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.

• Klíčová slova
• 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), CAY10591, adenosine monophosphate protein kinase (AMPK), enzyme activation, hepatocyte protection, sirtuin 1 (SIRT1),
• 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
• Názvy látek
• CAY10591 MeSH Prohlížeč
• cyklopentany MeSH
• paracetamol MeSH
• proteinkinasy aktivované AMP * MeSH
• Sirt1 protein, rat MeSH Prohlížeč
• sirtuin 1 * 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.

• Klíčová slova
• Lipogenesis, NAFLD, NASH, mTOR, mTOR inhibitors,
• 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
• Názvy látek
• MTOR protein, human MeSH Prohlížeč
• TOR serin-threoninkinasy 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
• Názvy látek
• polyfenoly MeSH
• sirtuin 1 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.

• Klíčová slova
• Carbon tetrachloride, Heme oxygenase 1, Hepatoprotection, Hepatotoxicity, Quercetin, Sirtuin 1,
• 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
• Názvy látek
• alanintransaminasa MeSH
• aspartátaminotransferasy MeSH
• bilirubin MeSH
• hemoxygenasa-1 MeSH
• ochranné látky MeSH
• quercetin MeSH
• sirtuin 1 MeSH

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.Key words: targeted drug delivery nanotechnology resveratrol.

• MeSH
• biologická dostupnost MeSH
• lékové transportní systémy * MeSH
• nanočástice * MeSH
• nanotechnologie MeSH
• resveratrol aplikace a dávkování   MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• resveratrol MeSH

UNLABELLED: 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. KEY WORDS: oral adverse drug reactions local anaesthetics corticosteroids.

• MeSH
• anestetika lokální škodlivé účinky   MeSH
• gingiva účinky léků   MeSH
• hormony kůry nadledvin škodlivé účinky   MeSH
• lidé MeSH
• nežádoucí účinky léčiv * MeSH
• ústní sliznice účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• anestetika lokální MeSH
• hormony kůry nadledvin 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.

• Klíčová slova
• Clinical trials, evidence-based hepatoprotectants, hepatotoxicity models, herbal medications, liver disease, oxidative stress,
• 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
• Názvy látek
• ochranné látky MeSH
• rostlinné extrakty MeSH

Estrogen-induced cholestasis is characterized by impaired hepatic uptake and biliary bile acids secretion because of changes in hepatocyte transporter expression. The induction of heme oxygenase-1 (HMOX1), the inducible isozyme in heme catabolism, is mediated via the Bach1/Nrf2 pathway, and protects livers from toxic, oxidative and inflammatory insults. However, its role in cholestasis remains unknown. Here, we investigated the effects of HMOX1 induction by heme on ethinylestradiol-induced cholestasis and possible underlying mechanisms. Wistar rats were given ethinylestradiol (5 mg/kg s.c.) for 5 days. HMOX1 was induced by heme (15 μmol/kg i.p.) 24 hrs prior to ethinylestradiol. Serum cholestatic markers, hepatocyte and renal membrane transporter expression, and biliary and urinary bile acids excretion were quantified. Ethinylestradiol significantly increased cholestatic markers (P ≤ 0.01), decreased biliary bile acid excretion (39%, P = 0.01), down-regulated hepatocyte transporters (Ntcp/Oatp1b2/Oatp1a4/Mrp2, P ≤ 0.05), and up-regulated Mrp3 (348%, P ≤ 0.05). Heme pre-treatment normalized cholestatic markers, increased biliary bile acid excretion (167%, P ≤ 0.05) and up-regulated hepatocyte transporter expression. Moreover, heme induced Mrp3 expression in control (319%, P ≤ 0.05) and ethinylestradiol-treated rats (512%, P ≤ 0.05). In primary rat hepatocytes, Nrf2 silencing completely abolished heme-induced Mrp3 expression. Additionally, heme significantly increased urinary bile acid clearance via up-regulation (Mrp2/Mrp4) or down-regulation (Mrp3) of renal transporters (P ≤ 0.05). We conclude that HMOX1 induction by heme increases hepatocyte transporter expression, subsequently stimulating bile flow in cholestasis. Also, heme stimulates hepatic Mrp3 expression via a Nrf2-dependent mechanism. Bile acids transported by Mrp3 to the plasma are highly cleared into the urine, resulting in normal plasma bile acid levels. Thus, HMOX1 induction may be a potential therapeutic strategy for the treatment of ethinylestradiol-induced cholestasis.

