BACKGROUND & AIMS: Growth Differentiation Factor 11 (GDF11) is an anti-aging factor, yet its role in liver diseases is not established. We evaluated the role of GDF11 in healthy conditions and in the transition from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). RESULTS: GDF11 mRNA levels positively correlated with NAFLD activity score and with CPT1, SREBP, PPARγ and Col1A1 mRNA levels, and associated to portal fibrosis, in morbidly obese patients with NAFLD/NASH. GDF11-treated mice showed mildly exacerbated hepatic collagen deposition, accompanied by weight loss and without changes in liver steatosis or inflammation. GDF11 triggered ALK5-dependent SMAD2/3 nuclear translocation and the pro-fibrogenic activation of HSC. CONCLUSIONS: GDF11 supplementation promotes mild liver fibrosis. Even considering its beneficial metabolic effects, caution should be taken when considering therapeutics that regulate GDF11. METHODS: We analyzed liver biopsies from a cohort of 33 morbidly obese adults with NAFLD/NASH. We determined the correlations in mRNA expression levels between GDF11 and genes involved in NAFLD-to-NASH progression and with pathological features. We also exposed wild type or obese mice with NAFLD to recombinant GDF11 by daily intra-peritoneal injection and monitor the hepatic pathological changes. Finally, we analyzed GDF11-activated signaling pathways in hepatic stellate cells (HSC).
- MeSH
- buněčné linie MeSH
- dospělí MeSH
- experimentální cirhóza jater chemicky indukované metabolismus patologie MeSH
- jaterní cirhóza diagnóza etiologie genetika metabolismus MeSH
- jaterní hvězdicovité buňky metabolismus patologie MeSH
- játra metabolismus patologie MeSH
- kostní morfogenetické proteiny genetika metabolismus toxicita MeSH
- lidé středního věku MeSH
- lidé MeSH
- morbidní obezita komplikace diagnóza MeSH
- myši inbrední C57BL MeSH
- nealkoholová steatóza jater diagnóza etiologie genetika metabolismus MeSH
- progrese nemoci MeSH
- růstové diferenciační faktory genetika metabolismus toxicita MeSH
- signální transdukce MeSH
- studie případů a kontrol MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Hepatocellular carcinoma (HCC) has a poor outcome. Most HCCs develop in the context of liver fibrosis and cirrhosis caused by chronic inflammation. Short-term fasting approaches enhance the activity of chemotherapy in preclinical cancer models, other than HCC. Multi-tyrosine kinase inhibitor Sorafenib is the mainstay of treatment in HCC. However, its benefit is frequently short-lived. Whether fasting can alleviate liver fibrosis and whether combining fasting with Sorafenib is beneficial remains unknown. A 24 hr fasting (2% serum, 0.1% glucose)-induced changes on human hepatic stellate cells (HSC) LX-2 proliferation/viability/cell cycle were assessed by MTT and flow cytometry. Expression of lypolysaccharide (LPS)-induced activation markers (vimentin, αSMA) was evaluated by qPCR and immunoblotting. Liver fibrosis and inflammation were evaluated in a mouse model of steatohepatitis exposed to cycles of fasting, by histological and biochemical analyses. A 24 hr fasting-induced changes were also analyzed on the proliferation/viability/glucose uptake of human HCC cells exposed to Sorafenib. An expression panel of genes involved in survival, inflammation, and metabolism was examined by qPCR in HCC cells exposed to fasting and/or Sorafenib. Fasting decreased the proliferation and the activation of HSC. Repeated cycles of short term starvation were safe in mice but did not improve fibrosis. Fasting synergized with Sorafenib in hampering HCC cell growth and glucose uptake. Finally, fasting normalized the expression levels of genes which are commonly altered by Sorafenib in HCC cells. Fasting or fasting-mimicking diet diets should be evaluated in preclinical studies as a mean to potentiate the activity of Sorafenib in clinical use.
- MeSH
- antitumorózní látky farmakologie MeSH
- buňky Hep G2 MeSH
- časové faktory MeSH
- experimentální cirhóza jater metabolismus patologie MeSH
- fenylmočovinové sloučeniny farmakologie MeSH
- glukosa metabolismus MeSH
- hepatocelulární karcinom farmakoterapie genetika metabolismus patologie MeSH
- jaterní hvězdicovité buňky účinky léků metabolismus patologie MeSH
- lidé MeSH
- lipopolysacharidy farmakologie MeSH
- myši inbrední C57BL MeSH
- nádory jater farmakoterapie genetika metabolismus patologie MeSH
- nealkoholová steatóza jater metabolismus patologie MeSH
- niacinamid analogy a deriváty farmakologie MeSH
- omezení příjmu potravy metabolismus MeSH
- proliferace buněk účinky léků MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
AIM/BACKGROUND: Pistacia terebinthus is used as a coffee substitute in the East and Southern Anatolia regions of Turkey. It contains unsaturated fatty acids, tocopherols, polyphenols and carotenoids. P. terebinthus has anti-inflammatory and potential antioxidant activity. In this study we evaluated the protective effects of P. terebinthus coffee (PTC) on thioacetamide (TAA)-induced liver injury in rats. MATERIALS AND METHODS: Twenty-eight male Sprague-Dawley rats were equally randomized into four groups. Chronic liver injury was induced with TAA (100 mg/kg i.p. three times weekly). The first group of rats served as control and received only tap water (G1), and the remaining groups of rats received PTC, p.o (G2); TAA (G3); TAA plus PTC, p.o (G4), respectively. RESULTS: After 8 weeks, PTC intake significantly reduced fibrosis/inflammation scores (p PTC intake reduced transforming growth factor beta (TGF-β) concentrations in the liver (p PTC intake. DISCUSSION AND CONCLUSION: PTC intake provided beneficial effects against TAA-induced liver injury in rats. PTC probably suppresses the proinflammatory cytokines through NF-κB signaling pathway.
- MeSH
- antioxidancia farmakologie MeSH
- bylinné čaje * MeSH
- experimentální cirhóza jater * chemicky indukované metabolismus patofyziologie prevence a kontrola MeSH
- játra * účinky léků metabolismus patologie MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech MeSH
- noxy toxicita MeSH
- oxidační stres účinky léků MeSH
- Pistacia * MeSH
- potkani Sprague-Dawley MeSH
- thioacetamid toxicita MeSH
- transformující růstový faktor beta metabolismus MeSH
- triterpeny farmakologie MeSH
- výsledek terapie MeSH
- zánět farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The objective of this work was to study the mechanism of liver parenchyma development under the influence of restriction of diet. Useful information is presented about the pathologic features associated with diet restriction in a chicken animal model of NAFLD. There were 96 chickens of two genotypes, Ross 308 and Cobb 500, in the experiment. The control group was fed a standard mixture ad libitum (ADL). The first experimental group, under restriction from the age of 2 weeks, was fed 80% ADL. The second experimental group was fed 65% ADL from the age of 2 weeks. There were 16 animals in each group. The experiment lasted 5 weeks. Liver parenchyma samples were obtained at the age of 35 days by the necropsy method and then processed by standard histologic methods. The slices were stained by standard staining: hematoxylin-eosin and by Sirius red kit for collagen type I and reticulin visualization. Hepatocyte diameter and the proportion of interstitial tissue to the parenchyma of the liver were measured objectively. Microvesicular liver steatosis was observed after 35 days of restriction. Hepatocyte diameter was significantly influenced by sex, genotype, and the experimental group. The proportion of interstitial tissue to the liver parenchyma was highly influenced by genotype and group, but there were no interactions. An increase in the steatosis histologic grade is associated with inflammatory changes, with decrease of hepatocyte diameter and with a decreasing proportion of interstitial tissue to the liver parenchyma. The results show that early restriction is not associated with the development of fibrosis of the liver tissue.
- MeSH
- experimentální cirhóza jater etiologie genetika patologie patofyziologie MeSH
- fenotyp MeSH
- fyziologie výživy zvířat MeSH
- genotyp MeSH
- hepatocyty patologie MeSH
- hladovění komplikace genetika patologie patofyziologie MeSH
- játra patologie MeSH
- kalorická restrikce MeSH
- kur domácí MeSH
- progrese nemoci MeSH
- sexuální faktory MeSH
- stárnutí MeSH
- věkové faktory MeSH
- velikost buňky MeSH
- ztučnělá játra etiologie genetika patologie patofyziologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Hepatic stellate cells (HSC) and liver myofibroblasts (MFB) are two cell populations most likely responsible for the synthesis of most connective tissue components in fibrotic liver. They differ in their origin and location, and possibly in patterns of gene expression. Normal and carbon tetrachloride-cirrhotic livers from rats were used to isolate HSC. Liver was perfused with pronase and collagenase solutions, followed by centrifugation of the cell suspension on a density gradient. HSC were quiescent 2 days after plating on plastic but they became activated after another 5 days in culture. When the culture was passaged 5 times, its character changed profoundly as HSC were replaced by MFB. Microarray analysis was used to determine gene expression in quiescent HSC, activated HSC and MFB. The expression of 49 genes coding for connective tissue proteins, proteoglycans, metalloproteinases and their inhibitors, growth factors and cellular markers was determined. The pattern of gene expression changed during HSC activation and there were distinct differences between HSC and MFB. Little difference between normal cells and cells isolated from cirrhotic liver was found.
- MeSH
- experimentální cirhóza jater metabolismus MeSH
- exprese genu MeSH
- extracelulární matrix chemie MeSH
- fibroblasty cytologie metabolismus účinky léků MeSH
- financování organizované MeSH
- imunohistochemie MeSH
- játra cytologie metabolismus účinky léků MeSH
- krysa rodu rattus MeSH
- kultivované buňky MeSH
- messenger RNA biosyntéza účinky léků MeSH
- metaloproteasy genetika metabolismus MeSH
- myocyty hladké svaloviny cytologie metabolismus účinky léků MeSH
- otrava chloridem uhličitým MeSH
- pojivová tkáň metabolismus účinky léků MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- proteoglykany genetika metabolismus MeSH
- sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
- tkáňové inhibitory metaloproteinas MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
- MeSH
- aktiny diagnostické užití MeSH
- cytoskeletální proteiny MeSH
- desmin diagnostické užití MeSH
- experimentální cirhóza jater chemicky indukované MeSH
- fibroblasty MeSH
- finanční podpora výzkumu jako téma MeSH
- gliový fibrilární kyselý protein diagnostické užití MeSH
- intermediární filamenta MeSH
- játra anatomie a histologie MeSH
- krysa rodu rattus MeSH
- vimentin diagnostické užití MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- MeSH
- buňky pojivové tkáně chemie patologie MeSH
- chlorid uhličitý farmakologie MeSH
- cytoskeletální proteiny chemie MeSH
- experimentální cirhóza jater chemicky indukované patologie MeSH
- finanční podpora výzkumu jako téma MeSH
- imunohistochemie MeSH
- modely nemocí na zvířatech MeSH
- potkani Wistar MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
- Klíčová slova
- ROOIBOS TEA,
- MeSH
- acetylcystein analogy a deriváty terapeutické užití MeSH
- chlorid uhličitý škodlivé účinky MeSH
- experimentální cirhóza jater terapie MeSH
- finanční podpora výzkumu jako téma MeSH
- krysa rodu rattus MeSH
- nemoci jater prevence a kontrola MeSH
- ochranné látky terapeutické užití MeSH
- rostlinné extrakty terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- MeSH
- experimentální cirhóza jater chemicky indukované MeSH
- isoleucin metabolismus MeSH
- ketokyseliny metabolismus MeSH
- krysa rodu rattus MeSH
- leucin metabolismus MeSH
- oxidace-redukce MeSH
- techniky in vitro MeSH
- valin metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- hodnotící studie MeSH
