Supermeres are functional extracellular nanoparticles replete with disease biomarkers and therapeutic targets

Extracellular vesicles and exomere nanoparticles are under intense investigation as sources of clinically relevant cargo. Here we report the discovery of a distinct extracellular nanoparticle, termed supermere. Supermeres are morphologically distinct from exomeres and display a markedly greater uptake in vivo compared with small extracellular vesicles and exomeres. The protein and RNA composition of supermeres differs from small extracellular vesicles and exomeres. Supermeres are highly enriched with cargo involved in multiple cancers (glycolytic enzymes, TGFBI, miR-1246, MET, GPC1 and AGO2), Alzheimer’s disease (APP) and cardiovascular disease (ACE2, ACE and PCSK9). The majority of extracellular RNA is associated with supermeres rather than small extracellular vesicles and exomeres. Cancer-derived supermeres increase lactate secretion, transfer cetuximab resistance and decrease hepatic lipids and glycogen in vivo. This study identifies a distinct functional nanoparticle replete with potential circulating biomarkers and therapeutic targets for a host of human diseases.

Serum Afamin a Novel Marker of Increased Hepatic Lipid Content

AimAfamin is a liver-produced glycoprotein, a potential early marker of metabolic syndrome. Here we investigated regulation of afamin in a course of the metabolic disease development and in response to 3-month exercise intervention.MethodsWe measured whole-body insulin sensitivity (euglycemic hyperinsulinemic clamp), glucose tolerance, abdominal adiposity, hepatic lipid content (magnetic resonance imaging/spectroscopy), habitual physical activity (accelerometers) and serum afamin (enzyme-linked immunosorbent assay) in 71 middle-aged men with obesity, prediabetes and newly diagnosed type 2 diabetes. Effects of 3-month exercise were investigated in 22 overweight-to-obese middle-aged individuals (16M/6F).ResultsPrediabetes and type 2 diabetes, but not obesity, were associated with increased serum afamin (p<0.001). Afamin correlated positively with hepatic lipids, fatty liver index and liver damage markers; with parameters of adiposity (waist circumference, %body fat, adipocyte diameter) and insulin resistance (fasting insulin, C-peptide, HOMA-IR; p<0.001 all). Moreover, afamin negatively correlated with whole-body insulin sensitivity (M-value/Insulin, p<0.001). Hepatic lipids and fasting insulinemia were the most important predictors of serum afamin, explaining >63% of its variability. Exercise-related changes in afamin were paralleled by reciprocal changes in insulinemia, insulin resistance and visceral adiposity. No significant change in hepatic lipid content was observed.ConclusionsSubjects with prediabetes and type 2 diabetes had the highest serum afamin levels. Afamin was more tightly related to hepatic lipid accumulation, liver damage and insulin resistance than to obesity.

Metabolic Effects of Hydrophobic Alginate Derivative and Tetrahydrolipstatin in Rats Fed Diet Supplemented With Palm Fat and Cholesterol

The effects of octadecylamide of alginic acid (amidated alginate) and tetrahydrolipstatin on serum and hepatic cholesterol, and the faecal output of fat and sterols were compared in rats. Amidated alginate is a sorbent of lipids, tetrahydrolipstatin is inhibitor of pancreatic lipase. Rats were fed diets containing cholesterol and palm fat at 10 and 70 g/kg, respectively. Palm fat was provided by coconut meal. Amidated alginate at 40 g/kg diet significantly decreased serum total cholesterol, LDL and hepatic cholesterol, hepatic lipids, and increased faecal output of fat and coprostanol. Tetrahydrolipstatin at 300 mg/kg diet significantly decreased LDL cholesterol, hepatic lipids and increased faecal output of fat. The intake of feed was not significantly influenced, however the weight gains in rats fed amidated alginate was lower than in rats of the control group. Both amidated alginate and tetrahydrolipstatin modified fatty acid profile in excreta lipids. Concentrations of saturated fatty acids were decreased and that of unsaturated fatty acids were increased. Despite different mode of action, amidated alginate and tetrahydrolipstatin were equally efficient in the removing dietary fat from the body.

