AIM: Currently available medicines have little to offer in terms of supporting the regeneration of injured hepatic cells. Previous experimental studies have shown that resveratrol and metformin, less specific activators of AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), can effectively attenuate acute liver injury. The aim of this experimental study was to elucidate whether modulation of AMPK and SIRT1 activity can modify drug/paracetamol (APAP)-induced hepatocyte damage in vitro. METHODS: Primary rat hepatocytes were pretreated with mutual combinations of specific synthetic activators and inhibitors of SIRT1 and AMPK and followed by a toxic dose of APAP. At the end of cultivation, medium samples were collected for biochemical analysis of alanine-aminotransferase and nitrite levels. Hepatocyte viability, thiobarbituric reactive substances, SIRT1 and AMPK activity and protein expression were also assessed. RESULTS: The harmful effect of APAP was associated with decreased AMPK and SIRT1 activity and protein expression alongside enhanced oxidative stress in hepatocytes. The addition of AMPK activator (AICAR) or SIRT1 activator (CAY10591) significantly attenuated the deleterious effects of AMPK inhibitor (Compound C) on the hepatotoxicity of APAP. Furthermore, CAY10591 but not AICAR markedly decreased the deleterious effect of APAP in combination with SIRT1 inhibitor (EX-527). CONCLUSION: Our findings demonstrate that decreased AMPK activity is associated with the hepatotoxic effect of APAP which can be significantly attenuated by the administration of a SIRT1 activator. These findings suggest that differentiated modulation of AMPK and SIRT1 activity could therefore provide an interesting and novel therapeutic opportunity in the future to combat hepatocyte injury.

• MeSH
• cyklopentany farmakologie   MeSH
• hepatocyty * metabolismus   MeSH
• krysa rodu rattus MeSH
• lékové postižení jater * etiologie   genetika   metabolismus   patologie   MeSH
• paracetamol toxicita   MeSH
• proteinkinasy aktivované AMP * chemie   metabolismus   farmakologie   MeSH
• sirtuin 1 * metabolismus   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Currently, non-alcoholic fatty liver disease (NAFLD) progressing into chronic non-alcoholic steatohepatitis (NASH), liver cirrhosis, and eventually hepatocellular cancer has emerged as an epidemiological concern due to lack of proven treatment. Our review briefly comprises of the mechanism of pathogenesis and inflammation corresponding to the disease, and all the offered insights of mechanistic pathways that could be targeted in the progression of NASH. The review principally focuses on mTOR (mammalian target of rapamycin) as a promising target highlighting its immense role in lipogenesis and alleviating inflammation and fibrosis. A detailed description of signaling pathways of mTORC1 and mTORC2 that are inhibited by rapamycin and other mTOR inhibitor analogues is accentuated. The exploration of mTOR inhibitors clearly explains the exigent molecular aspects of mTOR in regulating adipocyte and lipogenic marker genes (e.g. those encoding PPARγ, SREBP1c). The literature on available mTOR inhibitors and their classification so far could be extremely useful in highlighting mTOR as a favorable drug target in the indication of NASH in the near future.

• MeSH
• hepatocelulární karcinom * patologie   MeSH
• jaterní cirhóza patologie   MeSH
• játra metabolismus   MeSH
• lidé MeSH
• nádory jater * patologie   MeSH
• nealkoholová steatóza jater * metabolismus   MeSH
• TOR serin-threoninkinasy metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

This article is directed at highlighting the involvement of the endogenous stress sensor SIRT1 (silent information regulator T1) as a possible factor involved in hepatoprotection. The selective SIRT1 modulators whether activators (STACs) or inhibitors are being tried experimentally and clinically. We discuss the modulation of SIRT1 on cytoprotection or even cytotoxicity in the liver chemically injured by hepatotoxic agents in rats, to shed light on the crosstalk between SIRT1 and its modulators. A combination of D-galactosamine and lipopolysaccharide (D-GalN/LPS) downregulated SIRT1 expression, while SIRT1 activators, SRT1720, resveratrol, and quercetin, upregulated SIRT1 and alleviated D-GalN/LPS-induced acute hepatotoxicity. Liver injury markers exhibited an inverse relationship with SIRT1 expression. However, under subchronic hepatotoxicity, quercetin decreased the significant increase in SIRT1 expression to lower levels which are still higher than normal ones and mitigated the liver-damaging effects of carbon tetrachloride. Each of these STACs was hepatoprotective and returned the conventional antioxidant enzymes to the baseline. Polyphenols tend to fine-tune SIRT1 expression towards normal in the liver of intoxicated rats in both acute and subchronic studies. Together, all these events give an impression that the cytoprotective effects of SIRT1 are exhibited within a definite range of expression. The catalytic activity of SIRT1 is important in the hepatoprotective effects of polyphenols where SIRT1 inhibitors block and the allosteric SIRT1 activators mimic the hepatoprotective effects of polyphenols. Our findings indicate that the pharmacologic modulation of SIRT1 could represent both an important move in alleviating hepatic insults and a future major step in the treatment of xenobiotic-induced hepatotoxicity.

• MeSH
• lékové postižení jater farmakoterapie   enzymologie   MeSH
• lidé MeSH
• polyfenoly farmakologie   MeSH
• sirtuin 1 antagonisté a inhibitory   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Od systému cíleného podávání léků (DDS – drug delivery system) se očekává pro terapii zvýšená účinnost léčiv, cílená distribuce a snížení nežádoucích efektů. V přehledném článku jsou stručně popsány základní principy nanotechnologie vyvinuté pro DDS, jednotlivé úseky současného výzkumu a klíčové oblasti nutné pro budoucí zkoumání. Pozornost je věnována resveratrolu jako modelové látce se zajímavými farmakologickými vlastnostmi, které byly potvrzeny v řadě studií, a také pro jeho široké užívání ve formě doplňkové terapie. Vzhledem k nepříznivým farmakokinetickým parametrům resveratrolu, charakterizovaných velmi nízkou biodostupností přes dostatečně vysokou orální absorpci, se účinnost resveratrolu začala studovat v nových nanotechnologií připravených lékových formách. V přehledu jsou uvedeny výsledky dosavadních in vitro a in vivo studií s resveratrolem v novém typu lékových forem s využitím různorodých nanočástic jako jsou liposomy, pevné lipidní částice, cyklodextriny a micely.

Drug delivery system (DDS) is intended to increasing effectiveness of drugs through targeted distribution and to reducing of unwanted effects. In this mini-review, the basic principles of nanotechnology that were developed for DDS were reported including sections on the present research in key areas that are important for future investigations. Attention is paid on resveratrol as a model phytochemical with interesting pharmacologic profile which was demonstrated in great numbers of studies and for its wide use as supplemental therapy. Due to complicated pharmacokinetic profile of resveratrol that is characterized by very low bioavailability in spite of high oral absorption, the effects of resveratrol is being studied in new nanotechnology preparations of pharmaceutical formulation. Herein we report on results of present in vitro and in vivo investigations with resveratrol in new types of drug formulations using different nanoparticles as liposomes, solid lipid particles, cyclodextrins and micelles.

• MeSH
• antioxidancia * farmakokinetika   farmakologie   terapeutické užití   MeSH
• antitumorózní látky fytogenní terapeutické užití   MeSH
• apoptóza účinky léků   MeSH
• cyklodextriny fyziologie   MeSH
• lékové formy MeSH
• lidé MeSH
• liposomy MeSH
• nanočástice využití   MeSH
• nanotechnologie MeSH
• resveratrol MeSH
• stilbeny farmakokinetika   farmakologie   terapeutické užití   MeSH
• systémy cílené aplikace léků * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

The present study was designed to evaluate the therapeutic potential of quercetin in a sub-chronic model of hepatotoxicity. The roles of putative antioxidant enzymes, sirtuin 1 (SIRT1) and heme oxygenase 1 (HO-1), in hepatoprotection were also addressed. Sub-chronic liver injury was induced in rats by intraperitoneal administration of 0.5 ml/kg carbon tetrachloride (CTC), once every 3 days, for 2 weeks. Some CTC rats were concurrently treated with 100 mg/kg quercetin, intragastrically, once every day, for 2 weeks. The effects of these drugs in the liver were evaluated by biochemical, histological, immunohistochemical and molecular biological studies. CTC triggered oxidative damage to the liver as unanimously shown by altered biochemical parameters and liver morphology. Furthermore, CTC highly upregulated HO-1 and SIRT1 expression levels. Concomitant treatment of rats with quercetin downregulated SIRT1 expression and ameliorated the hepatotoxic effects of CTC. However, quercetin did not have any significant effect on HO-1 expression and bilirubin levels. Collectively, these results suggest that the antioxidant and cytoprotective effects of quercetin in CTC treated rats were SIRT1 mediated and less dependent on HO-1. Thus, pharmacologic modulation of SIRT1 could provide a logic therapeutic approach in sub-chronic hepatotoxicity.

