Effect of Eccentric Exercise on Metabolic Health in Diabetes and Obesity.

There is a growing body of evidence showing the importance of physical activity against civilization-induced metabolic diseases, including type 2 diabetes (T2DM) and obesity. Eccentric contraction, when skeletal muscles generate force by lengthening, is a unique type of skeletal muscle activity. Eccentric contraction may lead to better power production characteristics of the muscle because eccentric contraction requires less energy and can result in higher tension. Therefore, it is an ideal tool in the rehabilitation program of patients. However, the complex metabolic effect (i.e., fat mass reduction, increased lipid oxidation, improvement in blood lipid profile, and increased insulin sensitivity) of the eccentric contraction alone has scarcely been investigated. This paper aims to review the current literature to provide information on whether eccentric contraction can influence metabolic health and body composition in T2DM or obesity. We also discussed the potential role of myokines in mediating the effects of eccentric exercise. A better understanding of the mechanism of eccentric training and particularly their participation in the regulation of metabolic diseases may widen their possible therapeutic use and, thereby, may support the fight against the leading global risks for mortality in the world.

Acetylation State of Lysine 14 of Histone H3.3 Affects Mutant Huntingtin Induced Pathogenesis.

Huntington's Disease (HD) is a fatal neurodegenerative disorder caused by the expansion of a polyglutamine-coding CAG repeat in the Huntingtin gene. One of the main causes of neurodegeneration in HD is transcriptional dysregulation that, in part, is caused by the inhibition of histone acetyltransferase (HAT) enzymes. HD pathology can be alleviated by increasing the activity of specific HATs or by inhibiting histone deacetylase (HDAC) enzymes. To determine which histone's post-translational modifications (PTMs) might play crucial roles in HD pathology, we investigated the phenotype-modifying effects of PTM mimetic mutations of variant histone H3.3 in a Drosophila model of HD. Specifically, we studied the mutations (K→Q: acetylated; K→R: non-modified; and K→M: methylated) of lysine residues K9, K14, and K27 of transgenic H3.3. In the case of H3.3K14Q modification, we observed the amelioration of all tested phenotypes (viability, longevity, neurodegeneration, motor activity, and circadian rhythm defects), while H3.3K14R had the opposite effect. H3.3K14Q expression prevented the negative effects of reduced Gcn5 (a HAT acting on H3K14) on HD pathology, while it only partially hindered the positive effects of heterozygous Sirt1 (an HDAC acting on H3K14). Thus, we conclude that the Gcn5-dependent acetylation of H3.3K14 might be an important epigenetic contributor to HD pathology.

Diet-Induced Hypercholesterolemia Leads to Cardiac Dysfunction and Alterations in the Myocardial Proteome.

Elevated blood cholesterol is a major risk factor for coronary heart disease. Moreover, direct effects on the myocardium also contribute to the adverse effects of hypercholesterolemia. Here, we investigated the effect of hypercholesterolemia on the cardiac proteome. Male Wistar rats were fed with a laboratory rodent chow supplemented with 2% cholesterol for 8 weeks to induce hypercholesterolemia. The protein expression data obtained from the proteomic characterization of left ventricular samples from normo- and hypercholesterolemic animals were subjected to gene ontology (GO) and protein interaction analyses. Elevated circulating cholesterol levels were accompanied by diastolic dysfunction in cholesterol-fed rats. The proteomic characterization of left ventricular samples revealed altered expression of 45 proteins due to hypercholesterolemia. Based on the Gene Ontology analysis, hypercholesterolemia was associated with disturbed expression of cytoskeletal and contractile proteins. Beta-actin was downregulated in the hypercholesterolemic myocardium, and established a prominent hub of the protein interaction network. Analysis of the unfiltered dataset revealed concordant downregulated expression patterns in proteins associated with the arrangement of the contractile system (e.g., cardiac-specific troponins and myosin complex), and in subunits of the mitochondrial respiratory chain. We conclude that the observed changes in the cardiac proteome may contribute to the development of diastolic dysfunction in hypercholesterolemia.

Correlated Motions of Conserved Polar Motifs Lay out a Plausible Mechanism of G Protein-Coupled Receptor Activation.

Recent advancements in the field of experimental structural biology have provided high-resolution structures of active and inactive state G protein-coupled receptors (GPCRs), a highly important pharmaceutical target family, but the process of transition between these states is poorly understood. According to the current theory, GPCRs exist in structurally distinct, dynamically interconverting functional states of which populations are shifted upon binding of ligands and intracellular signaling proteins. However, explanation of the activation mechanism, on an entirely structural basis, gets complicated when multiple activation pathways and active receptor states are considered. Our unbiased, atomistic molecular dynamics simulations of the µ opioid receptor (MOP) revealed that transmission of external stimulus to the intracellular surface of the receptor is accompanied by subtle, concerted movements of highly conserved polar amino acid side chains along the 7th transmembrane helix. This may entail the rearrangement of polar species and the shift of macroscopic polarization in the transmembrane domain, triggered by agonist binding. Based on our observations and numerous independent indications, we suggest amending the widely accepted theory that the initiation event of GPCR activation is the shift of macroscopic polarization between the ortho- and allosteric binding pockets and the intracellular G protein-binding interface.

Androstano-arylpyrimidines: Novel small molecule inhibitors of MDR1 for sensitizing multidrug-resistant breast cancer cells.

Apart from the numerous physiological functions of MDR1, it is widely known for its role in granting multidrug resistance to cancer cells. This ATP-driven transmembrane protein exports a wide range of chemotherapeutic agents from cancer cells, thereby deterring drugs to reach effective intracellular concentrations. Thus, inhibition of MDR1 expression or function would be a viable option to enhance the accumulation of cytotoxic agents in cancer cells which in turn could improve significantly the success rate of chemotherapy. Although, several pharmacological inhibitors have been designed and tested in the past, due to their unsuccessful translation to clinical application, there is still ongoing research to find suitable compounds to manipulate MDR1 function and potentially overturn multidrug resistance. In the present study, we demonstrate that novel DHT-derived A-ring-fused arylpyrimidinone derivatives, based on their acetylation status, can inhibit MDR1 efflux activity in MDR1 overexpressing multidrug-resistant breast adenocarcinoma cells. Strikingly, all derivatives carrying an acetoxy group on the sterane d-ring were highly potent in hindering Rhodamine 123 export via MDR1, however deacetylated molecules were not capable to exert a similar effect on multidrug resistant cancer cells. The possible molecular and cellular mechanisms underlying the efflux pump inhibiting function of acetylated derivatives were dissected using the most potent MDR1 inhibitor, compound 10g and its deacetylated counterpart (11g). Importantly, molecule 10g was able to sensitize drug resistant cells to doxorubicin-induced apoptosis, further verifying the highly advantageous nature of efflux pump inhibition upon chemotherapy. Our experiments also revealed that neither mitochondrial damage, nor MDR1 gene regulation could lay behind the MDR1 inhibitory function of compound 10g. Molecular docking studies were carried out to analyze the interactions of 10g and 11g with MDR1, however no significant differences in their binding properties were observed. Nevertheless, our results indicate that the ER stress inducing potential of molecule 10g might be the fundamental mechanism behind its inhibitory action on MDR1. With additional studies, our work can yield a structural platform for a new generation of small molecule MDR1 inhibitors to sensitize drug resistant cancer cells and at the same time it elucidates the exemplary involvement of endoplasmic reticulum stress in the molecular events to defeat multidrug resistance.

Modulatory Effect of Myokines on Reactive Oxygen Species in Ischemia/Reperfusion.

There is a growing body of evidence showing the importance of physical activity against acute ischemic events in various organs. Ischemia/reperfusion injury (I/R) is characterized by tissue damage as a result of restriction and subsequent restoration of blood supply to an organ. Oxidative stress due to increased reactive oxygen species formation and/or insufficient antioxidant defense is considered to play an important role in I/R. Physical activity not only decreases the general risk factors for ischemia but also confers direct anti-ischemic protection via myokine production. Myokines are skeletal muscle-derived cytokines, representing multifunctional communication channels between the contracting skeletal muscle and other organs through an endocrine manner. In this review, we discuss the most prominent members of the myokines (i.e., brain-derived neurotrophic factor (BDNF), cathepsin B, decorin, fibroblast growth factors-2 and -21, follistatin, follistatin-like, insulin-like growth factor-1; interleukin-6, interleukin-7, interleukin-15, irisin, leukemia inhibitory factor, meteorin-like, myonectin, musclin, myostatin, and osteoglycin) with a particular interest in their potential influence on reactive oxygen and nitrogen species formation or antioxidant capacity. A better understanding of the mechanism of action of myokines and particularly their participation in the regulation of oxidative stress may widen their possible therapeutic use and, thereby, may support the fight against I/R.

Effect of Stellaria media Tea on Lipid Profile in Rats.

BACKGROUND: In folk medicine, common chickweed (Stellaria media) has traditionally been applied for the treatment of hypercholesterolemia; however, there is no firm experimental proof to support the rationale of this practice. Therefore, we aimed to assess the efficacy and safety of Stellaria media) has traditionally been applied for the treatment of hypercholesterolemia; however, there is no firm experimental proof to support the rationale of this practice. Therefore, we aimed to assess the efficacy and safety of Materials and Methods. Adult male Wistar rats were divided into 3 groups. The (i) control group received standard laboratory chow, the (ii) hypercholesterolemic group received cholesterol-enriched diet, and the (iii) chickweed-treated hypercholesterolemic group received cholesterol-enriched diet and 100 mg/kg body weight Stellaria media) has traditionally been applied for the treatment of hypercholesterolemia; however, there is no firm experimental proof to support the rationale of this practice. Therefore, we aimed to assess the efficacy and safety of. RESULTS: Cholesterol-enriched diet significantly increased serum total cholesterol, LDL- and HDL-cholesterol levels, but did not affect triacylglycerol concentrations. The addition of chickweed to the diet did not cause any significant change in serum lipid profile or body weight increase. Liver and kidney functions were unaltered and cardiac morphology and function were not changed due to Stellaria media) has traditionally been applied for the treatment of hypercholesterolemia; however, there is no firm experimental proof to support the rationale of this practice. Therefore, we aimed to assess the efficacy and safety of. CONCLUSION: Although chickweed does not seem to be toxic, our results do not support the rationale of its use in the treatment of hypercholesterolemia.

Cyclic mu-opioid receptor ligands containing multiple N-methylated amino acid residues.

In this study we report the in vitro activities of four cyclic opioid peptides with various sequence length/macrocycle size and N-methylamino acid residue content. N-Methylated amino acids were incorporated and cyclization was employed to enhance conformational rigidity to various extent. The effect of such modifications on ligand structure and binding properties were studied. The pentapeptide containing one endocyclic and one exocyclic N-methylated amino acid displayed the highest affinity to the mu-opioid receptor. This peptide was also shown to be a full agonist, while the other analogs failed to activate the mu opioid receptor. Results of molecular docking studies provided rationale for the explanation of binding properties on a structural basis.

Amyloid-like Fibril Formation by Trypsin in Aqueous Ethanol. Inhibition of Fibrillation by PEG.

The formation of amyloid-like fibrils was studied by using the well-known serine protease trypsin as a model protein in the presence of ethanol as organic solvent. Trypsin forms amyloid-like fibrils in aqueous ethanol at pH = 7.0. The dye Congo red (CR) was used to detect the presence of amyloid-like fibrils in the samples. The binding of CR to fibrils led to an increase in absorption intensity and a red shift in the absorption band of CR. Thioflavin T (ThT) and 8-anilino-1- naphthalenesulfonic acid (ANS) binding assays were employed to characterize amyloid-like fibril formation. The ThT binding assay revealed that the protein exhibited maximum aggregation in 60% (v/v) ethanol after incubation for 24 h at 24 (o)C. The ANS binding results indicated that the hydrophobic residues were more exposed to the solvent in the aggregated form of the protein. The effects of polyethylene glycol (PEG) on the formation of amyloid-like fibrils was studied in vitro. The aggregation of trypsin was followed via the kinetics of aggregation, the far-UV circular dichroism (CD) and transmission electron microscopy (TEM) in the presence and absence of PEG. The CD measurements indicated that the protein aggregates have a cross-beta structure in 60% ethanol. TEM revealed that trypsin forms fibrils with a thread-like structure. The inhibitory effect of PEG on the aggregation of trypsin increased with rising PEG concentration. PEG therefore inhibits the formation of amyloid-like fibrils of trypsin in aqueous ethanol.