breakdown of carbohydrate in the human colon has been sought by measuring short chain fatty acid (SCFA) concentrations in the contents of all regions of the large intestine and in portal, hepatic and peripheral venous blood obtained at autopsy of sudden death victims within four hours of death. Total SCFA concentration (mmol/kg) was low in the terminal ileum at 13 +/- 6 but high in all regions of the colon ranging from 131 +/- 9 in the caecum to 80 +/- 11 in the descending colon. The presence of branched chain fatty acids was also noted. A significant trend from high to low concentrations was found on passing distally from caecum to descending colon. pH also changed with region from 5.6 +/- 0.2 in the caecum to 6.6 +/- 0.1 in the descending colon. pH and SCFA concentrations were inversely related. Total SCFA (mumol/l) in blood was, portal 375 +/- 70, hepatic 148 +/- 42 and peripheral 79 +/- 22. In all samples acetate was the principal anion but molar ratios of the three principal SCFA changed on going from colonic contents to portal blood to hepatic vein indicating greater uptake of butyrate by the colonic epithelium and propionate by the liver. These data indicate that substantial carbohydrate, and possibly protein, fermentation is occurring in the human large intestine, principally in the caecum and ascending colon and that the large bowel may have a greater role to play in digestion than has previously been ascribed to it.

Refence centile curves show the distribution of a measurement as it changes according to some covariate, often age. The LMS method summarizes the changing distribution by three curves representing the median, coefficient of variation and skewness, the latter expressed as a Box-Cox power. Using penalized likelihood the three curves can be fitted as cubic splines by non-linear regression, and the extent of smoothing required can be expressed in terms of smoothing parameters or equivalent degrees of freedom. The method is illustrated with data on triceps skinfold in Gambian girls and women, and body weight in U.S.A. girls.

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Reference curves for stature and weight in British children have been available for the past 30 years, and have recently been updated. However weight by itself is a poor indicator of fatness or obesity, and there has never been a corresponding set of reference curves to assess weight for height. Body mass index (BMI) or weight/height has been popular for assessing obesity in adults for many years, but its use in children has developed only recently. Here centile curves for BMI in British children are presented, from birth to 23 years, based on the same large representative sample as used to update the stature and weight references. The charts were derived using Cole's LMS method, which adjusts the BMI distribution for skewness and allows BMI in individual subjects to be expressed as an exact centile or SD score. Use of the charts in clinical practice is aided by the provision of nine centiles, where the two extremes identify the fattest and thinnest four per 1000 of the population.

RATIONALE: This initiative is focused on building a global consensus around core diagnostic criteria for malnutrition in adults in clinical settings. METHODS: In January 2016, the Global Leadership Initiative on Malnutrition (GLIM) was convened by several of the major global clinical nutrition societies. GLIM appointed a core leadership committee and a supporting working group with representatives bringing additional global diversity and expertise. Empirical consensus was reached through a series of face-to-face meetings, telephone conferences, and e-mail communications. RESULTS: A two-step approach for the malnutrition diagnosis was selected, i.e., first screening to identify "at risk" status by the use of any validated screening tool, and second, assessment for diagnosis and grading the severity of malnutrition. The malnutrition criteria for consideration were retrieved from existing approaches for screening and assessment. Potential criteria were subjected to a ballot among the GLIM core and supporting working group members. The top five ranked criteria included three phenotypic criteria (weight loss, low body mass index, and reduced muscle mass) and two etiologic criteria (reduced food intake or assimilation, and inflammation or disease burden). To diagnose malnutrition at least one phenotypic criterion and one etiologic criterion should be present. Phenotypic metrics for grading severity as Stage 1 (moderate) and Stage 2 (severe) malnutrition are proposed. It is recommended that the etiologic criteria be used to guide intervention and anticipated outcomes. The recommended approach supports classification of malnutrition into four etiology-related diagnosis categories. CONCLUSION: A consensus scheme for diagnosing malnutrition in adults in clinical settings on a global scale is proposed. Next steps are to secure further collaboration and endorsements from leading nutrition professional societies, to identify overlaps with syndromes like cachexia and sarcopenia, and to promote dissemination, validation studies, and feedback. The diagnostic construct should be re-considered every 3-5 years.

We measured production of reactive oxygen species by intact mitochondria from rat skeletal muscle, heart, and liver under various experimental conditions. By using different substrates and inhibitors, we determined the sites of production (which complexes in the electron transport chain produced superoxide). By measuring hydrogen peroxide production in the absence and presence of exogenous superoxide dismutase, we established the topology of superoxide production (on which side of the mitochondrial inner membrane superoxide was produced). Mitochondria did not release measurable amounts of superoxide or hydrogen peroxide when respiring on complex I or complex II substrates. Mitochondria from skeletal muscle or heart generated significant amounts of superoxide from complex I when respiring on palmitoyl carnitine. They produced superoxide at considerable rates in the presence of various inhibitors of the electron transport chain. Complex I (and perhaps the fatty acid oxidation electron transfer flavoprotein and its oxidoreductase) released superoxide on the matrix side of the inner membrane, whereas center o of complex III released superoxide on the cytoplasmic side. These results do not support the idea that mitochondria produce considerable amounts of reactive oxygen species under physiological conditions. Our upper estimate of the proportion of electron flow giving rise to hydrogen peroxide with palmitoyl carnitine as substrate (0.15%) is more than an order of magnitude lower than commonly cited values. We observed no difference in the rate of hydrogen peroxide production between rat and pigeon heart mitochondria respiring on complex I substrates. However, when complex I was fully reduced using rotenone, rat mitochondria released significantly more hydrogen peroxide than pigeon mitochondria. This difference was solely due to an elevated concentration of complex I in rat compared with pigeon heart mitochondria. We measured production of reactive oxygen species by intact mitochondria from rat skeletal muscle, heart, and liver under various experimental conditions. By using different substrates and inhibitors, we determined the sites of production (which complexes in the electron transport chain produced superoxide). By measuring hydrogen peroxide production in the absence and presence of exogenous superoxide dismutase, we established the topology of superoxide production (on which side of the mitochondrial inner membrane superoxide was produced). Mitochondria did not release measurable amounts of superoxide or hydrogen peroxide when respiring on complex I or complex II substrates. Mitochondria from skeletal muscle or heart generated significant amounts of superoxide from complex I when respiring on palmitoyl carnitine. They produced superoxide at considerable rates in the presence of various inhibitors of the electron transport chain. Complex I (and perhaps the fatty acid oxidation electron transfer flavoprotein and its oxidoreductase) released superoxide on the matrix side of the inner membrane, whereas center o of complex III released superoxide on the cytoplasmic side. These results do not support the idea that mitochondria produce considerable amounts of reactive oxygen species under physiological conditions. Our upper estimate of the proportion of electron flow giving rise to hydrogen peroxide with palmitoyl carnitine as substrate (0.15%) is more than an order of magnitude lower than commonly cited values. We observed no difference in the rate of hydrogen peroxide production between rat and pigeon heart mitochondria respiring on complex I substrates. However, when complex I was fully reduced using rotenone, rat mitochondria released significantly more hydrogen peroxide than pigeon mitochondria. This difference was solely due to an elevated concentration of complex I in rat compared with pigeon heart mitochondria. The free radical theory of aging states that it is the mitochondrial production of reactive oxygen species (ROS), 1The abbreviations used are: ROS, reactive oxygen species; MLSP, maximum lifespan; ETF, electron transfer flavoprotein; QOR, quinone oxidoreductase; UCPs, uncoupling proteins; SOD, superoxide dismutase; BSA, bovine serum albumin. such as superoxide and hydrogen peroxide, and the resulting accumulation of damage to macromolecules that causes aging and determines maximum lifespan (MLSP) (1Harman D. J. Gerontol. 1956; 2: 298-300Google Scholar, 2Harman D. J. Am. Geriatr. Soc. 1972; 20: 145-147Google Scholar). Comparative approaches have shed considerable light on the relationship between ROS and MLSP. Notably, the rate of superoxide production by submitochondrial particles (3Sohal R.S. Svensson I. Sohal B.H. Brunk U.T. Mech. Ageing Dev. 1989; 49: 129-135Google Scholar) and the rate of H2O2 production by mitochondria (4Sohal R.S. Svensson I. Brunk U.T. Mech. Ageing Dev. 1990; 53: 209-215Google Scholar) are inversely related to MLSP in different species. A complicating factor is the association of longer MLSP with lower metabolic rates within mammals or other groups, but this complication has been resolved by the observation that birds tend to have longer MLSP than mammals with the same metabolic rate. Thus pigeons (long MLSP) have a lower rate of mitochondrial H2O2 production than rats (shorter MLSP), even though these two species have similar standard metabolic rates (5Ku H.H. Sohal R.S. Mech. Ageing Dev. 1993; 72: 67-76Google Scholar, 6Barja G. Cadenas S. Rojas C. Perez-Campo R. Lopez-Torres M. Free Radic. Res. 1994; 21: 317-327Google Scholar, 7Herrero A. Barja G. Mech. Ageing Dev. 1997; 98: 95-111Google Scholar, 8Herrero A. Barja G. J. Bioenerg. Biomembr. 1997; 29: 241-249Google Scholar). Similarly, canaries and parakeets (budgerigars) (long MLSP) have lower rates of mitochondrial H2O2 production than mice (shorter MLSP), although all three species have similar standard metabolic rates (9Herrero A. Barja G. Mech. Ageing Dev. 1998; 103: 133-146Google Scholar). Despite numerous studies reporting that mitochondria release H2O2, there is some controversy as to whether mitochondria are an important source of ROS under physiological and pathological conditions (10Forman H.J. Azzi A. FASEB J. 1997; 11: 374-375Google Scholar). In agreement with these concerns, Staniek and Nohl (12Staniek K. Nohl H. Biochim. Biophys. Acta. 2000; 1460: 268-275Google Scholar) reported that mitochondria respiring on complex I and complex II substrates do not generate H2O2 except in the presence of the complex III inhibitor antimycin A. They proposed that unspecific interactions between the commonly used methods of H2O2detection and mitochondria cause artificial rates of H2O2 production (11Staniek K. Nohl H. Biochim. Biophys. Acta. 1999; 1413: 70-80Google Scholar, 12Staniek K. Nohl H. Biochim. Biophys. Acta. 2000; 1460: 268-275Google Scholar). Two principal sites of superoxide generation have been identified in mitochondria: complex I and complex III. The relative importance of these two sites seems to vary with experimental conditions and between tissues and species (13Barja G. J. Bioenerg. Biomembr. 1999; 31: 347-366Google Scholar). There is no clear consensus in the literature about which side of the mitochondrial inner membrane superoxide is generated by complex I and complex III. In the traditional view, complex III generates superoxide on the matrix side of the mitochondrial inner membrane (14Turrens J.F. Biosci. Rep. 1997; 17: 3-8Google Scholar). The semiquinone at centero of complex III of heart mitochondria was shown to be the main producer of superoxide based on inhibitor studies (15Turrens J.F. Alexandre A. Lehninger A.L. Arch. Biochem. Biophys. 1985; 237: 408-414Google Scholar). However, the x-ray structure of complex III reveals that center o is oriented toward the intermembrane space (16Iwata S. Lee J.W. Okada K. Lee J.K. Iwata M. Rasmussen B. Link T.A. Ramaswamy S. Jap B.K. Science. 1998; 281: 64-71Google Scholar, 17Zhang Z. Huang L. Shulmeister V.M. Chi Y.I. Kim K.K. Hung L.W. Crofts A.R. Berry E.A. Kim S.H. Nature. 1998; 392: 677-684Google Scholar), suggesting that superoxide production by complex III is directed toward the cytoplasm and not toward the matrix. In support of this view, a recent study has reported that antimycin A-supplemented mitoplasts (mitochondria devoid of portions of outer membrane and cytochrome c) can release superoxide (18Han D. Williams E. Cadenas E. Biochem. J. 2001; 353: 411-416Google Scholar). In complex I, either the iron-sulfur centers (7Herrero A. Barja G. Mech. Ageing Dev. 1997; 98: 95-111Google Scholar, 19Genova M.L. Ventura B. Giuliano G. Bovina C. Formiggini G. Parenti Castelli G. Lenaz G. FEBS Lett. 2001; 505: 364-368Google Scholar) or the active site flavin (20Liu Y. Fiskum G. Schubert D. J. Neurochem. 2002; 80: 780-787Google Scholar) are thought to be mainly responsible for superoxide production. There is no x-ray crystal structure of complex I, but all of these centers are likely to face the matrix side of the membrane. 30 years ago, it was shown that the oxidation of palmitoyl carnitine by mitochondria leads to the generation of H2O2(21Boveris A. Oshino N. Chance B. Biochem. J. 1972; : 617-630Google Scholar, 22Boveris A. Chance B. Biochem. J. 1973; 134: 707-716Google Scholar). These results received little attention and, to our knowledge, no study has examined how lipid metabolism could cause ROS generation in mammalian mitochondria. The oxidation of fatty acids involves the electron transfer flavoprotein (ETF) and the electron transfer flavoprotein quinone oxidoreductase (ETF-QOR) that could act as potential sources of ROS production. The role of lipid metabolism in the generation of ROS by mitochondria gained our attention recently when it was shown that the expression of mitochondrial uncoupling proteins (UCPs) correlates with the use of lipid as fuel substrates (23Samec S. Seydoux J. Dulloo A.G. Faseb J. 1998; 12: 715-724Google Scholar, 24Cadenas S. Buckingham J.A. S. Seydoux J. N. Dulloo A.G. FEBS Lett. 1999; Scholar) and that are by superoxide D. J. Cadenas S. J.A. J.A. A. S. Nature. 2002; Scholar). is that the elevated expression of on lipid metabolism is a of a to of ROS production the oxidation of fatty In light of the controversy the production of H2O2 by mitochondria and its to studies to the generation of ROS by mitochondria are The of the study to the production of ROS by intact mitochondria from different to the electron transport sites in ROS to the topology of ROS on which side of the inner membrane ROS are and to in the production of ROS by heart mitochondria from rat and species with similar standard metabolic rate but different MLSP. The superoxide and hydrogen peroxide from The substrates and palmitoyl inhibitors antimycin and and bovine serum from rats between and by muscle, heart, and liver mitochondria as Biochim. Biophys. Acta. 1994; Scholar), in standard and at and on Mitochondria of in rate in the presence of an was determined using the A.G. J. Scholar) with as The rate of mitochondrial production of H2O2 was determined by its with acid in the presence of G. in Scholar) using a and pigeon mitochondria at at and in standard The to the standard at the in of from at and acid and a was for mitochondrial an inhibitor of the was to of H2O2 was by and for complex in the presence of for complex II or palmitoyl carnitine in the presence of as a of palmitoyl carnitine generates amounts of which the electron transport chain at complex I, and which the and by amounts of H2O2 to in the presence of the acid and They in the absence and presence of mitochondria to whether mitochondrial with the to H2O2 Mitochondria the the of the standard in the presence of skeletal muscle, and heart mitochondria and of the of the mitochondria the of various that we to the rates of H2O2 production using skeletal muscle as an and in in the the concentration of these did not the results not of mitochondrial H2O2 production using the standard with mitochondria than using the standard the and There significant rates of in the absence of mitochondria using the standard SOD, at the rate of of cytochrome by in a with and at at in a significant to the the under all conditions and The rates of H2O2 production in by the rates measured in the absence of mitochondria mitochondria: from the rates measured in the presence of mitochondria with the results fully rates of H2O2 of H2O2 production in the presence of and and The in the absence and presence of mitochondria the of with the inhibitors of electron transport used to more the sites of ROS production G. in Scholar). complex I, at and antimycin A at centero and center of complex III which side of the mitochondrial inner membrane superoxide was we measured the rate of H2O2 production in the presence and absence of exogenous mitochondria produce on the cytoplasmic face of the inner membrane, of exogenous the rate of (and that by or and with other side to an elevated rate of H2O2 production. mitochondria generate on the matrix side of the inner membrane, of it be to the matrix H2O2 and there be no difference in the rates of H2O2 in the presence and absence of exogenous Complex I concentration was measured as by H. Scholar). using The H2O2 production rate of mitochondria from a with a substrate was compared between different experimental conditions using of and the a between rat and pigeon heart mitochondria using a The of The rate of H2O2 production by skeletal muscle or heart mitochondria with and was and was not by of A and However, the of to mitochondria respiring on and a significant rate of A This H2O2 production from the matrix side of the inner membrane the was to of exogenous A and These results that complex I in skeletal muscle and heart mitochondria can generate superoxide on the matrix side of the inner membrane when it is fully reduced and by but that the rate measured when the complex is not by is of by rat heart mitochondria. are as as palmitoyl carnitine as in is by different There was no rate of H2O2 production when skeletal muscle or heart mitochondria the presence of in the absence or presence of and There was little or no rate of H2O2 production in the presence of in the absence or presence of that complex II the can produce significant amounts of on either side of the membrane when are of antimycin A to a but measurable rate of H2O2 production that was significantly by of exogenous and These results that center o of complex III can generate on the cytoplasmic face of the inner membrane of skeletal muscle or heart mitochondria when it is reduced of the complex at center by antimycin A but that the rate measured when the complex is not by antimycin A is There was some H2O2 production in the presence of antimycin A even exogenous SOD, which that center o can produce on the matrix side of the inner membrane. However, even mitochondria produce on the cytoplasmic face of the membrane, there be a rate of H2O2 production exogenous of or and the of In other a rate of H2O2 production has a and a we can that the from the cytoplasmic face of the membrane but we be whether the the rate of from the cytoplasmic face of the membrane or H2O2 from the matrix side of the membrane. muscle or heart mitochondria respiring on palmitoyl carnitine a significant rate of H2O2 production that was not significantly by of This that oxidation of palmitoyl carnitine oxidation of and or leads to significant ROS production and that this ROS is produced on the matrix side of the inner membrane. The of to a in the rate of H2O2 production that did not and was The rates of H2O2 production in the presence of palmitoyl carnitine and similar to in the presence of and A and suggesting that complex I was the source of this ROS with either substrate when complex I was fully reduced in the presence of In the absence of rotenone, perhaps complex I is more reduced with palmitoyl carnitine as substrate to electron transport and with for than it is with and to ROS production from complex I with palmitoyl carnitine. In the presence of palmitoyl the of to an in the rate of H2O2 production that did not in skeletal muscle mitochondria and was these conditions complex I, complex and the all be H2O2 production with palmitoyl carnitine was not than with palmitoyl carnitine this was it be that and can produce some on the matrix side of the membrane. Complex II and the not be the source of such there was no in the presence of and and of antimycin A to skeletal muscle or heart mitochondria with palmitoyl carnitine the rate of H2O2 production This rate was by of skeletal muscle that of it was due to production of on the cytoplasmic face of the inner membrane. these conditions complex I, complex the and center o of complex III all be In the presence of SOD, H2O2 production with palmitoyl carnitine antimycin A to be than the of the from complex I, complex the and center o of complex III. The for this is In the rates of of liver mitochondria lower than of skeletal muscle and heart with or with palmitoyl carnitine as substrate mitochondria respiring on and produced than mitochondrial in the absence or presence of The of did not H2O2 but to the rate of H2O2 production in the presence of These results to that complex I from liver mitochondria generates ROS on the cytoplasmic face of the inner membrane as as on the matrix but of the we to be mitochondria respiring on did not generate H2O2 except perhaps for a in the presence of and antimycin A or mitochondria respiring on palmitoyl carnitine did not produce H2O2 except perhaps for a in the presence of rotenone, antimycin or However, the rates of H2O2 production it to In a of rat pigeon heart mitochondria generated measurable amounts of H2O2 when with and The of the rate of H2O2 production in species In the presence of rotenone, the H2O2 production rate of mitochondrial was with rat mitochondria than pigeon mitochondria The of complex I in the two of mitochondria was measured to whether the of rat heart mitochondria to produce ROS in the presence of was by a concentration of complex I. Complex I was significantly in rat mitochondria than in pigeon mitochondria. that the different for ROS production between rat and pigeon heart mitochondria when H2O2 production rate was of complex I. Mitochondria from rat skeletal muscle, heart, and liver respiring on substrates to complex I or complex II in the absence of other inhibitors generated little or no measurable H2O2 and The absence of significant generation of H2O2 from mitochondria respiring on complex I and complex II substrates results from Staniek and Nohl (12Staniek K. Nohl H. Biochim. Biophys. Acta. 2000; 1460: 268-275Google Scholar) a of H2O2 production from rat heart mitochondria respiring on and J. Bioenerg. Biomembr. 1997; 29: Scholar) and (20Liu Y. Fiskum G. Schubert D. J. Neurochem. 2002; 80: 780-787Google Scholar) reported rates of H2O2 production from rat heart, or liver mitochondria with or as substrates. In the absence of rotenone, considerable ROS production from complex I by electron transport Y. Fiskum G. Schubert D. J. Neurochem. 2002; 80: 780-787Google this was not in the However, other studies have reported significant rates of H2O2 production in mitochondria in G. J. Bioenerg. Biomembr. 1999; 31: 347-366Google Scholar). of these studies used in the G. Cadenas S. Rojas C. Perez-Campo R. Lopez-Torres M. Free Radic. Res. 1994; 21: 317-327Google Scholar, 7Herrero A. Barja G. Mech. Ageing Dev. 1997; 98: 95-111Google Scholar, 8Herrero A. Barja G. J. Bioenerg. Biomembr. 1997; 29: 241-249Google Scholar, G. A. J. Bioenerg. Biomembr. 1998; Scholar). We considerable rates of H2O2 generation in the presence of we did not for some of the in production of H2O2 by mitochondria respiring on complex I and II substrates between various studies be due to the presence or absence of inhibitors of electron transport or to as by and Azzi (10Forman H.J. Azzi A. FASEB J. 1997; 11: 374-375Google Scholar) and Staniek and Nohl (12Staniek K. Nohl H. Biochim. Biophys. Acta. 2000; 1460: 268-275Google Scholar). In rat skeletal muscle and heart mitochondria produced H2O2 at measurable rates when respiring on palmitoyl carnitine with no inhibitors and This H2O2 was produced on the matrix side of the membrane, it was not significantly by of exogenous The H2O2 production with palmitoyl carnitine than with complex I substrates could be complex I is more reduced with palmitoyl due to electron transport and with for of complex I to matrix ROS production with palmitoyl carnitine as it could be that and can produce on the matrix side of the membrane when palmitoyl carnitine is from in the mitochondrial matrix of the is reduced to the semiquinone and more to the fully reduced suggesting that is the electron to M. Biochem. J. Scholar). can be fully reduced by three but it two when is the electron 1985; Scholar). was proposed that the of between the and semiquinone M. Biochem. J. Scholar). These that and could act as of superoxide to presence in reduced states lipid on the production of H2O2 by mitochondria that rat liver and pigeon heart mitochondria release H2O2 when respiring on palmitoyl carnitine A. Oshino N. Chance B. Biochem. J. 1972; : 617-630Google Scholar, 22Boveris A. Chance B. Biochem. J. 1973; 134: 707-716Google Scholar). These results gained little attention rates of H2O2 production. However, the lower rates of H2O2 production with palmitoyl carnitine in these the absence of carnitine and the use of of palmitoyl carnitine. is to that production of ROS by mitochondria lipid metabolism to an in the expression and of to the of ROS on mitochondria. In and expression is when fatty acids are (23Samec S. Seydoux J. Dulloo A.G. Faseb J. 1998; 12: 715-724Google Scholar, 24Cadenas S. Buckingham J.A. S. Seydoux J. N. Dulloo A.G. FEBS Lett. 1999; Scholar). acids and superoxide uncoupling by UCPs, and it was recently that the role of and be for ROS D. J. Cadenas S. J.A. J.A. A. S. Nature. 2002; Scholar). is commonly that of electron flow mitochondrial rise to H2O2 B. H. A. Scholar). J. Bioenerg. Biomembr. 1997; 29: Scholar) reported of free radical in the of for heart mitochondria respiring on physiological of than we our results with palmitoyl carnitine of of mitochondrial for skeletal muscle mitochondria of electron flow rise to conditions with a rate of of of mitochondrial This estimate of free radical be lower at physiological of the rate of H2O2 production by mitochondria with oxygen A. Chance B. Biochem. J. 1973; 134: 707-716Google Scholar). be even lower in more conditions of palmitoyl carnitine and lower mitochondrial membrane potential due to our upper estimate of free radical is to two of magnitude lower than the cited values. The results in this that rat heart and skeletal muscle mitochondria rates of H2O2 production than liver mitochondria either in the absence or presence of inhibitors, with the idea that tissues generate more ROS accumulation of damage S. Biochem. 1997; Scholar). A for these results is that liver mitochondria have a reduced of mitochondrial electron transport chain compared with heart and skeletal muscle Sohal R.S. Arch. Biochem. Biophys. 2000; Scholar). rat liver mitochondria have complex I and complex III than heart or skeletal muscle mitochondria Sohal R.S. Arch. Biochem. Biophys. 2000; Scholar). the potential sites of mitochondrial ROS production and the topology of ROS production from we used inhibitors of complex I and III of the electron transport chain. The inhibitors different complexes and cause to generate ROS to the of mitochondria. This to which complex has the to generate The presence and absence of the of the topology of ROS production. We that center o of complex III antimycin can generate more ROS than complex I and o of complex III generates superoxide in and on the cytoplasmic face of the mitochondrial inner membrane, whereas complex I ROS solely on the matrix side. using mitoplasts that complex III can release superoxide on the cytoplasmic face of the inner membrane (18Han D. Williams E. Cadenas E. Biochem. J. 2001; 353: 411-416Google Scholar). studies using intact mitochondria have reported in in the presence of antimycin A and (12Staniek K. Nohl H. Biochim. Biophys. Acta. 2000; 1460: 268-275Google Scholar, G. J. Bioenerg. Biomembr. 1999; 31: 347-366Google Scholar, 22Boveris A. Chance B. Biochem. J. 1973; 134: 707-716Google Scholar, J. Bioenerg. Biomembr. 1997; 29: Sohal R.S. Arch. Biochem. Biophys. 1998; Scholar). However, of these studies examined the topology of ROS production. Mitochondria respiring on complex I substrates H2O2 production in the presence of (13Barja G. J. Bioenerg. Biomembr. 1999; 31: 347-366Google Scholar, J. Bioenerg. Biomembr. 1997; 29: Scholar). the rates in the presence of in these studies are similar or than in the presence of it is that the ROS generated in the presence of from complex I. the in the rate of by mitochondria with palmitoyl carnitine and leads to that and produce ROS on the matrix side of the inner membrane and a physiological our results H2O2 production by mitochondria respiring on complex I and II substrates in the absence of inhibitors to support for the that there is an relationship between MLSP and H2O2 production by mitochondria from various species (4Sohal R.S. Svensson I. Brunk U.T. Mech. Ageing Dev. 1990; 53: 209-215Google Scholar) or that pigeon mitochondria respiring on complex I or II substrates generate H2O2 than rat mitochondria (5Ku H.H. Sohal R.S. Mech. Ageing Dev. 1993; 72: 67-76Google Scholar, 6Barja G. Cadenas S. Rojas C. Perez-Campo R. Lopez-Torres M. Free Radic. Res. 1994; 21: 317-327Google Scholar, 7Herrero A. Barja G. Mech. Ageing Dev. 1997; 98: 95-111Google Scholar, 8Herrero A. Barja G. J. Bioenerg. Biomembr. 1997; 29: 241-249Google Scholar, G. A. J. Bioenerg. Biomembr. 1998; Scholar). we that heart mitochondria from pigeons and rats respiring on did not generate measurable amounts of In the presence of rotenone, rat mitochondria produced more H2O2 of mitochondrial than did pigeon mitochondria that the of rat mitochondria to generate ROS is This was by a of complex I in rat heart mitochondria The rates of ROS production of complex I not in rat suggesting that complex I from pigeon heart mitochondria not have a for ROS production. These that the maximum of pigeon heart mitochondria to generate ROS from complex I is than in but to support for the theory that the elevated MLSP of pigeons compared with rats is due to lower mitochondrial production of be to mitochondrial H2O2 production between of different MLSP using palmitoyl carnitine. our results not be as that mitochondria produce no ROS under physiological the substrates be from or chain fatty from lipid Our results that complexes I and III of mitochondria do produce ROS oxidation of the these ROS are by and little or no H2O2 the the other fatty acid to release of ROS, from complex I on the matrix side of the inner membrane, which can to H2O2 the However, it is important to that the complex I, complex and perhaps and do have the to generate A of to oxygen that the metabolism be to cause accumulation of resulting in We and for of complex I and for

BACKGROUND: This initiative aims to build a global consensus around core diagnostic criteria for malnutrition in adults in clinical settings. METHODS: The Global Leadership Initiative on Malnutrition (GLIM) was convened by several of the major global clinical nutrition societies. Empirical consensus was reached through a series of face-to-face meetings, telephone conferences, and e-mail communications. RESULTS: A 2-step approach for the malnutrition diagnosis was selected, that is, first screening to identify at risk status by the use of any validated screening tool, and second, assessment for diagnosis and grading the severity of malnutrition. The malnutrition criteria for consideration were retrieved from existing approaches for screening and assessment. Potential criteria were subjected to a ballot among GLIM participants that selected 3 phenotypic criteria (non-volitional weight loss, low body mass index, and reduced muscle mass) and 2 etiologic criteria (reduced food intake or assimilation, and inflammation or disease burden). To diagnose malnutrition at least 1 phenotypic criterion and 1 etiologic criterion should be present. Phenotypic metrics for grading severity are proposed. It is recommended that the etiologic criteria be used to guide intervention and anticipated outcomes. The recommended approach supports classification of malnutrition into four etiology-related diagnosis categories. CONCLUSIONS: A consensus scheme for diagnosing malnutrition in adults in clinical settings on a global scale is proposed. Next steps are to secure endorsements from leading nutrition professional societies, to identify overlaps with syndromes like cachexia and sarcopenia, and to promote dissemination, validation studies, and feedback. The construct should be re-considered every 3-5 years.

The protein content in foodstuffs is estimated by multiplying the determined nitrogen content by a nitrogen-to-protein conversion factor. Jones' factors for a series of foodstuffs, including 6.25 as the standard, default conversion factor, have now been used for 75 years. This review provides a brief history of these factors and their underlying paradigm, with an insight into what is meant by "protein." We also review other compelling data on specific conversion factors which may have been overlooked. On the one hand, when 6.25 is used irrespective of the foodstuff, "protein" is simply nitrogen expressed using a different unit and says little about protein (s.s.). On the other hand, conversion factors specific to foodstuffs, such as those provided by Jones, are scientifically flawed. However, the nitrogen:protein ratio does vary according to the foodstuff considered. Therefore, from a scientific point of view, it would be reasonable not to apply current specific factors any longer, but they have continued to be used because scientists fear opening the Pandora's box. But because conversion factors are critical to enabling the simple conversion of determined nitrogen values into protein values and thus accurately evaluating the quantity and the quality of protein in foodstuffs, we propose a set of specific conversion factors for different foodstuffs, together with a default conversion factor (5.6). This would be far more accurate and scientifically sound, and preferable when specifically expressing nitrogen as protein. These factors are of particular importance when "protein" basically means "amino acids," this being the principal nutritional viewpoint.

Adenosine triphosphate (ATP) synthase contains a rotary motor involved in biological energy conversion. Its membrane-embedded F0 sector has a rotation generator fueled by the proton-motive force, which provides the energy required for the synthesis of ATP by the F1 domain. An electron density map obtained from crystals of a subcomplex of yeast mitochondrial ATP synthase shows a ring of 10 c subunits. Each c subunit forms an alpha-helical hairpin. The interhelical loops of six to seven of the c subunits are in close contact with the gamma and delta subunits of the central stalk. The extensive contact between the c ring and the stalk suggests that they may rotate as an ensemble during catalysis.

The prevalence of clinical obesity in Britain has doubled in the past decade. The Health of the Nation initiative has set ambitious targets for reversing the trend in recognition of the serious health burden which will accrue, but efforts to develop prevention and treatment strategies are handicapped by uncertainty as to the aetiology of the problem. It is generally assumed that ready access to highly palatable foods induces excess consumption and that obesity is caused by simple gluttony. There is evidence that a high fat diet does override normal satiety mechanisms. However, average recorded energy intake in Britain has declined substantially as obesity rates have escalated. The implication is that levels of physical activity, and hence energy needs, have declined even faster. Evidence suggests that modern inactive lifestyles are at least as important as diet in the aetiology of obesity and possibly represent the dominant factor.

The frequency of micronuclei (MN) in peripheral blood lymphocytes (PBL) is extensively used as a biomarker of chromosomal damage and genome stability in human populations. Much theoretical evidence has been accumulated supporting the causal role of MN induction in cancer development, although prospective cohort studies are needed to validate MN as a cancer risk biomarker. A total of 6718 subjects from of 10 countries, screened in 20 laboratories for MN frequency between 1980 and 2002 in ad hoc studies or routine cytogenetic surveillance, were selected from the database of the HUman MicroNucleus (HUMN) international collaborative project and followed up for cancer incidence or mortality. To standardize for the inter-laboratory variability subjects were classified according to the percentiles of MN distribution within each laboratory as low, medium or high frequency. A significant increase of all cancers incidence was found for subjects in the groups with medium (RR=1.84; 95% CI: 1.28-2.66) and high MN frequency (RR=1.53; 1.04-2.25). The same groups also showed a decreased cancer-free survival, i.e. P=0.001 and P=0.025, respectively. This association was present in all national cohorts and for all major cancer sites, especially urogenital (RR=2.80; 1.17-6.73) and gastro-intestinal cancers (RR=1.74; 1.01-4.71). The results from the present study provide preliminary evidence that MN frequency in PBL is a predictive biomarker of cancer risk within a population of healthy subjects. The current wide-spread use of the MN assay provides a valuable opportunity to apply this assay in the planning and validation of cancer surveillance and prevention programs.

OBJECTIVE: Ageing is accompanied by deterioration of multiple bodily functions and inflammation, which collectively contribute to frailty. We and others have shown that frailty co-varies with alterations in the gut microbiota in a manner accelerated by consumption of a restricted diversity diet. The Mediterranean diet (MedDiet) is associated with health. In the NU-AGE project, we investigated if a 1-year MedDiet intervention could alter the gut microbiota and reduce frailty. DESIGN: We profiled the gut microbiota in 612 non-frail or pre-frail subjects across five European countries (UK, France, Netherlands, Italy and Poland) before and after the administration of a 12-month long MedDiet intervention tailored to elderly subjects (NU-AGE diet). RESULTS: Adherence to the diet was associated with specific microbiome alterations. Taxa enriched by adherence to the diet were positively associated with several markers of lower frailty and improved cognitive function, and negatively associated with inflammatory markers including C-reactive protein and interleukin-17. Analysis of the inferred microbial metabolite profiles indicated that the diet-modulated microbiome change was associated with an increase in short/branch chained fatty acid production and lower production of secondary bile acids, p-cresols, ethanol and carbon dioxide. Microbiome ecosystem network analysis showed that the bacterial taxa that responded positively to the MedDiet intervention occupy keystone interaction positions, whereas frailty-associated taxa are peripheral in the networks. CONCLUSION: Collectively, our findings support the feasibility of improving the habitual diet to modulate the gut microbiota which in turn has the potential to promote healthier ageing.

BACKGROUND: Sports nutrition is a constantly evolving field with hundreds of research papers published annually. In the year 2017 alone, 2082 articles were published under the key words 'sport nutrition'. Consequently, staying current with the relevant literature is often difficult. METHODS: This paper is an ongoing update of the sports nutrition review article originally published as the lead paper to launch the Journal of the International Society of Sports Nutrition in 2004 and updated in 2010. It presents a well-referenced overview of the current state of the science related to optimization of training and performance enhancement through exercise training and nutrition. Notably, due to the accelerated pace and size at which the literature base in this research area grows, the topics discussed will focus on muscle hypertrophy and performance enhancement. As such, this paper provides an overview of: 1.) How ergogenic aids and dietary supplements are defined in terms of governmental regulation and oversight; 2.) How dietary supplements are legally regulated in the United States; 3.) How to evaluate the scientific merit of nutritional supplements; 4.) General nutritional strategies to optimize performance and enhance recovery; and, 5.) An overview of our current understanding of nutritional approaches to augment skeletal muscle hypertrophy and the potential ergogenic value of various dietary and supplemental approaches. CONCLUSIONS: This updated review is to provide ISSN members and individuals interested in sports nutrition with information that can be implemented in educational, research or practical settings and serve as a foundational basis for determining the efficacy and safety of many common sport nutrition products and their ingredients.

Polyphenols are a major class of bioactive phytochemicals whose consumption may play a role in the prevention of a number of chronic diseases such as cardiovascular diseases, type II diabetes and cancers. Phenol-Explorer, launched in 2009, is the only freely available web-based database on the content of polyphenols in food and their in vivo metabolism and pharmacokinetics. Here we report the third release of the database (Phenol-Explorer 3.0), which adds data on the effects of food processing on polyphenol contents in foods. Data on >100 foods, covering 161 polyphenols or groups of polyphenols before and after processing, were collected from 129 peer-reviewed publications and entered into new tables linked to the existing relational design. The effect of processing on polyphenol content is expressed in the form of retention factor coefficients, or the proportion of a given polyphenol retained after processing, adjusted for change in water content. The result is the first database on the effects of food processing on polyphenol content and, following the model initially defined for Phenol-Explorer, all data may be traced back to original sources. The new update will allow polyphenol scientists to more accurately estimate polyphenol exposure from dietary surveys.

INTRODUCTION: Loss of skeletal muscle mass and function (sarcopenia) is common in individuals with obesity due to metabolic changes associated with a sedentary lifestyle, adipose tissue derangements, comorbidities (acute and chronic diseases) and during the ageing process. Co-existence of excess adiposity and low muscle mass/function is referred to as sarcopenic obesity (SO), a condition increasingly recognized for its clinical and functional features that negatively influence important patient-centred outcomes. Effective prevention and treatment strategies for SO are urgently needed, but efforts are hampered by the lack of a universally established SO definition and diagnostic criteria. Resulting inconsistencies in the literature also negatively affect the ability to define prevalence as well as clinical relevance of SO for negative health outcomes. AIMS AND METHODS: The European Society for Clinical Nutrition and Metabolism (ESPEN) and the European Association for the Study of Obesity (EASO) launched an initiative to reach expert consensus on a definition and diagnostic criteria for SO. The jointly appointed international expert panel proposes that SO is defined as the co-existence of excess adiposity and low muscle mass/function. The diagnosis of SO should be considered in at-risk individuals who screen positive for a co-occurring elevated body mass index or waist circumference, and markers of low skeletal muscle mass and function (risk factors, clinical symptoms, or validated questionnaires). Diagnostic procedures should initially include assessment of skeletal muscle function, followed by assessment of body composition where presence of excess adiposity and low skeletal muscle mass or related body compartments confirm the diagnosis of SO. Individuals with SO should be further stratified into stage I in the absence of clinical complications or stage II if cases are associated with complications linked to altered body composition or skeletal muscle dysfunction. CONCLUSIONS: ESPEN and EASO, as well as the expert international panel, advocate that the proposed SO definition and diagnostic criteria be implemented into routine clinical practice. The panel also encourages prospective studies in addition to secondary analysis of existing data sets, to study the predictive value, treatment efficacy and clinical impact of this SO definition.

Ascorbic acid is an essential nutrient commonly regarded as an antioxidant. In this study, we showed that ascorbate at pharmacologic concentrations was a prooxidant, generating hydrogen-peroxide-dependent cytotoxicity toward a variety of cancer cells in vitro without adversely affecting normal cells. To test this action in vivo, normal oral tight control was bypassed by parenteral ascorbate administration. Real-time microdialysis sampling in mice bearing glioblastoma xenografts showed that a single pharmacologic dose of ascorbate produced sustained ascorbate radical and hydrogen peroxide formation selectively within interstitial fluids of tumors but not in blood. Moreover, a regimen of daily pharmacologic ascorbate treatment significantly decreased growth rates of ovarian (P < 0.005), pancreatic (P < 0.05), and glioblastoma (P < 0.001) tumors established in mice. Similar pharmacologic concentrations were readily achieved in humans given ascorbate intravenously. These data suggest that ascorbate as a prodrug may have benefits in cancers with poor prognosis and limited therapeutic options.

BACKGROUND: Studies of weight-control diets that are high in protein or low in glycemic index have reached varied conclusions, probably owing to the fact that the studies had insufficient power. METHODS: We enrolled overweight adults from eight European countries who had lost at least 8% of their initial body weight with a 3.3-MJ (800-kcal) low-calorie diet. Participants were randomly assigned, in a two-by-two factorial design, to one of five ad libitum diets to prevent weight regain over a 26-week period: a low-protein and low-glycemic-index diet, a low-protein and high-glycemic-index diet, a high-protein and low-glycemic-index diet, a high-protein and high-glycemic-index diet, or a control diet. RESULTS: A total of 1209 adults were screened (mean age, 41 years; body-mass index [the weight in kilograms divided by the square of the height in meters], 34), of whom 938 entered the low-calorie-diet phase of the study. A total of 773 participants who completed that phase were randomly assigned to one of the five maintenance diets; 548 completed the intervention (71%). Fewer participants in the high-protein and the low-glycemic-index groups than in the low-protein-high-glycemic-index group dropped out of the study (26.4% and 25.6%, respectively, vs. 37.4%; P=0.02 and P=0.01 for the respective comparisons). The mean initial weight loss with the low-calorie diet was 11.0 kg. In the analysis of participants who completed the study, only the low-protein-high-glycemic-index diet was associated with subsequent significant weight regain (1.67 kg; 95% confidence interval [CI], 0.48 to 2.87). In an intention-to-treat analysis, the weight regain was 0.93 kg less (95% CI, 0.31 to 1.55) in the groups assigned to a high-protein diet than in those assigned to a low-protein diet (P=0.003) and 0.95 kg less (95% CI, 0.33 to 1.57) in the groups assigned to a low-glycemic-index diet than in those assigned to a high-glycemic-index diet (P=0.003). The analysis involving participants who completed the intervention produced similar results. The groups did not differ significantly with respect to diet-related adverse events. CONCLUSIONS: In this large European study, a modest increase in protein content and a modest reduction in the glycemic index led to an improvement in study completion and maintenance of weight loss. (Funded by the European Commission; ClinicalTrials.gov number, NCT00390637.).