Reprograming of proteasomal degradation by branched chain amino acid metabolism

Branched‐chain amino acid (BCAA) metabolism is a central hub for energy production and regulation of numerous physiological processes. Controversially, both increased and decreased levels of BCAAs are associated with longevity. Using genetics and multi‐omics analyses in Caenorhabditis elegans, we identified adaptive regulation of the ubiquitin‐proteasome system (UPS) in response to defective BCAA catabolic reactions after the initial transamination step. Worms with impaired BCAA metabolism show a slower turnover of a GFP‐based proteasome substrate, which is suppressed by loss‐of‐function of the first BCAA catabolic enzyme, the branched‐chain aminotransferase BCAT‐1. The exogenous supply of BCAA‐derived carboxylic acids, which are known to accumulate in the body fluid of patients with BCAA metabolic disorders, is sufficient to regulate the UPS. The link between BCAA intermediates and UPS function presented here sheds light on the unexplained role of BCAAs in the aging process and opens future possibilities for therapeutic interventions.     

Motion Analytics of Trapezius Muscle Activity in an 18-Year-Old Female with Extended Upper Brachial Plexus Birth Palsy

Background  The trapezius muscle is often utilized as a muscle or nerve donor for repairing shoulder function in those with brachial plexus birth palsy (BPBP). To evaluate the native role of the trapezius in the affected limb, we demonstrate use of the Motion Browser, a novel visual analytics system to assess an adolescent with BPBP. Method  An 18-year-old female with extended upper trunk (C5–6–7) BPBP underwent bilateral upper extremity three-dimensional motion analysis with Motion Browser. Surface electromyography (EMG) from eight muscles in each limb which was recorded during six upper extremity movements, distinguishing between upper trapezius (UT) and lower trapezius (LT). The Motion Browser calculated active range of motion (AROM), compiled the EMG data into measures of muscle activity, and displayed the results in charts. Results  All movements, excluding shoulder abduction, had similar AROM in affected and unaffected limbs. In the unaffected limb, LT was more active in proximal movements of shoulder abduction, and shoulder external and internal rotations. In the affected limb, LT was more active in distal movements of forearm pronation and supination; UT was more active in shoulder abduction. Conclusion  In this female with BPBP, Motion Browser demonstrated that the native LT in the affected limb contributed to distal movements. Her results suggest that sacrificing her trapezius as a muscle or nerve donor may affect her distal functionality. Clinicians should exercise caution when considering nerve transfers in children with BPBP and consider individualized assessment of functionality before pursuing surgery.     

Oxidative stress-related risk of the multiple sclerosis development

BackgroundMultiple sclerosis (MS) is characterized by inflammation, demyelination and axonal degeneration. Oxidative stress (OS) plays a significant role in the pathogenesis of the disease. The aim of the study was to examine the association between OS and smoking on the MS development.MethodsThe study included 175 patients with relapsing-remitting multiple sclerosis (RRMS) (76 males, 99 females) and 254 healthy subjects (81 males and 173 females). Oxidative stress biomarkers in serum, Total Antioxidant Status (TAS) and Total Oxidative Status (TOS) were determined spectrophotometrically. Oxidative Stress Index (OSI) was calculated as the ratio of TOS and TAS. Urinary 8-oxo7,8-dihydro-2''-deoxyguanosine were determined by HPLC-MS/MS and expressed as 8-oxodG/creatinine.ResultsIn females with RRMS were higher TOS, OSI and 8-oxodG/creatinine than in females in control group. The group of males with RRMS had lower level of TAS than the males in control group. Higher levels of 8-oxodG/creatinine was obtained in active, passive and former smokers with RRMS than in control group with the same exposition to tobacco smoke. Independent predictors of MS are passive smoking, increased OSI and increased levels of urinary 8-oxodG/creatinine.ConclusionsOur results demonstrate that the OS parameters should be included in the assessment of the risk for MS development. Due to the more sensitivity to oxidative stress, females may be at higher risk of MS development. This data indicates the importance of introducing the antioxidant therapy as a complementary treatment in patients with RRMS.     

Higher mutation rate helps to rescue genes from the elimination by selection

Directional mutation pressure associated with replication processes is the main cause of the asymmetry between the leading and lagging DNA strands in bacterial genomes. On the other hand, the asymmetry between sense and antisense strands of protein coding sequences is a result of both mutation and selection pressures. Thus, there are two different ways of superposition of the sense strand, on the leading or lagging strand. Besides many other implications of these two possible situations, one seems to be very important - because of the asymmetric replication-associated mutation pressure, the mutation rate of genes depends on their location. Using Monte Carlo methods, we have simulated, under experimentally determined directional mutation pressure, the divergence rate and the elimination rate of genes depending on their location in respect to the leading/lagging DNA strands in the asymmetric prokaryotic genome. We have found that the best survival strategy for the majority of genes is to sometimes switch between DNA strands. Paradoxically, this strategy results in higher substitution rates but remains in agreement with observations in bacterial genomes that such inversions are very frequent and divergence rate between homologs lying on different DNA strands is very high.     

Haptoglobin and the inflammatory and oxidative status in experimental diabetic rats: antioxidant role of haptoglobin

Haptoglobin is a hemoglobin-binding acute-phase protein which possesses anti-inflammatory and antioxidative properties. In this study, we investigated changes in protein expression of rat haptoglobin under diabetes-related inflammatory and oxidative stress conditions induced by an i.p. injection of streptozotocin. The progress of diabetes during an 8-week follow-up period was associated with the increased presence of haptoglobin in the serum and in the liver. This increase was most prominent during the first 2 weeks after which it started to decline. Temporary changes in haptoglobin expression strongly correlated with the serum levels of TNF-α and IL-6. Lower haptoglobin expression at the fourth week and thereafter correlated with a decrease in TNF-α concentration and changes in the TNF-α/IL-6 ratio. Based on the decrease of GSH/GSSG ratio and antioxidant enzyme activities in the liver until the end of fourth week, it was concluded that the liver was exposed to oxidative stress and injury which in the presence of the abovementioned inflammatory mediators lead to different haptoglobin expression profiles at different stages of diabetes. An inverse correlation was observed between the haptoglobin and free iron serum levels in diabetic rats. The higher levels of haptoglobin during the first 2 weeks were accompanied by a lower level of free iron. In view of the established function of haptoglobin, we discuss its possible role in decreasing oxidative stress during the early stage of diabetes.     

The influence of ferrylhemoglobin and methemoglobin on the human erythrocyte membrane

The aim of the study was to examine and compare the effects of methemoglobin (metHb) and ferrylhemoglobin (ferrylHb) on the erythrocyte membrane. Kinetic studies of the decay of ferrylhemoglobin (*HbFe(IV)=O denotes ferryl derivative of hemoglobin present 5 min after initiation of the reaction of metHb with H(2)O(2); ferrylHb) showed that autoredecay of this derivative is slower than its decay in the presence of whole erythrocytes and erythrocyte membranes. It provides evidence for interactions between ferrylHb and the erythrocyte membrane. Both hemoglobin derivatives induced small changes in the structure and function of the erythrocyte membrane which were more pronounced for ferrylHb. The amount of ferrylHb bound to erythrocyte membranes increased with incubation time and, after 2 h, was twice that of membrane-bound metHb. The incubation of erythrocytes with metHb or ferrylHb did not influence osmotic fragility and did not initiate peroxidation of membrane lipids in whole erythrocytes as well as in isolated erythrocyte membranes. Membrane acetylcholinesterase activity increased by about 10% after treatment of whole erythrocytes with both metHb and ferrylHb. ESR spectra of membrane-bound maleimide spin label demonstrated minor changes in the conformation of label-binding proteins in ferrylHb-treated erythrocyte membranes. The fluidity of the membrane surface layer decreased slightly after incubation of erythrocytes and isolated erythrocyte membranes with ferrylHb and metHb. In whole erythrocytes, these changes were not stable and disappeared during longer incubation.