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      Effect of a low-protein diet supplemented with keto-acids on autophagy and inflammation in 5/6 nephrectomized rats

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          Abstract

          The present study demonstrated that autophagy/mitophagy was increased and inflammation was aggravated in skeletal muscle in chronic kidney disease (CKD) rats. A low-protein diet (LPD) supplemented with ketoacids (KA) improved the loss in muscle mass and blocked the activation of autophagy/mitophagy and inflammation in those rats.

          Abstract

          Ketoacids (KA) are known to preserve muscle mass among patients with chronic kidney disease (CKD) on a low-protein diet (LPD). The present study was to compare the effects of KA supplemented diet therapy in autophagy and inflammation in CKD rats' skeletal muscle. Rats with 5/6 nephrectomy were randomly divided into three groups and fed with either 11 g/kg/day protein [normal-protein diet (NPD)], 3 g/kg/day protein (LPD) or 3 g/kg/day protein which including 5% protein plus 1% KA (LPD + KA) for 24 weeks. Sham-operated rats with NPD intake were used as control. LPD could improve body weight, gastrocnemius muscle mass, as well as gastrocnemius muscle cross-sectional area, with the effect being more obvious in the LPD + KA group. The autophagy marker LC3 (microtubule-associated protein 1 light chain 3), p62, Parkin and PTEN induced putative kinase 1 (PINK1) were significantly attenuate in LPD + KA group than LPD group. LPD + KA group had the lower total mtDNA (mitochondiral DNA) and cytosol mtDNA, NACHT-PYD-containing protein 3 (NALP3) inflammasome than LPD group, but its reactive oxygen species (ROS), caspase-1 and apoptosis-associated speck-like protein containing a CARD (ASC) level was higher. Immunoblotting showed IL-1β (interleukin-1-beta) was lower in LPD and LPD + KA group than the NPD group, but IL-18 showed no significant difference among control and CKD group; toll-like receptor signalling-dependent IL-6 was higher in LPD + KA group than LPD group, but tumor necrosis factor-α (TNF-α) was not significantly changed between LPD + KA and LPD group. Systematic changes of the four cytokines were different from that of the tissue. Although LPD + KA could further ameliorate-activated autophagy than LPD, its effect on the activated inflammation state in CKD was not distinctly. Further study is still required to explore the method of ameliorating inflammation to provide new therapeutic approaches for CKD protein energy wasting (PEW).

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          Skeletal muscle is a primary target of SOD1G93A-mediated toxicity.

          The antioxidant enzyme superoxide dismutase 1 (SOD1) is a critical player of the antioxidative defense whose activity is altered in several chronic diseases, including amyotrophic lateral sclerosis. However, how oxidative insult affects muscle homeostasis remains unclear. This study addresses the role of oxidative stress on muscle homeostasis and function by the generation of a transgenic mouse model expressing a mutant SOD1 gene (SOD1(G93A)) selectively in skeletal muscle. Transgenic mice developed progressive muscle atrophy, associated with a significant reduction in muscle strength, alterations in the contractile apparatus, and mitochondrial dysfunction. The analysis of molecular pathways associated with muscle atrophy revealed that accumulation of oxidative stress served as signaling molecules to initiate autophagy, one of the major intracellular degradation mechanisms. These data demonstrate that skeletal muscle is a primary target of SOD1(G93A) -mediated toxicity and disclose the molecular mechanism whereby oxidative stress triggers muscle atrophy.
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            Appetite and inflammation, nutrition, anemia, and clinical outcome in hemodialysis patients.

            Malnutrition-inflammation complex syndrome, an outcome predictor in maintenance hemodialysis (MHD) patients, may be related to anorexia. We examined whether subjectively reported appetite is associated with adverse conditions and increased morbidity and mortality in MHD patients. A cohort of 331 MHD outpatients was asked to rate their recent appetite status on a scale from 1 to 4 (very good, good, fair, and poor appetite, respectively). Anemia indexes and nutritional and inflammatory markers-including serum concentrations of C-reactive protein, tumor necrosis factor alpha, and interleukin 6-were measured. The malnutrition-inflammation score was used to evaluate the malnutrition-inflammation complex syndrome, and the SF36 questionnaire was used to assess quality of life (QoL). Mortality and hospitalization were followed prospectively for up to 12 mo. Patients were aged 54.5 +/- 14.4 y. Diminished appetite (fair to poor) was reported by 124 patients (38%). Hemoglobin, protein intake, and QoL scores were progressively lower, whereas markers of inflammation, malnutrition-inflammation scores, and the required erythropoietin dose were higher across the worsening categories of appetite. The adjusted odds ratios of diminished versus normal appetite for increased serum tumor necrosis factor alpha and C-reactive protein concentrations were significant. Significant associations between a poor appetite and an increased rate of hospitalization and mortality were observed. The hazard ratio of death for diminished appetite was 4.74 (95% CI: 1.85, 12.16; P = 0.001). Diminished appetite (anorexia) is associated with higher concentrations of proinflammatory cytokines and higher levels of erythropoietin hyporesponsiveness and poor clinical outcome, including a 4-fold increase in mortality, greater hospitalization rates, and a poor QoL in MHD patients. Appetite status may yield significant insight into the clinical status of dialysis patients.
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              Revisiting mortality predictability of serum albumin in the dialysis population: time dependency, longitudinal changes and population-attributable fraction.

              Hypoalbuminaemia is a marker of malnutrition-inflammation complex syndrome (MICS) and a strong predictor of cardiovascular (CV) death in maintenance haemodialysis (MHD) patients. However, serum albumin may change over time. Hence, its time-varying associations with outcome may be different. Associations between 3-month averaged serum albumin levels, measured in a single laboratory using bromocresol green, and CV mortality were studied longitudinally in a 2-year cohort of 58,058 MHD patients. Mortality predictability of fixed baseline and trimonthly-varying serum albumin concentrations were compared. Hazard ratios (HRs) of CV death strictly increased across decrements of baseline serum albumin, whereas the HR for time-varying serum albumin decrements below 3.8 g/dl did not differ. A drop in serum albumin in the first 6 months was associated with increasing all-cause and CV death risks in the subsequent 18 months, while a rise in serum albumin was a predictor of better survival independent of baseline serum albumin. The multivariate adjusted population-attributable fraction of death due to baseline serum albumin 3.8 g/dl might reduce the number of MHD deaths in the USA by approximately 10,000 annually. Nutritional interventions examining benefits of increasing serum albumin in MHD patients are urgently needed.
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                Author and article information

                Journal
                Biosci Rep
                Biosci. Rep
                ppbioscirep
                BSR
                Bioscience Reports
                Portland Press Ltd.
                0144-8463
                1573-4935
                14 September 2015
                30 October 2015
                October 2015
                : 35
                : 5 ( displayID: 5 )
                : e00263
                Affiliations
                [* ]Department of Nephrology, Shanghai General Hospital, Shanghai Jiaotong University School of Medcine, Shanghai 200080, China
                Author notes
                [1]

                These authors should be viewed as the first author.

                [ 2 ]To whom correspondence should be addressed (email ywj4169@ 123456163.com ).
                Article
                e00263
                10.1042/BSR20150069
                4626871
                26371333
                d744e1ce-a606-4466-8d84-becadb1ea6c0
                © 2015 Authors

                This is an open access article published by Portland Press Limited and distributed under the Creative Commons Attribution License 3.0.

                History
                : 13 March 2015
                : 30 July 2015
                : 8 September 2015
                Page count
                Figures: 8, References: 44, Pages: 13
                Categories
                Original Papers
                Original Paper

                Life sciences
                autophagy,chronic kidney disease,inflammation,ketoacids,muscle atrophy
                Life sciences
                autophagy, chronic kidney disease, inflammation, ketoacids, muscle atrophy

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