Предсказание торсионных углов в аминокислотных последовательностях белков на основе байесовской процедуры распознавания на цепях Маркова

Запропоновано процедуру розпізнавання торсіонних кутів, утворених C^α атомами чотирьох сусідніх амінокислотних залишків. Отримана послідовність кутів використовується для побудови просторової структури білка на решітці Z³.Torsion angles defined on C^α atoms of four neighbouring residues are predicted using Bayesian pattern recognition procedure on non-stationary Markov chains. The predicted sequence of torsion angles is used for constructing protein 3-dimensional structure on Z³

Inflammatory signaling in skeletal muscle insulin resistance: green signal for nutritional intervention?

PURPOSE OF REVIEW: To review the evidence implying a role of inflammatory signaling pathways, specifically nuclear factor-kappaB and c-Jun NH2-terminal kinase, in fatty acid-induced skeletal muscle insulin resistance and to discuss the potential of dietary interventions to interfere with these processes. RECENT FINDINGS: Fatty acids can induce skeletal muscle insulin resistance via inflammatory signaling after binding Toll-like receptors at the cell membrane of muscle cells or after accumulating as intramyocellular lipid metabolites. In both processes, activation of intracellular inflammatory signaling is involved. The majority of literature addressing the causality of muscle nuclear factor-kappaB activation in skeletal muscle insulin resistance suggests that insulin resistance does not require muscle nuclear factor-kappaB activation. Recently, strong evidence was given that c-Jun NH2-terminal kinase signaling is an important inflammatory pathway involved in skeletal muscle insulin resistance. Furthermore, it is well established that proinflammatory cytokines originating from the enlarged adipose tissue or from activated adipose tissue macrophages can cause muscle insulin resistance. Recently, also macrophages resided in the muscle have been proposed to play an important role in muscle insulin resistance. Because of their anti-inflammatory characteristics, several dietary components like polyphenols may be interesting candidates for manipulating skeletal muscle insulin resistance. SUMMARY: Several dietary components, like polyphenols, have been reported to interfere with inflammatory signaling. To test whether these compounds can be used to prevent or reverse insulin resistance, well controlled human intervention studies have to be designed

Trans-10, cis-12 conjugated linoleic acid inhibits skeletal muscle differentiation and GLUT4 expression independently from NF-'B activation.

Scope: The capacity of skeletal muscle to contribute to glucose homeostasis depends on muscular insulin sensitivity. The expression of glucose transporter (GLUT)-4 is increased during myoblast differentiation, a process essential in maintenance of adult muscle. Therefore, processes that affect muscle differentiation may influence insulin dependent glucose homeostasis. Conjugated linoleic acids, and in particular trans-10, cis-12 CLA (t10, c12-CLA), are potent inducers of NF-kB in cultured skeletal myotubes, and NF-kB activation inhibits muscle differentiation. The aims of this study were to evaluate whether CLAs inhibit myogenic differentiation and lower GLUT4 mRNA expression and to address the involvement of NF-kB activation in potential effects of CLA on these processes.Methods and results: Incubation of C2C12 cells with t10, c12-CLA blocked the formation of myotubes, which was accompanied by reduced expression of the muscle specific genes creatine kinase, myogenin, myosin heavy chain perinatal and myosin heavy chain IIB, as well as decreased GLUT4 mRNA levels. However, genetic blockade of NF-kB was not sufficient to restore reduced myosin heavy chain protein expression following t10, c12-CLA treatment. Surprisingly, in contrast to myotubes, t10, c12-CLA was not able to activate NF-kB transcriptional activity in myoblasts. Conclusion: In conclusion, t10, c12-CLA inhibits myogenic differentiation and GLUT4 expression, independently from NF-kB activation

TNF-alpha impairs regulation of muscle oxidative phenotype: implications for cachexia?

Chronic obstructive pulmonary disease (COPD) is characterized by weight loss, muscle wasting (in advanced disease ultimately resulting in cachexia), and loss of muscle oxidative phenotype (oxphen). This study investigates the effect of inflammation (as a determinant of muscle wasting) on muscle oxphen by using cell studies combined with analyses of muscle biopsies of patients with COPD and control participants. We analyzed markers (citrate synthase, beta-hydroxyacyl-CoA dehydrogenase, and cytochrome c oxidase IV) and regulators (PGC-1alpha, PPAR-alpha, and Tfam) of oxphen in vastus lateralis muscle biopsies of patients with advanced COPD and healthy smoking control participants. Here 17 of 73 patients exhibited elevated muscle TNF-alpha mRNA levels. In these patients, significantly lower mRNA levels of all oxidative markers/regulators were found. Interestingly, these patients also had a significantly lower body mass index and tended to have less muscle mass. In cultured muscle cells, mitochondrial protein content and myosin heavy chain isoform I (but not II) protein and mRNA levels were reduced on chronic TNF-alpha stimulation. TNF-alpha also reduced mitochondrial respiration in a nuclear factor kappaB (NF-kappaB) -dependent manner. Importantly, TNF-alpha-induced NF-kappaB activation decreased promoter transactivation and transcriptional activity of regulators of mitochondrial biogenesis and muscle oxphen. In conclusion, these results demonstrate that TNF-alpha impairs muscle oxphen in a NF-kappaB-dependent manner.-Remels, A. H. V., Gosker, H. R., Schrauwen, P., Hommelberg, P. P. H., Sliwinski, P., Polkey, M., Galdiz, J., Wouters, E. F. M., Langen, R. C. J., Schols, A. M. W. J. TNF-alpha impairs regulation of muscle oxidative phenotype: implications for cachexia

Palmitate-induced skeletal muscle insulin resistance does not require NF-κB activation

Palmitate activates the NF-kappaB pathway, and induces accumulation of lipid metabolites and insulin resistance in skeletal muscle cells. Little information is available whether and how these processes are causally related. Therefore, the objectives were to investigate whether intra-cellular lipid metabolites are involved in FA-induced NF-kappaB activation and/or insulin resistance in skeletal muscle and to investigate whether FA-induced insulin resistance and NF-kappaB activation are causally related. Inhibiting DGAT or CPT-1 by using, respectively, amidepsine or etomoxir increased DAG accumulation and sensitized myotubes to palmitate-induced insulin resistance. While co-incubation of palmitate with etomoxir increased NF-kappaB transactivation, co-incubation with amidepsine did not, indicating that DAG accumulation is associated with insulin resistance but not with NF-kappaB activation. Furthermore, pharmacological or genetic inhibition of the NF-kappaB pathway could not prevent palmitate-induced insulin resistance. In conclusion, we have demonstrated that activation of the NF-kappaB pathway is not required for palmitate-induced insulin resistance in skeletal muscle cells

High-fat diet induced obesity primes inflammation in adipose tissue prior to liver in C57BL/6j mice.

Item does not contain fulltextMetabolic inflammation in adipose tissue and the liver is frequently observed as a result of diet-induced obesity in human and rodent studies. Although the adipose tissue and the liver are both prone to become chronically inflamed with prolonged obesity, their individual contribution to the development of metabolic inflammation remains speculative. Thus, we aimed to elucidate the sequence of inflammatory events in adipose and hepatic tissues to determine their contribution to the development of metabolic inflammation and insulin resistance (IR) in diet-induced obesity. To confirm our hypothesis that adipose tissue (AT) inflammation is initiated prior to hepatic inflammation, C57BL/6J male mice were fed a low-fat diet (LFD; 10% kcal fat) or high-fat diet (HFD; 45% kcal fat) for either 24, 40 or 52 weeks. Lipid accumulation and inflammation was measured in AT and liver. Glucose tolerance was assessed and plasma levels of glucose, insulin, leptin and adiponectin were measured at various time points throughout the study. With HFD, C57BL/6j mice developed a progressive obese phenotype, accompanied by IR at 24 and 40 weeks of HFD, but IR was attenuated after 52 weeks of HFD. AT inflammation was present after 24 weeks of HFD, as indicated by the increased presence of crown-like structures and up-regulation of pro-inflammatory genes Tnf, Il1beta, Mcp1 and F4/80. As hepatic inflammation was not detected until 40 weeks of HFD, we show that AT inflammation is established prior to the development of hepatic inflammation. Thus, AT inflammation is likely to have a greater contribution to the development of IR compared to hepatic inflammation.1 april 201