AGE-DEPENDENT PECULIARITIES OF THE OXIDATIVE STRESS PARAMETERS AND ANTIOXIDANTS CONTENT IN THE LIVER OF SCORPION FISH SCORPAENA PORCUS L. IN THE COASTAL WATERS OF THE BOLSHOI CAUCASUS

Comparative study of size-weight characteristics, lipid peroxidation (LPO) parameters and antioxidants content in the liver of marine scorpion fish Scorpaena porcus caught in the coastal waters of the Caucasus at the region of Shepsy village demonstrated age-related differences. The increase of the size and weight, the mass of the liver and gonads was observed in the elder fish, while the condition index varied less. Liver somatic index (LSI) increased in 2-3 years old animals, in the elder fish the growth of this parameters was slowly. Significant increase of gonadosomatic index (GSI) was noted in 4-5 years old animals, while the differences between 2 and 3 years groups were not observed. Lipid oxidation index and relative concentration of the ketodiens did not vary in age. Content of dien conjugates in hepatic lipids was significantly lower (p<0,001) in 3-4 years old fish as compared with the parameters of other studied age groups. TBA-reactive products concentration in the hepatic lipids increased with age and the highest values were observed in 5-6 years old animals. Significant correlation was shown between the content of TBA-reactive products in fish liver and the animals age (r = 0,88, p<0,05), while between the other studied parameters and fish age no significant relations were noted. Vitamin A and carotenoids concentration did not vary with age, however the tendency to increase was observed in 4 years old fish. The reasons of the growth of reactive oxygen species processes (ROS) and the increase of lipid peroxidation compounds concentration can be connected with the decrease of the defense mechanisms of the organism and the damage biomolecules, genetic defects, cell pathologies, tissues and organs and accumulation of xenobiotics in the fish, which impact the organism, accompanied with the oxidative stress. In elder animals the concentration of toxic substances is greater, and together with the decrease of the defense systems the cumulative toxic effect becomes mote considarable. The obtained results in this study provide the additional information for the understanding of the mechanisms of ROS theory of aging at the case of vertebrates of the natural populations. Further investigations could be strengthening to the study the role of endo- and exogenous conditions, modulating the age processes in aquatic organisms, which is important for the ontogenesis mechanisms and they dependence on natural and anthropogenic factors.

Toll-like receptor 5-mediated signaling enhances liver regeneration in mice

Background Toll-like receptor 5 (TLR5)-mediated pathways play critical roles in regulating hepatic immune response and show hepatoprotective effect in mouse models of liver injury. However, the role of TLR5 in experimental models of liver regeneration has not been investigated. This study aims to determine the role of TLR5 in the partial hepatectomy (PHx)-induced liver regeneration. Methods We performed 2/3 PHx in wild-type (WT) mice, TLR5 knockout mice, or TLR5 agonist CBLB502 treated mice as an established model of liver regeneration. Bacterial flagellin content was measured by ELISA, and hepatic TLR5 expression was determined by real-time PCR analyses and flow cytometry. To study the effects of TLR5 on hepatocyte proliferation, proliferating cell nuclear antigen (PCNA) and the incorporation of bromodeoxyuridine (BrdU) were analyzed by immunohistochemistry (IHC) staining. The role of TLR5 in the priming of liver regeneration was examined by real-time PCR analyses of immediate early gene mRNA levels, as well as western blot analysis of hepatic NF-κB and STAT3 activation. Cytokines and growth factors production after PHx were detected using real-time PCR analyses and cytometric bead array (CBA) assays. Oil Red O staining and hepatic lipids concentrations were analyzed to examine the effect of TLR5 on hepatic lipid accumulation after PHx. Results The bacterial flagellin content in serum and liver was increased and the hepatic TLR5 expression was significantly up-regulated in WT mice upon PHx. TLR5-deficient mice exhibited reduced numbers of BrdU- and PCNA-positive cells, suppressed immediate early gene expression, and decreased cytokines and growth factors production. Moreover, PHx-induced NF-κB and STAT3 activation was inhibited in the liver of Tlr5−/− mice compared with WT mice. Consistently, administration of CBLB502 significantly promoted PHx-mediated hepatocyte proliferation correlated with enhanced production of proinflammatory cytokines and recruitment of macrophages and neutrophils in liver. In addition, Tlr5−/− mice displayed significantly decreased hepatic lipids concentrations and Oil Red O positive areas compared with WT mice after PHx. Conclusions We reveal that TLR5 activation is involved in the initial events of liver regeneration after PHx. Our results demonstrate that TLR5 signaling positively regulates liver regeneration and suggest a potential application of TLR5 agonist in promoting liver regeneration.