Statínová intolerancia predstavuje významnú výzvu v liečbe dyslipidémie, najmä u pacientov s vysokým kardiovaskulárnym rizikom. Tento problém, definovaný ako neschopnosť pacienta tolerovať dávku statínu potrebnú na efektívne zníženie hladín LDL-cholesterolu (LDL-C), môže byť asociovaný so svalovými symptómami, zvýšením pečeňových enzýmov alebo inými nežiaducimi účinkami. Prevalencia statínovej intolerancie sa pohybuje od 7 % do 29 % v klinickej praxi, pričom úplná intolerancia sa vyskytuje iba u 3–6 % pacientov. Mierne formy svalových symptómov, ako sú myalgie, sú najčastejšie, zatiaľ čo závažné komplikácie, ako je rabdomyolýza, sú veľmi zriedkavé. Diagnóza statínovej intolerancie zahŕňa hodnotenie časovej súvislosti medzi začiatkom liečby a symptómami, vylúčenie alternatívnych príčin a potvrdenie kauzality pomocou opätovného nasadenia lieku. Zaujímavým fenoménom je nocebo efekt, ktorý môže zodpovedať za väčšinu subjektívnych sťažností na svalové symptómy bez priameho súvisu so statínmi. Manažment pacientov so statínovou intoleranciou zahŕňa nefarmakologické prístupy, ako je zmena životného štýlu, a farmakologické alternatívy, vrátane podávania ezetimibu, kyseliny bempedoovej a inhibítorov PCSK9. Väčšina pacientov aj napriek určitému stupňu statínovej intolerancie toleruje malú dávku statínu a ezetimibu, prípadne novú inovatívnu terapiu (ak je indikovaná) a u týchto pacientov vieme efektívne dosiahnuť cieľové hladiny LDL-C. Jedinou limitáciou pri využití alternatívnych liekov na dosiahnutie cieľového zníženia hladiny LDL-C je hradenie týchto postupov zo zdrojov verejného zdravotného poistenia.

Statin intolerance represents a significant challenge in the treatment of dyslipidemia, particularly in patients with high cardiovascular risk. This condition, defined as the inability of a patient to tolerate a statin dose required for effective LDL cholesterol reduction, can result from muscle symptoms, elevated liver enzymes, or other adverse effects. The prevalence of statin intolerance ranges from 7 % to 29 % in clinical practice, with complete intolerance observed in only 3–6 % of patients. Mild forms of muscle symptoms, such as myalgia, are the most common, while severe complications like rhabdomyolysis are very rare. The diagnosis of statin intolerance involves evaluating the temporal relationship between the onset of therapy and symptoms, excluding alternative causes, and confirming causality through rechallenge with the drug. An interesting phenomenon is the nocebo effect, which may account for the majority of subjective complaints of muscle symptoms without a direct link to statins. The management of patients with statin intolerance includes non-pharmacological approaches, such as lifestyle modifications, and pharmacological alternatives, including ezetimibe, PCSK9 inhibitors, and novel drugs like inklisiran. Inklisiran, an RNA interference-based drug, offers a significant reduction in LDL cholesterol of over 50 % with only biannual dosing and minimal side effects.

• MeSH
• dyslipidemie farmakoterapie   terapie   MeSH
• hypolipidemika farmakologie   klasifikace   terapeutické užití   MeSH
• LDL-cholesterol krev   účinky léků   MeSH
• lidé MeSH
• nemoci svalů chemicky indukované   diagnóza   patofyziologie   patologie   MeSH
• nežádoucí účinky léčiv diagnóza   epidemiologie   patologie   MeSH
• statiny * škodlivé účinky   MeSH
• tolerance léku * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Lipoproteín(a) [Lp(a)] má štrukturálnu podobnosť s LDL-cholesterolom, ale líši sa od neho tým, že obsahuje glykoproteín apolipoproteín(a) [apo(a)]. Vďaka svojim protrombotickým a prozápalovým vlastnostiam je Lp(a) nezávislým rizikovým faktorom pre aterosklerózou podmienených kardiovaskulárnych ochorení (ASKVO) a aortálnu stenózu. Hladiny Lp(a) sú prevažne geneticky podmienené, pričom približne 20–25 % svetovej populácie má hladiny ≥ 50 mg/dl (alebo ≥ 125 nmol/l). