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Angebault 2015 Am J Hum Genet + (Autosomal-recessive optic neuropathies are … Autosomal-recessive optic neuropathies are rare blinding conditions related to retinal ganglion cell (RGC) and optic-nerve degeneration, for which only mutations in ''TMEM126A'' and ''ACO2'' are known. In four families with early-onset recessive optic neuropathy, we identified mutations in ''RTN4IP1'', which encodes a mitochondrial ubiquinol oxydo-reductase. ''RTN4IP1'' is a partner of ''RTN4'' (also known as NOGO), and its ortholog Rad8 in ''C. elegans'' is involved in UV light response. Analysis of fibroblasts from affected individuals with a ''RTN4IP1'' mutation showed loss of the altered protein, a deficit of mitochondrial respiratory complex I and IV activities, and increased susceptibility to UV light. Silencing of RTN4IP1 altered the number and morphogenesis of mouse RGC dendrites ''in vitro'' and the eye size, neuro-retinal development, and swimming behavior in zebrafish ''in vivo''. Altogether, these data point to a pathophysiological mechanism responsible for RGC early degeneration and optic neuropathy and linking ''RTN4IP1'' functions to mitochondrial physiology, response to UV light, and dendrite growth during eye maturation.and dendrite growth during eye maturation.)
D'Souza 2018 J Lipid Res + (Autotaxin (ATX) is an adipokine that gener … Autotaxin (ATX) is an adipokine that generates the bioactive lipid, lysophosphatidic acid (LPA). ATX-LPA signaling has been implicated in diet-induced obesity and systemic insulin resistance. However, it remains unclear whether the ATX-LPA pathway influences insulin function and energy metabolism in target tissues, particularly skeletal muscle, the major site of insulin-stimulated glucose disposal. The objective of this study was to test whether the ATX-LPA pathway impacts tissue insulin signaling and mitochondrial metabolism in skeletal muscle during obesity. Male mice with heterozygous ATX deficiency (ATX+/-) were protected from obesity, systemic insulin resistance, and cardiomyocyte dysfunction following high-fat high-sucrose (HFHS) feeding. HFHS-fed ATX+/- mice also had improved insulin-stimulated AKT phosphorylation in white adipose tissue, liver, heart, and skeletal muscle. Preserved insulin-stimulated glucose transport in muscle from HFHS-fed ATX+/- mice was associated with improved mitochondrial pyruvate oxidation in the absence of changes in fat oxidation and ectopic lipid accumulation. Similarly, incubation with LPA decreased insulin-stimulated AKT phosphorylation and mitochondrial energy metabolism in C2C12 myotubes at baseline and following palmitate-induced insulin resistance. Taken together, our results suggest that the ATX-LPA pathway contributes to obesity-induced insulin resistance in metabolically relevant tissues. Our data also suggest that LPA directly impairs skeletal muscle insulin signaling and mitochondrial function.directly impairs skeletal muscle insulin signaling and mitochondrial function.)
Albertini 2012 Aging (Albany NY) + (Availability of methionine is known to mod … Availability of methionine is known to modulate the rate of aging in model organisms, best illustrated by the observation that dietary methionine restriction extends the lifespan of rodents. However, the underlying mechanisms are incompletely understood. In eukaryotic cells, methionine can be converted to cysteine through the reverse transsulfuration pathway thereby modulating intracellular methionine availability. Whereas previous results obtained in yeast and fruit flies suggest that alterations in the reverse transsulfuration pathway modulate the rate of aging, it is not known whether this function is conserved in evolution. Here we show that depletion of cystathionine beta synthase (CBS), a rate limiting enzyme in the reverse transsulfuration pathway, induces premature senescence in human endothelial cells. We found that CBS depletion induces mild mitochondrial dysfunction and increases the sensitivity of endothelial cells to homocysteine, a known inducer of endothelial cell senescence and an established risk factor for vascular disease. Our finding that CBS deficiency induces endothelial cell senescence ''in vitro'', involving both mitochondrial dysfunction and increased susceptibility of the cells to homocysteine, suggests a new mechanism linking CBS deficiency to vascular aging and disease. deficiency to vascular aging and disease.)
Ravera 2018 Biol Cell + (BACKGROUND INFORMATION: Energy demand in h … BACKGROUND INFORMATION: Energy demand in human platelets is very high, to carry out their functions. As for most human cells, the aerobic metabolism represents the primary energy source in platelets, even though mitochondria are negligibly represented. Following the hypothesis that other structures could be involved in chemical energy production, in this work, we have investigated the functional expression of an extramitochondrial aerobic metabolism in platelets.RESULTS: Oximetric and luminometric analyses showed that platelets consume large amounts of oxygen and produce ATP in the presence of common respiring substrates, such as pyruvate + malate or succinate, although morphological electron microscopy analysis showed that these contain few mitochondria. However, evaluation of the anaerobic glycolytic metabolism showed that only 13% of consumed glucose was converted to lactate. Interestingly, the highest OXPHOS activity was observed in the presence of NADH, not a readily permeant respiring substrate for mitochondria. Also, oxygen consumption and ATP synthesis fuelled by NADH were not affected by atractyloside, an inhibitor of the adenine nucleotide translocase, suggesting that these processes may not be ascribed to mitochondria. Functional data were confirmed by immunofluorescence microscopy and Western blot analyses, showing a consistent expression of the β subunit of F1 Fo -ATP synthase and COXII, a subunit of Complex IV, but a low signal of translocase of the inner mitochondrial membrane (a protein not involved in OXPHOS metabolism). Interestingly, the NADH-stimulated oxygen consumption and ATP synthesis increased in the presence of the physiological platelets agonists, thrombin or collagen.CONCLUSIONS: Data suggest that in platelets, aerobic energy production is mainly driven by an extramitochondrial OXPHOS machinery, originated inside the megakaryocyte, and that this metabolism plays a pivotal role in platelet activation.SIGNIFICANCE: This work represents a further example of the existence of an extramitochondrial aerobic metabolism, which can contribute to the cellular energy balance.contribute to the cellular energy balance.)
Regueira 2009 Liver Int + (BACKGROUND/AIMS: Genes encoding for some o … BACKGROUND/AIMS:Genes encoding for some of the mitochondrial proteins are under the control of the transcriptional factor hypoxia inducible factor-1 alpha (HIF-1 alpha), which can accumulate under normoxic conditions in inflammatory states. The aim of this study was to evaluate the effects of cobalt chloride (CoCl2, a hypoxia mimicking agent), tumour necrosis factor-alpha (TNF-alpha) and toll-like receptor (TLR) -2, -3 and -4 agonists on HIF-1 alpha accumulation, and further on HIF-1 alpha-mediated modulation of mitochondrial respiration in cultured human hepatocytes.METHODS:The human hepatoma cell line HepG2 was used in this study. Cells were treated with CoCl2, TNF-alpha and TLR-2, -3 and -4 agonists. HIF-1 alpha was determined by Western blotting and mitochondrial respiration in stimulated cells by high-resolution respirometry.RESULTS:CoCl2, TNF-alpha and TLR agonists induced the expression of HIF-1 alpha in a time-dependent fashion. TNF-alpha and CoCl2, but not TLR agonists, induced a reduction in complex I-, II- and IV-dependent mitochondrial oxygen consumption. TNF-alpha-associated reduction of cellular oxygen consumption was abolished through inhibition of HIF-1 alpha activity by chetomin (CTM). Pretreatment with cyclosporine A prevented CoCl2-induced reduction of complex I- and II-dependent mitochondrial oxygen consumption and TNF-alpha-induced reduction of complex-I-dependent respiration, implicating the involvement of the mitochondrial permeability transition pore openings. TNF-alpha and TLR-2, -3 and -4 agonists induced the expression of vascular endothelial growth factor, which was partially abolished by the blockage of HIF-1 alpha with CTM.CONCLUSIONS:The data suggest that HIF-1 alpha modulates mitochondrial respiration during CoCl2 and TNF-alpha stimulation, whereas it has no effect when induced with TLR-2, -3 and -4 agonists.>2 and TNF-alpha stimulation, whereas it has no effect when induced with TLR-2, -3 and -4 agonists.)
Escribano-Lopez 2019 Cell Physiol Biochem + (BACKGROUND/AIMS: Mitochondria-targeted ant … BACKGROUND/AIMS:Mitochondria-targeted antioxidants such as mitoquinone (MitoQ) have demonstrated protective effects against oxidative damage in several diseases. The increase in reactive oxygen species (ROS) production during glucose metabolism in β cells can be exacerbated under hyperglycaemic conditions such as type 2 diabetes (T2D), thus contributing to β cell function impairment. In the present work, we aimed to evaluate the effect of MitoQ on insulin secretion, oxidative stress, endoplasmic reticulum (ER) stress and nuclear factor kappa B (NFκB) signalling in a pancreatic β cell line under normoglycaemic (NG, 11.1 mM glucose), hyperglycaemic (HG, 25 mM glucose) and lipidic (palmitic acid (PA), 0.5mM) conditions.METHODS:We incubated the pancreatic β cell line INS-1E with or without MitoQ (0.5µM) under NG, HG and PA conditions. We then assessed the following parameters: glucose-induced insulin secretion, O₂ consumption (with a Clark-type electrode); mitochondrial function, oxidative stress parameters and calcium levels (by fluorescence microscopy); ER stress markers and NFκB-p65 protein levels (by western blotting).RESULTS:MitoQ increased insulin secretion and prevented the enhancement of ROS production and O₂ consumption and decrease in GSH levels that are characteristic under HG conditions. MitoQ also reduced protein levels of ER stress markers (GRP78 and P-eIF2α) and the proinflammatory nuclear transcription factor NFκB-p65, both of which increased under HG. MitoQ did not significantly alter ER stress markers under lipidic conditions.CONCLUSION:Our findings suggest that treatment with MitoQ modulates mitochondrial function, which in turn ameliorates endoplasmic reticulum stress and NFκB activation, thereby representing potential benefits for pancreatic β cell function.l benefits for pancreatic β cell function.)
Johnson 2016 Transfusion + (BACKGROUND: Alternatives to room temperat … BACKGROUND:Alternatives to room temperature storage of platelets (PLTs) may be beneficial to extend the limited shelf life and support transfusion logistics in rural and military areas. The aim of this study was to assess the morphologic, metabolic, and functional aspects of PLTs stored at room temperature or in refrigerated conditions or cryopreserved.STUDY DESIGN AND METHODS:A three-arm pool-and-split study was carried out using buffy coat-derived PLTs stored in 30% plasma/70% SSP+. The three matched treatment arms were room temperature stored (20-24°C), cold-stored (2-6°C), and cryopreserved (-80°C with dimethyl sulfoxide). Liquid-stored PLTs were tested over a 21-day period, while cryopreserved PLTs were examined immediately after thawing and after 6 and 24 hours of storage at room temperature.RESULTS:Cold-stored and cryopreserved PLTs underwent a significant shape change, although the cryopreserved PLTs appeared to recover from this during subsequent storage. Glycolytic metabolism was reduced in cold-stored PLTs, but accelerated in cryopreserved PLTs, while oxidative phosphorylation was negatively affected by both storage conditions. PLT aggregation was potentiated by cold storage and diminished by cryopreservation in comparison to room temperature-stored PLTs. Cold storage and cryopreservation resulted in faster clot formation (R-time; thromboelastography), which was associated with an increase in microparticles.CONCLUSION:Cold storage and cryopreservation of PLTs led to morphologic and metabolic changes. However, storage under these conditions appears to maintain or even enhance certain aspects of in vitro PLT function. certain aspects of in vitro PLT function.)
Johnson 2014 Transfusion + (BACKGROUND: Cryopreservation of platelets … BACKGROUND:Cryopreservation of platelets (PLTs) at -80°C with dimethyl sulfoxide (DMSO) can extend the shelf life from 5 days to 2 years. Cryopreserved PLTs are reported to have a greater in vivo hemostatic effect than liquid-stored PLTs. As such, the aim of this study was to understand the mechanisms responsible for the hemostatic potential of cryopreserved PLTs and the contribution of the reconstitution solution to this activity.STUDY DESIGN AND METHODS:DMSO (5% final concentration) was added to buffy coat-derived PLTs, followed by prefreeze removal of DMSO and storage at -80°C. Cryopreserved PLTs (n=8 per group) were thawed at 37°C, reconstituted with either 1 unit of thawed frozen plasma or PLT additive solution (PAS-G). In vitro assays were performed before freezing and after thawing to assess the hemostatic activity of PLTs.RESULTS:Cryopreserved PLTs expressed high levels of phosphatidylserine and contained significantly more phosphatidylserine-positive PLT microparticles than liquid-stored PLTs. This was accompanied by a significant decrease in the time to clot formation and clot strength, as measured by thromboelastography. The supernatant from cryopreserved PLTs was sufficient to reduce the phosphatidylserine-dependent clotting time and increase the thrombin generation potential. Overall, plasma-reconstituted cryopreserved PLTs were more procoagulant than those reconstituted in PAS-G.CONCLUSION:PLT cryopreservation results in the generation of phosphatidylserine-expressing PLT microparticles which contribute to the hemostatic activity. Understanding the hemostatic activity of these components may assist in extending the use of these specialized components beyond military applications.d components beyond military applications.)
Angiulli 2015 Biochim Biophys Acta + (BACKGROUND: ''Leishmania infantum'' is a p … BACKGROUND:''Leishmania infantum'' is a protozoan of the trypanosomatid family causing ''visceral leishmaniasis''. ''Leishmania'' parasites are transmitted by the bite of phlebotomine sand flies to the human host and are phagocyted by macrophages. The parasites synthesize N1-N8-bis(glutationyl)-spermidine (trypanothione, TS2), which furnishes electrons to the tryparedoxin-tryparedoxin peroxidase couple to reduce the reactive oxygen species produced by macrophages. Trypanothione is kept reduced by trypanothione reductase (TR), a FAD-containing enzyme essential for parasite survival.METHODS:The enzymatic activity has been studied by stopped-flow, absorption spectroscopy, and amperometric measurements.RESULTS:The study reported here demonstrates that the steady-state parameters change as a function of the order of substrates addition to the TR-containing solution. In particular, when the reaction is carried out by adding NADPH to a solution containing the enzyme and trypanothione, the KM for NADPH decreases six times compared to the value obtained by adding TS2 as last reagent to start the reaction (1.9 vs. 12 μM). More importantly, we demonstrate that TR is able to catalyze the oxidation of NADPH also in the absence of trypanothione. Thus, TR catalyzes the reduction of O2 to water through the sequential formation of C(4a)-(hydro)peroxyflavin and sulfenic acid intermediates. This NADPH:O2 oxidoreductase activity is shared by ''Saccharomyces cerevisiae'' glutathione reductase (GR).CONCLUSIONS:TR and GR, in the absence of their physiological substrates, may catalyze the electron transfer reaction from NADPH to molecular oxygen to yield water.GENERAL SIGNIFICANCE:TR and GR are promiscuous enzymes.d water. GENERAL SIGNIFICANCE: TR and GR are promiscuous enzymes.)
Montaigne 2014 Circulation + (BACKGROUND: -Obesity and diabetes mellitus … BACKGROUND:-Obesity and diabetes mellitus (DM) are independently associated with the development of heart failure. In this study, we determined the respective effects of obesity, insulin resistance and DM on intrinsic contraction and mitochondrial function of the human myocardium before the onset of cardiomyopathy.METHODS AND RESULTS:-Right atrial myocardium was obtained from 141 consecutive patients, presenting no sign of cardiomyopathy. We investigated (i) ex vivo isometric contraction (ii) mitochondrial respiration and calcium retention capacity (iii) respiratory chain complex activities and oxidative stress status. DM was associated with a pronounced impairment of intrinsic contraction, mitochondrial dysfunction and increased myocardial oxidative stress, irrespective of weight status. By contrast, obesity was associated with less pronounced contractile dysfunction without any significant perturbation of mitochondrial function or oxidative stress status. Tested as continuous variables, glycated haemoglobin (HbA1C), but neither body mass index nor the insulin resistance index HOMA-IR, was independently associated with cardiac mitochondrial function. Furthermore, DM was associated with cardiac mitochondrial network fragmentation and significant decreased expression of the mitochondrial fusion related protein MFN1. Myocardial MFN1 content was inversely proportional to HbA1C.CONCLUSIONS:-Worsening of intrinsic myocardial contraction in the transition from obesity to DM is likely related to worsening of cardiac mitochondrial function, since impaired mitochondrial function and dynamics, as well as contractile dysfunction are observed in diabetic patients but not in "metabolically healthy" obese patients at early stage in insulin resistance.ents at early stage in insulin resistance.)
Syrjanen 2015 Front Zool + (BACKGROUND: Carbonic anhydrases (CAs, EC 4 … BACKGROUND:Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous enzymes that catalyze the reversible hydration reaction of carbon dioxide. CAs are present as six structurally divergent enzyme families: α, β, γ, δ, ζ and η. β-CAs have a wide distribution across different species including invertebrates. Previously, we showed that Drosophila melanogaster β-CA is a highly active mitochondrial enzyme. In this study, we investigated the function of Drosophila β-CA by silencing the expression of the β-CA gene using UAS/GAL4-based RNA interference (RNAi) in Drosophila in vivo.RESULTS:Crossing β-CA RNAi lines over ubiquitous Actin driver flies did not produce any viable progeny, indicating that β-CA expression is required for fly development. RNAi silencing of β-CA ubiquitously in adult flies did not affect their survival rate or function of mitochondrial electron transport chain. Importantly, β-CA RNAi led to impaired reproduction. All β-CA knockdown females were sterile, and produced few or no eggs. Whole ovaries of knockdown females looked normal but upon cadherin staining, there was an apparent functional defect in migration of border cells, which are considered essential for normal fertilization.CONCLUSIONS:These results indicate that although Drosophila β-CA is dispensable for survival of adult flies, it is essential for female fertility.ies, it is essential for female fertility.)
Jackson 2014 J Med Genet + (BACKGROUND: Defects of the mitochondrial r … BACKGROUND:Defects of the mitochondrial respiratory chain complex II (succinate dehydrogenase (SDH) complex) are extremely rare. Of the four nuclear encoded proteins composing complex II, only mutations in the 70 kDa flavoprotein (SDHA) and the recently identified complex II assembly factor (SDHAF1) have been found to be causative for mitochondrial respiratory chain diseases. Mutations in the other three subunits (SDHB, SDHC, SDHD) and the second assembly factor (SDHAF2) have so far only been associated with hereditary paragangliomas and phaeochromocytomas. Recessive germline mutations in SDHB have recently been associated with complex II deficiency and leukodystrophy in one patient.METHODS AND RESULTS:We present the clinical and molecular investigations of the first patient with biochemical evidence of a severe isolated complex II deficiency due to compound heterozygous SDHD gene mutations. The patient presented with early progressive encephalomyopathy due to compound heterozygous p.E69 K and p.*164Lext*3 SDHD mutations. Native polyacrylamide gel electrophoresis and western blotting demonstrated an impaired complex II assembly. Complementation of a patient cell line additionally supported the pathogenicity of the novel identified mutations in SDHD.CONCLUSIONS:This report describes the first case of isolated complex II deficiency due to recessive SDHD germline mutations. We therefore recommend screening for all SDH genes in isolated complex II deficiencies. It further emphasises the importance of appropriate genetic counselling to the family with regard to SDHD mutations and their role in tumorigenesis.mutations and their role in tumorigenesis.)
Errea 2015 J Neuroinflammation + (BACKGROUND: In brain inflammatory diseases … BACKGROUND:In brain inflammatory diseases, axonal damage is one of the most critical steps in the cascade that leads to permanent disability. Thus, identifying the initial events triggered by inflammation or oxidative stress that provoke axonal damage is critical for the development of neuroprotective therapies. Energy depletion due to mitochondrial dysfunction has been postulated as an important step in the damage of axons. This prompted us to study the effects of acute inflammation and oxidative stress on the morphology, transport, and function of mitochondria in axons.METHODS:Mouse cerebellar slice cultures were challenged with either lipopolysaccharide (LPS) or hydrogen peroxide (H2O2) ex vivo for 24 h. Axonal mitochondrial morphology was evaluated by transmission electron microscopy (TEM) and mitochondrial transportation by time-lapse imaging. In addition, mitochondrial function in the cerebellar slice cultures was analyzed through high-resolution respirometry assays and quantification of adenosine triphosphate (ATP) production.RESULTS:Both conditions promoted an increase in the size and complexity of axonal mitochondria evident in electron microscopy images, suggesting a compensatory response. Such compensation was reflected at the tissue level as increased respiratory activity of complexes I and IV and as a transient increase in ATP production in response to acute inflammation. Notably, time-lapse microscopy indicated that mitochondrial transport (mean velocity) was severely impaired in axons, increasing the proportion of stationary mitochondria in axons after LPS challenge. Indeed, the two challenges used produced different effects: inflammation mostly reducing retrograde transport and oxidative stress slightly enhancing retrograde transportation.CONCLUSIONS:Neuroinflammation acutely impairs axonal mitochondrial transportation, which would promote an inappropriate delivery of energy throughout axons and, by this way, contribute to axonal damage. Thus, preserving axonal mitochondrial transport might represent a promising avenue to exploit as a therapeutic target for neuroprotection in brain inflammatory diseases like multiple sclerosis.ammatory diseases like multiple sclerosis.)
Vijgen 2013 Surg Obes Relat Dis + (BACKGROUND: Obesity and type 2 diabetes ar … BACKGROUND:Obesity and type 2 diabetes are associated with impaired skeletal muscle mitochondrial metabolism. As an intrinsic characteristic of an individual, skeletal muscle mitochondrial dysfunction could be a risk factor for weight gain and obesity-associated co-morbidities, such as type 2 diabetes. On the other hand, impaired skeletal muscle metabolism could be a consequence of obesity. We hypothesize that marked weight loss after bariatric surgery recovers skeletal muscle mitochondrial function.METHODS:Skeletal muscle mitochondrial function as assessed by high-resolution respirometry was measured in 8 morbidly obese patients (body mass index [BMI], 41.3±4.7 kg/m2; body fat, 48.3%±5.2%) before and 1 year after bariatric surgery (mean weight loss: 35.0±8.6 kg). The results were compared with a lean (BMI 22.8±1.1 kg/m2; body fat, 15.6%±4.7%) and obese (BMI 33.5±4.2 kg/m2; body fat, 34.1%±6.3%) control group.RESULTS:Before surgery, adenosine diphosphate (ADP)-stimulated (state 3) respiration on glutamate/succinate was decreased compared with lean patients (9.5±2.4 versus 15.6±4.4 O2 flux/mtDNA; P<.05). One year after surgery, mitochondrial function was comparable to that of lean controls (after weight loss, 12.3±5.5; lean, 15.6±4.4 O2 flux/mtDNA). In addition, we observed an increased state 3 respiration on a lipid substrate after weight loss (10.0±3.2 versus 14.0±6.6 O2 flux/mtDNA; P< .05).CONCLUSIONS:We conclude that impaired skeletal muscle mitochondrial function is a consequence of obesity that recovers after marked weight loss. obesity that recovers after marked weight loss.)
Leo 2017 Front Zool + (BACKGROUND: Ocean acidification and warmin … BACKGROUND:Ocean acidification and warming are happening fast in the Arctic but little is known about the effects of ocean acidification and warming on the physiological performance and survival of Arctic fish.RESULTS:In this study we investigated the metabolic background of performance through analyses of cardiac mitochondrial function in response to control and elevated water temperatures and PCO2 of two gadoid fish species, Polar cod (Boreogadus saida), an endemic Arctic species, and Atlantic cod (Gadus morhua), which is a temperate to cold eurytherm and currently expanding into Arctic waters in the wake of ocean warming. We studied their responses to the above-mentioned drivers and their acclimation potential through analysing the cardiac mitochondrial function in permeabilised cardiac muscle fibres after 4 months of incubation at different temperatures (Polar cod: 0, 3, 6, 8 °C and Atlantic cod: 3, 8, 12, 16 °C), combined with exposure to present (400μatm) and year 2100 (1170μatm) levels of CO2. OXPHOS, proton leak and ATP production efficiency in Polar cod were similar in the groups acclimated at 400μatm and 1170μatm of CO2, while incubation at 8 °C evoked increased proton leak resulting in decreased ATP production efficiency and decreased Complex IV capacity. In contrast, OXPHOS of Atlantic cod increased with temperature without compromising the ATP production efficiency, whereas the combination of high temperature and high PCO2 depressed OXPHOS and ATP production efficiency.CONCLUSIONS:Polar cod mitochondrial efficiency decreased at 8 °C while Atlantic cod mitochondria were more resilient to elevated temperature; however, this resilience was constrained by high PCO2. In line with its lower habitat temperature and higher degree of stenothermy, Polar cod has a lower acclimation potential to warming than Atlantic cod.on potential to warming than Atlantic cod.)
Bosy-Westphal 2004 Int J Obes Relat Metab Disord + (BACKGROUND: In normal-weight subjects, r … BACKGROUND: In normal-weight subjects, resting energy expenditure (REE) can be accurately calculated from organ and tissue masses applying constant organ-specific metabolic rates. This approach allows a precise correction for between-subjects variation in REE, explained by body composition. Since a decrease in organ metabolic rate with increasing organ mass has been deduced from interspecies comparison including human studies, the validity of the organ- and tissue-specific REE calculation remains to be proved over a wider range of fat-free mass (FFM).DESIGN: In a cross-sectional study on 57 healthy adults (35 females and 22 males, 19-43 y; 14 underweight, 25 intermediate weight and 18 obese), magnetic resonance imaging (MRI) and dual-energy X-ray absorptiometry (DXA) were used to assess the masses of brain, internal organs, skeletal muscle (MM), bone and adipose tissue. REE was measured by indirect calorimetry (REEm) and calculated from detailed organ size determination by MRI and DXA (REEc1), or in a simplified approach exclusively from DXA (REEc2).RESULTS: We found a high agreement between REEm and REEc1 over the whole range of FFM (28-86 kg). REE prediction errors were -17 +/- 505, -145 +/- 514 and -141 +/- 1058 kJ/day in intermediate weight, underweight and obese subjects, respectively (n.s.). Regressing REEm on FFM resulted in a significant positive intercept of 1.6 MJ/day that could be reduced to 0.5 MJ/day by adjusting FFM for the proportion of MM/organ mass. In a multiple regression analysis, MM and liver mass explained 81% of the variance in REEm. DXA-derived REE prediction showed a good agreement with measured values (mean values for REEm and REEc2 were 5.72 +/- 1.87 and 5.82 +/- 1.51 MJ/day; difference n.s.).CONCLUSION: Detailed analysis of metabolically active components of FFM allows REE prediction over a wide range of FFM. The data provide indirect evidence for a view that, for practical purposes within humans, the specific metabolic rate is constant with increasing organ mass. Nonlinearity of REE on FFM was partly explained by FFM composition. A simplified REE prediction algorithm from regional DXA measurements has to be validated in future studies.nts has to be validated in future studies.)
Haugen 2003 Am J Clin Nutr + (BACKGROUND: The necessity of a 12-h fast … BACKGROUND: The necessity of a 12-h fast before resting metabolic rate (RMR) is measured is often a barrier to measuring RMR.OBJECTIVE: We compared RMR measurements obtained in the morning and afternoon and across repeated days to elucidate the magnitude and sources of variability.DESIGN: Healthy men (n = 12) and women (n = 25) aged 21-67 y, with body mass indexes (in kg/m(2)) ranging from 17 to 34 and body fat ranging from 6% to 54%, completed 4 RMR measurements. RMR measurements were made in the morning (after a 12-h fast and 12 h postexercise) and in the afternoon (after a 4-h fast and 12 h postexercise) on 2 separate days with the ventilated-hood technique. Body composition was assessed by dual-energy X-ray absorptiometry.RESULTS: Mean (+/- SE) afternoon RMR was significantly higher than morning RMR on both visit 1 (1593.5 +/- 35.6 compared with 1508.0 +/- 31.5 kcal/d; P = 0.001) and visit 2 (1602 +/- 29.3 compared with 1511.4 +/- 35.9 kcal/d; P = 0.001). The 2 morning measurements (r = 0.93) and the 2 afternoon measurements (r = 0.93) were highly correlated, and no significant differences between measurements were observed. The mean difference between the morning and afternoon measurements was 99.0 +/- 35.8 kcal/d (6%).CONCLUSIONS: Repeated morning and evening measurements of RMR were stable and highly correlated. Day-to-day measurements of RMR were not significantly different. RMR measured in the afternoon after a 4-h fast and exercise was approximately 100 kcal/d higher than RMR measured in the morning.d higher than RMR measured in the morning.)
Sabia 2009 Am J Clin Nutr + (BACKGROUND: The extent to which cognition … BACKGROUND: The extent to which cognition in late midlife is influenced by lifetime obesity is unclear.OBJECTIVE: We examined the association between body mass index (BMI) over the adult life course and cognition in late midlife and assessed the cumulative effects of obesity and underweight.DESIGN: Data from the Whitehall II Study were examined. BMI at 25 y (early adulthood) was self-reported at phase 1 and was measured in early midlife (mean age = 44 y; phase 1) and in late midlife (mean age = 61 y; phase 7). Cognition (''n'' = 5131) was assessed in late midlife (phase 7) by using the Mini-Mental State Examination and tests of memory and executive function, all of which were standardized to ''T'' scores (mean +/- SD: 50 +/- 10).RESULTS: Both underweight and obesity were associated with lower cognition in late midlife and with early adulthood, early midlife, and late midlife measures of BMI. Being obese at 2 or 3 occasions was associated with lower Mini-Mental State Examination scores and scores of memory and executive function in analyses adjusted for age, sex, and education [difference (95% CI) in mean ''T'' scores compared with normal-weight group: -1.51 (-2.77, -0.25), -1.27 (-2.46, -0.07), and -1.35 (-2.45, -0.24), respectively]. Participants who were underweight at > or =2 occasions from early adulthood to late midlife had lower executive function [difference (95% CI) in mean ''T'' score: -4.57 (-6.94, -2.20)]. A large increase in BMI from early to late midlife was associated with lower executive function.CONCLUSIONS: Long-term obesity and long-term underweight in adulthood are associated with lower cognitive scores in late midlife. Public health messages should promote a healthy weight at all ages. should promote a healthy weight at all ages.)
Pon 2011 Malar J + (BACKGROUND: ''Anopheles stephensi'' mitoch … BACKGROUND: ''Anopheles stephensi'' mitochondrial malic enzyme (ME) emerged as having a relevant role in the provision of pyruvate for the Krebs' cycle because inhibition of this enzyme results in the complete abrogation of oxygen uptake by mitochondria. Therefore, the identification of ME in mitochondria from immortalized A. stephensi (ASE) cells and the investigation of the stereoselectivity of malate analogues are relevant in understanding the physiological role of ME in cells of this important malaria parasite vector and its potential as a possible novel target for insecticide development.METHODS: To characterize the mitochondrial ME from immortalized ASE cells (Mos. 43; ASE), mass spectrometry analyses of trypsin fragments of ME, genomic sequence analysis and biochemical assays were performed to identify the enzyme and evaluate its activity in terms of cofactor dependency and inhibitor preference.RESULTS: The encoding gene sequence and primary sequences of several peptides from mitochondrial ME were found to be highly homologous to the mitochondrial ME from Anopheles gambiae (98%) and 59% homologous to the mitochondrial NADP+-dependent ME isoform from Homo sapiens. Measurements of ME activity in mosquito mitochondria isolated from ASE cells showed that (i) Vmax with NAD+ was 3-fold higher than that with NADP+, (ii) addition of Mg2+ or Mn2+ increased the Vmax by 9- to 21-fold, with Mn2+ 2.3-fold more effective than Mg2+, (iii) succinate and fumarate increased the activity by 2- and 5-fold, respectively, at sub-saturating concentrations of malate, (iv) among the analogs of L-malate tested as inhibitors of the NAD+-dependent ME catalyzed reaction, small (2- to 3-carbons) organic diacids carrying a 2-hydroxyl/keto group behaved as the most potent inhibitors of ME activity (e.g., oxaloacetate, tartronic acid and oxalate).CONCLUSIONS: The biochemical characterization of Anopheles stephensi ME is of critical relevance given its important role in bioenergetics, suggesting that it is a suitable target for insecticide development.itable target for insecticide development.)
Ejarque 2019 Int J Obes (Lond) + (BACKGROUND: A functional population of adi … BACKGROUND: A functional population of adipocyte precursors, termed adipose-derived stromal/stem cells (ASCs), is crucial for proper adipose tissue (AT) expansion, lipid handling, and prevention of lipotoxicity in response to chronic positive energy balance. We previously showed that obese human subjects contain a dysfunctional pool of ASCs. Elucidation of the mechanisms underlying abnormal ASC function might lead to therapeutic interventions for prevention of lipotoxicity by improving the adipogenic capacity of ASCs.METHODS: Using epigenome-wide association studies, we explored the impact of obesity on the methylation signature of human ASCs and their differentiated counterparts. Mitochondrial phenotyping of lean and obese ASCs was performed. TBX15 loss- and gain-of-function experiments were carried out and western blotting and electron microscopy studies of mitochondria were performed in white AT biopsies from lean and obese individuals.RESULTS: We found that DNA methylation in adipocyte precursors is significantly modified by the obese environment, and adipogenesis, inflammation, and immunosuppression were the most affected pathways. Also, we identified TBX15 as one of the most differentially hypomethylated genes in obese ASCs, and genetic experiments revealed that TBX15 is a regulator of mitochondrial mass in obese adipocytes. Accordingly, morphological analysis of AT from obese subjects showed an alteration of the mitochondrial network, with changes in mitochondrial shape and number.CONCLUSIONS: We identified a DNA methylation signature in adipocyte precursors associated with obesity, which has a significant impact on the metabolic phenotype of mature adipocytes. metabolic phenotype of mature adipocytes.)
Heymsfield 2007 Am J Clin Nutr + (BACKGROUND: Although Quetelet first report … BACKGROUND: Although Quetelet first reported in 1835 that adult weight scales to the square of stature, limited or no information is available on how anatomical body compartments, including adipose tissue (AT), scale to height.OBJECTIVE: We examined the critical underlying assumptions of adiposity-body mass index (BMI) relations and extended these analyses to major anatomical compartments: skeletal muscle (SM), bone, residual mass, weight (AT+SM+bone), AT-free mass, and organs (liver, brain).DESIGN: This was a cross-sectional analysis of 2 body-composition databases: one including magnetic resonance imaging and dual-energy X-ray absorptiometry (DXA) estimates of evaluated components in adults (total ''N''=411; organs=76) and the other a larger DXA database (''N''=1346) that included related estimates of fat, fat-free mass, and bone mineral mass.RESULTS: Weight, primary lean components (SM, residual mass, AT-free mass, and fat-free mass), and liver scaled to height with powers of approximately 2 (all ''P''<0.001); bone and bone mineral mass scaled to height with powers >2 (2.31-2.48), and the fraction of weight as bone mineral mass was significantly (''P''<0.001) correlated with height in women. AT scaled weakly to height with powers of approximately 2, and adiposity was independent of height. Brain mass scaled to height with a power of 0.83 (''P''=0.04) in men and nonsignificantly in women; the fraction of weight as brain was inversely related to height in women (''P''=0.002).CONCLUSIONS: These observations suggest that short and tall subjects with equivalent BMIs have similar but not identical body composition, provide new insights into earlier BMI-related observations and thus establish a foundation for height-normalized indexes, and create an analytic framework for future studies.nd create an analytic framework for future studies.)
Morse 2012 J Infect Dis + (BACKGROUND: Although human immunodeficienc … BACKGROUND: Although human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) affect mitochondrial DNA (mtDNA) content and function, comprehensive evaluations of their effects on mitochondria in muscle, adipose tissue, and blood cells are limited.METHODS: Mitochondrial DNA quantification, mitochondrial genome sequencing, and gene expression analysis were performed on muscle, adipose tissue, and peripheral blood mononuclear cell (PBMC) samples from untreated HIV-positive patients, HIV-positive patients receiving nucleoside reverse transcriptase inhibitor (NRTI)-based ART, and HIV-negative controls.RESULTS: The adipose tissue mtDNA/nuclear DNA (nDNA) ratio was increased in untreated HIV-infected patients (ratio, 353) and decreased in those receiving ART (ratio, 162) compared with controls (ratio, 255; P < .05 for both comparisons); the difference between the 2 HIV-infected groups was also significant (P = .002). In HIV-infected participants, mtDNA/nDNA in adipose tissue correlated with the level of activation (CD38+ /HLA-DR+) for CD4+ and CD8+ lymphocytes. No significant differences in mtDNA content were noted in muscle or PMBCs among groups. Exploratory DNA microarray analysis identified differential gene expression between patient groups, including a subset of adipose tissue genes.CONCLUSIONS: HIV infection and ART have opposing effects on mtDNA content in adipose tissue; immune activation may mediate the effects of HIV, whereas NRTIs likely mediate the effects of ART.reas NRTIs likely mediate the effects of ART.)
Gallagher 2000 Am J Clin Nutr + (BACKGROUND: Although international interes … BACKGROUND: Although international interest in classifying subject health status according to adiposity is increasing, no accepted published ranges of percentage body fat currently exist. Empirically identified limits, population percentiles, and z scores have all been suggested as means of setting percentage body fat guidelines, although each has major limitations.OBJECTIVE: The aim of this study was to examine a potential new approach for developing percentage body fat ranges. The approach taken was to link healthy body mass index (BMI; in kg/m(2)) guidelines established by the National Institutes of Health and the World Health Organization with predicted percentage body fat.DESIGN: Body fat was measured in subjects from 3 ethnic groups (white, African American, and Asian) who were screened and evaluated at 3 universities [Cambridge (United Kingdom), Columbia (United States), and Jikei (Japan)] with use of reference body-composition methods [4-compartment model (4C) at 2 laboratories and dual-energy X-ray absorptiometry (DXA) at all 3 laboratories]. Percentage body fat prediction equations were developed based on BMI and other independent variables.RESULTS: A convenient sample of 1626 adults with BMIs < or =35 was evaluated. Independent percentage body fat predictor variables in multiple regression models included 1/BMI, sex, age, and ethnic group (''R'': values from 0.74 to 0.92 and SEEs from 2.8 to 5.4 % fat). The prediction formulas were then used to prepare provisional healthy percentage body fat ranges based on published BMI limits for underweight (<18.5), overweight (> or =25), and obesity (> or =30).CONCLUSION: This proposed approach and initial findings provide the groundwork and stimulus for establishing international healthy body fat ranges.or establishing international healthy body fat ranges.)
Bredholt T 2009 Mol Cancer + (BACKGROUND: An organic extract of the recr … BACKGROUND: An organic extract of the recreational herb khat (''Catha edulis'' Forsk.) triggers cell death in various leukemia cell lines ''in vitro''. The chemotherapeutics camptothecin, a plant alkaloid topoisomerase I inhibitor, was tested side-by-side with khat in a panel of acute myeloid leukemia cell lines to elucidate mechanisms of toxicity.RESULTS: Khat had a profound effect on MOLM-13 cells inducing mitochondrial damage, chromatin margination and morphological features of autophagy. The effects of khat on mitochondrial ultrastructure in MOLM-13 correlated with strongly impaired routine respiration, an effect neither found in the khat-resistant MV-4-11 cells nor in camptothecin treated cells. Enforced expression of anti-apoptotic Bcl-2 protein provided protection against camptothecin-induced cell death and partly against khat toxicity. Khat-induced cell death in MOLM-13 cells included reduced levels of anti-apoptotic Mcl-1 protein, while both khat and camptothecin induced c-FLIPL cleavage and procaspase-8 activation.CONCLUSION: Khat activated a distinct cell death pathway in sensitive leukemic cells as compared to camptothecin, involving mitochondrial damage and morphological features of autophagy. This suggests that khat should be further explored in the search for novel experimental therapeutics.earch for novel experimental therapeutics.)
Heymsfield 2014 Am J Clin Nutr + (BACKGROUND: Body mass index (BMI) is formu … BACKGROUND: Body mass index (BMI) is formulated on the assumption that body weight (BW) scales to height with a power of 2 (BW∝height(2)), independent of sex and race-ethnicity. Powers differing from 2 are observed in studies of selected samples, thus raising the question if BMI is a generalizable metric that makes BW independent of height across populations.OBJECTIVES: The objectives were to test the hypothesis that adult BW scales to height with a power of 2 independent of sex and race-ethnicity and to advance an understanding of BMI as a measure of shape by extending allometric analyses to waist circumference (WC).DESIGN: We conducted cross-sectional subject evaluations, including body composition, from the NHANES and the Korean NHANES (KNHANES). Variations of the allometric model (Y = αX(β)) were used to establish height scaling powers (β ± SE) across non-Hispanic white and black, Mexican American, and Korean men and women.RESULTS: Exploratory analyses in population samples established age and adiposity as important independent determinants of height scaling powers (i.e., β). After age and adiposity in the next series of analyses were controlled for, BW scaling powers were nonsignificantly different between race/ethnic groups within each sex group; WC findings were similar in women, whereas small but significant between-race differences were observed in the men. Sex differences in β values were nonsignificant except for BW in non-Hispanic blacks and WC in Koreans (''P'' < 0.05). Nationally representative powers for BW were (NHANES/KNHANES) 2.12 ± 0.05/2.11 ± 0.06 for men and 2.02 ± 0.04/1.99 ± 0.06 for women and for WC were 0.66 ± 0.03/0.67 ± 0.05 for men and 0.61 ± 0.04/0.56 ± 0.05 for women.CONCLUSIONS: Adult BW scales to height with a power of ∼2 across the 8 sex and race/ethnic groups, an observation that makes BMI a generalizable height-independent measure of shape across most populations. WC also follows generalizable scaling rules, a finding that has implications for defining body shape in populations who differ in stature.y shape in populations who differ in stature.)
Romero-Corral 2008 Int J Obes (Lond) + (BACKGROUND: Body mass index (BMI) is the m … BACKGROUND: Body mass index (BMI) is the most widely used measure to diagnose obesity. However, the accuracy of BMI in detecting excess body adiposity in the adult general population is largely unknown.METHODS: A cross-sectional design of 13 601 subjects (age 20-79.9 years; 49 % men) from the Third National Health and Nutrition Examination Survey. Bioelectrical impedance analysis was used to estimate body fat percent (BF%). We assessed the diagnostic performance of BMI using the World Health Organization reference standard for obesity of BF%>25 % in men and>35 % in women. We tested the correlation between BMI and both BF% and lean mass by sex and age groups adjusted for race.RESULTS: BMI-defined obesity (> or =30 kg m(-2)) was present in 19.1 % of men and 24.7 % of women, while BF%-defined obesity was present in 43.9 % of men and 52.3 % of women. A BMI> or =30 had a high specificity (men=95 %, 95 % confidence interval (CI), 94-96 and women=99 %, 95 % CI, 98-100), but a poor sensitivity (men=36 %, 95 % CI, 35-37 and women=49 %, 95 % CI, 48-50) to detect BF%-defined obesity. The diagnostic performance of BMI diminished as age increased. In men, BMI had a better correlation with lean mass than with BF%, while in women BMI correlated better with BF% than with lean mass. However, in the intermediate range of BMI (25-29.9 kg m(-2)), BMI failed to discriminate between BF% and lean mass in both sexes.CONCLUSIONS: The accuracy of BMI in diagnosing obesity is limited, particularly for individuals in the intermediate BMI ranges, in men and in the elderly. A BMI cutoff of> or =30 kg m(-2) has good specificity but misses more than half of people with excess fat. These results may help to explain the unexpected better survival in overweight/mild obese patients.pected better survival in overweight/mild obese patients.)
Hood 2019 Nutr Diabetes + (BACKGROUND: Body mass index (BMI) represen … BACKGROUND: Body mass index (BMI) represents a normalization of weight to height and is used to classify adiposity. While the capacity of BMI as an adiposity index has been experimentally validated in Caucasians, but there has been little testing Asian populations.METHODS: To determine whether weight scales to height squared in Asian Indians across the general population and in Asian Indian tribes an allometric analysis on the power law model, ''W'' =''αHβ'', where ''W'' is weight (kg) and ''H'' is height (m) was performed on cross-sectional weight and height data from India (''N'' = 43,880) collected through the Anthropological Survey of India. The database contained males 18-84 years of age spanning 161 districts of 14 states and including 33 different tribes (''N'' = 5,549). Models were developed that were unadjusted and adjusted for tribe membership. The Korean National Health and Nutrition Examination Survey (KNHANES) was used to compare to height-weight data from the Anthropological Survey of India and to calculate BMI thresholds for obesity status using a receiver operating characteristic.RESULTS: The unadjusted power was ''β'' = 2.08 (s = 0.02). The power for the general population (non-tribal) was ''β'' = 2.11 (s = 0.02). Powers when adjusted for tribe ranged from 1.87 to 2.35 with 24 of the 33 tribes resulting in statistically significant (''p'' < 0.05) differences in powers from the general population. The coefficients of the adjusted terms ranged from -0.22 to 0.26 and therefore the scaling exponent does not deviate far from 2. Thresholds for BMI classification of overweight in the KNHANES database were BMI = 21 kg/m2 (AUC = 0.89) for males 18 kg/m2 (AUC = 0.97) for females. Obesity classification was calculated as BMI = 26 kg/m2 (AUC = 0.81) and 23 kg/m2 (AUC = 0.83) for females.CONCLUSIONS: Our study confirms that weight scales to height squared in Asian Indian males even after adjusting for tribe membership. We also demonstrate that optimal BMI thresholds are lower in a Korean population in comparison to currently used BMI thresholds. These results support the application of BMI in Asian populations with potentially lower thresholds.opulations with potentially lower thresholds.)
Sperrin 2016 J Public Health (Oxf) + (BACKGROUND: Body mass index (BMI) tends to … BACKGROUND: Body mass index (BMI) tends to be higher among shorter adults, especially women. The dependence of BMI-height correlation on age and calendar time may inform us about temporal determinants of BMI.METHODS: Series of cross-sectional surveys: Health Survey for England, 1992-2011. We study the Benn Index, which is the coefficient in a regression of log(weight) on log(height). This is adjusted for age, gender and calendar time, allowing for non-linear terms and interactions.RESULTS: By height quartile, mean BMI decreased with increasing height, more so in women than in men (P < 0.001). The decrease in mean BMI in the tallest compared with the shortest height quartile was 0.77 in men (95% CI 0.69, 0.86) and 1.98 in women (95% CI 1.89, 2.08). Regression analysis of log(weight) on log(height) revealed that the inverse association between BMI and height was more pronounced in older adults and stronger in women than in men, with little change over calendar time.CONCLUSIONS: Unlike early childhood, where taller children tend to have higher BMI, adults, especially women and older people, show an inverse BMI-height association. BMI is a heterogeneous measure of weight-for-height; height may be an important and complex determinant of BMI trajectory over the life course.© The Author 2015. Published by Oxford University Press on behalf of Faculty of Public Health. Press on behalf of Faculty of Public Health.)
Silbert 2016 J Alzheimers Dis + (BACKGROUND: Computer use is becoming a com … BACKGROUND: Computer use is becoming a common activity in the daily life of older individuals and declines over time in those with mild cognitive impairment (MCI). The relationship between daily computer use (DCU) and imaging markers of neurodegeneration is unknown.OBJECTIVE: The objective of this study was to examine the relationship between average DCU and volumetric markers of neurodegeneration on brain MRI.METHODS: Cognitively intact volunteers enrolled in the Intelligent Systems for Assessing Aging Change study underwent MRI. Total in-home computer use per day was calculated using mouse movement detection and averaged over a one-month period surrounding the MRI. Spearman's rank order correlation (univariate analysis) and linear regression models (multivariate analysis) examined hippocampal, gray matter (GM), white matter hyperintensity (WMH), and ventricular cerebral spinal fluid (vCSF) volumes in relation to DCU. A voxel-based morphometry analysis identified relationships between regional GM density and DCU.RESULTS: Twenty-seven cognitively intact participants used their computer for 51.3 minutes per day on average. Less DCU was associated with smaller hippocampal volumes (''r'' = 0.48, ''p'' = 0.01), but not total GM, WMH, or vCSF volumes. After adjusting for age, education, and gender, less DCU remained associated with smaller hippocampal volume (''p'' = 0.01). Voxel-wise analysis demonstrated that less daily computer use was associated with decreased GM density in the bilateral hippocampi and temporal lobes.CONCLUSIONS: Less daily computer use is associated with smaller brain volume in regions that are integral to memory function and known to be involved early with Alzheimer's pathology and conversion to dementia. Continuous monitoring of daily computer use may detect signs of preclinical neurodegeneration in older individuals at risk for dementia.in older individuals at risk for dementia.)
Pearson-Stuttard 2018 Lancet Diabetes Endocrinol + (BACKGROUND: Diabetes and high body-mass in … BACKGROUND: Diabetes and high body-mass index (BMI) are associated with increased risk of several cancers, and are increasing in prevalence in most countries. We estimated the cancer incidence attributable to diabetes and high BMI as individual risk factors and in combination, by country and sex.METHODS: We estimated population attributable fractions for 12 cancers by age and sex for 175 countries in 2012. We defined high BMI as a BMI greater than or equal to 25 kg/m2. We used comprehensive prevalence estimates of diabetes and BMI categories in 2002, assuming a 10-year lag between exposure to diabetes or high BMI and incidence of cancer, combined with relative risks from published estimates, to quantify contribution of diabetes and high BMI to site-specific cancers, individually and combined as independent risk factors and in a conservative scenario in which we assumed full overlap of risk of diabetes and high BMI. We then used GLOBOCAN cancer incidence data to estimate the number of cancer cases attributable to the two risk factors. We also estimated the number of cancer cases in 2012 that were attributable to increases in the prevalence of diabetes and high BMI from 1980 to 2002. All analyses were done at individual country level and grouped by region for reporting.FINDINGS: We estimated that 5·7 % of all incident cancers in 2012 were attributable to the combined effects of diabetes and high BMI as independent risk factors, corresponding to 804 100 new cases. 187 600 (24·5 %) of 766 000 cases of liver cancer and 121 700 (38·4 %) of 317 000 cases of endometrial cancer were attributable to these risk factors. In the conservative scenario, about 4·5 % (629 000 new cases) of all incident cancers assessed were attributable to diabetes and high BMI combined. Individually, high BMI (544 300 cases) was responsible for almost twice as many cancer cases as diabetes (293 300 cases). 25·8 % of diabetes-related cancers (equating to 75 600 new cases) and 31·9 % of high BMI-related cancers (174 040 new cases) were attributable to increases in the prevalence of these risk factors from 1980 to 2002.INTERPRETATION: A substantial number of cancer cases are attributable to diabetes and high BMI. As the prevalence of these cancer risk factors increases, clinical and public health efforts should focus on identifying optimal preventive and screening measures for whole populations and individual patients.FUNDING: NIHR and Wellcome Trust.Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd. All rights reserved.Corrected and republished from: Worldwide burden of cancer attributable to diabetes and high body-mass index: a comparative risk assessment [Lancet Diabetes Endocrinol 2018]sessment [Lancet Diabetes Endocrinol 2018])
Cohen 2008 Am J Clin Nutr + (BACKGROUND: During the past 40 y, there ha … BACKGROUND: During the past 40 y, there has been a trend toward more eating away from home, increased food availability, the opportunity to order extra-large portion sizes, and general weight gain.OBJECTIVE: Because shorter people need fewer calories than taller people to maintain their weight, our goal was to determine whether the body mass index (BMI)-height relation has changed over time.DESIGN: Data are from 3581 nonpregnant women and 3091 men examined in the 1959-1962 National Health Examination Survey and 4651 nonpregnant women and 4691 men examined in the 2001-2004 National Health and Nutrition Examination Survey. We tested whether the relation between BMI and height has changed for men and women, after adjustment for other demographic changes.RESULTS: In the past, on average, shorter American men and women had significantly higher BMIs than taller people. However, taller people have been increasing their BMI during the past 40 y at a faster rate than shorter people.CONCLUSIONS: This study documents that the obesity epidemic has changed the height-BMI relation. The data cannot identify causal pathways, and there are numerous explanations. A plausible hypothesis is that changes in the food environment may have eliminated constraints on weight gain for taller people that existed in a more calorie-constrained environment.in a more calorie-constrained environment.)
Rhein 2010 PloS One + (BACKGROUND: Energy deficiency and mitochon … BACKGROUND: Energy deficiency and mitochondrial failure have been recognized as a prominent, early event in Alzheimer's disease (AD). Recently, we demonstrated that chronic exposure to amyloid-beta (Abeta) in human neuroblastoma cells over-expressing human wild-type amyloid precursor protein (APP) resulted in (i) activity changes of Complexes III and IV of the oxidative phosphorylation system (OXPHOS) and in (ii) a drop of ATP levels which may finally instigate loss of synapses and neuronal cell death in AD. Therefore, the aim of the present study was to investigate whether standardized Ginkgo biloba extract LI 1370 (GBE) is able to rescue Abeta-induced defects in energy metabolism.METHODOLOGY/PRINCIPAL FINDINGS: We used a high-resolution respiratory protocol to evaluate OXPHOS respiratory capacity under physiological condition in control (stably transfected with the empty vector) and APP cells after treatment with GBE. In addition, oxygen consumption of isolated mitochondria, activities of mitochondrial respiratory enzymes, ATP and reactive oxygen species (ROS) levels as well as mitochondrial membrane mass and mitochondrial DNA content were determined. We observed a general antioxidant effect of GBE leading to an increase of the coupling state of mitochondria as well as energy homeostasis and a reduction of ROS levels in control cells and in APP cells. GBE effect on OXPHOS was even preserved in mitochondria after isolation from treated cells. Moreover, these functional data were paralleled by an up-regulation of mitochondrial DNA. Improvement of the OXPHOS efficiency was stronger in APP cells than in control cells. In APP cells, the GBE-induced amelioration of oxygen consumption most likely arose from the modulation and respective normalization of the Abeta-induced disturbance in the activity of mitochondrial Complexes III and IV restoring impaired ATP levels possibly through decreasing Abeta and oxidative stress level.CONCLUSIONS/SIGNIFICANCE: Although the underlying molecular mechanisms of the mode of action of GBE remain to be determined, our study clearly highlights the beneficial effect of GBE on the cellular OXPHOS performance and restoration of Abeta-induced mitochondrial dysfunction.f Abeta-induced mitochondrial dysfunction.)
Ekelund 2016 Lancet + (BACKGROUND: High amounts of sedentary beha … BACKGROUND: High amounts of sedentary behaviour have been associated with increased risks of several chronic conditions and mortality. However, it is unclear whether physical activity attenuates or even eliminates the detrimental effects of prolonged sitting. We examined the associations of sedentary behaviour and physical activity with all-cause mortality.METHODS: We did a systematic review, searching six databases (PubMed, PsycINFO, Embase, Web of Science, Sport Discus, and Scopus) from database inception until October, 2015, for prospective cohort studies that had individual level exposure and outcome data, provided data on both daily sitting or TV-viewing time and physical activity, and reported effect estimates for all-cause mortality, cardiovascular disease mortality, or breast, colon, and colorectal cancer mortality. We included data from 16 studies, of which 14 were identified through a systematic review and two were additional unpublished studies where pertinent data were available. All study data were analysed according to a harmonised protocol, which categorised reported daily sitting time and TV-viewing time into four standardised groups each, and physical activity into quartiles (in metabolic equivalent of task [MET]-hours per week). We then combined data across all studies to analyse the association of daily sitting time and physical activity with all-cause mortality, and estimated summary hazard ratios using Cox regression. We repeated these analyses using TV-viewing time instead of daily sitting time.FINDINGS: Of the 16 studies included in the meta-analysis, 13 studies provided data on sitting time and all-cause mortality. These studies included 1 005 791 individuals who were followed up for 2-18·1 years, during which 84 609 (8·4%) died. Compared with the referent group (ie, those sitting <4 h/day and in the most active quartile [>35·5 MET-h per week]), mortality rates during follow-up were 12-59% higher in the two lowest quartiles of physical activity (from HR=1·12, 95% CI 1·08-1·16, for the second lowest quartile of physical activity [<16 MET-h per week] and sitting <4 h/day; to HR=1·59, 1·52-1·66, for the lowest quartile of physical activity [<2·5 MET-h per week] and sitting >8 h/day). Daily sitting time was not associated with increased all-cause mortality in those in the most active quartile of physical activity. Compared with the referent (<4 h of sitting per day and highest quartile of physical activity [>35·5 MET-h per week]), there was no increased risk of mortality during follow-up in those who sat for more than 8 h/day but who also reported >35·5 MET-h per week of activity (HR=1·04; 95% CI 0·99-1·10). By contrast, those who sat the least (<4 h/day) and were in the lowest activity quartile (<2·5 MET-h per week) had a significantly increased risk of dying during follow-up (HR=1·27, 95% CI 1·22-1·31). Six studies had data on TV-viewing time (N=465 450; 43 740 deaths). Watching TV for 3 h or more per day was associated with increased mortality regardless of physical activity, except in the most active quartile, where mortality was significantly increased only in people who watched TV for 5 h/day or more (HR=1·16, 1·05-1·28).sed only in people who watched TV for 5 h/day or more (HR=1·16, 1·05-1·28).)
Bienholz 2011 Abstract IOC65 + (BACKGROUND: Hypoxia/reoxygenation (H/R) of … BACKGROUND: Hypoxia/reoxygenation (H/R) of proximal tubules leads to persistent ATP depletion due to decreased mitochondrial membrane potential (MMP) resulting from nonesterified fatty acid (NEFA)-mediated uncoupling that is paradoxically accompanied by respiratory inhibition rather than the stimulation expected for uncoupled states.METHODS: Since NEFA have been reported to directly inhibit electron transport in some settings we assessed respiratory function in isolated, permeabilized rabbit tubules after H/R as a function of NEFA availability.RESULTS: Compared to respiration supported by the complex II-dependent substrate, succinate, which was highly uncoupled after H/R but relatively well preserved (ADP-stimulated respiration (S3) of permeabilized tubules 71.0±8.5% of normoxic control (NC)), respiration supported by complex I-dependent substrates that normally predominate in cells was also uncoupled, but S3 was reduced to 26.9±3.3% of NC, P < 0.001 vs. succinate, N=5. With complex I substrates, acutely lowering NEFA after permeabilization improved coupling but only minimally increased S3. In contrast, lowering NEFA during 60 min. of reoxygenation prior to permeabilization increased S3 supported by complex I substrates, but it remained lower (55.7±7.5% of NC) than with succinate after the same treatment, 80.0±4.8%, p < 0.02. MMP at the end of H/R was much lower with complex I substrates (30.7±9.2% NC) than with succinate (67.4±4.5%), P < 0.004. Lowering NEFA during 60 min. of reoxygenation strongly improved recovery and decreased the MMP difference between complex I substrates (73.3±5.1% of NC) and succinate (83.4±6.6%).CONCLUSION: The studies indicate that selectively impaired utilization of complex I substrates to support respiration after H/R promotes NEFA-induced deenergization and is only minimally improved by acutely removing NEFA. In the presence of NEFA, the higher efficiency of complex I substrates to support electron transport does not mitigate the impact of the impaired respiration on MMP. However, lowering NEFA within cells for 60 min. allows strong recovery of MMP despite persistence of some respiratory impairment.despite persistence of some respiratory impairment.)
Bonthuis 2013 PLOS ONE + (BACKGROUND: In children with either delaye … BACKGROUND: In children with either delayed or accelerated growth, expressing the body mass index (BMI) to chronological age might lead to invalid body composition estimates. Reference to height-age has been suggested for such populations; however its validity has not been demonstrated.METHODS: Anthropometric data of healthy children were obtained from the German KiGGS survey. We selected three samples with different height distributions representing short stature (mean height SDS: -1.6), normal stature (height SDS: 0), and tall stature (height SDS: +1.6), and compared BMI-for-age and BMI-for-height-age between these samples across the paediatric age range. Differences between samples were tested using Kruskal-Wallis one-way analysis of variance and permutation tests.RESULTS: At a given age, BMI was distributed towards lower values in short, and towards higher values in tall subjects as compared to a population with average height distribution. Expressing BMI to height-age eliminated these differences in boys with a short stature from 4 years to 14 years of age, in tall boys from 4 to 16 years, in short girls aged 2-10 years or tall girls aged 2-17 years.CONCLUSION: From late infancy to adolescent age, BMI distribution co-varies with height distribution and referencing to height-age appears appropriate within this age period. However, caution is needed when data about pubertal status are absent.hen data about pubertal status are absent.)
Tompuri 2015 Clin Physiol Funct Imaging + (BACKGROUND: In the exercise testing measur … BACKGROUND: In the exercise testing measures of cardiorespiratory fitness need to be scaled by body size or composition to enable comparison between individuals. Traditionally used weight-proportional measures are potentially confounded by body adiposity that hampers their interpretation and applicability in the clinical assessment of cardiorespiratory fitness.OBJECTIVE: We aimed to find the most appropriate measure of body size or composition for scaling of measures of cardiorespiratory fitness among children.METHODS: We assessed body weight and height, maximal workload (''W''max) and maximal oxygen uptake (''V''O2max) using cycle ergometer exercise test with respiratory gas analysis and body lean mass (LM) and fat mass (FM) by dual-energy X-ray absorptiometry and by bioimpedance analysis among 38 children. The data were analysed using Pearson's coefficients for correlation and stepwise linear regression models.RESULTS: Lean mass (''r'' > 0.54) and height (''r'' > 0.51) had stronger positive correlations with absolute ''W''max and ''V''O2max than weight (''r'' > 0.30) in girls and boys. None of the measures of body size or composition correlated with LM-proportional ''W''max or ''V''O2max in girls or boys. Only LM correlated positively with height-proportional ''W''max (''r'' = 0.65) and ''V''O2max (''r'' = 0.71) in boys. FM correlated negatively with weight-proportional ''W''max (''r'' < -0.58) and ''V''O2max (''r'' < -0.64) in girls and boys. FM was even stronger determinant of weight-proportional ''W''max (''β'' = -0.68) and ''V''O2max (''β'' = -0.61) than exercise performance in multivariate linear regression models.CONCLUSIONS: While assessing cardiorespiratory fitness, LM is the most appropriate measure of body size or composition for scaling of ''W''max and ''V''O2max, because scaling by body weight introduces confounding by body adiposity.ss, LM is the most appropriate measure of body size or composition for scaling of ''W''max and ''V''O2max, because scaling by body weight introduces confounding by body adiposity.)
Kuper 2014 BMC Public Health + (BACKGROUND: Indians may be particularly vu … BACKGROUND: Indians may be particularly vulnerable to cardiometabolic disease, potentially due to higher body fat for a given BMI, or a tendency towards depositing abdominal adiposity. The aim of the study is to assess whether different measures of the distribution of adiposity (abdominal versus whole body) or amount of adiposity (DXA versus traditional anthropometric) are better at predicting prevalent cardiometabolic risk markers in an Indian population.METHODS: Participants were recruited from the Indian Migration Study (IMS) and the Andhra Pradesh Children and Parent Study (APCAPS). Participants attended a clinic in Hyderabad, India, January 2009-December 2010. Adiposity was measured by conventional anthropometry (including weight, height, waist) and DXA scanning (whole body and abdominal). Blood samples were taken and assessed for fasting plasma glucose, insulin, cholesterol, and triglycerides and blood pressure was measured. Lifestyle data were collected by questionnaire.RESULTS: We invited 4 617 participants to the clinic (1 995 IMS; 2 622 APCAPS) and examined 918 from IMS (46 %) and 1 451 from APCAPS (55 %). There were strong and consistent relationships between adiposity and cardiometabolic risk factors. Cardiometabolic risk factors did not appear to be more strongly associated with DXA measures as opposed to BMI, or skinfold measures of body fat. There was some evidence that WHR was more closely related to diabetes than total body adiposity, but this was not apparent for the other measures of abdominal adiposity (DXA measures, waist circumference) or other cardiometablic risk factors.CONCLUSIONS: No strong evidence supports that DXA measures or abdominal measures of adiposity are better at predicting the prevalence of cardiometabolic risk factors in comparison to BMI.tabolic risk factors in comparison to BMI.)
Nouette-Gaulain 2009 Anesthesiology + (BACKGROUND: Local anesthetics offer the be … BACKGROUND: Local anesthetics offer the benefits of extended analgesia with greater patient satisfaction and faster rehabilitation compared with intravenous morphine. These benefits, however, can be offset by adverse iatrogenic muscle pain caused by bupivacaine. Here, the authors describe the mechanisms of local anesthetic-induced myotoxicity and a partial protective effect of recombinant human erythropoietin (rhEPO).METHODS: The authors developed a rat analgesia model with femoral nerve catheter and a cell culture model of human skeletal muscle myoblasts to study local anesthetic effects. Rats were randomly assigned to four different groups: daily intraperitoneal injection with 5,000 U/kg rhEPO or saline coupled to a perineural catheter injection with 1 ml/kg bupivacaine, 0.25%, or saline. In psoas rat muscle, oxygen consumption rates were measured using a Clark-type electrode in saponin-skinned fibers. Mitochondrial adenosine triphosphate synthesis rates were determined by bioluminescence. Enzymatic activity of mitochondrial respiratory chain complexes was measured on tissue homogenates using spectrophotometric procedures, and mitochondrial morphology was analyzed by transmission electron microscopy. In addition, the interaction between bupivacaine and rhEPO was investigated on human skeletal muscle myoblasts by fluorescence microscopy using mitotracker green and using the lipophilic cation JC-1.RESULTS: Bupivacaine caused impairment of mitochondrial structure and bioenergetics in rats. Human myoblasts treated with bupivacaine showed a dose-dependent decrease in mitochondrial membrane potential associated with unusual morphologies. Impairment of mitochondrial bioenergetics was prevented partially by the use of rhEPO coadministered with bupivacaine.CONCLUSIONS: The authors demonstrated a dose- and time-dependent protective effect of rhEPO against bupivacaine-induced myotoxicity in regional analgesia.induced myotoxicity in regional analgesia.)
Xu 1999 Structure + (BACKGROUND: Malic enzymes catalyze the oxi … BACKGROUND: Malic enzymes catalyze the oxidative decarboxylation of malate to pyruvate and CO2 with the concomitant reduction of NAD(P)+ to NAD(P)H. They are widely distributed in nature and have important biological functions. Human mitochondrial NAD(P)+-dependent malic enzyme (mNAD-ME) may have a crucial role in the metabolism of glutamine for energy production in rapidly dividing cells and tumors. Moreover, this isoform is unique among malic enzymes in that it is a cooperative enzyme, and its activity is controlled allosterically.RESULTS: The crystal structure of human mNAD-ME has been determined at 2.5 A resolution by the selenomethionyl multiwavelength anomalous diffraction method and refined to 2.1 A resolution. The structure of the monomer can be divided into four domains; the active site of the enzyme is located in a deep cleft at the interface between three of the domains. Three acidic residues (Glu255, Asp256 and Asp279) were identified as ligands for the divalent cation that is required for catalysis by malic enzymes.CONCLUSIONS: The structure reveals that malic enzymes belong to a new class of oxidative decarboxylases. The tetramer of the enzyme appears to be a dimer of dimers. The active site of each monomer is located far from the tetramer interface. The structure also shows the binding of a second NAD+ molecule in a pocket 35 A away from the active site. The natural ligand for this second binding site may be ATP, an allosteric inhibitor of the enzyme.TP, an allosteric inhibitor of the enzyme.)
Lucchinetti 2012 Anesthesiology + (BACKGROUND: Mesenchymal stem cells (MSC) a … BACKGROUND: Mesenchymal stem cells (MSC) are self-renewing clonal progenitor cells of nonhematopoietic tissues that exhibit a marked tropism to wounds and tumors. The authors' studies aimed at exploring how local anesthetics would affect MSC biology.METHODS: Proliferation, colony formation, ''in vitro'' wound healing, and bone differentiation assays of culture-expanded bone-marrow-derived murine MSC were performed in the presence of increasing concentrations of lidocaine, ropivacaine, and bupivacaine. Cytotoxicity was monitored by measuring lactate dehydrogenase activity and phosphatidylserine exposure/propidium iodide staining (early apoptotic cells/necrotic cells). Measurements of mitochondrial function in intact and permeabilized cells, transcriptional changes, and changes in nuclear factor κ-light-chain-enhancer of activated B cells signaling in MSC treated with ropivacaine were used to further characterize the biologic effects of local anesthetics on MSC.RESULTS: All local anesthetics reduced MSC proliferation at 100 μM, consistent with cell cycle delay or arrest at the G0/1-S phase transition. They increased lactate dehydrogenase release and the number of annexin V-positive MSC but not necrotic MSC. Colony formation was decreased, differentiation into osteoblasts impaired, and ''in vitro'' wound healing delayed. Mitochondrial respiration and adenosine 5'-triphosphate concentrations were reduced. Microarray analysis revealed significant expression changes in lysosomal genes and genes controlling sterol metabolism, indicating an impaired phospholipid metabolism in the lysosome. Multiple transcriptional programs related to cell differentiation, tumorigenesis, and metastasis were negatively affected by ropivacaine.CONCLUSIONS: The authors' studies demonstrate that local anesthetics significantly affect important aspects of MSC biology. These experiments provide novel rationales for the perioperative use of local anesthetics in patients with cancer but also highlight the potentially detrimental effects of local anesthetics on wound healing.cts of local anesthetics on wound healing.)
Gispert 2009 PLoS One + (BACKGROUND: Parkinson's disease (PD) is an … BACKGROUND: Parkinson's disease (PD) is an adult-onset movement disorder of largely unknown etiology. We have previously shown that loss-of-function mutations of the mitochondrial protein kinase PINK1 (PTEN induced putative kinase 1) cause the recessive PARK6 variant of PD.METHODOLOGY/PRINCIPAL FINDINGS: Now we generated a PINK1 deficient mouse and observed several novel phenotypes: A progressive reduction of weight and of locomotor activity selectively for spontaneous movements occurred at old age. As in PD, abnormal dopamine levels in the aged nigrostriatal projection accompanied the reduced movements. Possibly in line with the PARK6 syndrome but in contrast to sporadic PD, a reduced lifespan, dysfunction of brainstem and sympathetic nerves, visible aggregates of α-synuclein within Lewy bodies or nigrostriatal neurodegeneration were not present in aged PINK1-deficient mice. However, we demonstrate PINK1 mutant mice to exhibit a progressive reduction in mitochondrial preprotein import correlating with defects of core mitochondrial functions like ATP-generation and respiration. In contrast to the strong effect of PINK1 on mitochondrial dynamics in ''Drosophila melanogaster'' and in spite of reduced expression of fission factor ''Mtp18'', we show reduced fission and increased aggregation of mitochondria only under stress in PINK1-deficient mouse neurons.CONCLUSION: Thus, aging ''Pink1(-/-)'' mice show increasing mitochondrial dysfunction resulting in impaired neural activity similar to PD, in absence of overt neuronal death.to PD, in absence of overt neuronal death.)
Raji 2016 J Alzheimers Dis + (BACKGROUND: Physical activity (PA) can be … BACKGROUND: Physical activity (PA) can be neuroprotective and reduce the risk for Alzheimer's disease (AD). In assessing physical activity, caloric expenditure is a proxy marker reflecting the sum total of multiple physical activity types conducted by an individual.OBJECTIVE: To assess caloric expenditure, as a proxy marker of PA, as a predictive measure of gray matter (GM) volumes in the normal and cognitively impaired elderly persons.METHODS: All subjects in this study were recruited from the Institutional Review Board approved Cardiovascular Health Study (CHS), a multisite population-based longitudinal study in persons aged 65 and older. We analyzed a sub-sample of CHS participants 876 subjects (mean age 78.3, 57.5% F, 42.5% M) who had i) energy output assessed as kilocalories (kcal) per week using the standardized Minnesota Leisure-Time Activities questionnaire, ii) cognitive assessments for clinical classification of normal cognition, mild cognitive impairment (MCI), and AD, and iii) volumetric MR imaging of the brain. Voxel-based morphometry modeled the relationship between kcal/week and GM volumes while accounting for standard covariates including head size, age, sex, white matter hyperintensity lesions, MCI or AD status, and site. Multiple comparisons were controlled using a False Discovery Rate of 5 percent.RESULTS: Higher energy output, from a variety of physical activity types, was associated with larger GM volumes in frontal, temporal, and parietal lobes, as well as hippocampus, thalamus, and basal ganglia. High levels of caloric expenditure moderated neurodegeneration-associated volume loss in the precuneus, posterior cingulate, and cerebellar vermis.CONCLUSION: Increasing energy output from a variety of physical activities is related to larger gray matter volumes in the elderly, regardless of cognitive status.e elderly, regardless of cognitive status.)
Meyer 2010 Eur J Cardiovasc Prev Rehabil + (BACKGROUND: Population strategies to incre … BACKGROUND: Population strategies to increase physical activity are an essential part of cardiovascular disease prevention. However, little data exist on lifestyle interventions that are easy to integrate into everyday life such as using stairs instead of elevators at the workplace.DESIGN: Pre and postintervention study.METHODS: A 12-week promotional campaign for stair use consisting in posters and floor stickers at the point of choice between stairs and elevators at each hospital floor was organized in a university hospital building. In 77 selected employees with an inactive lifestyle, physical activity, aerobic fitness, anthropometrics, blood pressure, lipids, insulin sensitivity, and C-reactive protein were assessed at baseline, 12 weeks, and 6 months.RESULTS: During the intervention median daily number of ascended and descended one-story staircase units was 20.6/day (14.2-28.1) compared with 4.5/day (1.8-7.2) at baseline (''P''<0.001). At 12 weeks, estimated maximal aerobic capacity had increased by 9.2±15.1% (''P''<0.001) corresponding with approximately 1 MET. There were significant declines in waist circumference (-1.7±2.9%), weight (-0.7±2.6%), fat mass (-1.5±8.4%), diastolic blood pressure (-1.8±8.9%), and low-density lipoprotein cholesterol (-3.0±13.5%). At 6 months, the median daily number of ascended and descended one-story staircase units had decreased to 7.2 (3.5-14.0). Benefits on estimated maximal aerobic capacity (+5.9±12.2%, ''P''=0.001) and fat mass (-1.4±8.4%, ''P''=0.038) persisted.CONCLUSION: Encouraging stair use at work is effective for improving fitness, body composition, blood pressure, and lipid profile in asymptomatic individuals with an inactive lifestyle and thus may be a simple way to significantly reduce cardiovascular disease risk at the population level.iovascular disease risk at the population level.)
Grocott 2009 N Engl J Med + (BACKGROUND: The level of environmental hyp … BACKGROUND: The level of environmental hypobaric hypoxia that affects climbers at the summit of Mount Everest (8848 m [29,029 ft]) is close to the limit of tolerance by humans. We performed direct field measurements of arterial blood gases in climbers breathing ambient air on Mount Everest.METHODS: We obtained samples of arterial blood from 10 climbers during their ascent to and descent from the summit of Mount Everest. The partial pressures of arterial oxygen (PaO(2)) and carbon dioxide (PaCO(2)), pH, and hemoglobin and lactate concentrations were measured. The arterial oxygen saturation (SaO(2)), bicarbonate concentration, base excess, and alveolar-arterial oxygen difference were calculated.RESULTS: PaO(2) fell with increasing altitude, whereas SaO(2) was relatively stable. The hemoglobin concentration increased such that the oxygen content of arterial blood was maintained at or above sea-level values until the climbers reached an elevation of 7100 m (23,294 ft). In four samples taken at 8400 m (27,559 ft)--at which altitude the barometric pressure was 272 mm Hg (36.3 kPa)--the mean PaO(2) in subjects breathing ambient air was 24.6 mm Hg (3.28 kPa), with a range of 19.1 to 29.5 mm Hg (2.55 to 3.93 kPa). The mean PaCO(2) was 13.3 mm Hg (1.77 kPa), with a range of 10.3 to 15.7 mm Hg (1.37 to 2.09 kPa). At 8400 m, the mean arterial oxygen content was 26% lower than it was at 7100 m (145.8 ml per liter as compared with 197.1 ml per liter). The mean calculated alveolar-arterial oxygen difference was 5.4 mm Hg (0.72 kPa).CONCLUSIONS: The elevated alveolar-arterial oxygen difference that is seen in subjects who are in conditions of extreme hypoxia may represent a degree of subclinical high-altitude pulmonary edema or a functional limitation in pulmonary diffusion.ctional limitation in pulmonary diffusion.)
Ding 2016 Lancet + (BACKGROUND: The pandemic of physical inact … BACKGROUND: The pandemic of physical inactivity is associated with a range of chronic diseases and early deaths. Despite the well documented disease burden, the economic burden of physical inactivity remains unquantified at the global level. A better understanding of the economic burden could help to inform resource prioritisation and motivate efforts to increase levels of physical activity worldwide.METHODS: Direct health-care costs, productivity losses, and disability-adjusted life-years (DALYs) attributable to physical inactivity were estimated with standardised methods and the best data available for 142 countries, representing 93·2% of the world's population. Direct health-care costs and DALYs were estimated for coronary heart disease, stroke, type 2 diabetes, breast cancer, and colon cancer attributable to physical inactivity. Productivity losses were estimated with a friction cost approach for physical inactivity related mortality. Analyses were based on national physical inactivity prevalence from available countries, and adjusted population attributable fractions (PAFs) associated with physical inactivity for each disease outcome and all-cause mortality.FINDINGS: Conservatively estimated, physical inactivity cost health-care systems international $ (INT$) 53·8 billion worldwide in 2013, of which $31·2 billion was paid by the public sector, $12·9 billion by the private sector, and $9·7 billion by households. In addition, physical inactivity related deaths contribute to $13·7 billion in productivity losses, and physical inactivity was responsible for 13·4 million DALYs worldwide. High-income countries bear a larger proportion of economic burden (80·8% of health-care costs and 60·4% of indirect costs), whereas low-income and middle-income countries have a larger proportion of the disease burden (75·0% of DALYs). Sensitivity analyses based on less conservative assumptions led to much higher estimates.INTERPRETATION: In addition to morbidity and premature mortality, physical inactivity is responsible for a substantial economic burden. This paper provides further justification to prioritise promotion of regular physical activity worldwide as part of a comprehensive strategy to reduce non-communicable diseases.ategy to reduce non-communicable diseases.)
Sarti 2011 Biochim Biophys Acta + (BACKGROUND: The reactions between Complex … BACKGROUND: The reactions between Complex IV (cytochrome c oxidase, CcOX) and nitric oxide (NO) were described in the early 60's. The perception, however, that NO could be responsible for physiological or pathological effects, including those on mitochondria, lags behind the 80's, when the identity of the endothelial derived relaxing factor (EDRF) and NO synthesis by the NO synthases were discovered. NO controls mitochondrial respiration, and cytotoxic as well as cytoprotective effects have been described. The depression of OXPHOS ATP synthesis has been observed, attributed to the inhibition of mitochondrial Complex I and IV particularly, found responsible of major effects.SCOPE OF REVIEW: The review is focused on CcOX and NO with some hints about pathophysiological implications. The reactions of interest are reviewed, with special attention to the molecular mechanisms underlying the effects of NO observed on cytochrome c oxidase, particularly during turnover with oxygen and reductants. MAJOR CONCLUSIONS ANDGENERAL SIGNIFICANCE: The NO inhibition of CcOX is rapid and reversible and may occur in competition with oxygen. Inhibition takes place following two pathways leading to formation of either a relatively stable nitrosyl-derivative (CcOX-NO) of the enzyme reduced, or a more labile nitrite-derivative (CcOX-NO(2)(-)) of the enzyme oxidized, and during turnover. The pathway that prevails depends on the turnover conditions and concentration of NO and physiological substrates, cytochrome c and O(2). All evidence suggests that these parameters are crucial in determining the CcOX vs NO reaction pathway prevailing in vivo, with interesting physiological and pathological consequences for cells. This article is part of a Special Issue entitled: Respiratory Oxidases.cial Issue entitled: Respiratory Oxidases.)
Hereng 2011 Hum Reprod + (BACKGROUND: There has been an ongoing deba … BACKGROUND: There has been an ongoing debate in the reproductive field about whether mammalian spermatozoa rely on glycolysis, oxidative phosphorylation or both for their energy production. Recent studies have proposed that human spermatozoa depend mainly on glucose for motility and fertilization but the mechanism behind an efficient glycolysis in human spermatozoa is not well understood. Here, we demonstrate how human spermatozoa utilize exogenous pyruvate to enhance glycolytic ATP production, motility, hyperactivation and capacitation, events that are crucial for male fertility.METHODS: Purified human spermatozoa from healthy donors were incubated under capacitating conditions (including albumin, bicarbonate and glucose) and tested for changes in ATP levels, motility, hyperactivation and tyrosine phosphorylation after treatment with pyruvate. The experiments were repeated in the presence of sodium cyanide in order to assess the contribution from mitochondrial respiration. The metabolism of (13)C labeled glucose and pyruvate was traced by a combination of liquid chromatography and mass spectrometry.RESULTS: The treatment of human spermatozoa with exogenous pyruvate increased intracellular ATP levels, progressive motility and hyperactivation by 56, 21 and 130%, respectively. In addition, added pyruvate induced a significant increase in tyrosine phosphorylation levels. Blocking of the electron transport chain did not markedly affect the results, indicating that the mechanism is independent of oxidative phosphorylation. However, the observed effects could be counteracted by oxamate, an inhibitor of lactate dehydrogenase (LDH). Metabolic tracing experiments revealed that the observed rise in ATP concentration resulted from an enhanced glycolytic flux, which was increased by more than 50% in the presence of exogenous pyruvate. Moreover, all consumed (13)C labeled pyruvate added was converted to lactate rather than oxidized in the tricarboxylic acid cycle.CONCLUSIONS: Human spermatozoa seem to rely mainly, if not entirely, on glycolysis as the source of ATP fueling the energy-demanding processes of motility and capacitation. The efficient glycolysis is dependent on exogenous pyruvate, which indirectly feeds the accelerated glycolysis with NAD(+) through the LDH-mediated conversion of pyruvate to lactate. Pyruvate is present in the human female reproductive tract at concentrations in accordance with our results. As seen in other mammals, the motility and fertility of human spermatozoa seem to be dictated by the available energy substrates present in the conspecific female.strates present in the conspecific female.)
Hoeks 2011 PLoS One + (BACKGROUND: Type 2 diabetes mellitus and m … BACKGROUND: Type 2 diabetes mellitus and muscle insulin resistance have been associated with reduced capacity of skeletal muscle mitochondria, possibly as a result of increased intake of dietary fat. Here, we examined the hypothesis that a prolonged high-fat diet consumption (HFD) increases the saturation of muscle mitochondrial membrane phospholipids causing impaired mitochondrial oxidative capacity and possibly insulin resistance.METHODOLOGY: C57BL/6J mice were fed an 8-week or 20-week low fat diet (10 kcal%; LFD) or HFD (45 kcal%). Skeletal muscle mitochondria were isolated and fatty acid (FA) composition of skeletal muscle mitochondrial phospholipids was analyzed by thin-layer chromatography followed by GC. High-resolution respirometry was used to assess oxidation of pyruvate and fatty acids by mitochondria. Insulin sensitivity was estimated by HOMA-IR.PRINCIPAL FINDINGS: At 8 weeks, mono-unsaturated FA (16∶1n7, 18∶1n7 and 18∶1n9) were decreased (-4.0%, p<0.001), whereas saturated FA (16∶0) were increased (+3.2%, p<0.001) in phospholipids of HFD vs. LFD mitochondria. Interestingly, 20 weeks of HFD descreased mono-unsaturated FA while n-6 poly-unsaturated FA (18∶2n6, 20∶4n6, 22∶5n6) showed a pronounced increase (+4.0%, p<0.001). Despite increased saturation of muscle mitochondrial phospholipids after the 8-week HFD, mitochondrial oxidation of both pyruvate and fatty acids were similar between LFD and HFD mice. After 20 weeks of HFD, the increase in n-6 poly-unsaturated FA was accompanied by enhanced maximal capacity of the electron transport chain (+49%, p = 0.002) and a tendency for increased ADP-stimulated respiration, but only when fuelled by a lipid-derived substrate. Insulin sensitivity in HFD mice was reduced at both 8 and 20 weeks.CONCLUSIONS/INTERPRETATION: Our findings do not support the concept that prolonged HF feeding leads to increased saturation of skeletal muscle mitochondrial phospholipids resulting in a decrease in mitochondrial fat oxidative capacity and (muscle) insulin resistance.oxidative capacity and (muscle) insulin resistance.)
NCD-RisC 2017 Lancet + (BACKGROUND: Underweight, overweight, and o … BACKGROUND: Underweight, overweight, and obesity in childhood and adolescence are associated with adverse health consequences throughout the life-course. Our aim was to estimate worldwide trends in mean body-mass index (BMI) and a comprehensive set of BMI categories that cover underweight to obesity in children and adolescents, and to compare trends with those of adults.METHODS: We pooled 2416 population-based studies with measurements of height and weight on 128·9 million participants aged 5 years and older, including 31·5 million aged 5-19 years. We used a Bayesian hierarchical model to estimate trends from 1975 to 2016 in 200 countries for mean BMI and for prevalence of BMI in the following categories for children and adolescents aged 5-19 years: more than 2 SD below the median of the WHO growth reference for children and adolescents (referred to as moderate and severe underweight hereafter), 2 SD to more than 1 SD below the median (mild underweight), 1 SD below the median to 1 SD above the median (healthy weight), more than 1 SD to 2 SD above the median (overweight but not obese), and more than 2 SD above the median (obesity).FINDINGS: Regional change in age-standardised mean BMI in girls from 1975 to 2016 ranged from virtually no change (-0·01 kg/m2 per decade; 95% credible interval -0·42 to 0·39, posterior probability [PP] of the observed decrease being a true decrease=0·5098) in eastern Europe to an increase of 1·00 kg/m2 per decade (0·69-1·35, PP>0·9999) in central Latin America and an increase of 0·95 kg/m2 per decade (0·64-1·25, PP>0·9999) in Polynesia and Micronesia. The range for boys was from a non-significant increase of 0·09 kg/m2 per decade (-0·33 to 0·49, PP=0·6926) in eastern Europe to an increase of 0·77 kg/m2 per decade (0·50-1·06, PP>0·9999) in Polynesia and Micronesia. Trends in mean BMI have recently flattened in northwestern Europe and the high-income English-speaking and Asia-Pacific regions for both sexes, southwestern Europe for boys, and central and Andean Latin America for girls. By contrast, the rise in BMI has accelerated in east and south Asia for both sexes, and southeast Asia for boys. Global age-standardised prevalence of obesity increased from 0·7% (0·4-1·2) in 1975 to 5·6% (4·8-6·5) in 2016 in girls, and from 0·9% (0·5-1·3) in 1975 to 7·8% (6·7-9·1) in 2016 in boys; the prevalence of moderate and severe underweight decreased from 9·2% (6·0-12·9) in 1975 to 8·4% (6·8-10·1) in 2016 in girls and from 14·8% (10·4-19·5) in 1975 to 12·4% (10·3-14·5) in 2016 in boys. Prevalence of moderate and severe underweight was highest in India, at 22·7% (16·7-29·6) among girls and 30·7% (23·5-38·0) among boys. Prevalence of obesity was more than 30% in girls in Nauru, the Cook Islands, and Palau; and boys in the Cook Islands, Nauru, Palau, Niue, and American Samoa in 2016. Prevalence of obesity was about 20% or more in several countries in Polynesia and Micronesia, the Middle East and north Africa, the Caribbean, and the USA. In 2016, 75 (44-117) million girls and 117 (70-178) million boys worldwide were moderately or severely underweight. In the same year, 50 (24-89) million girls and 74 (39-125) million boys worldwide were obese.INTERPRETATION: The rising trends in children's and adolescents' BMI have plateaued in many high-income countries, albeit at high levels, but have accelerated in parts of Asia, with trends no longer correlated with those of adults.h trends no longer correlated with those of adults.)
Paech 2017 Arch Toxicol + (BAL30072 is a new monocyclic β-lactam anti … BAL30072 is a new monocyclic β-lactam antibiotic under development which provides a therapeutic option for the treatment of severe infections caused by multi-drug-resistant Gram-negative bacteria. Despite the absence of liver toxicity in preclinical studies in rats and marmosets and in single dose clinical studies in humans, increased transaminase activities were observed in healthy subjects in multiple-dose clinical studies. We, therefore, initiated a comprehensive program to find out the mechanisms leading to hepatocellular injury using HepG2 cells (human hepatocellular carcinoma cell line), HepaRG cells (inducible hepatocytes derived from a human hepatic progenitor cell line), and human liver microtissue preparations. Our investigations demonstrated a concentration- and time-dependent reduction of the ATP content of BAL30072-treated HepG2 cells and liver microtissues. BAL30072 impaired oxygen consumption by HepG2 cells at clinically relevant concentrations, inhibited complexes II and III of the mitochondrial electron transport chain, increased the production of reactive oxygen species (ROS), and reduced the mitochondrial membrane potential. Furthermore, BAL 30072 impaired mitochondrial fatty acid metabolism, inhibited glycolysis, and was associated with hepatocyte apoptosis. Co-administration of N-acetyl-L-cysteine partially protected hepatocytes from BAL30072-mediated toxicity, underscoring the role of oxidative damage in the observed hepatocellular toxicity. In conclusion, BAL30072 is toxic for liver mitochondria and inhibits glycolysis at clinically relevant concentrations. Impaired hepatic mitochondrial function and inhibition of glycolysis can explain liver injury observed in human subjects receiving long-term treatment with this compound.ng long-term treatment with this compound.)

10th World Gene Convention 2019 Qingdao CN + (BIT’s 10th World Gene Convention-2019 (WGC-2019), Qingdao, China, 2019)

Gururaja Rao 2019 Cells + (BKCa channels, orig … BKCa channels, originally discovered in ''Drosophila melanogaster'' as slowpoke (slo), are recognized for their roles in cellular and organ physiology. Pharmacological approaches implicated BKCa channels in cellular and organ protection possibly for their ability to modulate mitochondrial function. However, the direct role of BKCa channels in regulating mitochondrial structure and function is not deciphered. Here, we demonstrate that BKCa channels are present in fly mitochondria, and slo mutants show structural and functional defects in mitochondria. slo mutants display an increase in reactive oxygen species and the modulation of ROS affected their survival. We also found that the absence of BKCa channels reduced the lifespan of ''Drosophila'', and overexpression of human BKCa channels in flies extends life span in males. Our study establishes the presence of BKCa channels in mitochondria of ''Drosophila'' and ascertains its novel physiological role in regulating mitochondrial structural and functional integrity, and lifespan.a'' and ascertains its novel physiological role in regulating mitochondrial structural and functional integrity, and lifespan.)
Crislip 2022 Biomolecules + (BMAL1 is a core mammalian circadian clock … BMAL1 is a core mammalian circadian clock transcription factor responsible for the regulation of the expression of thousands of genes. Previously, male skeletal-muscle-specific BMAL1-inducible-knockout (iMS-BMAL1 KO) mice have been described as a model that exhibits an aging-like phenotype with an altered gait, reduced mobility, muscle weakness, and impaired glucose uptake. Given this aging phenotype and that chronic kidney disease is a disease of aging, the goal of this study was to determine if iMS-BMAL1 KO mice exhibit a renal phenotype. Male iMS-BMAL1 KO and control mice were challenged with a low potassium diet for five days. Both genotypes responded appropriately by conserving urinary potassium. The iMS-BMAL1 KO mice excreted less potassium during the rest phase during the normal diet but there was no genotype difference during the active phase. Next, iMS-BMAL1 KO and control mice were used to compare markers of kidney injury and assess renal function before and after a phase advance protocol. Following phase advance, no differences were detected in renal mitochondrial function in iMS-BMAL1 KO mice compared to control mice. Additionally, the glomerular filtration rate and renal morphology were similar between groups in response to phase advance. Disruption of the clock in skeletal muscle tissue activates inflammatory pathways within the kidney of male mice, and there is evidence of this affecting other organs, such as the lungs. However, there were no signs of renal injury or altered function following clock disruption of skeletal muscle under the conditions tested.eletal muscle under the conditions tested.)
BMES-SIG & MIG Conclave 2023 Virtual + (BMES-SIG & MIG Conclave, Virtual, 2023)
BMT 2022 Innsbruck AT + (BMT 2022, Innsbruck, 2022)
Osiki 2016 FASEB J + (Background Beta-oxidation is often measure … BackgroundBeta-oxidation is often measured using respirometry with octanoylcarnitine + malate as substrates in cells. Malate is necessary to ensure continuous oxidation of octanoylcarnitine. However, since malate is metabolized in the TCA cycle, it is not clear if its inclusion as a co-substrate allows for a valid assessment of beta-oxidation when TCA cycle function is compromised.AimTo investigate the validity of beta-oxidation assessment using octanoylcarnitine + malate as a substrate combination in skeletal muscle when mitochondrial (mt) aconitase is inhibited.MethodsSoleus muscle fibres (1.5–2mg) from healthy male Wistar rats were permeabilized with saponin and incubated for 45 minutes with 1mM oxalomalic acid (aconitase inhibitor) or 1mM 2-mercaptoacetate, an inhibitor of MCAD – the rate-limiting enzyme of octanoylcarnitine oxidation. Respiration at Leak, Oxphos and ET-pathway states were measured using an Oroboros oxygraph. Citrate and 2-oxoglutarate in the respiratory media were measured using CG-MS. Activities of aconitase and MCAD were determined spectrophotometrically.ResultsOxalomalic acid (1mM) and 1mM of 2-mercaptoacetate caused 24% and 58% inhibition of acnonitase and MCAD, respectively. Oxygen flux at Oxphos (0.5 ± 0.3 pmol.S−1.mg−1) and ET-pathway (0.6 ± 0.2 pmol.S−1.mg−1) decreased in 2-mercaptoacetate-treated samples by 62.5% and 60%, respectively, but were unchanged with oxalomalic acid treatment. Respiration at leak state was similar for all treatments. Citrate level in the medium increased by 2-fold at Oxphos state after 30 minutes.ConclusionOctanoylcarnitine + malate allows for a valid assessment of beta-oxidation capacity using respirometry under conditions where mt-aconitase has been inhibited.Support or Funding InformationSupport: 1. The research unit for Exercise Science & Sports Medicine at the University of Cape Town 2. The National Research Foundation (NRF), South Africa, for funding the research.FootnotesThis abstract is from the Experimental Biology 2016 Meeting. There is no full text article associated with this abstract published in The FASEB Journal. this abstract published in The FASEB Journal.)
Nesci 2016 Biochim Biophys Acta + (Background The mitochondrial F1FO-ATP synt … BackgroundThe mitochondrial F1FO-ATP synthase has not only the known life function in building most cellular ATP, but also, as recently hinted, an amazing involvement in cell death. Accordingly, the two-faced enzyme complex, which catalyzes both ATP synthesis and ATP hydrolysis, has been involved in the mitochondrial permeability transition, the master player in apoptosis and necrosis. Nitrite, a cellular nitric oxide reservoir, has a recognized role in cardiovascular protection, through still unclear mechanisms.MethodsIn swine heart mitochondria the effect of nitrite on the F1FO-ATPase activity activated by Ca2+, henceforth defined as Ca-ATPase(s), or by the natural cofactor Mg2+, was investigated by evaluating ATP hydrolysis under different assay conditions.ResultsCa2+ is far less efficient than the natural cofactor Mg2+ in the ATPase activation. However, when activated by Ca2+ the ATPase activity is especially responsive to nitrite, which acts as uncompetitive inhibitor and up to 2 mM inhibits the Ca2+-activated-ATPase(s), probably by promoting dytirosine formation on the enzyme proteins, leaving the Mg-ATPase(s) unaffected. Most likely these ATPases refer to the same F1FO complex, even if coexistent ATPases may overlap.ConclusionsThe preferential inhibition by nitrite of the Ca-ATPase(s), due to post-translational tyrosine modifications, may prevent the calcium-dependent functionality of the mitochondrial F1FO complex and related events.General significanceIn mitochondria the preferential inhibition of the Ca-ATPase activity/ies by nitrite concentrations which do not affect the coexistent Mg-ATPase(s) may quench the negative events linked to the calcium-dependent functioning mode of the F1FO complex under pathological conditions.egative events linked to the calcium-dependent functioning mode of the F1FO complex under pathological conditions.)
Rector 2010 J Hepatol + (Background & aims: In this study, we s … Background & aims: In this study, we sought to determine the temporal relationship between hepatic mitochondrial dysfunction, hepatic steatosis and insulin resistance, and to examine their potential role in the natural progression of non-alcoholic fatty liver disease (NAFLD) utilising a sedentary, hyperphagic, obese, Otsuka Long-Evans Tokushima Fatty (OLETF) rat model.Methods: OLETF rats and their non-hyperphagic control Long-Evans Tokushima Otsuka (LETO) rats were sacrificed at 5, 8, 13, 20, and 40 weeks of age (n=6-8 per group).Results: At 5 weeks of age, serum insulin and glucose and hepatic triglyceride (TG) concentrations did not differ between animal groups; however, OLETF animals displayed significant (p<0.01) hepatic mitochondrial dysfunction as measured by reduced hepatic carnitine palmitoyl-CoA transferase-1 activity, fatty acid oxidation, and cytochrome c protein content compared with LETO rats. Hepatic TG levels were significantly elevated by 8 weeks of age, and insulin resistance developed by 13 weeks in the OLETF rats. NAFLD progressively worsened to include hepatocyte ballooning, perivenular fibrosis, 2.5-fold increase in serum ALT, hepatic mitochondrial ultrastructural abnormalities, and increased hepatic oxidative stress in the OLETF animals at later ages. Measures of hepatic mitochondrial content and function including beta-hydroxyacyl-CoA dehydrogenase activity, citrate synthase activity, and immunofluorescence staining for mitochondrial carbamoyl phosphate synthetase-1, progressively worsened and were significantly reduced at 40 weeks in OLETF rats compared to LETO animals.Conclusions: Our study documents that hepatic mitochondrial dysfunction precedes the development of NAFLD and insulin resistance in the OLETF rats. This evidence suggests that progressive mitochondrial dysfunction contributes to the natural history of obesity-associated NAFLD. the natural history of obesity-associated NAFLD.)
Noz 2019 J Am Heart Assoc + (Background Low-grade inflammation, largely … Background Low-grade inflammation, largely mediated by monocyte-derived macrophages, contributes to atherosclerosis. Sedentary behavior is associated with atherosclerosis and cardiovascular diseases (CVD). We examined whether reducing sedentary behavior and improving walking time improves monocyte inflammatory phenotype in subjects with increased cardiovascular risk. Methods and Results Across 2 waves, 16 individuals with increased cardiovascular risk performed a 16-week intervention study (age 64±6 years, body mass index 29.9±4.3 kg/m2), using a device with vibration feedback to promote physical activity. Before and after intervention, we objectively examined physical activity (ActivPAL), cytokine production capacity after ''ex vivo'' stimulation in peripheral blood mononuclear cells, metabolism of peripheral blood mononuclear cells, circulating cytokine concentrations, and monocyte immunophenotype. Overall, no significant increase in walking time was found (1.9±0.7 to 2.2±1.2 h/day, P=0.07). However, strong, inverse correlations were observed between the change in walking time and the change in production of interleukin (IL)-1β, IL-6, IL-8, and IL-10 after lipopolysaccharide stimulation (rs=-0.655, -0.844, -0.672, and -0.781, respectively, all P<0.05). After intervention optimization based on feedback from wave 1, participants in wave 2 (n=8) showed an increase in walking time (2.2±0.8 to 3.0±1.3 h/day, P=0.001) and attenuated cytokine production of IL-6, IL-8, and IL-10 (all P<0.05). Glycolysis (P=0.08) and maximal OXPHOS (P=0.04) of peripheral blood mononuclear cells decreased after intervention. Lower IL-6 concentrations (P=0.06) and monocyte percentages (P<0.05), but no changes in monocyte subsets were found. Conclusions Successfully improving walking time shifts innate immune function towards a less proinflammatory state, characterized by a lower capacity to produce inflammatory cytokines, in individuals with increased cardiovascular risk.y cytokines, in individuals with increased cardiovascular risk.)
Poles 2021 Front Immunol + (Background and aims: The systemic host res … Background and aims: The systemic host response in sepsis is frequently accompanied by central nervous system (CNS) dysfunction. Evidence suggests that excessive formation of neutrophil extracellular traps (NETs) can increase the permeability of the blood-brain barrier (BBB) and that the evolving mitochondrial damage may contribute to the pathogenesis of sepsis-associated encephalopathy. Kynurenic acid (KYNA), a metabolite of tryptophan catabolism, exerts pleiotropic cell-protective effects under pro-inflammatory conditions. Our aim was to investigate whether exogenous KYNA or its synthetic analogues SZR-72 and SZR-104 affect BBB permeability secondary to NET formation and influence cerebral mitochondrial disturbances in a clinically relevant rodent model of intraabdominal sepsis.Methods: Sprague-Dawley rats were subjected to fecal peritonitis (0.6 g kg-1 ip) or a sham operation. Septic animals were treated with saline or KYNA, SZR-72 or SZR-104 (160 µmol kg-1 each ip) 16h and 22h after induction. Invasive monitoring was performed on anesthetized animals to evaluate respiratory, cardiovascular, renal, hepatic and metabolic parameters to calculate rat organ failure assessment (ROFA) scores. NET components (citrullinated histone H3 (CitH3); myeloperoxidase (MPO)) and the NET inducer IL-1β, as well as IL-6 and a brain injury marker (S100B) were detected from plasma samples. After 24h, leukocyte infiltration (tissue MPO) and mitochondrial complex I- and II-linked (CI-CII) oxidative phosphorylation (OXPHOS) were evaluated. In a separate series, Evans Blue extravasation and the edema index were used to assess BBB permeability in the same regions.Results: Sepsis was characterized by significantly elevated ROFA scores, while the increased BBB permeability and plasma S100B levels demonstrated brain damage. Plasma levels of CitH3, MPO and IL-1β were elevated in sepsis but were ameliorated by KYNA and its synthetic analogues. The sepsis-induced deterioration in tissue CI-CII-linked OXPHOS and BBB parameters as well as the increase in tissue MPO content were positively affected by KYNA/KYNA analogues.Conclusion: This study is the first to report that KYNA and KYNA analogues are potential neuroprotective agents in experimental sepsis. The proposed mechanistic steps involve reduced peripheral NET formation, lowered BBB permeability changes and alleviation of mitochondrial dysfunction in the CNS.n of mitochondrial dysfunction in the CNS.)
Distefano 2012 Abstract IOC68 + (Background: Aging is associated with reduc … Background: Aging is associated with reductions in skeletal muscle mitochondria function as evidenced by a decreased capacity for ATP production and mitochondrial protein content [1,2,3]. Aging is also associated with changes in body composition, including increased adiposity, and a loss of aerobic fitness. Both are factors that confound an examination of the relationship between mitochondrial function and aging per se. The objective of this study was to determine whether the respiratory properties of permeabilized skeletal muscle fibers are altered with chronological age, or more related to age associated changes in adiposity and aerobic fitness.Methods: A total of 63 participants were assigned to one of the following groups: Young (Y, 26.9 ± 0.9 yrs, ''n''=30), Middle-aged (M, 41.2 ± 2.4 yrs, ''n''=13), or Elderly (77.7 ± 1.1 yrs, ''n''=20). Following an overnight fast, a percutaneous muscle biopsy of vastus lateralis was obtained. Maximal coupled (St.''P''), maximal non-coupled (St.''E''), and LEAK state (St.''L'') respiration was determined in saponin permeabilized muscle fiber bundles using high-resolution respirometry. ''V''O2peak was determined by a graded exercise test. Total body fat and fat free mass were assessed by whole body DEXA.Results: The Y group had significantly greater levels of St.''P'' respiration (220 ± 15 pmol O2 s-1mg-1) compared to M (166 ± 13 pmol O2 s-1mg-1, ''P'' = 0.02) and O groups (170 ± 13 pmol O2 s-1mg-1, ''P'' = 0.014). There was no difference in St.''P'' respiration between M and O groups. Similar group differences were also observed for St.''E'' and St.''L'' respiration. The Y group exhibited a higher ''V''O2peak (46 ± 2.9 ml min-1kg-1) compared to M (28 ± 1.8 ml min-1kg-1, ''P''<0.01) and O (21 ± 2.2 ml min-1kg-1, ''P''<0.01) groups. When the three groups were combined, St.''P'' respiration was positively correlated with ''V''O2peak (''R'' = 0.631, ''P''<0.01), and negatively correlated with age (''R'' = -0.324, ''P'' = 0.01), BMI (''R'' =-0.371, ''P''<0.01), fasting glucose (''R'' = -0.252, ''P'' = 0.047), and fat mass (''R'' = -0.516, ''P'' = <0.01).Conclusions: Our data suggest that age related changes in body composition and aerobic fitness may be more important to mitochondrial dysfunction than chronological age per se.References: 1. Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW, Shulman GI (2003) Mitochondrial dysfunction in the elderly: Possible role in insulin resistance. Science 300: 1140-1142.2. Conley KE, Jubrias SA, Esselman PC (2000) Oxidative capacity and ageing in human muscle. J Physiol 526: 203-210.3. Short KR, Bigelow ML, Kahl J, Singh R, Coenen-Schimke J, Raghavakaimal S, Nair KS (2005) Decline in skeletal muscle mitochondrial function with aging in humans. Proc Natl Acad Sci U S A 102: 5618-5623.idative capacity and ageing in human muscle. J Physiol 526: 203-210. 3. Short KR, Bigelow ML, Kahl J, Singh R, Coenen-Schimke J, Raghavakaimal S, Nair KS (2005) Decline in skeletal muscle mitochondrial function with aging in humans. Proc Natl Acad Sci U S A 102: 5618-5623.)
Haslam 2007 Obes Rev + (Background: Although there have been major … Background: Although there have been major advances in the study of obesity, Aibo clearly demonstrates that the one thing the battle against obesity does not need is new scientific invention. Reaven’s utterances proved pivotal, and nothing since has carried the gravitas of his proclamation. Aibo, on the other hand, will be consigned to history’s waste bin. Uniquely among chronic diseases, lack of scientific knowledge is not a barrier to the successful treatment of a person who is obese. Whereas cancer treatment requires new drugs and heart disease updated techniques, obesity is different. We already know enough about the causes and how to manage it by diet, activity, drugs and surgery. The history of obesity is a history of failure. Looking back in time, however, gives us many insights as to treatment in the future. Obesity in history: Obesity is changing, but its origins can be traced back 30 000 years, to our prehistoric ancestors. Survival of the fittest dictated that individuals who stored energy in the most efficient way would survive the inevitable fast and famine that would follow times of plenty. This has been attributed to the ‘thrifty gene’ (although no such individual gene exists), ensuring the continued dominance of our hunter–gatherer predecessors. But natural selection has turned on us. Life now favours inefficient phenotypes who fail to store energy in adipose depots, while those who lay down fat in the abdomen are condemned to premature death. To fight obesity, we are flying in the face of evolution and instinct, consciously countermanding the urge to eat for survival, and be as inactive as possible in order to conserve energy.The situation today: The UK is now in the throes of an obesity epidemic, and risks following in the footsteps of America, where obesity has already delivered an epidemic of diabetes. Writers and physicians over many centuries have dedicated their life’s work to teach the preservation of health, and warn of the dire consequences of ignoring good diet and activity. However, their wisdom has been disregarded. Life expectancy has been improving for centuries; advances in hygiene, science, public health and medicine have allowed longer and more productive lives. Obesity threatens to undo many of these gains. Could it even herald a reduction in life expectancy in coming generations? Instead of spending precious resources inventing novel scientific gadgets, the works of our forefathers should be revisited, and the simple lessons learned from history used to once again prioritize the preservation of health.ain prioritize the preservation of health.)
Pühringer 2021 High Alt Med Biol + (Background: Altitude exposure reduces maxi … Background: Altitude exposure reduces maximal oxygen uptake (''V''O2max). Usually, the reduction is not restored with acclimatization (at least at altitudes above 2500 m) and is more pronounced in highly trained athletes compared to nonathletes. It still remains to be elucidated whether these also apply for well-acclimatized individuals (i.e., mountain guides) acutely exposed to moderate altitude (i.e., 2000 m). Methods: A total of 128 acclimatized male mountain guides of the Austrian armed forces (42.2 ± 7.0 years, 177.8 ± 5.6 cm, 77.2 ± 7.0 kg) of different fitness levels performed 2 incremental cycle ergometer tests 1 week apart, one at low (600 m) and one at moderate altitude (2000 m). Oxygen uptake, heart rate (HR), and lactate concentration were measured during the tests. Results: In acclimatized mountain guides, lower baseline ''V''O2max levels were associated with better preservation of ''V''O2max at moderate altitude compared to higher levels. At moderate altitude, physiological responses (HR and blood lactate at 100 W) at a submaximal exercise intensity of 100 W remained unchanged or were even slightly reduced in both groups. Conclusions: Long-term acclimatization to moderate altitude may prevent the ''V''O2max decline at a moderate altitude of 2 000 m particularly in subjects with lower ''V''O2max levels, that is, below the 80th percentile (for age and sex). In people with higher fitness levels, ''V''O2max may still be negatively affected. These results are of practical relevance, for example, for workers, athletes, ski and mountain guides, military staff, or rescue staff who regularly or continuously have to perform at moderate altitude.e of practical relevance, for example, for workers, athletes, ski and mountain guides, military staff, or rescue staff who regularly or continuously have to perform at moderate altitude.)
Reiss 2022 Exp Gerontol + (Background: Alzheimer's disease (AD) is th … Background: Alzheimer's disease (AD) is the most prevalent form of dementia worldwide and is characterized by progressive memory loss and cognitive impairment. Our understanding of AD pathogenesis is limited and no effective disease-modifying treatment is available. Mitochondria are cytoplasmic organelles critical to the homeostatic regulation of glucose and energy in the cell.Methods: Mitochondrial abnormalities are found early in the course of AD and dysfunctional mitochondria are involved in AD progression. The resulting respiratory chain impairment, neuronal apoptosis, and generation of reactive oxygen species are highly damaging to neurons. Restoration of mitochondrial function may provide a novel therapeutic strategy for AD.Results: This review discusses the specifics of mitochondrial fragmentation, imbalances in fission and fusion, and DNA damage seen in AD and the contribution of compromised mitochondrial activity to AD etiopathogenesis. It explores how an understanding of the processes underlying mitochondrial failure may lead to urgently needed treatment innovations. It considers individual mitochondrial proteins that have emerged as promising drug targets and evaluates neuroprotective agents that could improve the functional state of mitochondria in the setting of AD.Conclusions: There is great promise in exploring original approaches to preserving mitochondrial viability as a means to achieve breakthroughs in treating AD.s to achieve breakthroughs in treating AD.)
Wider 2023 Crit Care + (Background: Brain injury is a leading caus … Background: Brain injury is a leading cause of morbidity and mortality in patients resuscitated from cardiac arrest. Mitochondrial dysfunction contributes to brain injury following cardiac arrest; therefore, therapies that limit mitochondrial dysfunction have the potential to improve neurological outcomes. Generation of reactive oxygen species (ROS) during ischemia-reperfusion injury in the brain is a critical component of mitochondrial injury and is dependent on hyperactivation of mitochondria following resuscitation. Our previous studies have provided evidence that modulating mitochondrial function with specific near-infrared light (NIR) wavelengths can reduce post-ischemic mitochondrial hyperactivity, thereby reducing brain injury during reperfusion in multiple small animal models.Methods: Isolated porcine brain cytochrome c oxidase (COX) was used to investigate the mechanism of NIR-induced mitochondrial modulation. Cultured primary neurons from mice expressing mitoQC were utilized to explore the mitochondrial mechanisms related to protection with NIR following ischemia-reperfusion. Anesthetized pigs were used to optimize the delivery of NIR to the brain by measuring the penetration depth of NIR to deep brain structures and tissue heating. Finally, a model of out-of-hospital cardiac arrest with CPR in adult pigs was used to evaluate the translational potential of NIR as a noninvasive therapeutic approach to protect the brain after resuscitation.Results: Molecular evaluation of enzyme activity during NIR irradiation demonstrated COX function was reduced in an intensity-dependent manner with a threshold of enzyme inhibition leading to a moderate reduction in activity without complete inhibition. Mechanistic interrogation in neurons demonstrated that mitochondrial swelling and upregulation of mitophagy were reduced with NIR treatment. NIR therapy in large animals is feasible, as NIR penetrates deep into the brain without substantial tissue heating. In a translational porcine model of CA/CPR, transcranial NIR treatment for two hours at the onset of return of spontaneous circulation (ROSC) demonstrated significantly improved neurological deficit scores and reduced histologic evidence of brain injury after resuscitation from cardiac arrest.Conclusions: NIR modulates mitochondrial function which improves mitochondrial dynamics and quality control following ischemia/reperfusion. Noninvasive modulation of mitochondria, achieved by transcranial treatment of the brain with NIR, mitigates post-cardiac arrest brain injury and improves neurologic functional outcomes.d improves neurologic functional outcomes.)
Serafim 2021 Eur J Clin Invest + (Background: Changes in the nutritional env … Background: Changes in the nutritional environment in utero induced by maternal obesity (MO) lead to foetal metabolic dysfunction predisposing offspring to later-life metabolic diseases. Since mitochondria play a crucial role in hepatic metabolism and function, we hypothesized that MO prior to conception and throughout pregnancy programmes foetal sheep liver mitochondrial phenotype.Material and methods: Ewes ate an obesogenic diet (150% requirements; MO), or 100% requirements (CTR), from 60 days prior to conception. Foetal livers were removed at 0.9 gestation. We measured foetal liver mitochondrial DNA copy number, activity of superoxide dismutase, cathepsins B and D and selected protein content, total phospholipids and cardiolipin and activity of mitochondrial respiratory chain complexes.Results: A significant decrease in activities of mitochondrial complexes I, II-III and IV, but not aconitase, was observed in MO. In the antioxidant machinery, there was a significant increase in activity of total superoxide dismutase (SOD) and SOD2 in MO. However, no differences were found regarding autophagy-related protein content (p62, beclin-I, LC3-I, LC3-II and Lamp2A) and cathepsin B and D activities. A 21.5% decrease in total mitochondrial phospholipid was observed in MO.Conclusions: The data indicate that MO impairs foetal hepatic mitochondrial oxidative capacity and affects total mitochondrial phospholipid content. In addition, MO affects the regulation of foetal liver redox pathways, indicating metabolic adaptations to the higher foetal lipid environment. Consequences of in utero programming of foetal hepatic metabolism may persist and compromise mitochondrial bioenergetics in later life, and increase susceptibility to metabolic diseases.ease susceptibility to metabolic diseases.)
Picard 2018 Biol Psychiatry + (Background: Chronic life stress, such as t … Background: Chronic life stress, such as the stress of caregiving, can promote pathophysiology, but the underlying cellular mechanisms are not well understood. Chronic stress may induce recalibrations in mitochondria leading to changes either in mitochondrial content per cell, or in mitochondrial functional capacity (i.e., quality).Methods: Here we present a functional index of mitochondrial health (MHI) for human leukocytes that can distinguish between these two possibilities. The MHI integrates nuclear and mitochondrial DNA-encoded respiratory chain enzymatic activities and mitochondrial DNA copy number. We then use the MHI to test the hypothesis that daily emotional states and caregiving stress influence mitochondrial function by comparing healthy mothers of a child with an autism spectrum disorder (high-stress caregivers, ''n'' = 46) with mothers of a neurotypical child (control group, ''n'' = 45).Results: The MHI outperformed individual mitochondrial function measures. Elevated positive mood at night was associated with higher MHI, and nightly positive mood was also a mediator of the association between caregiving and MHI. Moreover, MHI was correlated to positive mood on the days preceding, but not following the blood draw, suggesting for the first time in humans that mitochondria may respond to proximate emotional states within days. Correspondingly, the caregiver group, which had higher perceived stress and lower positive and greater negative daily affect, exhibited lower MHI. This effect was not explained by a mismatch between nuclear and mitochondrial genomes.Conclusions: Daily mood and chronic caregiving stress are associated with mitochondrial functional capacity. Mitochondrial health may represent a nexus between psychological stress and health.s between psychological stress and health.)
Bhatraju 2020 N Engl J Med + (Background: Community transmission of coro … Background: Community transmission of coronavirus 2019 (Covid-19) was detected in the state of Washington in February 2020.Methods: We identified patients from nine Seattle-area hospitals who were admitted to the intensive care unit (ICU) with confirmed infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Clinical data were obtained through review of medical records. The data reported here are those available through March 23, 2020. Each patient had at least 14 days of follow-up.Results: We identified 24 patients with confirmed Covid-19. The mean (±SD) age of the patients was 64±18 years, 63 % were men, and symptoms began 7±4 days before admission. The most common symptoms were cough and shortness of breath; 50 % of patients had fever on admission, and 58 % had diabetes mellitus. All the patients were admitted for hypoxemic respiratory failure; 75 % (18 patients) needed mechanical ventilation. Most of the patients (17) also had hypotension and needed vasopressors. No patient tested positive for influenza A, influenza B, or other respiratory viruses. Half the patients (12) died between ICU day 1 and day 18, including 4 patients who had a do-not-resuscitate order on admission. Of the 12 surviving patients, 5 were discharged home, 4 were discharged from the ICU but remained in the hospital, and 3 continued to receive mechanical ventilation in the ICU.Conclusions: During the first 3 weeks of the Covid-19 outbreak in the Seattle area, the most common reasons for admission to the ICU were hypoxemic respiratory failure leading to mechanical ventilation, hypotension requiring vasopressor treatment, or both. Mortality among these critically ill patients was high. (Funded by the National Institutes of Health.).ed by the National Institutes of Health.).)
Catania 2019 Orphanet J Rare Dis + (Background: Complex I (CI or NADH:ubiquino … Background: Complex I (CI or NADH:ubiquinone oxidoreductase) deficiency is the most frequent cause of mitochondrial respiratory chain defect. Successful attempts to rescue CI function by introducing an exogenous NADH dehydrogenase, such as the NDI1 from Saccharomyces cerevisiae (ScNDI1), have been reported although with drawbacks related to competition with CI. In contrast to ScNDI1, which is permanently active in yeast naturally devoid of CI, plant alternative NADH dehydrogenases (NDH-2) support the oxidation of NADH only when the CI is metabolically inactive and conceivably when the concentration of matrix NADH exceeds a certain threshold. We therefore explored the feasibility of CI rescue by NDH-2 from Arabidopsis thaliana (At) in human CI defective fibroblasts.Results: We showed that, other than ScNDI1, two different NDH-2 (AtNDA2 and AtNDB4) targeted to the mitochondria were able to rescue CI deficiency and decrease oxidative stress as indicated by a normalization of SOD activity in human CI-defective fibroblasts. We further demonstrated that when expressed in human control fibroblasts, AtNDA2 shows an affinity for NADH oxidation similar to that of CI, thus competing with CI for the oxidation of NADH as opposed to our initial hypothesis. This competition reduced the amount of ATP produced per oxygen atom reduced to water by half in control cells.Conclusions: In conclusion, despite their promising potential to rescue CI defects, due to a possible competition with remaining CI activity, plant NDH-2 should be regarded with caution as potential therapeutic tools for human mitochondrial diseases.ic tools for human mitochondrial diseases.)
Furihata 2021 BMC Pharmacol Toxicol + (Background: Doxorubicin (DOX) is widely us … Background: Doxorubicin (DOX) is widely used as an effective chemotherapeutic agent for cancers; however, DOX induces cardiac toxicity, called DOX-induced cardiomyopathy. Although DOX-induced cardiomyopathy is known to be associated with a high cumulative dose of DOX, the mechanisms of its long-term effects have not been completely elucidated. Pioglitazone (Pio) is presently contraindicated in patients with symptomatic heart failure owing to the side effects. The concept of drug repositioning led us to hypothesize the potential effects of Pio as a premedication before DOX treatment, and to analyze this hypothesis in mice.Methods: First, for the hyperacute (day 1) and acute (day 7) DOX-induced dysfunction models, mice were fed a standard diet with or without 0.02% (wt/wt) Pio for 5 days before DOX treatment (15 mg/kg body weight [BW] via intraperitoneal [i.p.] administration). The following 3 treatment groups were analyzed: standard diet + vehicle (Vehicle), standard diet + DOX (DOX), and Pio + DOX. Next, for the chronic model (day 35), the mice were administrated DOX once a week for 5 weeks (5 mg/kg BW/week, i.p.).Results: In the acute phase after DOX treatment, the percent fractional shortening of the left ventricle (LV) was significantly decreased in DOX mice. This cardiac malfunction was improved in Pio + DOX mice. In the chronic phase, we observed that LV function was preserved in Pio + DOX mice.Conclusions: Our findings may provide a new pathophysiological explanation by which Pio plays a role in the treatment of DOX-induced cardiomyopathy, but the molecular links between Pio and DOX-induced LV dysfunction remain largely elusive.ced LV dysfunction remain largely elusive.)
Zuccolotto-dos-Reis 2021 Eur J Clin Invest + (Background: Freezing human biopsies is com … Background: Freezing human biopsies is common in clinical practice for storage. However, this technique disrupts mitochondrial membranes, hampering further analyses of respiratory function. To contribute to laboratorial diagnosis of mitochondrial diseases, this study sought to develop a respirometry approach using O2k (Oroboros Ins.) to measure the whole electron transport chain (ETC) activity in homogenates of frozen skeletal muscle biopsies.Patients and methods: We enrolled 16 patients submitted to muscle biopsy in the process of routine diagnostic investigation: four with mitochondrial disease and severe mitochondrial dysfunction; seven with exercise intolerance and multiple deletions of mitochondrial DNA, presenting mild to moderate mitochondrial dysfunction; five without mitochondrial disease, as controls. Whole homogenates of muscle fragments were prepared using grinder-type equipment. O2 consumption rates were normalized using citrate synthase activity.Results: Transmission electron microscopy confirmed mitochondrial membrane discontinuation, indicating increased permeability of mitochondrial membranes in homogenates from frozen biopsies. O2 consumption rates in the presence of acetyl-CoA lead to maximum respiratory rates sensitive to rotenone, malonate and antimycin. This protocol of acetyl-CoA-driven respiration (ACoAR), applied in whole homogenates of frozen muscle, was sensitive enough to identify ETC abnormality, even in patients with mild to moderate mitochondrial dysfunction. We demonstrated adequate repeatability of ACoAR and found significant correlation between O2 consumption rates and enzyme activity assays of individual ETC complexes.Conclusions: We present preliminary data on a simple, low cost and reliable procedure to measure respiratory function in whole homogenates of frozen skeletal muscle biopsies, contributing to diagnosis of mitochondrial diseases in humans.Keywords: acetyl-CoA-driven respiration; electron transport chain; frozen skeletal muscle biopsy; high-resolution respirometry; mitochondrial diseases; oxygen consumption rate.ondrial diseases; oxygen consumption rate.)
Guralnik 1995 N Engl J Med + (Background: Functional assessment is an im … Background: Functional assessment is an important part of the evaluation of elderly persons. We conducted this study to determine whether objective measures of physical function can predict subsequent disability in older persons.Methods: This prospective cohort study included men and women 71 years of age or older who were living in the community, who reported no disability in the activities of daily living, and who reported that they were able to walk one-half mile (0.8 km) and climb stairs without assistance. The subjects completed a short battery of physical-performance tests and participated in a follow-up interview four years later. The tests included an assessment of standing balance, a timed 8-ft (2.4-m) walk at a normal pace, and a timed test of five repetitions of rising from a chair and sitting down.Results: Among the 1122 subjects who were not disabled at base line and who participated in the four-year follow-up, lower scores on the base-line performance tests were associated with a statistically significant, graduated increase in the frequency of disability in the activities of daily living and mobility-related disability at follow-up. After adjustment for age, sex, and the presence of chronic disease, those with the lowest scores on the performance tests were 4.2 to 4.9 times as likely to have disability at four years as those with the highest performance scores, and those with intermediate performance scores were 1.6 to 1.8 times as likely to have disability.Conclusions: Among nondisabled older persons living in the community, objective measures of lower-extremity function were highly predictive of subsequent disability. Measures of physical performance may identify older persons with a preclinical stage of disability who may benefit from interventions to prevent the development of frank disability.event the development of frank disability.)
Lin 2017 Neuro Oncol + (Background: Glioma is the most common form … Background: Glioma is the most common form of primary malignant brain tumor in adults, with approximately 4 cases per 100 000 people each year. Gliomas, like many tumors, are thought to primarily metabolize glucose for energy production; however, the reliance upon glycolysis has recently been called into question. In this study, we aimed to identify the metabolic fuel requirements of human glioma cells.Methods: We used database searches and tissue culture resources to evaluate genotype and protein expression, tracked oxygen consumption rates to study metabolic responses to various substrates, performed histochemical techniques and fluorescence-activated cell sorting-based mitotic profiling to study cellular proliferation rates, and employed an animal model of malignant glioma to evaluate a new therapeutic intervention.Results: We observed the presence of enzymes required for fatty acid oxidation within human glioma tissues. In addition, we demonstrated that this metabolic pathway is a major contributor to aerobic respiration in primary-cultured cells isolated from human glioma and grown under serum-free conditions. Moreover, inhibiting fatty acid oxidation reduces proliferative activity in these primary-cultured cells and prolongs survival in a syngeneic mouse model of malignant glioma.Conclusions: Fatty acid oxidation enzymes are present and active within glioma tissues. Targeting this metabolic pathway reduces energy production and cellular proliferation in glioma cells. The drug etomoxir may provide therapeutic benefit to patients with malignant glioma. In addition, the expression of fatty acid oxidation enzymes may provide prognostic indicators for clinical practice.ognostic indicators for clinical practice.)
Agrillo 2020 PLOS ONE + (Background: Humans and non-human animals s … Background: Humans and non-human animals share an approximate non-verbal system for representing and comparing numerosities that has no upper limit and for which accuracy is dependent on the numerical ratio. Current evidence indicates that the mechanism for keeping track of individual objects can also be used for numerical purposes; if so, its accuracy will be independent of numerical ratio, but its capacity is limited to the number of items that can be tracked, about four. There is, however, growing controversy as to whether two separate number systems are present in other vertebrate species.Methodology/Principal Findings: In this study, we compared the ability of undergraduate students and guppies to discriminate the same numerical ratios, both within and beyond the small number range. In both students and fish the performance was ratio-independent for the numbers 1–4, while it steadily increased with numerical distance when larger numbers were presented.Conclusions/Significance: Our results suggest that two distinct systems underlie quantity discrimination in both humans and fish, implying that the building blocks of uniquely human mathematical abilities may be evolutionarily ancient, dating back to before the divergence of bony fish and tetrapod lineages.rgence of bony fish and tetrapod lineages.)
Kaczynski FENS Forum 2010 + (Background: L-arginine (2-amino-5-guanidin … Background: L-arginine (2-amino-5-guanidino-pentanoic acid) is an important amino acid for birds, carnivores and mammals. Its metabolism is complex and is only partially known. L-arginine is a substrate for nitric oxide (NO) which penetrates freely across cell membranes. The enhanced generation of NO may reduce necrosis and apoptosis in ischemia/reperfusion-induced injury in ratliver. NO donors also protect the ischemic heart from apoptosis and mitochondrial dysfunction via PKG-mediated blockage of mitochondrial permeability transition pores and subsequenced cytochrome ''c'' release. It is anticipated that NO through cGMP-dependent mechanisms can activatesurvival paths in hippocampal neurons and prevent apoptosis.Aims: The study of the mitochondria-related antiapoptotic influence of L-arginine against proapoptotic, proinflammatory, and metabolic stressor staurosporine in human glioblastoma LN-18 (brain cell line).Methods: The cultured glioblastoma LN-18 cells were preincubated with L-arginine (L-arg; 0.1, 0.3 or 1 mM) for 24 hours and were challenged with staurosporine (STS; 0.025 microM) for the last four hours of incubation. Measurement of the mitochondrial respiration rates was performed using Oxygraph-2k (OROBOROS®). The ATP generation was followed by using luminescence method withLuciferase/Luciferine (ATP Lite, Parkin Elmer) commercial kits. Additionally the changes in the internal mitochondrial membrane potential by the high-content cell analysis confocal fluorescent microscopy which allows prolonged imaging of live cells in controlled environment (BD Pathway 855 Bioimager) are presently performed with the usage of TMRM (for active mitochondria staining) andHoechst (for nucleus staining).Results: L-arginine per se at 0.3 mM to 1 mM increased ATP generation, but this effect was reduced by the presence of the proapoptotic staurosporine.Conclusions: L-arginine seems to increase ATP generation in LN-18 cells, however this effect could not overcome the influence of staurosporine. The possible influence on mitochondrial membrane potential will be presented.Supported by the Polish-Norwegian Research Found no. PNRF-104-Al-1/07.egian Research Found no. PNRF-104-Al-1/07.)
Kaczynski 2010 FENS Abstr + (Background: L-arginine (2-amino-5-guanidin … Background: L-arginine (2-amino-5-guanidino-pentanoic acid) is an important amino acid for birds, carnivores and mammals. Its metabolism is complex and is only partially known. L-arginine is a substrate for nitric oxide (NO) which penetrates freely across cell membranes. The enhanced generation of NO may reduce necrosis and apoptosis in ischemia/reperfusion-induced injury in ratliver. NO donors also protect the ischemic heart from apoptosis and mitochondrial dysfunction via PKG-mediated blockage of mitochondrial permeability transition pores and subsequenced cytochrome c release. It is anticipated that NO through cGMP-dependent mechanisms can activatesurvival paths in hippocampal neurons and prevent apoptosis.Aims: The study of the mitochondria-related antiapoptotic influence of L-arginine against proapoptotic, proinflammatory, and metabolic stressor staurosporine in human glioblastoma LN-18 (brain cell line).Methods: The cultured glioblastoma LN-18 cells were preincubated with L-arginine (L-arg; 0.1, 0.3 or 1 mM) for 24 hours and were challenged with staurosporine (STS; 0.025 microM) for the last four hours of incubation. Measurement of the mitochondrial respiration rates was performed usingOxygraph-2k (OROBOROS®). The ATP generation was followed by using luminescence method with Luciferase/Luciferine (ATP Lite, Parkin Elmer) commercial kits. Additionally the changes in the internal mitochondrial membrane potential by the high-content cell analysis confocal fluorescent microscopy which allows prolonged imaging of live cells in controlled environment (BD Pathway 855Bioimager) are presently performed with the usage of TMRM (for active mitochondria staining) and Hoechst (for nucleus staining).Results: L-arginine per se at 0.3 mM to 1 mM increased ATP generation, but this effect was reduced by the presence of the proapoptotic staurosporine.Conclusions: L-arginine seems to increase ATP generation in LN-18 cells, however this effect could not overcome the influence of staurosporine. The possible influence on mitochondrial membrane potential will be presented.rial membrane potential will be presented.)
Petrilli 2020 medRxiv + (Background: Little is known about factors … Background: Little is known about factors associated with hospitalization and critical illness in Covid-19 positive patients. Methods: We conducted a cross-sectional analysis of all patients with laboratory-confirmed Covid-19 treated at a single academic health system in New York City between March 1, 2020 and April 2, 2020, with follow up through April 7, 2020. Primary outcomes were hospitalization and critical illness (intensive care, mechanical ventilation, hospice and/or death). We conducted multivariable logistic regression to identify risk factors for adverse outcomes, and maximum information gain decision tree classifications to identify key splitters. Results: Among 4,103 Covid-19 patients, 1,999 (48.7 %) were hospitalized, of whom 981/1,999 (49.1 %) have been discharged home, and 292/1,999 (14.6 %) have died or were discharged to hospice. Of 445 patients requiring mechanical ventilation, 162/445 (36.4 %) have died. Strongest hospitalization risks were age ≥75 years (OR 66.8, 95 % CI, 44.7-102.6), age 65-74 (OR 10.9, 95 % CI, 8.35-14.34), BMI>40 (OR 6.2, 95 % CI, 4.2-9.3), and heart failure (OR 4.3 95 % CI, 1.9-11.2). Strongest critical illness risks were admission oxygen saturation <88 % (OR 6.99, 95 % CI 4.5-11.0), d-dimer>2500 (OR 6.9, 95 % CI, 3.2-15.2), ferritin >2500 (OR 6.9, 95 % CI, 3.2-15.2), and C-reactive protein (CRP) >200 (OR 5.78, 95 % CI, 2.6-13.8). In the decision tree for admission, the most important features were age >65 and obesity; for critical illness, the most important was SpO2<88, followed by procalcitonin >0.5, troponin <0.1 (protective), age >64 and CRP>200. Conclusions: Age and comorbidities are powerful predictors of hospitalization; however, admission oxygen impairment and markers of inflammation are most strongly associated with critical illness.markers of inflammation are most strongly associated with critical illness.)
Stensvold 2012 Metab Syndr Relat Disord + (Background: Metabolic syndrome is associat … Background: Metabolic syndrome is associated with chronic low-grade inflammation, a condition thought to play a key role in the pathogenesis of the syndrome. Among a number of proinflammatory cytokines, interleukin-18 (IL-18) seems to be the best marker for inflammation among people with metabolic syndrome. The aim of this study was to examine the effect of aerobic training versus strength training on circulating IL-18 and other proinflammatory markers in people with metabolic syndrome. Methods: Thirty-one inactive men and women with metabolic syndrome were randomized to either high-intensity aerobic interval training ('''AIT''', ''n''=11), strength training ('''ST''', ''n''=10), or a control group (''n''=10). Exercise training was carried out three times per week for 12 weeks. Serum insulin, high-sensitivity C-reactive protein (hsCRP), IL-18, IL-6, and tumor necrosis factor-α (TNF-α) were measured before and after the intervention. Results: Serum IL-18 was reduced by 43% after AIT (''P''<0.001). Although there was no change in TNF-α from baseline after AIT, the levels were lower compared to the ST (''P''=0.032) and control groups (''P''=0.039) after the intervention. Total body fat was reduced after AIT (from 33.9±7.3% to 32.2±7.9%, ''P''<0.001) and ST (from 31.2±3.9% to 29.7±3.4%, ''P''=0.025). There were no changes in serum IL-6, insulin, or hsCRP within or between the groups. Conclusion: Both ST and AIT reduced fat mass. However, only the latter intervention was associated with a more favorable inflammatory status among people with metabolic syndrome. Clinical Trial Registration Information: http://clinicaltrials.gov/show/NCT00986024/ion: http://clinicaltrials.gov/show/NCT00986024/)
Huete-Ortega 2018 Biotechnol Biofuels + (Background: Microalgae accumulate lipids w … Background: Microalgae accumulate lipids when exposed to stressful conditions such as nutrient limitation that can be used to generate biofuels. Nitrogen limitation or deprivation is a strategy widely employed to elicit this response. However, this strategy is associated with a reduction in the microalgal growth, leading to overall poor lipid productivities. Here, we investigated the combined effect of a reduced source of nitrogen (ammonium) and super-saturating light intensities on the growth and induction of lipid accumulation in two model but diverse microalgal species, Phaeodactylum tricornutum and Nannochloropsis oceanica. We hypothesized that the lower energy cost of assimilating ammonium would allow the organisms to use more reductant power for lipid biosynthesis without compromising growth and that this would be further stimulated by the effect of high light (1000 µmol m-2 s-1) stress. We studied the changes in growth and physiology of both species when grown in culture media that either contained nitrate or ammonium as the nitrogen source, and an additional medium that contained ammonium with tungsten in place of molybdenum and compared this with growth in media without nitrogen. We focused our investigation on the early stages of exposure to the treatments to correspond to events relevant to induction of lipid accumulation in these two species.Results: At super-saturating light intensities, lipid productivity in P. tricornutum increased twofold when grown in ammonium compared to nitrogen free medium that increased further when tungsten was present in the medium in place of molybdenum. Conversely, N. oceanica growth and physiology was not compromised by the high light intensities used, and the use of ammonium had a negative effect on the lipid productivity, which was even more marked when tungsten was present.Conclusions: Whilst the use of ammonium and super-saturating light intensities in P. tricornutum was revealed to be a good strategy for increasing lipid biosynthesis, no changes in the lipid productivity of N. oceanica were observed, under these conditions. Both results provide relevant direction for the better design of processes to produce biofuels in microalgae by manipulating growth conditions without the need to subject them to genetic engineering manipulation. them to genetic engineering manipulation.)
Szczerbinski 2021 Cells + (Background: Mitochondrial dysfunction has … Background: Mitochondrial dysfunction has been implicated in the pathogenesis of type 2 diabetes, but its contribution to the early stages of dysglycemia remains poorly understood. By collecting a high-resolution stage-based spectrum of dysglycemia, our study fills this gap by evaluating derangement in both the function and quantity of mitochondria. We sampled mitochondria in skeletal muscle and subcutaneous adipose tissues of subjects with progressive advancement of dysglycemia under a three-month exercise intervention. Methods: We measured clinical metabolic parameters and gathered skeletal muscle and adipose tissue biopsies before and after the three-month exercise intervention. We then assayed the number of mitochondria via citrate synthase (CS) activity and functional parameters with high-resolution respirometry. Results: In muscle, there were no differences in mitochondrial quantity or function at baseline between normoglycemics and prediabetics. However, the intervention caused improvement in CS activity, implying an increase in mitochondrial quantity. By contrast in adipose tissue, baseline differences in CS activity were present, with the lowest CS activity coincident with impaired fasting glucose and impaired glucose tolerance (IFG + IGT). Finally, CS activity, but few of the functional metrics, improved under the intervention. Conclusions: We show that in prediabetes, no differences in the function or amount of mitochondria (measured by CS activity) in skeletal muscle are apparent, but in adipose tissue of subjects with IFG + IGT, a significantly reduced activity of CS was observed. Finally, metabolic improvements under the exercise correlate to improvements in the amount, rather than function, of mitochondria in both tissues.function, of mitochondria in both tissues.)
Zhang 2021 PLOS ONE + (Background: Mitochondrial dysfunction is i … Background: Mitochondrial dysfunction is involved in many complex diseases. Efficient and accurate evaluation of mitochondrial functionality is crucial for understanding pathology as well as facilitating novel therapeutic developments. As a popular platform, Seahorse extracellular flux (XF) analyzer is widely used for measuring mitochondrial oxygen consumption rate (OCR) in living cells. A hidden feature of Seahorse XF OCR data is that it has a complex data structure, caused by nesting and crossing between measurement cycles, wells and plates. Surprisingly, statistical analysis of Seahorse XF data has not received sufficient attention, and current methods completely ignore the complex data structure, impairing the robustness of statistical inference.Results: To rigorously incorporate the complex structure into data analysis, here we developed a Bayesian hierarchical modeling framework, OCRbayes, and demonstrated its applicability based on analysis of published data sets.Conclusions: We showed that OCRbayes can analyze Seahorse XF OCR experimental data derived from either single or multiple plates. Moreover, OCRbayes has potential to be used for diagnosing patients with mitochondrial diseases.sing patients with mitochondrial diseases.)
Besancon 2020 Res Integr Peer Rev + (Background: Our aim is to highlight the be … Background: Our aim is to highlight the benefits and limitations of open and non-anonymized peer review. Our argument is based on the literature and on responses to a survey on the reviewing process of alt.chi, a more or less open review track within the so-called Computer Human Interaction (CHI) conference, the predominant conference in the field of human-computer interaction. This track currently is the only implementation of an open peer review process in the field of human-computer interaction while, with the recent increase in interest in open scientific practices, open review is now being considered and used in other fields.Methods: We ran an online survey with 30 responses from alt.chi authors and reviewers, collecting quantitative data using multiple-choice questions and Likert scales. Qualitative data were collected using open questions.Results: Our main quantitative result is that respondents are more positive to open and non-anonymous reviewing for alt.chi than for other parts of the CHI conference. The qualitative data specifically highlight the benefits of open and transparent academic discussions. The data and scripts are available on https://osf.io/vuw7h/, and the figures and follow-up work on http://tiny.cc/OpenReviews.Conclusion: While the benefits are quite clear and the system is generally well-liked by alt.chi participants, they remain reluctant to see it used in other venues. This concurs with a number of recent studies that suggest a divergence between support for a more open review process and its practical implementation. process and its practical implementation.)
Qingxian 2020 Lancet + (Background: Patients with obesity are at i … Background: Patients with obesity are at increased risk of exacerbations from viral respiratory infections. However, the association of obesity with severity of corona virus disease 2019 (COVID-19) is unclear. We hereby examined this association using data from the only referral hospital in Shenzhen, China.Methods: 383 COVID-19 patients admitted from 11 January to 16 February 2020 in the Third People’s Hospital of Shenzhen, China were included. Underweight was defined by body mass index (BMI) lower than 18·5 kg/m2, normal weight by 18·5-23·9 kg/m2 , overweight by 24·0- 27·9 kg/m2 and obesity as ≥28 kg/m2.Findings: Of them, 53·1 % were normal weight, 4·2 % were underweight, 32·0 % were overweight, and 10·7 % were obese. Patients with obesity, versus without, were tended to have cough (''P''=0·03) and fever (''P''=0·06). After adjusting for potential confounders, compared to normal weight, overweight showed 86 % higher, and obesity group showed 2·42-fold higher odds of developing severe pneumonia. Despite a non-significant sex interaction was found (''P''=0·09), the association appeared to be more pronounced in men than in women. The odds ratios (95 % confidence intervals) for severe pneumonia in overweight and obesity was 1·96 (0·78-4·98) and 5·70 (1·83-17·76) in men, and 1·51 (0·57-4·01) and 0·71 (0·07-7·3) in women, respectively.Interpretation: This is the first study showing that obesity, especially in men, significantly increases the risk of developing severe pneumonia in COVID-19 patients. As the 2019n-Cov may continue to spread worldwide, clinicians should maintain a high level of attention in obese patients. Obese patients should be carefully managed with prompt and aggressive treatment.aged with prompt and aggressive treatment.)
Caspi 2020 J Am Heart Assoc + (Background: People with chronic heart fail … Background: People with chronic heart failure (CHF) experience severe skeletal muscle dysfunction, characterized by mitochondrial abnormalities, which exacerbates the primary symptom of exercise intolerance. However, the molecular triggers and characteristics underlying mitochondrial abnormalities caused by CHF remain poorly understood.Methods and Results: We recruited 28 patients with CHF caused by reduced ejection fraction and 9 controls. We simultaneously biopsied skeletal muscle from the pectoralis major in the upper limb and from the vastus lateralis in the lower limb. We phenotyped mitochondrial function in permeabilized myofibers from both sites and followed this by complete RNA sequencing to identify novel molecular abnormalities in CHF skeletal muscle. Patients with CHF presented with upper and lower limb skeletal muscle impairments to mitochondrial function that were of a similar deficit and indicative of a myopathy. Mitochondrial abnormalities were strongly correlated to symptoms. Further RNA sequencing revealed a unique transcriptome signature in CHF skeletal muscle characterized by a novel triad of differentially expressed genes related to deficits in energy metabolism including adenosine monophosphate deaminase 3, pyridine nucleotide‐disulphide oxidoreductase domain 2, and lactate dehydrogenase C.Conclusions: Our data suggest an upper and lower limb metabolic myopathy that is characterized by a unique transcriptome signature in skeletal muscle of humans with CHF.ure in skeletal muscle of humans with CHF.)
Mehta 2008 Chest + (Background: Pulmonary vasoconstriction in … Background: Pulmonary vasoconstriction in response to hypoxia is unusual inasmuch as local exposure of nonpulmonary vasculature to hypoxia results in vasodilation. It has been suggested that pulmonary artery smooth-muscle cells may relax in response to intracellular generation of reactive oxygen species (ROS) and that the production of ROS decreases under hypoxia. However, other workers report increased ROS production in human pulmonary artery smooth-muscle cells (HPASMC) during hypoxia.Methods: Using dihydrodichlorofluorescein diacetate, dihydroethidium, and Amplex Red (Molecular Probes; Eugene, OR), we estimated ROS generation by confluent primary cultures of HPASMC and human coronary artery smooth-muscle cells (HCASMC) under normoxia (20%) and acute hypoxia (5%).Results: All three assay systems showed that HPASMC production of ROS is decreased under hypoxia and to a greater extent than the decrease in ROS production by HCASMC. A substantially greater percentage of normoxic ROS production by HPASMC is mitochondrial (> 60%) compared to HCASMC (< 30%).Conclusions: These results support the conclusion that ROS generation decreases, rather than increases, in HPASMC during hypoxia. However, as ROS production also decreases in HCASMC during hypoxia, the reason for the opposite change in vascular tone is not yet apparent.ite change in vascular tone is not yet apparent.)
Liu 2009 J Biomed Sci + (Background: Reactive oxygen species (ROS) … Background: Reactive oxygen species (ROS) play an important role in aging and age-related diseases such as Parkinson's disease and Alzheimer's disease. Much of the ROS production under conditions of toxic stress is from mitochondria, and multiple antioxidants prevent ROS accumulation. The aim of this study is to examine the specificity of the interaction between the antioxidants and ROS production in stressed cells.Methods: Using fluorescent dyes for ROS detection and mitochondrial inhibitors of known specificities, we studied ROS production under three conditions where ROS are produced by mitochondria: oxidative glutamate toxicity, state IV respiration induced by oligomycin, and tumor necrosis factor-induced cell death.Results: We demonstrated that there are at least four mitochondrial ROS-generating sites in cells, including the flavin mononucleotide (FMN) group of complex I and the three ubiquinone-binding sites in complexes I, II and III. ROS production from these sites is modulated in an insult-specific manner and the sites are differentially accessible to common antioxidants.Conclusion: The inhibition of ROS accumulation by different antioxidants is specific to the site of ROS generation as well as the antioxidant. This information should be useful for devising new interventions to delay aging or treat ROS-related diseases.delay aging or treat ROS-related diseases.)
Pollack 2017 J Gerontol A Biol Sci Med Sci + (Background: Resveratrol, a plant-derived p … Background: Resveratrol, a plant-derived polyphenol, has been reported to improve glucose metabolism and vascular function and to extend life span in animal models, but studies in humans have been inconclusive.Methods: In a randomized, double-blind crossover study, we treated older glucose-intolerant adults (''N'' = 30) with resveratrol (2-3 g/daily) or placebo, each for 6 weeks. A standard mixed-meal test was used to assess insulin sensitivity (Matsuda index) and secretion (C-peptide deconvolution) and vascular function by reactive hyperemia peripheral arterial tonometry. Skeletal muscle samples were obtained for gene expression using RNA-Seq analysis and to assess mitochondrial morphology.Results: There were no changes in glucose tolerance, insulin sensitivity, weight, blood pressure, or lipid profile following resveratrol treatment. Fasting reactive hyperemia index improved with resveratrol (2.02 ± 0.2 vs 1.76 ± 0.02, p = .002). RNA-Seq analysis yielded 140 differentially expressed transcripts (corrected p-value ≤ .05), predominantly associated with mitochondrial genes and noncoding RNA. Ingenuity Pathway Analysis confirmed that mitochondrial dysfunction (p = 2.77 × 10-12) and oxidative phosphorylation (p = 1.41 × 10-11) were the most significantly perturbed pathways. Mitochondrial number, but not size, was increased.Conclusions: Resveratrol treatment of older adults with impaired glucose regulation may have beneficial effects on vascular function, but not glucose metabolism or insulin sensitivity. Changes in gene expression suggest effects similar to those observed with caloric restriction, which has been shown to increase life and health span in animal models, although its significance for humans is uncertain. Future human studies should address the appropriate dose range and low bioavailability of resveratrol.© The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: [email protected].ease e-mail: [email protected].)
Aya 2022 Eur J Pharmacol + (Background: Sodium-glucose cotransporter 2 … Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been demonstrated to have beneficial effects on HF in large clinical trials; however, the mechanisms remain to be elucidated. The aim of this study was to clarify the mechanisms by which empagliflozin, one of SGLT2 inhibitors, affects heart failure.Method and results: Eight-week-old male mice deficient for heart and skeletal muscle-specific manganese superoxide dismutase (MnSOD-cKO mice), a murine model of dilated cardiomyopathy, were given food mixed with or without 10 mg/kg empagliflozin for 7 weeks and evaluated. Both the survival rate and cardiac fibrosis were significantly improved in the empagliflozin group. The capacity for oxidative phosphorylation in cardiac mitochondria was significantly upregulated as measured with Oxygraph-2k respirometer, and blood lactate levels produced by anaerobic metabolism were significantly lower in the empagliflozin group. Energy expenditure was significantly improved in the empagliflozin group, measured by respiratory gas analysis, with a concomitant reduction in serum leptin concentration and increase in food intake. A moderate amount of glucose was excreted in urine in the empagliflozin group; however, the available energy substrate in the body nonetheless expanded because of the much higher caloric intake.Conclusions: We conclude that empagliflozin improved cardiac mitochondrial function and upregulated energy metabolism even in HF in mice. These findings provide novel mechanisms for the beneficial effects of SGLT2 inhibitors on HF.eficial effects of SGLT2 inhibitors on HF.)
Cronshaw 2019 Photobiomodul Photomed Laser Surg + (Background: The clinical therapeutic benef … Background: The clinical therapeutic benefits of Photobiomodulation (PBM) therapy have been well established in many clinical scenarios. However, we are far from having developed a complete understanding of the underlying mechanisms of photon-biological tissue interactions. Concurrent to ongoing PBM studies, there are several parallel fields with evidences from cell and tissue physiology such as evolutionary biology, photobiology, and microbiology among others. Objective: This review is focused on extrapolating evidences from an expanded range of studies that may contribute to a better understanding of PBM mechanisms especially focusing on analgesia. Further, the choice of a PBM device source and relevant dosimetry with regards to specific mechanisms are discussed to enable broader clinical use of PBM therapies. Materials and methods: This discussion article is referenced from an expanded range of peer reviewed publications, including literature associated with evolutionary biology, microbiology, oncology, and photo-optical imaging technology, amongst others. Results and discussion: Materials drawn from many disparate disciplines is described. By inference from the current evidence base, a novel theory is offered to partially explain the cellular basis of PBM-induced analgesia. It is proposed that this may involve the activity of a class of transmembrane proteins known as uncoupling proteins. Furthermore, it is proposed that this may activate the heat stress protein response and that intracellur microthermal inclines may be of significance in PBM analgesia. It is suggested that the PBM dose response as a simple binary model of PBM effects as represented by the Arndt-Schulz law is clinically less useful than a multiphasic biological response. Finally, comments are made concerning the nature of photon to tissue interaction that can have significance in regard to the effective choice and delivery of dose to clinical target. Conclusions: It is suggested that a re-evaluation of phototransduction pathways may lead to an improvement in outcome in phototheraphy. An enhanced knowledge of safe parameters and a better knowledge of the mechanics of action at target level will permit more reliable and predictable clinical gain and assist the acceptance of PBM therapy within the wider medical community.herapy within the wider medical community.)
Ward 2015 Abstract IOC106 + (Background: The heart is a highly aerobic … Background: The heart is a highly aerobic organ with more than 90% of ATP regenerated by oxidative phosphorylation (OXPHOS) in the mitochondria. Mitochondrial dysfunction has been identified as a hallmark in the transition of compensatory hypertrophy to heart failure. However, the contribution of mitochondrial dysfunction to the contractile deficit is debated.Objectives: To determine if mitochondrial energy supply compromises contractile function in right ventricular (RV) hypertrophy.Methods: Rats were injected with monocrotaline (MCT) to induce pulmonary artery hypertension and RV hypertrophy, or saline (CON) for age-matched controls. Four weeks post-injection, multicellular cardiac trabeculae (length 2-3 mm, diameter 150-250 µm) were micro-dissected from the RV and mounted on an inverted microscope between a force transducer and a length changer. Steady-state force and intracellular Ca2+ transients were measured prior to saponin "skinning" of the sarcolemma to allow buffer access to the cytosol without damaging organelle membranes. Contraction and relaxation of the trabeculae was then assessed using buffered Ca2+ solutions, with and without exogenous ATP added to the superfusate.Results: MCT trabeculae produced similar force to CON despite having lower Ca2+ transients. Following skinning, CON trabeculae showed no change in the maximum Ca2+-activated force when exogenous ATP was removed from superfusate, while MCT trabeculae showed smaller contractures without exogenous ATP when stimulated with saturating Ca2+.Discussion: In this MCT model of compensated right ventricular hypertrophy there appears to be only a small contribution of mitochondrial dysfunction to contraction/relaxation when intracellular Ca2+ is controlled. This protocol can be used to further examine energy specific deficits in the failing heart, and to investigate the effects of drugs that modulate mitochondrial energy supply on contractile function. heart, and to investigate the effects of drugs that modulate mitochondrial energy supply on contractile function.)
Bociaga-Jasik 2013 Pharmacol Rep + (Background: The iatrogenic, HIV-related li … Background: The iatrogenic, HIV-related lipodystrophy is associated with development of the significant metabolic and cardiovascular complications. The underlying mechanisms of antiretroviral (ARV) drugs are not completely explored. Methods: The aim of the study was to characterize effects of the protease inhibitor (PI) - saquinavir (SQV) on metabolic functions, and gene expression during differentiation in cells (Chub-S7) culture. Results: SQV in concentrations observed during antiretroviral therapy (ART) significantly decreased mitochondrial membrane potential (MMP), oxygen consumption and ATP generation. The effects were greater in already differentiated cells. This was accompanied by characteristic changes in the expression of the genes involved in endoplasmic reticulum (ER) stress, and differentiation (lipid droplet formation) process such as: WNT10a, C/EBPa, AFT4, CIDEC, ADIPOQ, LPIN1. Conclusions: The results indicate that SQV affects not only metabolic (mitochondrial) activity of adipocytes, but affects the expression of genes related to differentiation and to a lesser extent to cell apoptosis. and to a lesser extent to cell apoptosis.)
Wohlwend 2013 Thesis + (Background: The mechanistically relation b … Background: The mechanistically relation between low oxygen metabolism and poor health remains unresolved.Methods: To pursue this aspect further, we measured mitochondrial oxidative phosphorylation (OXPHOS) capacity in permeabilized fibres of gastrocnemius (GASTRO) and left ventricle (LV) of the heart in 22 female rats artificially inbred for low- and high running capacity (LCR; HCR, respectively) for 30 generations. The rats were randomized to either sedate (LCRsed; HCRsed) or aerobic interval training (AIT) sessions 5 times a week for 1 month and then 2 times a week for 8 months (LCRext; HCRext).Results: There was a significant effect of training and inbreeding on maximal oxygen uptake in these rats. Baseline results for GASTRO in LCRsed compared to HCRsed showed reduced fat oxidation, CI-, CII linked respiration and maximal OXPHOS (CI- and CII linked respiration). Activity of the TCA cycle enzyme citrate synthase (CS) was lower in LCR compared to HCR. Mitochondrial content independent calculations indicated an enzyme defect in β-oxidation, and that mitochondrial coupling efficiency of electron transfer during β-oxidationwas impaired in LCRsed compared to HCRsed. AIT improved all these variables such that there was no difference in fat oxidation, CI-, CII linked respiration or maximal OXPHOS between LCRext and HCRext. These improvements were likely due to an increase in mitochondrial density, but also qualitative improvementsparticularly in fat oxidation (coupling efficiency and relative flux) were found.Baseline results for LV in LCRsed compared to HCRsed showed reduced CII linked respiration, maximal OXPHOS and similar activity of CS in LCRsed compared to HCRsed. Flux ratios as well as mitochondrial coupling efficiency during β-oxidation were similar between LCRsed and HCRsed. AIT improved maximalOXPHOS such that there was no difference between LCRext and HCRext. Interestingly, AIT had no effect on CS-activity in neither LCR nor HCR, suggesting primarily qualitative adjustments to exercise training in heart,mainly within β-oxidation and CII linked respiration. There was no dyscoupling effect as a result of phosphorylative constraint on electron transfer through complex I-IV by ATPsynthase in GASTRO or in LV, suggesting that ET-pathway rather than the phosphorylation system is limiting maximal ATP production in rats.Conclusions: Sedentary rats that contrast in intrinsic low- and high aerobic capacity differ significantly in OXHPOS, mitochondrial coupling efficiency and coupling control in GASTRO as well as in maximal OXPHOS in LV. Nine months of AIT was able to reverse all these initial impairments of mitochondrial function both in the heart and in the periphery, possibly through an interplay of different mechanisms. These findings might explain some of the poor health features of low capacity rats and suggest training-induced plasticity.s and suggest training-induced plasticity.)
Bilan 2014 Biochim Biophys Acta + (Background: The ratio of NAD(+)/NADH is a … Background: The ratio of NAD(+)/NADH is a key indicator that reflects the overall redox state of the cells. Until recently, there were no methods for real time NAD(+)/NADH monitoring in living cells. Genetically encoded fluorescent probes for NAD(+)/NADH are fundamentally new approach for studying the NAD(+)/NADH dynamics.Methods: We developed a genetically encoded probe for the nicotinamide adenine dinucleotide, NAD(H), redox state changes by inserting circularly permuted YFP into redox sensor T-REX from Thermus aquaticus. We characterized the sensor in vitro using spectrofluorometry and in cultured mammalian cells using confocal fluorescent microscopy.Results: The sensor, named RexYFP, reports changes in the NAD(+)/NADH ratio in different compartments of living cells. Using RexYFP, we were able to track changes in NAD(+)/NADH in cytoplasm and mitochondrial matrix of cells under a variety of conditions. The affinity of the probe enables comparison of NAD(+)/NADH in compartments with low (cytoplasm) and high (mitochondria) NADH concentration. We developed a method of eliminating pH-driven artifacts by normalizing the signal to the signal of the pH sensor with the same chromophore.Conclusion: RexYFP is suitable for detecting the NAD(H) redox state in different cellular compartments.General significance: RexYFP has several advantages over existing NAD(+)/NADH sensors such as smallest size and optimal affinity for different compartments. Our results show that normalizing the signal of the sensor to the pH changes is a good strategy for overcoming pH-induced artifacts in imaging.vercoming pH-induced artifacts in imaging.)
Lettieri-Barbato 2019 Mol Metab + (Background: Thermogenic adipocytes reorgan … Background: Thermogenic adipocytes reorganize their metabolism during cold exposure. Metabolic reprogramming requires readily available bioenergetics substrates, such as glucose and fatty acids, to increase mitochondrial respiration and produce heat via the uncoupling protein 1 (UCP1). This condition generates a finely-tuned production of mitochondrial reactive oxygen species (ROS) that support non-shivering thermogenesis.Scope of review: Herein, the findings underlining the mechanisms that regulate ROS production and control of the adaptive responses tuning thermogenesis in adipocytes are described. Furthermore, this review describes the metabolic responses to substrate availability and the consequence of mitochondrial failure to switch fuel oxidation in response to changes in nutrient availability. A framework to control mitochondrial ROS threshold to maximize non-shivering thermogenesis in adipocytes is provided.Major conclusions: Thermogenesis synchronizes fuel oxidation with an acute and transient increase of mitochondrial ROS that promotes the activation of redox-sensitive thermogenic signaling cascade and UCP1. However, an overload of substrate flux to mitochondria causes a massive and damaging mitochondrial ROS production that affects mitochondrial flexibility. Finding novel thermogenic redox targets and manipulating ROS concentration in adipocytes appears to be a promising avenue of research for improving thermogenesis and counteracting metabolic diseases.esis and counteracting metabolic diseases.)
Mikulas 2020 Materials + (Background: Triethylene glycol dimethacryl … Background: Triethylene glycol dimethacrylate (TEGDMA) monomers released from resin matrix are toxic to dental pulp cells, induce apoptosis, oxidative stress and decrease viability. Recently, mitochondrial complex I (CI) was identified as a potential target of TEGDMA. In isolated mitochondria supported by CI, substrates oxidation and ATP synthesis were inhibited, reactive oxygen species production was stimulated. Contrary to that, respiratory Complex II was not impaired by TEGDMA. The beneficial effects of electron carrier compound methylene blue (MB) are proven in many disease models where mitochondrial involvement has been detected. In the present study, the bioenergetic effects of MB on TEGDMA-treated isolated mitochondria and on human dental pulp stem cells (DPSC) were analyzed.Methods: Isolated mitochondria and DPSC were acutely exposed to low millimolar concentrations of TEGDMA and 2 μM concentration of MB. Mitochondrial and cellular respiration and glycolytic flux were measured by high resolution respirometry and by Seahorse XF extracellular analyzer. Mitochondrial membrane potential was measured fluorimetrically.Results: MB partially restored the mitochondrial oxidation, rescued membrane potential in isolated mitochondria and significantly increased the impaired cellular O2 consumption in the presence of TEGDMA.Conclusion: MB is able to protect against TEGDMA-induced CI damage, and might provide protective effects in resin monomer exposed cells.Copyright © 2018. Published by Elsevier Inc.pyright © 2018. Published by Elsevier Inc.)
Matsumoto 2021 Circ Heart Fail + (Background: We recently reported that trea … Background: We recently reported that treatment with rhBDNF (recombinant human brain-derived neurotrophic factor) improved the reduced exercise capacity of mice with heart failure (HF) after myocardial infarction (MI). Since BDNF is reported to enhance fatty acid oxidation, we herein conducted an in vivo investigation to determine whether the improvement in exercise capacity is due to the enhancement of the fatty acid oxidation of skeletal muscle via the AMPKα-PGC1α (adenosine monophosphate-activated protein kinase-ɑ-proliferator-activated receptor-r coactivator-1ɑ) axis.Methods: MI and sham operations were conducted in C57BL/6J mice. Two weeks postsurgery, we randomly divided the MI mice into groups treated with rhBDNF or vehicle for 2 weeks. AMPKα-PGC1α signaling and mitochondrial content in the skeletal muscle of the mice were evaluated by Western blotting and transmission electron microscopy. Fatty acid β-oxidation was examined by high-resolution respirometry using permeabilized muscle fiber. BDNF-knockout mice were treated with 5-aminoimidazole-4-carboxamide-1-beta-d-riboruranoside, an activator of AMPK.Results: The rhBDNF treatment significantly increased the expressions of phosphorylated AMPKα and PGC1α protein and the intermyofibrillar mitochondrial density in the MI mice. The lowered skeletal muscle mitochondrial fatty acid oxidation was significantly improved in the rhBDNF-treated MI mice. The reduced exercise capacity and mitochondrial dysfunction of the BDNF-knockout mice were improved by 5-aminoimidazole-4-carboxamide-1-beta-d-riboruranoside.Conclusions: Beneficial effects of BDNF on the exercise capacity of mice with HF are mediated through an enhancement of fatty acid oxidation via the activation of AMPKα-PGC1α in skeletal muscle. BDNF may become a therapeutic option to improve exercise capacity as an alternative or adjunct to exercise training.ternative or adjunct to exercise training.)
Zucker 2020 Biol Sex Differ + (Background: Women experience adverse drug … Background: Women experience adverse drug reactions, ADRs, nearly twice as often as men, yet the role of sex as a biological factor in the generation of ADRs is poorly understood. Most drugs currently in use were approved based on clinical trials conducted on men, so women may be overmedicated. We determined whether sex differences in drug pharmacokinetics, PKs, predict sex differences in ADRs.Methods: Searches of the ISI Web of Science and PubMed databases were conducted with combinations of the terms: drugs, sex or gender, pharmacokinetics, pharmacodynamics, drug safety, drug dose, and adverse drug reaction, which yielded over 5000 articles with considerable overlap. We obtained information from each relevant article on significant sex differences in PK measures, predominantly area under the curve, peak/maximum concentrations, and clearance/elimination rates. ADRs were identified from every relevant article and recorded categorically as female-biased, male-biased, or not sex-biased.Results: For most of the FDA-approved drugs examined, elevated blood concentrations and longer elimination times were manifested by women, and these PKs were strongly linked to sex differences in ADRs. Of the 86 drugs evaluated, 76 had higher PK values in women; for 59 drugs with clinically identifiable ADRs, sex-biased PKs predicted the direction of sex-biased ADRs in 88 % of cases. Ninety-six percent of drugs with female-biased PK values were associated with a higher incidence of ADRs in women than men, but only 29 % of male-biased PKs predicted male-biased ADRs. Accessible PK information is available for only a small fraction of all drugs.Conclusions: Sex differences in pharmacokinetics strongly predict sex-specific ADRs for women but not men. This sex difference was not explained by sex differences in body weight. The absence of sex-stratified PK information in public records for hundreds of drugs raises the concern that sex differences in PK values are widespread and of clinical significance. The common practice of prescribing equal drug doses to women and men neglects sex differences in pharmacokinetics and dimorphisms in body weight, risks overmedication of women, and contributes to female-biased adverse drug reactions. We recommend evidence-based dose reductions for women to counteract this sex bias.ons for women to counteract this sex bias.)
Forte 2019 Biochim Biophys Acta Bioenerg + (Bacteria can not only encounter carbon mon … Bacteria can not only encounter carbon monoxide (CO) in their habitats but also produce the gas endogenously. Bacterial respiratory oxidases, thus, represent possible targets for CO. Accordingly, host macrophages were proposed to produce CO and release it into the surrounding microenvironment to sense viable bacteria through a mechanism that in ''Escherichia'' (''E.'') ''coli'' was suggested to involve the targeting of a bd-type respiratory oxidase by CO. The aerobic respiratory chain of ''E. coli'' possesses three terminal quinol:O2-oxidoreductases: the heme-copper oxidase bo3 and two copper-lacking bd-type oxidases, bd-I and bd-II. Heme-copper and bd-type oxidases differ in the mechanism and efficiency of proton motive force generation and in resistance to oxidative and nitrosative stress, cyanide and hydrogen sulfide. Here, we investigated at varied O2 concentrations the effect of CO gas on the O2 reductase activity of the purified cytochromes bo3, bd-I and bd-II of ''E. coli''. We found that CO, in competition with O2, reversibly inhibits the three enzymes. The inhibition constants Ki for the bo3, bd-I and bd-II oxidases are 2.4 ± 0.3, 0.04 ± 0.01 and 0.2 ± 0.1 μM CO, respectively. Thus, in ''E. coli'', bd-type oxidases are more sensitive to CO inhibition than the heme-copper cytochrome bo3. The possible physiological consequences of this finding are discussed.Copyright © 2019 Elsevier B.V. All rights reserved.The possible physiological consequences of this finding are discussed. Copyright © 2019 Elsevier B.V. All rights reserved.)
Luef 2015 Nat Commun + (Bacteria from phyla lacking cultivated rep … Bacteria from phyla lacking cultivated representatives are widespread in natural systems and some have very small genomes. Here we test the hypothesis that these cells are small and thus might be enriched by filtration for coupled genomic and ultrastructural characterization. Metagenomic analysis of groundwater that passed through a ~0.2-μm filter reveals a wide diversity of bacteria from the WWE3, OP11 and OD1 candidate phyla. Cryogenic transmission electron microscopy demonstrates that, despite morphological variation, cells consistently have small cell size (0.009±0.002 μm3). Ultrastructural features potentially related to cell and genome size minimization include tightly packed spirals inferred to be DNA, few densely packed ribosomes and a variety of pili-like structures that might enable inter-organism interactions that compensate for biosynthetic capacities inferred to be missing from genomic data. The results suggest that extremely small cell size is associated with these relatively common, yet little known organisms.h these relatively common, yet little known organisms.)
Kaila 2021 Nat Rev Microbiol + (Bacteria power their energy metabolism usi … Bacteria power their energy metabolism using membrane-bound respiratory enzymes that capture chemical energy and transduce it by pumping protons or Na+ ions across their cell membranes. Recent breakthroughs in molecular bioenergetics have elucidated the architecture and function of many bacterial respiratory enzymes, although key mechanistic principles remain debated. In this Review, we present an overview of the structure, function and bioenergetic principles of modular bacterial respiratory chains and discuss their differences from the eukaryotic counterparts. We also discuss bacterial supercomplexes, which provide central energy transduction systems in several bacteria, including important pathogens, and which could open up possible avenues for treatment of disease.possible avenues for treatment of disease.)
MiPNet28.08 Oroboros O2k Series J manual + (Baglivo E, Grings M, Gnaiger E (2023) Mitochondr Physiol Network 28.08(02)1-22.)