Dejstvo betaina i neuregulina-1 na tkivne, ćelijske i molekularne promene na in vivo i in vitro modelima nealkoholne masne bolesti i fibroze jetre

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver diseases in the general population. NAFLD consists of three major entities including steatosis, nonalcoholic steatohepatitis (NASH) and cirrhosis. The principal causes of steatosis are insulin resistance and hyperinsulinemia, which lead to increased lipolysis in adipose tissue with subsequent inflow of free fatty acids (FFA) to the liver and stimulation of hepatic de novo lipogenesis. Lipotoxic effects of FFAs cause mitochondrial dysfunction and oxidative stress that lead to the activation of inflammatory response and progression of steatosis to NASH. Autophagy is impaired in NAFLD and contributes to the accumulation of damaged organelles and proteins in hepatocytes, ultimately leading to apoptosis. Chronic liver injury and inflammation stimulate fibrogenic pathways and ultimately may result in liver cirrhosis. Hepatic stellate cells (HSCs) play a central role in hepatic fibrogenesis and are a major source of collagen and other extracellular matrix proteins. Transforming growth factor beta (TGF-β) induces a transdifferentiation of HSCs into myofibroblast-like cells which express collagen I gene and alpha-smooth muscle actin. Neuregulin-1 (NRG-1) belongs to epidermal growth factor family and is involved in cell differentiation, proliferation, growth and survival. Recombinant human NRG-1 (rhNRG-1) exerts antifibrotic effects in the heart, lungs, kidneys and skin. However, the exact role of NRG-1 in liver fibrogenesis has not been elucidated. Betaine, 3-methyl glycine is a nontoxic amino acid, a methyl-group donor and exerts antioxidative effects by increasing the amount of sulfur-containing amino acids. Additionally, betaine may induce epigenetic silencing of genes involved in lipogenesis contributing to alleviation of steatosis. On the other hand, the effects of betaine on inflammation, autophagy and apoptosis, as well as on signaling pathways involved in NAFLD pathogenesis are still not clarified...od najčešćih uzročnika hroničnih oboljenja jetre u razvijenim zemljama, s obzirom na sve veću učestalost gojaznosti i dijabetes melitusa tipa 2 pre svega u mlađoj populaciji. NAFLD predstavlja hepatičnu manifestaciju metaboličkog sindroma, koja se može ispoljiti u tri oblika: kao masna promena jetre, nealkoholni steatohepatitis (eng. non-alcoholic steatohepatitis; NASH) ili ciroza jetre, sa mogućnošću progresije u hepatocelularni karcinom. Patogeneza NAFLD je kompleksna i još uvek nedovoljno rasvetljena. Savremena teorija ukazuje na značaj interakcije brojnih mehanizama na ćelijskom i molekularnom nivou u patogenezi NAFLD, tzv.teorija višestrukih udara. Smatra se da centralnu ulogu u njenom razvoju ima insulinska rezistencija, što uslovljava povećanje de novo lipogeneze u jetri, povećanje lipolize u masnom tkivu, povećan priliv masnih kiselina u jetru i nastanak steatoze. Slobodne masne kiseline ispoljavaju lipotoksično dejstvo i uzrokuju mitohondrijsku disfunkciju, oksidativni stres, kao i stres endoplazmatskog retikuluma. Usled povećanja permeabilnosti sluznice u digestivnom traktu i prolaska endotoksina bakterija crevne flore u cirkulaciju, dolazi do pokretanja zapaljenskog odgovora i oslobađanja proinflamatornih citokina, kao što su interleukini (IL-1, IL-6, IL-8) i faktor tumorske nekroze alfa (TNF-α). Oštećenja ćelija usled zapaljenja i oksidativnog strresa dovode do apoptoze i nekroze hepatocita. Ovi mehanizmi dovode do pogoršanja steatoze usled oksidativne modifikacije apoB100 i smanjenog efluksa lipoproteina veoma male gustine (eng. very low density lipoprotein; VLDL), kao i do progresije steatoze u NASH kod genetski predisponiranih osoba.Skorašnje studije ukazuju da su izmenjeni procesi apoptoze i autofagije verovatno uključeni u patogenezu NAFLD. Hronično oštećenje jetre i inflamacija podstiču razvoj fibroze posredstvom brojnih proinflamatornih citokina, faktora rasta i slobodnih kiseoničnih radikala..

Shvatanje nacionalnog identiteta političke elite

Osnovni cilj ovog dela studije jeste da se utvrdi kako savremena politička elita u Srbiji shvata nacionalni identitet. Pri tome, nacionalni identitet se posmatra kao specifična vrsta vrednosne orijentacije i uzima se kao jedan od kriterijuma za procenu stepena konsolidacije ove društvene grupe. Konceptualni okvir rada počiva na Smitovom razlikovanju dva modela nacionalnog identiteta: teritorijalnog, odnosno građanskog, i demotskog, odnosno narodnog. Ispituje se i uticaj nekih sociodemografskih faktora na shvatanje identiteta, zatim uticaj ideološko-političke identifikacije na liniji levo-desno, kao i odnosa prema nacionalnom pitanju definisanog u političkom programu stranke kojoj pripadnici elite pripadaju. Na kraju, komparativno je analizirano shvatanje nacionalnog identiteta od strane aktuelne političke elite Srbije, i shvatanje njenih prethodnika, kao i stanovništva i političkih elita drugih evropskih zemalja. Empirijsku osnovu analize predstavljaju podaci prikupljeni 2015. godine od strane Instituta za sociološka istraživanja Filozofskog fakulteta u Beogradu, koji su dopunjeni podacima INTUNE projekta realizovanog u dva talasa u više evropskih zemalja

Shvatanje nacionalnog identiteta političke elite

Osnovni cilj ovog dela studije jeste da se utvrdi kako savremena politička elita u Srbiji shvata nacionalni identitet. Pri tome, nacionalni identitet se posmatra kao specifična vrsta vrednosne orijentacije i uzima se kao jedan od kriterijuma za procenu stepena konsolidacije ove društvene grupe. Konceptualni okvir rada počiva na Smitovom razlikovanju dva modela nacionalnog identiteta: teritorijalnog, odnosno građanskog, i demotskog, odnosno narodnog. Ispituje se i uticaj nekih sociodemografskih faktora na shvatanje identiteta, zatim uticaj ideološko-političke identifikacije na liniji levo-desno, kao i odnosa prema nacionalnom pitanju definisanog u političkom programu stranke kojoj pripadnici elite pripadaju. Na kraju, komparativno je analizirano shvatanje nacionalnog identiteta od strane aktuelne političke elite Srbije, i shvatanje njenih prethodnika, kao i stanovništva i političkih elita drugih evropskih zemalja. Empirijsku osnovu analize predstavljaju podaci prikupljeni 2015. godine od strane Instituta za sociološka istraživanja Filozofskog fakulteta u Beogradu, koji su dopunjeni podacima INTUNE projekta realizovanog u dva talasa u više evropskih zemalja

Hronična niskostepena inflamacija u procesu starenja kao karika u lancu vaskularnih poremećaja koji su povezani sa gojaznošću

The pathogenesis of obesity-related vascular disorders has not been fully elucidated. The fundamental role of inflammation in aging process is now widely recognized, particularly for atherosclerotic disease which begins before birth. The number of obese individuals worldwide has reached two billion, leading to an explosion of obesity-related vascular disorders associated with increased morbidity and mortality. Obesity, as a chronic low grade inflammatory process, is important risk factor for metabolic and cardiovascular disease. Despite a well-known genetic component, this risk appears to originate from several abnormalities in adipose tissue function associated with a chronic inflammatory state. In particular, obesity as the most common nutritional disorder in industrialized countries, is closely related to impaired endothelial function, a well-known marker of preatherosclerotic disease. These conditions disrupt vascular homeostasis by causing an imbalance between the nitric oxide pathway and the endothelin-1 system, with impaired insulin- stimulated endothelium-dependent vasodilation. Having in mind the growing population of overweight and obese people worldwide, along with an increasingly aging population, understanding the pathophysiology of obesity on cardiovascular system is essential. The mechanisms linking obesity-related vascular disorders and low grade inflammation in aging process are the focus of this paper.Patogeneza vaskularnih poremećaja koji su povezani sa gojaznošću nije u potpunosti razjašnjena. Danas je poznata fundamentalna uloga inflamacije u procesu starenja, naročito kod aterosklerozne bolesti, koja počinje pre rođenja. Broj gojaznih osoba širom sveta je dostigao cifru dva biliona i doveo do “eksplozije” vaskularnih poremećaja koji su povezani sa gojaznošću i povećanim morbiditetom i mortalitetom. Gojaznost, kao hronični niskostepeni inflamacijski proces, je važan faktor rizika za nastanak metaboličkih i kardiovaskularnih bolesti. Pored dobro proučene genetske komponente, izgleda da je za ovaj rizik zaslužno i nekoliko poremećaja funkcije masnog tkiva koji se dovode u vezu sa stanjem hronične inflamacije. U tom smislu prednjači gojaznost, pošto je kao najčešći poremećaj ishrane u razvijenim zemljama blisko povezana sa endotelnom disfunkcijom, koja predstavlja uveliko poznat marker preaterosklerozne bolesti. Takvi uslovi narušavaju vaskularnu homeostazu, dovodeći do dizbalansa između metaboličkog puta azot monoksida i sistema endotelina-1, što je praćeno otežanim odvijanjem insulinom podstaknute vazodilatacije. Imajući u vidu globalni zajednički porast broja kako osoba sa viškom kilograma i gojaznih osoba, tako i starije populacije, razumevanje patogeneze gojaznosti i njenog uticaja na kardiovaskularni sistem je od esencijalnog značaja. Mehanizmi koji čine sponu između vaskularnih poremećaja povezanih sa gojaznošću i niskostepene inflamacije u procesu starenja nalaze se u fokusu ovog rada

Shortened Daily Photoperiod Alleviates Anxiety-like Behaviour by Antioxidant Effect and Changes Serum Fatty Acid Profile in Diabetic Rats

The aim of our study was to investigate the effects of a shortened daily photoperiod on anxiety-like behaviour, brain oxidative stress, lipid status and fatty acid composition of serum lipids in a streptozotocin (STZ)-induced model of diabetes mellitus in rats. Male Wistar rats were divided into the following groups: first group—control group (C12/12); second group—diabetic group (DM12/12; 100 mg/kg STZ); third group—control group exposed to a light/dark cycle 6/18 h (C6/18); fourth group—diabetic group exposed to a light/dark cycle 6/18 h (DM6/18). Anxiety-like behaviour was tested three weeks following STZ injection by elevated plus maze (EPM) and open-field test (OFT). Oxidative stress parameters were measured in the cortex, hippocampus and thalamus, while lipid status and fatty acid methyl esters (FAMEs) were measured in the serum. Both EPM and OFT showed a lower degree of anxiety-like behaviour in the DM6/18 vs. DM12/12 group. Lipid peroxidation in the cortex, hippocampus and thalamus was significantly lower in the DM6/18 vs. DM12/12 group (p < 0.05), associated with an increased level of antioxidant enzymes and protein thiols in the cortex and thalamus. In the DM6/18 group, oleic, vaccenic, dihomo-γ-linolenic and docosahexaenoic acid concentrations were significantly higher in comparison to the DM12/12 group. A shortened daily photoperiod alleviates anxiety-like behaviour in diabetic rats by reduced lipid peroxidation and changes in the serum fatty acids profile

Dejstvo betaina i neuregulina-1 na tkivne, ćelijske i molekularne promene na in vivo i in vitro modelima nealkoholne masne bolesti i fibroze jetre

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver diseases in the general population. NAFLD consists of three major entities including steatosis, nonalcoholic steatohepatitis (NASH) and cirrhosis. The principal causes of steatosis are insulin resistance and hyperinsulinemia, which lead to increased lipolysis in adipose tissue with subsequent inflow of free fatty acids (FFA) to the liver and stimulation of hepatic de novo lipogenesis. Lipotoxic effects of FFAs cause mitochondrial dysfunction and oxidative stress that lead to the activation of inflammatory response and progression of steatosis to NASH. Autophagy is impaired in NAFLD and contributes to the accumulation of damaged organelles and proteins in hepatocytes, ultimately leading to apoptosis. Chronic liver injury and inflammation stimulate fibrogenic pathways and ultimately may result in liver cirrhosis. Hepatic stellate cells (HSCs) play a central role in hepatic fibrogenesis and are a major source of collagen and other extracellular matrix proteins. Transforming growth factor beta (TGF-β) induces a transdifferentiation of HSCs into myofibroblast-like cells which express collagen I gene and alpha-smooth muscle actin. Neuregulin-1 (NRG-1) belongs to epidermal growth factor family and is involved in cell differentiation, proliferation, growth and survival. Recombinant human NRG-1 (rhNRG-1) exerts antifibrotic effects in the heart, lungs, kidneys and skin. However, the exact role of NRG-1 in liver fibrogenesis has not been elucidated. Betaine, 3-methyl glycine is a nontoxic amino acid, a methyl-group donor and exerts antioxidative effects by increasing the amount of sulfur-containing amino acids. Additionally, betaine may induce epigenetic silencing of genes involved in lipogenesis contributing to alleviation of steatosis. On the other hand, the effects of betaine on inflammation, autophagy and apoptosis, as well as on signaling pathways involved in NAFLD pathogenesis are still not clarified...od najčešćih uzročnika hroničnih oboljenja jetre u razvijenim zemljama, s obzirom na sve veću učestalost gojaznosti i dijabetes melitusa tipa 2 pre svega u mlađoj populaciji. NAFLD predstavlja hepatičnu manifestaciju metaboličkog sindroma, koja se može ispoljiti u tri oblika: kao masna promena jetre, nealkoholni steatohepatitis (eng. non-alcoholic steatohepatitis; NASH) ili ciroza jetre, sa mogućnošću progresije u hepatocelularni karcinom. Patogeneza NAFLD je kompleksna i još uvek nedovoljno rasvetljena. Savremena teorija ukazuje na značaj interakcije brojnih mehanizama na ćelijskom i molekularnom nivou u patogenezi NAFLD, tzv.teorija višestrukih udara. Smatra se da centralnu ulogu u njenom razvoju ima insulinska rezistencija, što uslovljava povećanje de novo lipogeneze u jetri, povećanje lipolize u masnom tkivu, povećan priliv masnih kiselina u jetru i nastanak steatoze. Slobodne masne kiseline ispoljavaju lipotoksično dejstvo i uzrokuju mitohondrijsku disfunkciju, oksidativni stres, kao i stres endoplazmatskog retikuluma. Usled povećanja permeabilnosti sluznice u digestivnom traktu i prolaska endotoksina bakterija crevne flore u cirkulaciju, dolazi do pokretanja zapaljenskog odgovora i oslobađanja proinflamatornih citokina, kao što su interleukini (IL-1, IL-6, IL-8) i faktor tumorske nekroze alfa (TNF-α). Oštećenja ćelija usled zapaljenja i oksidativnog strresa dovode do apoptoze i nekroze hepatocita. Ovi mehanizmi dovode do pogoršanja steatoze usled oksidativne modifikacije apoB100 i smanjenog efluksa lipoproteina veoma male gustine (eng. very low density lipoprotein; VLDL), kao i do progresije steatoze u NASH kod genetski predisponiranih osoba.Skorašnje studije ukazuju da su izmenjeni procesi apoptoze i autofagije verovatno uključeni u patogenezu NAFLD. Hronično oštećenje jetre i inflamacija podstiču razvoj fibroze posredstvom brojnih proinflamatornih citokina, faktora rasta i slobodnih kiseoničnih radikala..

The Interconnection between Hepatic Insulin Resistance and Metabolic Dysfunction-Associated Steatotic Liver Disease—The Transition from an Adipocentric to Liver-Centric Approach

The central mechanism involved in the pathogenesis of MAFLD is insulin resistance with hyperinsulinemia, which stimulates triglyceride synthesis and accumulation in the liver. On the other side, triglyceride and free fatty acid accumulation in hepatocytes promotes insulin resistance via oxidative stress, endoplasmic reticulum stress, lipotoxicity, and the increased secretion of hepatokines. Cytokines and adipokines cause insulin resistance, thus promoting lipolysis in adipose tissue and ectopic fat deposition in the muscles and liver. Free fatty acids along with cytokines and adipokines contribute to insulin resistance in the liver via the activation of numerous signaling pathways. The secretion of hepatokines, hormone-like proteins, primarily by hepatocytes is disturbed and impairs signaling pathways, causing metabolic dysregulation in the liver. ER stress and unfolded protein response play significant roles in insulin resistance aggravation through the activation of apoptosis, inflammatory response, and insulin signaling impairment mediated via IRE1/PERK/ATF6 signaling pathways and the upregulation of SREBP 1c. Circadian rhythm derangement and biological clock desynchronization are related to metabolic disorders, insulin resistance, and NAFLD, suggesting clock genes as a potential target for new therapeutic strategies. This review aims to summarize the mechanisms of hepatic insulin resistance involved in NAFLD development and progression

Rimonabant Improves Oxidative/Nitrosative Stress in Mice with Nonalcoholic Fatty Liver Disease

The present study deals with the effects of rimonabant on oxidative/nitrosative stress in high diet- (HFD-) induced experimental nonalcoholic fatty liver disease (NAFLD). Male mice C57BL/6 were divided into the following groups: control group fed with control diet for 20 weeks (C; n=6); group fed with HFD for 20 weeks (HF; n=6); group fed with standard diet and treated with rimonabant after 18 weeks (R; n=9); group fed with HFD and treated with rimonabant after 18 weeks (HFR; n=10). Daily dose of rimonabant (10 mg/kg) was administered to HFR and R group by oral gavage for two weeks. Treatment induced a decrease in hepatic malondialdehyde concentration in HFR group compared to HF group (P<0.01). The concentration of nitrites + nitrates in liver was decreased in HFR group compared to HF group (P<0.01). Liver content of reduced glutathione was higher in HFR group compared to HF group (P<0.01). Total liver superoxide dismutase activity in HFR group was decreased in comparison with HF group (P<0.01). It was found that rimonabant may influence hepatic iron, zinc, copper, and manganese status. Our study indicates potential usefulness of cannabinoid receptor type 1 blockade in the treatment of HFD-induced NAFLD

A Study on the Ethanolic Extract of Onosma aucheriana. Biological and toxicological evaluation

This research studies the antioxidant activity and efficacy of the ethanolic extract of the plant species Onosma aucheriana DC. This plant growing wild in Serbia, in inhibiting the development of selected fungi and bacteria. The most sensitive to the ethanolic extracts were bacteria B. subtilis and S. aureus (MIC = 15.62 mg/mL), while the fungi, A. niger (MIC = 15.62 mg/mL) showed the highest susceptibility. Total phenolic, flavonoid, condensed tannin and gallotannin contents were 90.26 mg GA/g, 35.24 mg RU/g, 74.65 mg GA/g and 31.74 mg GA/g, respectively. Phenolic compounds are found as dominant in the extract of rosmarinic acid. Total antioxidant capacity was 78.45 mg AA/g. IC50 values were determined for each measurement: 21.45 mg/mL for DPPH free radical scavenging activity, 36.46 mg/mL for inhibitory activity against lipid peroxidation, 99.11 mg/mL for hydroxyl radical scavenging activity and 45.91 mg/mL for chelating ability. A potent inhibitor of cell growth to all three cell lines (Hep2c, RD, L2OB) is the ethanol extract of plant species O. aucheriana . Results of Allium anaphase-telophase genotoxicity assay revealed that the ethanolic extract of O. aucheriana at concentrations of 62.5 mg/mL does not produce toxic or genotoxic effects.Revista de Chimie (2016), 67(12): 2511-251

Betaine modulates oxidative stress, inflammation, apoptosis, autophagy, and Akt/mTOR signaling in methionine-choline deficiency-induced fatty liver disease

We examined the effects of betaine, an endogenous and dietary methyl donor essential for the methionine-homocysteine cycle, on oxidative stress, inflammation, apoptosis, and autophagy in methionine-choline deficient diet (MCD)-induced non-alcoholic fatty liver disease (NAFLD). Male C57BL/6 mice received standard chow (control), standard chow and betaine (1.5% w/v in drinking water), MCD, or MCD and betaine. After six weeks, serum and liver samples were collected for analysis. Betaine reduced MCD-induced increase in liver transaminases and inflammatory infiltration, as well as hepatosteatosis and serum levels of low-density lipoprotein, while it increased that of high-density lipoprotein. MCD-induced hepatic production of reactive oxygen and nitrogen species was significantly reduced by betaine, which also improved liver antioxidative defense by increasing glutathione content and superoxide-dismutase, catalase, glutathione peroxidase, and paraoxonase activity. Betaine reduced the liver expression of proinflammatory cytokines tumor necrosis factor and interleukin-6, as well as that of proapoptotic mediator Box, while increasing the levels of anti-inflammatory cytokine interleukin-10 and antiapoptotic Bcl-2 in MCD-fed mice. In addition, betaine increased the expression of autophagy activators beclin 1, autophagy-related (Atg)4 and Atg5, as well as the presence of autophagic vesicles and degradation of autophagic target sequestosome 1/p62 in the liver of NAFLD mice. The observed effects of betaine coincided with the increase in the hepatic phosphorylation of mammalian target of rapamycin (mTOR) and its activator Akt. In conclusion, the beneficial effect of betaine in MCD-induced NAFLD is associated with the reduction of liver oxidative stress, inflammation, and apoptosis, and the increase in cytoprotective Akt/mTOR signaling and autophagy