Metformin is the most widely prescribed treatment of hyperglycemia and type II diabetes since 1970s. During the last 15 years, its popularity increased due to epidemiological evidence, that metformin administration reduces incidence of cancer. However, despite the ongoing effort of many researchers, the molecular mechanisms underlying antihyperglycemic or antineoplastic action of metformin remain elusive. Most frequently, metformin is associated with modulation of mitochondrial metabolism leading to lowering of blood glucose or activation of antitumorigenic pathways. Here we review the reported effects of metformin on mitochondrial metabolism and their potential relevance as effective molecular targets with beneficial therapeutic outcome.

• MeSH
• antitumorózní látky terapeutické užití   MeSH
• diabetes mellitus 2. typu farmakoterapie   genetika   metabolismus   patologie   MeSH
• glycerolfosfátdehydrogenasa genetika   metabolismus   MeSH
• hyperglykemie farmakoterapie   genetika   metabolismus   patologie   MeSH
• hypoglykemika terapeutické užití   MeSH
• lidé MeSH
• metformin terapeutické užití   MeSH
• mitochondrie účinky léků   genetika   metabolismus   MeSH
• nádory genetika   metabolismus   patologie   prevence a kontrola   MeSH
• oxidativní fosforylace MeSH
• protein-serin-threoninkinasy genetika   metabolismus   MeSH
• proteinkinasy aktivované AMP genetika   metabolismus   MeSH
• reaktivní formy kyslíku antagonisté a inhibitory   metabolismus   MeSH
• regulace genové exprese účinky léků   MeSH
• respirační komplex I genetika   metabolismus   MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Vitamin C (kyselina askorbová) má mnohostranné biologické účinky. Jeho antioxidační vlastnosti mohou ovlivnit kancerogenezi potlačením aktivity kyslíkových radikálů. Prooxidační přímý protinádorový účinek vysokých dávek podaných nitrožilně (předpokládaný na základě výsledků laboratorního výzkumu) nebyl dosud v klinických studiích prokázán. Nicméně vitamin C zůstává významným komplementárním léčivem, který zlepšuje kvalitu života nemocných, zejména v kombinaci s gluthationem.

Vitamin C (ascorbic acid) is a mikronutrient with multiple functions. The most important of them is its antioxidant property, which may play the role in carcinogenesis. It neutralizes action of reactive oxygen species. The intravenous administration of high dose of ascorbate can modified antioxidant role to pro-oxidant effect, which could have direct anticancer property. However, this has not been confirmed in clinical trials. The main role of ascorbate remain as very useful complementary therapy, particularly when combined with glutathione.

• MeSH
• antioxidancia farmakologie   MeSH
• glutathion agonisté   farmakologie   MeSH
• karcinogeneze účinky léků   MeSH
• klinická studie jako téma MeSH
• kyselina askorbová * farmakologie   fyziologie   imunologie   krev   metabolismus   MeSH
• lidé MeSH
• nedostatek vitaminu C epidemiologie   MeSH
• oxidační stres účinky léků   MeSH
• reaktivní formy kyslíku antagonisté a inhibitory   škodlivé účinky   MeSH
• Check Tag
• lidé MeSH

Oxidative stress plays an important role in pressure overload-induced cardiac remodeling. The purpose of this study was to determine whether apocynin, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, attenuates pressure overload-induced cardiac remodeling in rats. After abdominal aorta constriction, the surviving rats were randomly divided into four groups: sham group, abdominal aorta constriction group, apocynin group, captopril group. Left ventricular pathological changes were studied using Masson's trichrome staining. Metalloproteinase-2 (MMP-2) levels in the left ventricle were analyzed by western blot and gelatin zymography. Oxidative stress and apoptotic index were also examined in cardiomyocytes using dihydroethidium and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), respectively. Our results showed that abdominal aorta constriction significantly caused excess collagen deposition and cardiac insult. Treatment with apocynin significantly inhibited deposition of collagen and reduced the level of MMP-2. Furthermore, apocynin also decreased the NADPH oxidase activity, reactive oxygen species production and cardiomyocyte apoptotic index. Interestingly, apocynin only inhibited NADPH oxidase activity without affecting its expression or the level of angiotensin II in the left ventricle. In conclusion, apocynin reduced collagen deposition, oxidative stress, and inhibited apoptosis, ultimately ameliorating cardiac remodeling by mechanisms that are independent of the renin-angiotensin system.

• MeSH
• acetofenony farmakologie   MeSH
• antioxidancia farmakologie   MeSH
• apoptóza účinky léků   fyziologie   MeSH
• krevní tlak účinky léků   fyziologie   MeSH
• krysa rodu rattus MeSH
• oxidační stres účinky léků   fyziologie   MeSH
• potkani Sprague-Dawley MeSH
• reaktivní formy kyslíku antagonisté a inhibitory   metabolismus   MeSH
• remodelace komor účinky léků   fyziologie   MeSH
• srdeční frekvence účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

A common problem in management of polytrauma - a simultaneous injury to more than one organ or organ system, at least one of them lethal without intervention - is a discrepancy between a relatively good initial state and a serious subsequent development. Since nitric oxide (NO) is produced in high quantities during tissue injury, we assumed that serum levels of NO (and its oxidation products, NOx) might serve as a prognostic marker of polytrauma severity. However, we found recently that NOx was increased in polytrauma, but not in the most severe cases. The present study was undertaken to test the hypothesis that serum NOx is reduced in severe polytrauma by concomitant overproduction of reactive oxygen species (ROS). Polytrauma was induced in rats under anesthesia by bilateral fracture of femurs and tibiae plus incision of the right liver lobe through laparotomy. Serum NOx was measured by chemiluminescence after hot acidic reduction. The role of ROS was assessed by treatment with an antioxidant, N-acetyl-L-cysteine (NAC). Experimental polytrauma elevated NOx from 11.0+/-0.7 to 23.8+/-4.5 ppb. This was completely prevented by NAC treatment (9.1+/-2.2 ppb). Serum NOx is elevated in severe polytrauma, and this is not reduced by ROS. On the contrary, ROS are necessary for the NOx elevation, probably because ROS produced by inflammatory cells activated by the polytrauma induce massive NO production.

• MeSH
• antioxidancia farmakologie   terapeutické užití   MeSH
• biologické markery krev   MeSH
• krysa rodu rattus MeSH
• oxid dusnatý antagonisté a inhibitory   krev   MeSH
• polytrauma krev   farmakoterapie   MeSH
• potkani Wistar MeSH
• reaktivní formy kyslíku antagonisté a inhibitory   krev   MeSH
• volné radikály antagonisté a inhibitory   krev   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Autozómovo dominantná polycystická choroba obličiek (ADPKD) je genetické ochorenie s vysokou incidenciou, ktoré patrí medzi najčastejšie príčiny renálneho zlyhania. Napriek intenzívnemu vývoju nových liečebných možností zostáva dialýza a transplantácia obličky jedinou efektívnou liečbou konečného štádia ochorenia. V súčasnosti však nastal výrazný progres v pochopení molekulovej patogenézy vzniku ochorenia, a to odhalením úlohy primárneho cília. Zmena dĺžky primárneho cília je spojená s mnohými patologickými procesmi súvisiacimi so vznikom a progresiou ADPKD. Súčasné štúdie jednoznačne potvrdili, že obnovením dĺžky primárneho cília farmakologickou reguláciou možno dosiahnuť zastavenie cystického rastu, prevenciu vzniku fibrózy a zlepšenie funkcie obličiek. Otvára sa tak nová éra tzv. „cilioterapie“, ktorá predstavuje sľubný cieľ pre vývoj nových liečebných možností nielen pre ADPKD, ale aj pre celý rad iných ciliopatií.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease with high incidence, which is among the most common cause of renal failure. Despite the intensive development of new treatment options, dialysis and transplantation of kidney remain the only effective treatment of end-stage renal disease. Currently, however, there was significant progress in understanding the molecular pathogenesis of the disease and its discovery of the role of the primary cilium. The change of length of the primary cilium is associated with many pathological processes related to the development and progression of ADPKD. Recent studies have unequivocally confirmed that the resumption of the primary cilium length by the pharmacological regulation can be achieved the stopping the cystic growth, prevention of fibrosis and improved of the kidney function. Its open a new era so called „ciliotherapy“ , which represents a promising target for the development of new therapeutic option not only for ADPKD, but for a number of other ciliopathies.

• Klíčová slova
• inhibitory proteinů GLI,
• MeSH
• buněčný cyklus MeSH
• cílená molekulární terapie * MeSH
• cilie * fyziologie   účinky léků   MeSH
• cyklin-dependentní kinasa 5 antagonisté a inhibitory   terapeutické užití   MeSH
• inhibitory histondeacetylas terapeutické užití   MeSH
• lidé MeSH
• polycystické ledviny autozomálně dominantní * etiologie   farmakoterapie   MeSH
• reaktivní formy kyslíku antagonisté a inhibitory   terapeutické užití   MeSH
• receptory dopaminu D5 antagonisté a inhibitory   terapeutické užití   MeSH
• signální transdukce MeSH
• transkripční faktory Krüppel-like antagonisté a inhibitory   terapeutické užití   MeSH
• transkripční faktory antagonisté a inhibitory   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

Oxidative stress and NF-κB signaling plays a major role in pathogenesis of osteoarthritis. In the present study, we analyzed the potent role of carnosol against osteoarthritis in cells treated using monosodium iodoacetate (MIA) model through in vitro studies. MIA caused dose-dependent cell death and induced programmed cell death by increasing subG1 accumulation and caspase-3 expressions. MIA caused oxidative stress by increasing reactive oxygen species, lipid peroxidation and further induced NF-κB expression and down regulated Nrf-2 levels. Pre-treatment with carnosol significantly protected the cells by reducing the oxidative stress markers and improved the cell viability up to 98%. Further, carnosol down regulated NF-κB nuclear expression with a concomitant increase in Nrf-2 nuclear localization and up regulated the nuclear Nrf-2 levels. Carnosol also inhibited MIA-induced subG1 accumulation and caspase-3 activation. This study demonstrates that, carnosol might act as potent antioxidant and regulate MIA-induced oxidative stress, NF-κB signaling and programmed cell death by up regulating the Nrf-2 levels.

• MeSH
• antioxidancia metabolismus   MeSH
• apoptóza účinky léků   MeSH
• chondrocyty patologie   účinky léků   MeSH
• chrupavka MeSH
• diterpeny abietanové farmakologie   metabolismus   terapeutické užití   MeSH
• faktor 1 související s NF-E2 aplikace a dávkování   MeSH
• jodacetáty farmakologie   škodlivé účinky   MeSH
• kultivované buňky MeSH
• NF-kappa B antagonisté a inhibitory   MeSH
• osteoartróza * metabolismus   patofyziologie   MeSH
• oxidační stres účinky léků   MeSH
• potkani Sprague-Dawley MeSH
• reaktivní formy kyslíku antagonisté a inhibitory   MeSH
• zánět genetika   chemicky indukované   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH

• MeSH
• diabetes mellitus 2. typu farmakoterapie   MeSH
• interleukiny antagonisté a inhibitory   metabolismus   MeSH
• lipopolysacharidy toxicita   MeSH
• makrofágy metabolismus   patologie   MeSH
• metformin * aplikace a dávkování   metabolismus   MeSH
• NAD * metabolismus   MeSH
• reaktivní formy kyslíku * antagonisté a inhibitory   MeSH

Two mechanisms contribute in the development of pulmonary hypertension in pulmonary embolism (PE) - obstruction of pulmonary blood vessels and vasoconstriction. We hypothesize that hypoxia, increased shear stress and/or activation of gathered leukocytes in the PE may cause a release of reactive oxygen species (ROS). Therefore our aim was to determine the influence of the ROS scavenger Tempol on pulmonary hypertension and to describe NO synthase activity and production of NO oxidative products (NOx) after PE. In general anesthesia sephadex microspheres suspended in PSS were applied in right jugular vein as the pulmonary microembolism. Than we measured in isolated salt solution-perfused lungs the changes in perfusion pressure, activity of NO synthase and NOx plasma concentration in 7 groups of rats: C: control group (n=5), CN: C + sodium nitroprusside (SN) (n=5), EN: PE + SN (n=5), ETN: Tempol + PE + SN (n=5), CL: C + L-NAME (n=5), EL: PE + L-NAME (n=5), ETL: Tempol + PE + L-NAME (n=5). Tempol was applied intraperitoneally before PE. Animals that received Tempol (groups TN, TL) had significantly lower basal perfusion pressure than those which did not receive Tempol (EN, EL). Overall we measured a higher decrease of perfusion pressure than in the control group (C) after application of SN. Administration of L-NAME after PE (EL) increased the pressure more than in the control group (NL). NOx concentration was higher after PE. We found that preventive administration of Tempol decreases the increase in perfusion pressure after PE. PE increased NO release and concentration of NOx.

• MeSH
• aktivace enzymů účinky léků   fyziologie   MeSH
• cyklické N-oxidy farmakologie   terapeutické užití   MeSH
• krevní tlak účinky léků   fyziologie   MeSH
• krysa rodu rattus MeSH
• mikrocirkulace účinky léků   fyziologie   MeSH
• NG-nitroargininmethylester farmakologie   MeSH
• orgánové kultury - kultivační techniky MeSH
• plicní embolie farmakoterapie   metabolismus   MeSH
• plicní oběh účinky léků   fyziologie   MeSH
• potkani Wistar MeSH
• reaktivní formy kyslíku antagonisté a inhibitory   metabolismus   MeSH
• scavengery volných radikálů farmakologie   terapeutické užití   MeSH
• spinové značení MeSH
• synthasa oxidu dusnatého antagonisté a inhibitory   metabolismus   MeSH
• vazokonstrikce 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

Thin films of binary C60/Ti composites, with various concentrations of Ti ranging from ~ 25% to ~ 70%, were deposited on microscopic glass coverslips and were tested for their potential use in bone tissue engineering as substrates for the adhesion and growth of bone cells. The novelty of this approach lies in the combination of Ti atoms (i.e., widely used biocompatible material for the construction of stomatological and orthopedic implants) with atoms of fullerene C60, which can act as very efficient radical scavengers. However, fullerenes and their derivatives are able to generate harmful reactive oxygen species and to have cytotoxic effects. In order to stabilize C60 molecules and to prevent their possible cytotoxic effects, deposition in the compact form of Ti/C60 composites (with various Ti concentrations) was chosen. The reactivity of C60/Ti composites may change in time due to the physicochemical changes of molecules in an air atmosphere. In this study, we therefore tested the dependence between the age of C60/Ti films (from one week to one year) and the adhesion, morphology, proliferation, viability, metabolic activity and potential DNA damage to human osteosarcoma cells (lines MG-63 and U-2 OS). After 7 days of cultivation, we did not observe any negative influence of fresh or aged C60/Ti layers on cell behavior, including the DNA damage response. The presence of Ti atoms resulted in improved properties of the C60 layers, which became more suitable for cell cultivation.

• MeSH
• buněčná adheze účinky léků   MeSH
• časové faktory MeSH
• fullereny chemie   farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• osteoblasty cytologie   účinky léků   metabolismus   MeSH
• poškození DNA MeSH
• proliferace buněk účinky léků   MeSH
• reaktivní formy kyslíku antagonisté a inhibitory   metabolismus   MeSH
• titan chemie   farmakologie   MeSH
• tkáňové inženýrství MeSH
• tkáňové podpůrné struktury * MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Coumarins represent a large group of 1,2-benzopyrone derivatives which have been identified in many natural sources and synthetized as well. Several studies have shown that their antioxidant capacity is not based only on direct scavenging of reactive oxygen and nitrogen species (RONS) but other mechanisms are also involved. These include: a) the chelation of transient metals iron and copper, which are known to catalyse the Fenton reaction; and b) the inhibition of RONS-producing enzymes (e.g. xanthine oxidase, myeloperoxidase and lipoxygenase), suggesting that mechanism(s) involved on cellular level are complex and synergistic. Moreover, many factors must be taken into account when analysing structure-antioxidant capacity relationships of coumarins due to different in vitro/in vivo methodological approaches. The structural features necessary for the direct RONS scavenging and metal chelation are apparently similar and the ideal structures are 6,7-dihydroxy- or 7,8-dihydroxycoumarins. However, the clinical outcome is unknown, because these coumarins are able to reduce copper and iron, and may thus paradoxically potentiate the Fenton chemistry. The similar structural features appear to be associated with inhibition of lipoxygenase, probably due to interference with iron in its active site. Contrarily, 6,7-dihydroxycoumarin seems to be the most active coumarin in the inhibition of xanthine oxidase while its derivative bearing the 4-methyl group or 7,8-dihydroxycoumarin are less active or inactive. In addition, coumarins may hinder the induction of inducible NO-synthase and cyclooxygenase- 2. Sparse data on inhibition of myeloperoxidase do not enable any clear conclusion, but some coumarins may block it.

• MeSH
• chelátory chemie   metabolismus   farmakologie   MeSH
• cyklooxygenasa 2 metabolismus   MeSH
• inhibitory enzymů chemie   metabolismus   farmakologie   MeSH
• kumariny chemie   metabolismus   farmakologie   MeSH
• lidé MeSH
• lipoxygenasa metabolismus   MeSH
• měď chemie   metabolismus   MeSH
• oxidační stres účinky léků   MeSH
• peroxidasa antagonisté a inhibitory   metabolismus   MeSH
• reaktivní formy kyslíku antagonisté a inhibitory   metabolismus   MeSH
• scavengery volných radikálů chemie   metabolismus   farmakologie   MeSH
• synthasa oxidu dusnatého, typ II antagonisté a inhibitory   metabolismus   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• xanthinoxidasa antagonisté a inhibitory   metabolismus   MeSH
• železo chemie   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH