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A list of all pages that have property "Has abstract" with value "BIT’s 10th World Gene Convention-2019 (WGC-2019), Qingdao, China, 2019". Since there have been only a few results, also nearby values are displayed.

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  • Romero-Corral 2008 Int J Obes (Lond)  + (BACKGROUND: Body mass index (BMI) is the mBACKGROUND: 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.</br></br>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.</br></br>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.</br></br>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) represenBACKGROUND: 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.</br></br>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.</br></br>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.</br></br>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 toBACKGROUND: 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.</br></br>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.</br></br>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.</br></br>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.</br></br>© 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 comBACKGROUND: 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.</br></br>OBJECTIVE: The objective of this study was to examine the relationship between average DCU and volumetric markers of neurodegeneration on brain MRI.</br></br>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.</br></br>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.</br></br>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 inBACKGROUND: 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.</br></br>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.</br></br>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.</br></br>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.</br></br>FUNDING: NIHR and Wellcome Trust.</br></br>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.</br></br>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 haBACKGROUND: 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.</br></br>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.</br></br>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.</br></br>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.</br></br>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 mitochonBACKGROUND: 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.</br></br>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.</br></br>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 behaBACKGROUND: 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.</br></br>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.</br></br>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) ofBACKGROUND: 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.</br>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.</br>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%).</br>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 delayeBACKGROUND: 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.</br></br>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.</br></br>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.</br></br>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 measurBACKGROUND: 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.</br></br>OBJECTIVE: We aimed to find the most appropriate measure of body size or composition for scaling of measures of cardiorespiratory fitness among children.</br></br>METHODS: We assessed body weight and height, maximal workload (''W''<sub>max</sub>) and maximal oxygen uptake (''V''<sub>O2max</sub>) 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.</br></br>RESULTS: Lean mass (''r'' > 0.54) and height (''r'' > 0.51) had stronger positive correlations with absolute ''W''<sub>max</sub> and ''V''<sub>O2max</sub> than weight (''r'' > 0.30) in girls and boys. None of the measures of body size or composition correlated with LM-proportional ''W''<sub>max</sub> or ''V''<sub>O2max</sub> in girls or boys. Only LM correlated positively with height-proportional ''W''<sub>max</sub> (''r'' = 0.65) and ''V''<sub>O2max</sub> (''r'' = 0.71) in boys. FM correlated negatively with weight-proportional ''W''<sub>max</sub> (''r'' < -0.58) and ''V''<sub>O2max</sub> (''r'' < -0.64) in girls and boys. FM was even stronger determinant of weight-proportional ''W''<sub>max</sub> (''β'' = -0.68) and ''V''<sub>O2max</sub> (''β'' = -0.61) than exercise performance in multivariate linear regression models.</br></br>CONCLUSIONS: While assessing cardiorespiratory fitness, LM is the most appropriate measure of body size or composition for scaling of ''W''<sub>max</sub> and ''V''<sub>O2max</sub>, 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''<sub>max</sub> and ''V''<sub>O2max</sub>, because scaling by body weight introduces confounding by body adiposity.)
  • Kuper 2014 BMC Public Health  + (BACKGROUND: Indians may be particularly vuBACKGROUND: 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.</br></br>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.</br></br>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.</br></br>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 beBACKGROUND: 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).</br></br>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.</br></br>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.</br></br>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 oxiBACKGROUND: 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.</br></br>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.</br></br>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) aBACKGROUND: 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.</br>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.</br>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.</br>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 anBACKGROUND: 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.</br></br>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.</br></br>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.</br></br>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.</br></br>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.</br></br>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.</br></br>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 increBACKGROUND: 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.</br></br>DESIGN: Pre and postintervention study.</br></br>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.</br></br>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.</br></br>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 hypBACKGROUND: 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.</br></br>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.</br></br>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).</br></br>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 inactBACKGROUND: 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.</br></br>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.</br></br>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.</br></br>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.</br></br>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 AND</br></br>GENERAL 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 debaBACKGROUND: 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.</br></br>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.</br></br>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.</br></br>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 mBACKGROUND: 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.</br></br>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.</br></br>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.</br></br>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 oBACKGROUND: 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.</br></br>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).</br></br>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.</br></br>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 antiBAL30072 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.)
  • Gururaja Rao 2019 Cells  + (BK<sub>Ca</sub> channels, origBK<sub>Ca</sub> channels, originally discovered in ''Drosophila melanogaster'' as slowpoke (slo), are recognized for their roles in cellular and organ physiology. Pharmacological approaches implicated BK<sub>Ca</sub> channels in cellular and organ protection possibly for their ability to modulate mitochondrial function. However, the direct role of BK<sub>Ca</sub> channels in regulating mitochondrial structure and function is not deciphered. Here, we demonstrate that BK<sub>Ca</sub> 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 BK<sub>Ca</sub> channels reduced the lifespan of ''Drosophila'', and overexpression of human BK<sub>Ca</sub> channels in flies extends life span in males. Our study establishes the presence of BK<sub>Ca</sub> 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 measureBackground</br>Beta-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.</br></br>Aim</br>To investigate the validity of beta-oxidation assessment using octanoylcarnitine + malate as a substrate combination in skeletal muscle when mitochondrial (mt) aconitase is inhibited.</br></br>Methods</br>Soleus 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.</br></br>Results</br>Oxalomalic 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.</br></br>Conclusion</br>Octanoylcarnitine + malate allows for a valid assessment of beta-oxidation capacity using respirometry under conditions where mt-aconitase has been inhibited.</br></br>Support or Funding Information</br>Support: 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.</br></br>Footnotes</br>This 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 syntBackground</br>The 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.</br></br>Methods</br>In swine heart mitochondria the effect of nitrite on the F1FO-ATPase activity activated by Ca<sup>2+</sup>, henceforth defined as Ca-ATPase(s), or by the natural cofactor Mg<sup>2+</sup>, was investigated by evaluating ATP hydrolysis under different assay conditions.</br></br>Results</br>Ca<sup>2+</sup> is far less efficient than the natural cofactor Mg<sup>2+</sup> in the ATPase activation. However, when activated by Ca<sup>2+</sup> the ATPase activity is especially responsive to nitrite, which acts as uncompetitive inhibitor and up to 2 mM inhibits the Ca<sup>2+</sup>-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.</br></br>Conclusions</br>The 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.</br></br>General significance</br>In 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 sBackground & 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.</br></br>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).</br></br>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.</br></br>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, largelyBackground 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/m<sup>2</sup>), 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 resBackground 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.</br></br>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.</br></br>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.</br></br>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 reducBackground: 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.</br></br>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''<sub>O2peak</sub> was determined by a graded exercise test. Total body fat and fat free mass were assessed by whole body DEXA.</br></br>Results: The Y group had significantly greater levels of St.''P'' respiration (220 ± 15 pmol O<sub>2</sub> s<sup>-1</sup>mg<sup>-1</sup>) compared to M (166 ± 13 pmol O<sub>2</sub> s<sup>-1</sup>mg<sup>-1</sup>, ''P'' = 0.02) and O groups (170 ± 13 pmol O<sub>2</sub> s<sup>-1</sup>mg<sup>-1</sup>, ''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''<sub>O2peak</sub> (46 ± 2.9 ml min<sup>-1</sup>kg<sup>-1</sup>) compared to M (28 ± 1.8 ml min<sup>-1</sup>kg<sup>-1</sup>, ''P''<0.01) and O (21 ± 2.2 ml min<sup>-1</sup>kg<sup>-1</sup>, ''P''<0.01) groups. When the three groups were combined, St.''P'' respiration was positively correlated with ''V''<sub>O2peak</sub> (''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).</br></br>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.</br></br>References: </br>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.</br>2. Conley KE, Jubrias SA, Esselman PC (2000) Oxidative capacity and ageing in human muscle. J Physiol 526: 203-210.</br>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 majorBackground: 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. </br></br>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.</br></br>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 maxiBackground: Altitude exposure reduces maximal oxygen uptake (''V''<sub>O<sub>2</sub>max</sub>). 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''<sub>O<sub>2</sub>max</sub> levels were associated with better preservation of ''V''<sub>O<sub>2</sub>max</sub> 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''<sub>O<sub>2</sub>max</sub> decline at a moderate altitude of 2 000 m particularly in subjects with lower ''V''<sub>O<sub>2</sub>max</sub> levels, that is, below the 80th percentile (for age and sex). In people with higher fitness levels, ''V''<sub>O<sub>2</sub>max</sub> 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 thBackground: 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.</br></br>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.</br></br>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.</br></br>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 causBackground: 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.</br></br>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.</br></br>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.</br></br>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 envBackground: 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.</br></br>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.</br></br>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.</br></br>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 tBackground: 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).</br></br>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).</br></br>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.</br></br>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 coroBackground: Community transmission of coronavirus 2019 (Covid-19) was detected in the state of Washington in February 2020.</br></br>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.</br></br>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.</br></br>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:ubiquinoBackground: 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.</br></br>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.</br></br>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 usBackground: 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.</br></br>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.).</br></br>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.</br></br>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 comBackground: 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.</br></br>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.</br></br>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.</br></br>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.</br></br>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 imBackground: 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.</br></br>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.</br></br>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.</br></br>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 formBackground: 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.</br></br>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.</br></br>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.</br></br>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 sBackground: 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.</br></br>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.</br></br>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-guanidinBackground: 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 rat</br>liver. 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 activate</br>survival paths in hippocampal neurons and prevent apoptosis.</br>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).</br>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 with</br>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 855 Bioimager) are presently performed with the usage of TMRM (for active mitochondria staining) and</br>Hoechst (for nucleus staining).</br>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.</br>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.</br>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-guanidinBackground: 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 rat</br>liver. 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 activate</br>survival paths in hippocampal neurons and prevent apoptosis.</br>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).</br>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</br>Oxygraph-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 855</br>Bioimager) are presently performed with the usage of TMRM (for active mitochondria staining) and Hoechst (for nucleus staining).</br>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.</br>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.)