• Klíčová slova
• 17α- ethinylestradiol, bile acids, heme, multidrug resistance-associated protein 3, nuclear factor erythroid-2-related factor-2,
• MeSH
• ABC transportéry genetika   MeSH
• alkalická fosfatasa krev   MeSH
• bilirubin krev   farmakologie   MeSH
• cholestáza krev   chemicky indukované   enzymologie   MeSH
• enzymová indukce účinky léků   MeSH
• ethinylestradiol MeSH
• exprese genu účinky léků   MeSH
• hem farmakologie   MeSH
• hemová oxygenasa (decyklizující) biosyntéza   genetika   MeSH
• hepatocyty účinky léků   enzymologie   MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• kyselina taurocholová farmakologie   MeSH
• ochranné látky farmakologie   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• potkani Wistar MeSH
• primární buněčná kultura MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům genetika   MeSH
• žlučové kyseliny a soli krev   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ABC transportéry MeSH
• Abcc2 protein, rat MeSH Prohlížeč
• Abcc4 protein, rat MeSH Prohlížeč
• alkalická fosfatasa MeSH
• bilirubin MeSH
• ethinylestradiol MeSH
• hem MeSH
• hemová oxygenasa (decyklizující) MeSH
• kyselina taurocholová MeSH
• ochranné látky MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům MeSH
• žlučové kyseliny a soli MeSH

Purified active plant constituents were isolated and assessed for their pharmacological activities that constitute a basis of modern drug development. The situation with herbal supplements is different because the extract or dried herb or mixture of herbs contains several substances beside the beneficial one(s) that might produce drug interaction with the conventional medicine(s). Most patients are misinformed and believe that anything "natural" must be safe. This article is focusing on plant-based substances referred as dietary supplements (DS). Examples of reported drug interactions and contraindications associated with DS with two case studies are presented. As supplements are typically not prescribed, many doctors seem to have no interest in drug-DS interactions since a typical medical history of the patients does not include any questions about self-prescribed remedies of this nature. Rather, patients are left alone when they are tempted to try this or that DS and tend to rely on advice from friends, or on material they read on internet. A better quality control, compliance, public awareness and healthcare professionals vigilance for potential interactions are needed. It is of utmost importance to appreciate the impact of supplements on different stages of pharmacokinetics, especially on drug absorption and metabolism.

• MeSH
• fytoterapie * MeSH
• interakce bylin a léků * MeSH
• internet MeSH
• lékové interakce * MeSH
• lidé MeSH
• potravní doplňky * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

The objective of this study was to evaluate potential hepatoprotective capabilities of quercetin in relation to its modulation of the HO-1 and NOS-2 activities in an experimental model of fulminant liver failure. Liver insult was induced by in vivo administration of D-galactosamine (d-GalN, 400 mg/kg, i.p.) and lipopolysaccharide (LPS, 10 μg/kg, i.p.). The effects of quercetin (50 mg/kg, i.p) on D-GalN toxicity was evaluated by standard biochemical, RT-PCR and Western blot methods. Administration of d-GalN/LPS combination resulted in significantly higher plasma levels of aminotransferases, as well as increased mRNA and protein expressions of both HO-1 and NOS-2 enzymes. Quercetin exhibited cytoprotective effects on the liver, as evidenced by decreased aminotransferase plasma levels. Additionally, quercetin treatment in D-GalN/LPS treated rats significantly increased HO-1 mRNA and its protein expressions. On the contrary, quercetin did not exhibit any significant effects on the levels of nitrites, and NOS-2 mRNA and protein expressions in D-GalN/LPS treated rats. Quercetin when given alone did not have any significant changes on liver enzymes nor HO-1 and NOS-2 mRNA and protein expressions. It can be concluded that the quercetin's induction of HO-1 and its byproducts, without concomitant NOS-2 activity reduction, is among mechanisms contributing to the hepatoprotective effect in D-GalN/LPS hepatotoxicity.

• MeSH
• antioxidancia farmakologie   terapeutické užití   MeSH
• dusitany metabolismus   MeSH
• fytoterapie MeSH
• galaktosamin toxicita   MeSH
• hemoxygenasa-1 metabolismus   MeSH
• játra účinky léků   enzymologie   metabolismus   MeSH
• králíci MeSH
• krysa rodu Rattus MeSH
• lékové postižení jater farmakoterapie   genetika   metabolismus   MeSH
• lipopolysacharidy MeSH
• messenger RNA metabolismus   MeSH
• myši MeSH
• potkani Wistar MeSH
• quercetin farmakologie   terapeutické užití   MeSH
• rostlinné extrakty farmakologie   terapeutické užití   MeSH
• selhání jater farmakoterapie   genetika   metabolismus   MeSH
• synthasa oxidu dusnatého metabolismus   MeSH
• transaminasy krev   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antioxidancia MeSH
• dusitany MeSH
• galaktosamin MeSH
• hemoxygenasa-1 MeSH
• lipopolysacharidy MeSH
• messenger RNA MeSH
• quercetin MeSH
• rostlinné extrakty MeSH
• synthasa oxidu dusnatého MeSH
• transaminasy MeSH