V profylaxi aterotrombotických příhod má léčba dyslipidemie, zejména vysoké koncentrace aterogenního lipoproteinu o nízké hustotě (low density lipoprotein, LDL), klíčové postavení. Se stále se snižujícími cílovými hodnotami LDL cholesterolu je potřeba zavádět nové inovativní postupy. Ne vždy vystačíme se statiny a ezetimibem. Inhibitory proproteinové konvertázy subtilisin-kexinového typu 9 (PCSK9) na bázi monoklonálních protilátek jsou nákladné a rezervujeme je pro zvláště rizikové nemocné. Vývoj spěje k perorálně účinným inhibitorům konvertázy PCSK9 či k mikro-řetězcům kyseliny ribonukleové (ribonucleic acid, RNA) - inclisiranu, které brzdí transkripci genu a snižují nabídku vlastního izoenzymu PCSK9. Podobně se prověřuje efekt účinnější a bezpečnější inhibice syntézy cholesterolu. K užití, zpravidla v kombinaci se statiny, je schválena kyselina bempedová. Vedle vlastního lipoproteinu LDL je významný lipoprotein Lp(a). Ten akceleruje jak aterogenezi, tak inhibicí fibrinolýzy zvyšuje riziko trombotické okluze. V intervenci vysokých koncentrací Lp(a) se prověřuje účinnost oligonukleotidu inhibujícího syntézu apolipoproteinu (a) - pelacarsenu. Nálezy z prvých fází klinického hodnocení jsou slibné. Poslední strategií, kde je vidět výrazný pokrok, je léčba zaměřená na snížení hypertriglyceridemie. Dosavadní léčba fibráty sice snížila koncentraci triglyceridů, vliv na pokles vaskulárních příhod však nebyl přesvědčivě doložen. Prověřuje se účinnost a bezpečnost nových postupů. Ty jsou zaměřeny zejména na zvýšení aktivity lipoproteinové lipázy. Je však otázkou, zda snížení hypertriglyceridemie povede též ke zlepšení prognózy, přesvědčivý důkaz zatím podán nebyl.

In the prophylaxis of atherothrombotic events, the treatment of dyslipidemia, especially the effort to reduce the high concentration of atherogenic low-density lipoprotein (LDL), plays a key role. With ever-decreasing LDL-cholesterol targets, new innovative approaches need to be introduced. Statins and ezetimibe are not always sufficient. Monoclonal antibody-based subtilisin-kexin type 9 (PCSK9) proprotein convertase inhibitors are expensive and are reserved for particularly at-risk patients. Development leads to orally active inhibitors of PCSK9 convertase or to ribonucleic acid (RNA) - inclisirane micro-chains, which inhibit gene transcription and reduce the supply of the PCSK9 isoenzyme itself. Similarly, the effect of more effective and safer inhibition of cholesterol synthesis is being investigated. Bempedic acid is approved for use, usually in combination with statins. In addition to the LDL lipoprotein itself, the Lp (a) lipoprotein is important. It accelerates both atherogenesis and increases the risk of thrombotic occlusion by inhibiting fibrinolysis. In the intervention of high concentrations of Lp (a), the efficacy of an oligonucleotide inhibiting the synthesis of apolipoprotein (a) - pelacarsene is examined. The findings from the first phases of the clinical trial are promising. The last strategy, where significant progress is seen, is treatment to reduce hypertriglyceridemia. Although current fibrate treatment has reduced triglyceride levels, the effect on the decrease in vascular events has not been convincingly demonstrated. The effectiveness and safety of new procedures are being tested. These are mainly aimed at increasing lipoprotein lipase activity. However, the question is whether reducing pertriglyceridemia will also improve the prognosis, no convincing evidence has been provided yet.

• Klíčová slova
• bempedová kyselina, inclisiran, mipomersen, pelacarsen, evinacumab, volanesorsen,
• MeSH
• angiopoetinu podobné proteiny antagonisté a inhibitory   MeSH
• antisense oligonukleotidy terapeutické užití   MeSH
• apolipoprotein B-100 antagonisté a inhibitory   metabolismus   MeSH
• apolipoprotein C-III antagonisté a inhibitory   MeSH
• aterosklerotický plát patofyziologie   prevence a kontrola   MeSH
• ateroskleróza metabolismus   patofyziologie   prevence a kontrola   MeSH
• cholesterol metabolismus   škodlivé účinky   MeSH
• deriváty kyseliny fibrové farmakologie   terapeutické užití   MeSH
• dyslipidemie * farmakoterapie   patofyziologie   MeSH
• HDL-cholesterol metabolismus   účinky léků   MeSH
• hydroxymethylglutaryl-CoA-reduktasy metabolismus   účinky léků   MeSH
• hypertriglyceridemie farmakoterapie   MeSH
• kardiovaskulární nemoci prevence a kontrola   MeSH
• kyselina eikosapentaenová farmakologie   terapeutické užití   MeSH
• LDL-cholesterol metabolismus   škodlivé účinky   účinky léků   MeSH
• lidé MeSH
• lipoprotein (a) antagonisté a inhibitory   metabolismus   účinky léků   MeSH
• malá interferující RNA terapeutické užití   MeSH
• monoklonální protilátky terapeutické užití   MeSH
• niacin terapeutické užití   MeSH
• PCSK9 inhibitory MeSH
• proproteinkonvertasa subtilisin/kexin typu 9 účinky léků   MeSH
• rizikové faktory kardiovaskulárních chorob MeSH
• triglyceridy metabolismus   škodlivé účinky   MeSH
• Check Tag
• lidé MeSH

The sesquiterpenes alantolactone (ATL) and germacrone (GER) are potential anticancer agents of natural origin. Their toxicity and biological activity have been evaluated using the differentiated HepaRG (dHepaRG) cells, a hepatocyte-like model. The half-maximal inhibitory concentrations of cell viability after 24-h treatment of dHepaRG cells are approximately 60 µM for ATL and 250 µM for GER. However, both sesquiterpenes induce reactive oxygen species (ROS) formation in non-toxic concentrations and significantly dysregulate the mRNA expression of several functional markers of mature hepatocytes. They similarly decrease the protein level of signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and their transcription target, intercellular adhesion molecule 1 (ICAM-1). Based on the results of a BATMAN-TCM analysis, the effects of sesquiterpenes on cholesterol and lipid metabolism were studied. Sesquiterpene-mediated dysregulation of both cholesterol and lipid metabolism was observed, during which these compounds influenced the protein expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and sterol regulatory element-binding protein 2 (SREBP-2), as well as the mRNA expression of HMGCR, CYP19A1, PLIN2, FASN, SCD, ACACB, and GPAM genes. In conclusion, the two sesquiterpenes caused ROS induction at non-toxic concentrations and alterations in cholesterol and lipid metabolism at slightly toxic and toxic concentrations, suggesting a risk of liver damage if administered to humans.

• MeSH
• antitumorózní látky fytogenní toxicita   MeSH
• buňky Hep G2 MeSH
• cholesterol metabolismus   MeSH
• exprese genu účinky léků   MeSH
• hydroxymethylglutaryl-CoA-reduktasy genetika   metabolismus   MeSH
• játra metabolismus   MeSH
• laktony toxicita   MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• metabolismus lipidů účinky léků   MeSH
• mezibuněčná adhezivní molekula-1 metabolismus   MeSH
• NF-kappa B metabolismus   MeSH
• protein SREBP2 genetika   metabolismus   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• seskviterpeny eudesmanové toxicita   MeSH
• seskviterpeny germakranové toxicita   MeSH
• transkripční faktor STAT3 metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Water extracts from Pleurotus ostreatus containing no statins showed 3-hydroxy-3-methyl-glutaryl CoA reductase (HMGCR) inhibitory activity (in vitro) that might be due to specific water-soluble polysaccharides (WSPs); when isolated and deproteinized, increasing concentrations of the WSP extract induced higher inhibition. The WSP extract contained mainly β-glucans, mannogalactans, and glycogen (e.g., α-glucans), although derivatives or fragments with lower molecular weights (between 14 and 3.5 kDa) were present and were able to induce the inhibitory activity. The extract contained more β-(1→3)-glucans than β-(11→3),(11→6)-glucans, and they partially survived digestion and managed to pass through Caco2 cell monolayers to the lower compartment after in vitro digestion and transport experiments. The WSP might also modulate Caco2 membrane integrity.

• MeSH
• buněčná membrána účinky léků   MeSH
• Caco-2 buňky MeSH
• epitelové buňky účinky léků   MeSH
• hydroxymethylglutaryl-CoA-reduktasy metabolismus   MeSH
• inhibitory enzymů chemie   izolace a purifikace   metabolismus   MeSH
• lidé MeSH
• molekulová hmotnost MeSH
• Pleurotus chemie   MeSH
• polysacharidy chemie   izolace a purifikace   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

This study sought to characterize the soluble free and bound phenolic compounds from shaddock (Citrus maxima) peels and investigate their effect on 3-hydroxy-methyl-3-glutaryl coenzyme A reductase (HMG-CoA reductase) and glutathione-linked enzymes in colon (Caco-2) cells. The radicals scavenging ability and the protective ability of the phenolic extracts against pro-oxidant induced oxidative damage in Caco-2 cells and rat colon homogenates were also investigated. The free phenolics were extracted with 80% acetone (v/v), while bound phenolics were extracted from the alkaline (NaOH) and acid (HCl) hydrolyzed residue with ethyl acetate. HPLC fingerprinting revealed the presence of gallic acid, catechin, chlorogenic acid, caffeic acid, ellagic acid, epicatechin, rutin, quercitrin and quercetin in the extracts. The results revealed that the extracts inhibited HMG-CoA reductase activity and increased the activities of glutathione reductase and glutathione peroxidase in Caco-2 cells. The extracts inhibited peroxyl radical induced oxidation of membrane lipids in Caco-2 cells and malondialdehyde production in rat colon homogenates. Furthermore, the phenolic extracts scavenged radicals [2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl (OH)] and chelated Fe2+ in a concentration-dependent manner. This study showed that shaddock peels could serve as a dietary means or nutraceutical source for protecting the colon from degeneration.

• MeSH
• Citrus chemie   MeSH
• fenoly metabolismus   MeSH
• glutathionreduktasa metabolismus   účinky léků   MeSH
• hydroxymethylglutaryl-CoA-reduktasy metabolismus   účinky léků   MeSH
• kolon * enzymologie   metabolismus   účinky léků   MeSH
• oxidační stres účinky léků   MeSH
• potkani Wistar MeSH
• rostlinné extrakty MeSH
• scavengery volných radikálů metabolismus   MeSH
• techniky in vitro MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH

Much like other microorganisms, wild yeasts preferentially form surface-associated communities, such as biofilms and colonies, that are well protected against hostile environments and, when growing as pathogens, against the host immune system. However, the molecular mechanisms underlying the spatiotemporal development and environmental resistance of biofilms and colonies remain largely unknown. In this paper, we show that a biofilm yeast colony is a finely tuned, complex multicellular organism in which specialized cells jointly execute multiple protection strategies. These include a Pdr1p-regulated mechanism whereby multidrug resistance transporters Pdr5p and Snq2p expel external compounds solely within the surface cell layers as well as developmentally regulated production by internal cells of a selectively permeable extracellular matrix. The two mechanisms act in concert during colony development, allowing growth of new cell generations in a well-protected internal cavity of the colony. Colony architecture is strengthened by intercellular fiber connections.

• MeSH
• ABC transportéry genetika   metabolismus   MeSH
• biofilmy růst a vývoj   MeSH
• biologické modely MeSH
• delece genu MeSH
• DNA vazebné proteiny genetika   metabolismus   MeSH
• extracelulární matrix fyziologie   MeSH
• galaktokinasa genetika   metabolismus   MeSH
• galaktosa metabolismus   MeSH
• hydroxymethylglutaryl-CoA-reduktasy genetika   metabolismus   MeSH
• měď metabolismus   MeSH
• membránové glykoproteiny genetika   metabolismus   MeSH
• metalothionein genetika   metabolismus   MeSH
• oxaziny metabolismus   MeSH
• permeabilita MeSH
• profiliny genetika   MeSH
• proteiny buněčného cyklu genetika   MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům genetika   metabolismus   MeSH
• rekombinantní fúzní proteiny genetika   metabolismus   MeSH
• Saccharomyces cerevisiae - proteiny genetika   metabolismus   MeSH
• Saccharomyces cerevisiae cytologie   růst a vývoj   metabolismus   MeSH
• transkripční faktory genetika   metabolismus   MeSH
• zelené fluorescenční proteiny genetika   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

We investigated the hypolipidemic effect of glycyrrhizic acid (GA) focused on the mRNA expression and hepatic HMG-CoA reductase (HMGR) activity in hamsters fed a high-fat diet. Male Syrian Golden hamsters were fed a high fat diet for 8 weeks for induction of dyslipidemia and were treated with GA and fenofibrate. The concentrations of plasma total cholesterol and triglyceride were significantly lower in the GA-treated group than in the control group. The GA treatment significantly decreased Apo B, Lp(a), and cholesterol-ester-transport protein (CETP) concentrations, but increased Apo A-I levels and the Apo A-I/ Apo B ratio. The contents of cholesterol and triglyceride in hepatic tissue were significantly lower in the GA group than in the control group. Real-time PCR analysis revealed that HMGR mRNA expression was significantly lower in the GA group than in the control group. These results indicate that GA treatment reduces plasma cholesterol by down-regulating hepatic HMGR mRNA expression in hamsters fed a high fructose-fat diet.

• MeSH
• dietní tuky aplikace a dávkování   MeSH
• dyslipidemie farmakoterapie   metabolismus   MeSH
• financování organizované MeSH
• fruktosa aplikace a dávkování   MeSH
• hydroxymethylglutaryl-CoA-reduktasy genetika   metabolismus   MeSH
• hypolipidemika farmakologie   MeSH
• játra metabolismus   MeSH
• křečci praví MeSH
• křeček rodu Mesocricetus MeSH
• kyselina glycyrrhizinová farmakologie   MeSH
• lipidy krev   MeSH
• messenger RNA metabolismus   MeSH
• zvířata MeSH
• Check Tag
• křečci praví MeSH
• mužské pohlaví MeSH
• zvířata MeSH

OBJECTIVE: There is evidence to suppose that cholesterol-lowering medicine might confer protection against dementia, probably via modulation of cholesterol synthesis in the brain. The aim of the present study was to investigate the potential influence of statins and cholesterol diet on selected parameters relevant to Alzheimer's disease pathophysiology. METHODS: For 15 days, rats were orally administered simvastatin (10 or 20mg/kg b.wt.), atorvastatin (10 or 20mg/kg b.wt.), or aqua (control group); and one group was fed high-cholesterol (2%) diet. At the end of experiments brain (and plasma) cholesterol, lathosterol, hydroxymethylglutaryl-coenzyme A reductase protein, acetylcholinesterase activity, amyloid beta (40 and 42) and cholesterol synthesis rate (using the incorporation of deuterium from deuterated water) were determined and statistically compared to those of aqua. RESULTS: Both statins were able to lower cholesterol in the plasma, but none elicited an effect on total brain cholesterol. Significant reductions of brain lathosterol and cholesterol synthesis rate were observed after simvastatin and atorvastatin treatment. Acetylcholinesterase activity, amyloid beta and hydroxymethylglutaryl-coenzyme A reductase levels remained unaffected by the two drugs. CONCLUSIONS: This study brings additional evidence of a role for statins in cholesterol synthesis in the brain. Our data question the relationship between amyloid beta, acetylcholinesterase activity and cholesterol synthesis in the rat brain as well as the assumption about no exchange between peripheral and brain cholesterol pools.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• amyloidní beta-protein biosyntéza   MeSH
• anticholesteremika farmakologie   MeSH
• cholesterol dietní farmakologie   MeSH
• cholesterol biosyntéza   MeSH
• dieta MeSH
• financování organizované MeSH
• hydroxymethylglutaryl-CoA-reduktasy metabolismus   MeSH
• krysa rodu rattus MeSH
• kyseliny heptylové farmakologie   MeSH
• lidé MeSH
• mozek - chemie účinky léků   MeSH
• mozek metabolismus   MeSH
• potkani Wistar MeSH
• pyrroly farmakologie   MeSH
• simvastatin farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH

• MeSH
• ateroskleróza farmakoterapie   metabolismus   prevence a kontrola   MeSH
• hodnocení postupů (zdravotní péče) MeSH
• hydroxymethylglutaryl-CoA-reduktasy metabolismus   terapeutické užití   MeSH
• hypercholesterolemie * farmakoterapie   metabolismus   prevence a kontrola   MeSH
• ischemická choroba srdeční farmakoterapie   metabolismus   prevence a kontrola   MeSH
• klinické zkoušky jako téma * MeSH
• LDL-cholesterol škodlivé účinky   účinky léků   MeSH
• lidé MeSH
• lovastatin * farmakokinetika   farmakologie   terapeutické užití   MeSH
• preventivní lékařství MeSH
• rizikové faktory MeSH
• statistika jako téma MeSH
• Check Tag
• lidé MeSH

• MeSH
• ateroskleróza * etiologie   metabolismus   prevence a kontrola   MeSH
• fyziologie buňky fyziologie   účinky léků   MeSH
• hodnocení postupů (zdravotní péče) MeSH
• hydroxymethylglutaryl-CoA-reduktasy metabolismus   MeSH
• hypercholesterolemie diagnóza   etiologie   komplikace   MeSH
• hyperhomocysteinemie * etiologie   metabolismus   prevence a kontrola   MeSH
• kardiovaskulární nemoci * etiologie   metabolismus   prevence a kontrola   MeSH
• LDL-cholesterol izolace a purifikace   škodlivé účinky   MeSH
• lidé MeSH
• methionin metabolismus   MeSH
• preventivní lékařství metody   MeSH
• vitaminy * metabolismus   terapeutické užití   MeSH
• Check Tag
• lidé MeSH

• MeSH
• cholesterol dietní aplikace a dávkování   MeSH
• cholesterol krev   metabolismus   MeSH
• hepatektomie MeSH
• hydroxymethylglutaryl-CoA-reduktasy metabolismus   MeSH
• krysa rodu rattus MeSH
• pravastatin farmakologie   metabolismus   MeSH
• regenerace jater účinky léků   MeSH
• statiny farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH