[Show abstract][Hide abstract] ABSTRACT: Disuse atrophy is the loss of skeletal muscle mass due to inactivity or lower than 'normal' use. It is not only a furtive component of the 'modern' sedentary lifestyle but also a part of numerous pathologies, where muscle loss is linked to disease specific and/or other toxicity factors, eventually leading to wasting (cachexia). Whether disuse-or-disease induced, muscle loss leads to weakness and metabolic comorbidities with a high societal and financial cost. This review discusses the intricate network of interacting signalling pathways including Atrogin-1/MAFbx, IGF1-Akt, myostatin, glucocorticoids, NF-kB, MAPKs and caspases that seem to regulate disuse atrophy but also share common activation patterns in other states of muscle loss such as sarcopenia or cachexia. Reactive oxygen species are also important regulators of cell signalling pathways that can accelerate proteolysis and depress protein synthesis. Exercise is an effective countermeasure and antioxidants may show some benefit. We discuss how the experimental model used can crucially affect the outcome and hence our understanding of atrophy. Timing of sampling is crucial as some signalling mechanisms reach their peak early during the atrophy process to rapidly decline thereafter, while other present high levels even weeks and months after study initiation. The importance of such differences lays in future consideration of appropriate treatment targets. Apart from attempting to correct defective genes or negate their effects, technological advances in new rational ways should aim to regulate specific gene expression at precise time points for the treatment of muscle atrophy in therapeutic protocols depending on the origin of atrophy induction.
Full-text · Article · Jan 2016 · Journal of Muscle Research and Cell Motility
[Show abstract][Hide abstract] ABSTRACT: Indoleamine 2,3‑dioxygenase (IDO), through L‑tryptophan depletion, activates general control non‑derepressible (GCN) 2 kinase and suppresses T‑cell proliferation, in addition to suppressing aerobic glycolysis and glutaminolysis, which are required for these rapidly proliferating cells. A number of, however not all of these alterations, are partially mediated through IDO‑induced p53 upregulation. In two‑way mixed lymphocyte reactions (MLRs), IDO reduced cellular proliferation. In MLR‑derived T‑cells, IDO induced the expression levels of p53 and p21, however concurrently reduced the levels of ζ‑chain, c‑Myc, lactate dehydrogenase A (LDH‑A) and glutaminase (GLS)2. However, p53 had no effect on the expression of the above proteins. These results were recapitulated in T‑cells activated with anti‑CD2, anti‑CD3 and anti‑CD28 by direct activation of the GCN2 kinase with tryptophanol. In conclusion, IDO, through GCN2 kinase activation, downregulates the levels of TCR‑complex ζ‑chain and c‑Myc, resulting in the suppression of T‑cell proliferation and a reduction in the levels of LDH‑A and GLS2, which are key enzymes involved in aerobic glycolysis and glutaminolysis, respectively.
No preview · Article · Nov 2015 · Molecular Medicine Reports
[Show abstract][Hide abstract] ABSTRACT: Background: A candidate-gene association study in a south eastern Mediterranean population was conducted to investigate the association of five AKR1B1 gene variants (rs2259458 G/T, rs2734653 G/A, rs2670230 C/A, rs1790998 C/A, rs17188118 A/C) with i) diabetes progression and ii) risk of diabetes leading to microvascular complications.
Materials and Methods: The cohort consisted of 169 diabetic cases with complications, 107 diseased controls and 315 healthy controls. The disease progression was tested using the generalized odds ratio (ORG). The risk of diabetes leading to complications was tested using the ORs of the additive and co-dominant models. The mode of inheritance was assessed using the degree of dominance index.
Results: The analysis showed that the five AKR1B1 gene variants are not implicated in disease progression. However, the same AKR1B1 variants are associated with the risk of diabetes leading to complications. Significant results were derived for the additive model of the variant rs2259458 G/T [OR= 1.87 (1.01-3.50)] and the co-dominant model of the variant rs2670230 C/A [OR=1.45 (1.01-2.04)]. The modes of inheritance for the variants rs2259458 G/T and rs2670230 C/A were “non-dominance” and “dominance of allele A”, respectively. The frequencies of three haplotypes (T-G-A-C-A, G-G-C-C-A and G-A-C-C-A) were significantly different (P≤0.05) between cases and healthy controls.
Conclusion: Genetic variation in AKR1B1 gene may alter susceptibility to diabetes leading to complications.
[Show abstract][Hide abstract] ABSTRACT: Activated T cells rely on aerobic glycolysis and glutaminolysis in order to proliferate and differentiate into effector cells. Therefore, intervention in these metabolic pathways inhibits proliferation. The aim of the present study was to evaluate the effects of Krebs' cycle inhibition at the level of malate dehydrogenase‑2 (MDH2) in human activated T cells using the MDH2 inhibitor LW6. Activated T cells from healthy volunteers were cultured in the presence or absence of LW6 and cytotoxicity, cell proliferation and the expression levels of hypoxia‑inducible factor (HIF)‑1α, c‑Myc, p53, cleaved caspase‑3 and certain enzymes involved in glucose metabolism and glutaminolysis were evaluated. The results revealed that LW6 was not toxic and decreased apoptosis and the levels of the pro‑apoptotic tumor suppressor p53. In addition, LW6 inhibited T‑cell proliferation and decreased the levels of c‑Myc, HIF‑1α, glucose transporter‑1, hexokinase‑II, lactate dehydrogenase‑A and phosphorylated pyruvate dehydrogenase. By contrast, LW6 increased the levels of pyruvate dehydrogenase. These alterations may lead to decreased production of pyruvate, which preferentially enters into the Krebs' cycle. Furthermore, LW6 decreased the levels of glutaminase‑2, while increasing those of glutaminase‑1, which may preserve glutaminolysis, and possibly pyruvate‑malate cycling, potentially protecting the cells from energy collapse. In summary, the inhibition of MDH2 in activated T cells abrogates proliferation without adversely affecting cell survival. Adaptations of cellular glucose and glutamine metabolism may prevent energy collapse.
Preview · Article · Nov 2015 · Experimental and therapeutic medicine
[Show abstract][Hide abstract] ABSTRACT: Both exercise training and treatment with dopamine agonists (DA) have been used with success for the amelioration of uremic Restless Legs Syndrome (RLS) symptoms. However, no data are available combining those two approaches. The aim of the current randomized double blind placebo controlled study was to investigate the effects of a 6-month intradialytic exercise training in combination with a low dose of dopamine agonists in patients suffering from uremic RLS symptoms. Fourteen stable hemodialysis patients with RLS were randomly assigned into the exercise training plus DA group and the exercise training plus placebo group. Both combinations were found to equally reduce uremic RLS symptoms by approximately 60%. The combination of low dose of DA with aerobic exercise training could be considered an alternative approach to high DA dosage regimes in reducing RLS symptoms' severity.
No preview · Article · Aug 2015 · ASAIO journal (American Society for Artificial Internal Organs: 1992)
[Show abstract][Hide abstract] ABSTRACT: Indoleamine 2,3-dioxygenase (IDO) is expressed in antigen presenting cells and exerts immunosuppressive effects on CD4+ T-cells. One mechanism is through the inhibition of aerobic glycolysis. Another prerequisite for T-cell proliferation and differentiation into effector cells is the increased fatty acid (FA) synthesis. The effect of IDO on enzymes involved in FA synthesis was evaluated in primary human cells both in MLRs in the presence or not of the IDO inhibitor 1-DL-methyl-tryptophan (1-MT), and in stimulated CD4+ T-cells in the presence or not of the general control nonderepressible 2 (GCN2) kinase activator tryptophanol (TRP). IDO or TRP inhibited cell proliferation. By assessing the level of GCN2 kinase or mammalian target of rapamycin complex 1 (mTORC1) substrates along with a kynurenine free system we showed that IDO exerts its effect mainly through activation of GCN2 kinase. IDO or TRP downregulated ATP-citrate lyase (ACL) and acetyl coenzyme A carboxylase 1 (ACC1), key enzymes involved in FA synthesis. Also, IDO or TRP altered the expression of enzymes that control carbon atoms availability for FA synthesis, such as lactate dehydrogenase-A (LDH-A), pyruvate dehydrogenase (PDH), glutaminase 1 (GLS1) and glutaminase 2 (GLS2), in a way that inhibits FA synthesis. In conclusion, IDO through GCN2 kinase activation inhibits CD4+ T-cell proliferation and downregulates key enzymes that directly or indirectly promote FA synthesis, a prerequisite for CD4+ T-cell proliferation and differentiation into effector cell lineages. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Background:
Urate through NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-dependent caspase-1 activation stimulates macrophages to secrete inteleukin-1β (IL-1β). Urate also enhances adaptive immunity indirectly through its effect on antigen presenting cells. In this study, the direct effect of urate on isolated primary human T-cells was evaluated.
Isolated T-cells were cultured with or without monosodium urate crystals in the presence or not of the NLRP3 inflammasome inhibitor glyburide. Activated cleaved caspase-1 was assessed by means of western blotting, whereas caspase-1 activity was measured colorimetrically in the cell lysates. IL-1β was measured in the supernatants by means of enzyme-linked immunosorbent assay. T-cell proliferation was assessed by means of bromodeoxyuridine labelling and immunoenzymatic detection.
Urate induced caspase-1 activation and IL-1β release by T-cells. It also induced proliferation of T-cells. Glyburide inhibited urate-induced caspase-1 activation, IL-1β secretion and proliferation.
Urate, a well defined danger signal, stimulates directly human T-cells in a NLRP3 infmmasomela-dependent way. The subsequent IL-1β secretion could enhance inflammation, whereas expansion of T-cell clones could facilitate a subsequent adaptive immune response. Hippokratia 2015, 19 (1): 41-46.
[Show abstract][Hide abstract] ABSTRACT: Introduction and Aims: Cardiac autonomic nervous system (ANS) dysfunction is a common feature in patients receiving hemodialysis (HD) therapy. Until today, spectral analysis of heart rate variability (HRV) is the most commonly used noninvasive method for the assessment of ANS activity. Pupillometry is a valid and low-cost method for the evaluation of ANS activity which reveals the sub-clinical defects in autonomic function of various diseases but also it has been proposed to be used as a complementary tool in the evaluation of cardiac autonomic function. Decreased HRV due to dysfunction of the cardiac autonomic function is a known complication of HD patients and is associated with an increased risk of ventricular arrhythmias and sudden death. However, the effect of HD on autonomic regulation of pupillary light reflex is not known. Furthermore, there are limited data available regarding alterations in HRV and pupillary light reflex during intradialytic exercise or without in HD patients. The aims of the current study were to investigate and compare the hemodynamic
[Show abstract][Hide abstract] ABSTRACT: Ranolazine (RAN) and nicardipine (NIC) have been studied for their vasorelaxing effects but the combination of these agents against adrenergic vasoconstriction has not been tested. The present study aimed at investigating the vasorelaxing effect by the combination of the two agents on alpha1-adrenoceptor-mediated contraction on isolated rabbit aorta. Aortic rings were mounted for isometric tension recording in organ baths containing Krebs-Henseleit solution. Concentration-response curves of RAN (10–9 to 10–4 M), NIC (10–9 to 10–5 M), and RAN + NIC (3 × 10–6 M) were obtained in a cumulative manner using phenylephrine (PE, 2 × 10–6 M) as constrictor agent. The effective concentration (EC)50 values for RAN and NIC were 6.5 × 10–6 M and 1.4 × 10–5 M, respectively. The treatment of PE-precontracted aortic rings with either RAN or NIC up to 65 min revealed that both agents displayed a biphasic pattern of initial rising and late sustained phases of relaxation. At 35 min of incubation, RAN and NIC induced relaxation by 23 ± 3% and 14 ± 4%, respectively (N = 7, P = NS, RAN vs NIC); their combination resulted in a 34 ± 4% relaxation (N = 7; P < 0.01, RAN + NIC vs NIC). At 65 min the effect of NIC prevailed and tended to be closer to the values of the combination treatment (P < 0.01, RAN + NIC vs RAN). The results indicate that RAN at therapeutic concentrations exerts a significant additive vasorelaxing effect when combined with NIC in rabbit aorta.
[Show abstract][Hide abstract] ABSTRACT: Specialty section: This article was submitted to Striated Muscle Physiology, a section of the journal Frontiers in Physiology Renal failure is accompanied by progressive muscle weakness and premature fatigue, in part linked to hypokinesis and in part to uremic toxicity. These changes are associated with various detrimental biochemical and morphological alterations. All of these pathological parameters are collectively termed uremic myopathy. Various interventions while helpful can't fully remedy the pathological phenotype. Complex mechanisms that stimulate muscle dysfunction in uremia have been proposed, and oxidative stress could be implicated. Skeletal muscles continuously produce reactive oxygen species (ROS) and reactive nitrogen species (RNS) at rest and more so during contraction. The aim of this mini review is to provide an update on recent advances in our understanding of how ROS and RNS generation might contribute to muscle dysfunction in uremia. Thus, a systematic review was conducted searching PubMed and Scopus by using the Cochrane and PRISMA guidelines. While few studies met our criteria their findings are discussed making reference to other available literature data. Oxidative stress can direct muscle cells into a catabolic state and chronic exposure to it leads to wasting. Moreover, redox disturbances can significantly affect force production per se. We conclude that oxidative stress can be in part responsible for some aspects of uremic myopathy. Further research is needed to discern clear mechanisms and to help efforts to counteract muscle weakness and exercise intolerance in uremic patients.
Full-text · Article · Apr 2015 · Frontiers in Physiology
[Show abstract][Hide abstract] ABSTRACT: Introduction and Aims: Chronic kidney disease (CKD) leads to muscle atrophy, metabolic disorders, diminished exercise capacity and fatigue. Complex mechanisms causing dysfunction have been proposed, and oxidative stress may be implicated. The presence of oxidative stress in CKD is evidenced by an overabundance of lipid, carbohydrate and protein oxidation products in blood and skeletal muscle of patients. The aim of this study was to evaluate the effects of uremia on skeletal muscle (psoas, soleus) and blood redox status in a rabbit model of renal insufficiency.
[Show abstract][Hide abstract] ABSTRACT: Hepatitis B virus (HBV) is a major global health problem. Despite the success of the general measures against blood transmitted infections in hemodialysis (HD) units, the prevalence of HBV infection among the HD patients is still high. Thus vaccination against HBV is indicating in this population. However, compared with the general population the seroprotection achieved in HD patients remains relatively low, at about 70%. In this review patient, HD procedure and vaccine-associated factors that affect the efficacy of HBV vaccination are analyzed. Also alternative routes of HBV vaccine administration as well as new and more immunogenic vaccine formulations are discussed. However, besides scientific progress, vigilance of HD physicians and staff regarding the general measures against the transmission of blood borne infections and the vaccination against HBV is also required for reducing the prevalence of this viral infection.
Preview · Article · Sep 2014 · World Journal of Gastroenterology
[Show abstract][Hide abstract] ABSTRACT: Restless legs syndrome (RLS) affects almost one out of three end-stage renal disease patients. This review assesses the current treatment options of uremic RLS and its potential benefits of those treatments on quality of life parameters, cardiovascular mortality and survival. A systematic review was conducted searching PubMed and Scopus by using the Cochrane and PRISMA guidelines. Fourteen studies met the inclusion criteria in which the international RLS study group criteria were used as the primary diagnostic tool. Both pharmacological and non-pharmacological approaches were found to reduce the severity of uremic RLS symptoms. Only four studies had reported changes on aspects related to quality of life while those changes were also associated with health benefits that resulted in reduced cardiovascular risk. The severity of uremic RLS symptoms can be ameliorated by using dopamine agonists and gabapentin, intravenous iron, exercise or supplementation with vitamins C and E, while some of those treatment benefits can be attenuated rapidly. There is a lack of strong evidence regarding the effects of the pharmacological approaches on quality of life and cardiovascular survival and mortality. In contrast exercise has been proven beneficial in both reducing the RLS symptoms’ severity score and improving the quality of life.
No preview · Article · Aug 2014 · Sleep Medicine Reviews
[Show abstract][Hide abstract] ABSTRACT: Purpose:
The relative effectiveness and tolerability of treatments for type 2 diabetes mellitus (T2DM) is not well understood because few randomized, controlled trials (RCTs) have compared these treatments directly. The purpose of the present study was to evaluate the relative effectiveness and tolerability of treatments of T2DM.
We performed a network meta-analysis of available RCTs with pharmacologic interventions in T2DM and compared antidiabetic drugs and combination regimens with metformin (the reference drug). Glycemic control (proportion achieving HbA1c goal) and tolerability (risk of hypoglycemia) were the primary outcomes of interest. Direct and indirect relative effects (unadjusted) were expressed as odds ratios and 95% CIs.
Eight treatments (glucagon-like peptide-1 [GLP-1] agonists plus metformin, sulfonylureas plus metformin, dipeptidyl peptidase-4 [DPP-4] inhibitors] plus metformin, colesevelan plus metformin, thiazolidinediones plus metformin, meglitinides plus metformin, α-glucosidase inhibitor plus metformin, and rosiglitazone monotherapy) outperformed metformin (direct effects). Triple combinations of GLP-1, thiazolinedione, insulin, metiglinide, or sulfonylureas added to a metformin backbone improved glycemic control (indirect effects). Higher risk of hypoglycemia was noted for sulfonylureas, α-glycosidases, and metiglinides when added to metformin (direct effects). Across indirect effects, only 17% of comparisons yielded less risk of hypoglycemia (70% were worse and 13% were comparable).
Our results point out the relative superiority of 2- and 3-drug combination regimens over metformin and summarize treatment effects and tolerability in a comprehensive manner, which adds to our knowledge regarding T2DM treatment options.
No preview · Article · Aug 2014 · Clinical Therapeutics