• MeSH
• alanintransaminasa krev   MeSH
• aspartátaminotransferasy krev   MeSH
• bilirubin krev   MeSH
• down regulace účinky léků   MeSH
• hemoxygenasa-1 metabolismus   MeSH
• imunohistochemie MeSH
• játra metabolismus   patologie   MeSH
• krysa rodu rattus MeSH
• ochranné látky farmakologie   MeSH
• otrava chloridem uhličitým metabolismus   patologie   prevence a kontrola   MeSH
• potkani Wistar MeSH
• quercetin farmakologie   MeSH
• sirtuin 1 metabolismus   MeSH
• upregulace účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Sirtuin activating compounds (STACs) attenuate various type of liver insults through mechanisms which are not fully understood. In the present study, we investigated the ameliorative potential of quercetin (natural polyphenol) and SRT1720 (synthetic SIRT1 activator) against D-galactosamine/lipopolysaccharide-induced hepatotoxicity (an experimental model of acute liver failure). Moreover, we compared and contrasted the roles of stress responsive enzymes, sirtuin 1 (SIRT1) and heme oxygenase 1 (HO-1) in hepatoprotection/ hepatotoxicity. Liver injury was induced in male Wistar rats by intraperitoneal injection of D-galactosamine (400 mg/kg) and lipopolysaccharide (10 microg/kg). Some animals were pretreated with quercetin (50 mg/kg i.p.) or SRT1720 (5 mg/kg i.p.). Twenty-four hours later, the effects of these treatments were evaluated by biochemical studies and Western blot. D-GalN/LPS treatment upregulated HO-1 expression, downregulated SIRT1 expression, decreased AST: ALT ratio and markedly increased bilirubin, catalase and conjugated diene levels. Pretreatment of D-GalN/LPS rats with either quercetin or SRT1720 returned SIRT1 expression, HO-1 expression and all the aforementioned markers towards normal. Collectively, these findings suggest that elevated HO-1 and low SIRT1 expressions are involved in the pathogenesis of D-GalN/LPS-induced hepatotoxicity. Drugs that downregulate HO-1 and/or upregulate SIRT1 seem to have antihepatotoxic effects and need further exploration.

• MeSH
• galaktosamin toxicita   MeSH
• hemová oxygenasa (decyklizující) antagonisté a inhibitory   metabolismus   MeSH
• heterocyklické sloučeniny tetra- a více cyklické farmakologie   terapeutické užití   MeSH
• krysa rodu rattus MeSH
• lékové postižení jater farmakoterapie   metabolismus   MeSH
• lipopolysacharidy toxicita   MeSH
• náhodné rozdělení MeSH
• potkani Wistar MeSH
• sirtuin 1 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Cílem článku je zdůraznit skutečnost, že k nežádoucím účinkům léků, které se projevují v dutině ústní, může dojít dvěma způsoby. Jejich manifestace může být vyvolána jednak na základě orální aplikace přípravků přímo užívaných ve stomatologické praxi, nebo také po užívání léčivých přípravků mimo dentální praxi. Proto s nežádoucími účinky léků předepisovanými klinickými specialisty různých lékařských oborů by měli zubní lékaři počítat ve své vlastní stomatologické praxi. V textu jsou uvedeny příklady některých vážných nežádoucích reakcí manifestujících se na dásních a sliznicích dutiny ústní. Pozornost je věnována některým skupinám léků, po jejichž aplikaci se objevily nežádoucí efekty, zejména však po podání lokálních anestetik a kortikosteroidů.

The goal of the article is to emphasize the fact that adverse drug effects which are manifested in the oral cavity are exhibited in two ways. This may occur either after a direct application of the preparation used in dental practice, or due to the application of the drug for nondental purpose. That is why the adverse effects of medicines prescribed by various clinical specialists should be considered by stomatologists in their own clinical practice. Examples are reported of some serious drug adverse effects manifested on the oral mucous membrane and gum. Attention is paid to the classes which reveal adverse reactions after applications as local anaesthetics, corticosteroids and others.

• MeSH
• analgetika škodlivé účinky   MeSH
• antihistaminika škodlivé účinky   MeSH
• antihypertenziva škodlivé účinky   MeSH
• antikoagulancia škodlivé účinky   MeSH
• cytostatické látky škodlivé účinky   MeSH
• lidé MeSH
• lokální anestezie škodlivé účinky   MeSH
• nežádoucí účinky léčiv * klasifikace   MeSH
• opioidní analgetika škodlivé účinky   MeSH
• ústní sliznice * účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

This mini-review highlights our and others' experience about in vitro and in vivo models that are being used to follow up events of liver injuries under various hepatotoxic agents and potential hepatoprotective drugs. Due to limitations of the outcomes in each model, we focus primarily on two models. First, a developed perfusion method for isolated immobilized hepatocytes that improves the process of oxygenation and helps in end-product removal is of considerable value in improving cell maintenance. This cellular model is presented as a short-term research-scale laboratory bioreactor with various physiological, biochemical, molecular, toxicological and pharmacological applications. Second, the in vivo model of D-galactosamine and lipopolysaccharide (D-GalN/LPS) combination-induced liver damage is described with some details. Recently, we have revealed that resveratrol and other natural polyphenols attenuate D-GalN/LPS-induced hepatitis. Moreover, we reported that D-GalN/LPS down-regulates sirtuin 1 in rat liver. Therefore, we discuss here the role of sirtuin 1 modulation in hepatoprotection. A successful development of pharmacotherapy for liver diseases depends on the suitability of in vitro and in vivo hepatic injury systems. Several models are available to screen the hepatotoxic or hepatoprotective activity of any substance. It is important to combine different methods for confirmation of the findings.

• MeSH
• akutní selhání jater chemicky indukované   metabolismus   prevence a kontrola   MeSH
• biomedicínský výzkum metody   MeSH
• down regulace účinky léků   fyziologie   MeSH
• galaktosamin toxicita   MeSH
• lidé MeSH
• lipopolysacharidy toxicita   MeSH
• modely nemocí na zvířatech * MeSH
• objevování léků metody   MeSH
• ochranné látky farmakologie   terapeutické užití   MeSH
• sirtuin 1 antagonisté a inhibitory   metabolismus   MeSH
• stilbeny farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

CONTEXT: We focused on certain plant active constituents considered to be the most promising/studied for liver disease and that were critically investigated from the basic science point of view and, to some extent, the clinical one. Due to insufficient pharmacological data, most of the herbal formulations containing these molecules cannot be recommended for the treatment of liver disease. OBJECTIVE: To present the most promising compounds tested experimentally and/or clinically and describe in brief popular models in experimental testing of potential hepatoprotective compounds. METHODS: A literature search using Web of Science (WOS), PubMed, and Google search was performed. RESULTS: Focusing on a few herbal hepatoprotective active constituents is useful to health professionals working in the field of therapeutics to develop evidence-based hepatoprotective agents by conducting research on pure chemical structures or on molecular modifications using computational chemistry. This review demonstrates that multi-pathways in the liver pathobiology can be interrupted at one or more levels by natural hepatoprotective studied, such as interference with the oxidative stress at multiple levels to reduce reactive oxygen/nitrogen species, resulting in ameliorating hepatotoxicity. CONCLUSION: Hepatoprotective constituents of herbal medications are poorly absorbed after oral administration; methods that can improve their bioavailability are being developed. It is recommended that controlled prospective double-blind multicenter studies on isolated active plant constituents, or on related newly designed molecules after structural modifications, should be performed. This effort will lead to expanding the existing, limited drugs for the vast majority of liver diseases.

• MeSH
• léčivé rostliny chemie   MeSH
• lékové postižení jater prevence a kontrola   MeSH
• lidé MeSH
• nemoci jater prevence a kontrola   MeSH
• ochranné látky farmakologie   MeSH
• rostlinné extrakty farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Sirtuin 1 (SIRT1) is involved in important biological processes such as energy metabolism and regulatory functions of the cell cycle, apoptosis, and inflammation. Our previous studies have shown hepatoprotective effect of polyphenolic compound resveratrol, which is also an activator of SIRT1. Therefore, the aim of our present study was to clarify the role of SIRT1 in process of hepatoprotection in animal model of drug-induced liver damage. Male Wistar rats were used for both in vivo and in vitro studies. Hepatotoxicity was induced by single dose of acetaminophen (APAP). Some rats and hepatocytes were treated by resveratrol or synthetic selective activator of sirtuin 1 (CAY10591). The degree of hepatotoxicity, the activity and expression of the SIRT1 were determined by biochemical, histological and molecular-biological assessments of gained samples (plasma, liver tissue, culture media and hepatocytes). Resveratrol and CAY attenuated APAP-induced hepatotoxicity in vivo and in vitro. Moreover, both drugs enhanced APAP-reduced SIRT1 activity. Our results show that modulation of the SIRT1 activity plays a role in hepatoprotection. Synthetic activators of SIRT1 would help in understanding the role of SIRT1 and are therefore a major boost towards the search for specific treatment of liver disease.

• MeSH
• hepatocyty účinky léků   metabolismus   MeSH
• krysa rodu rattus MeSH
• kultivované buňky MeSH
• lékové postižení jater farmakoterapie   metabolismus   MeSH
• modely nemocí na zvířatech * MeSH
• paracetamol toxicita   MeSH
• potkani Wistar MeSH
• sirtuin 1 fyziologie   MeSH
• stilbeny farmakologie   terapeutické užití   MeSH
• viabilita buněk účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH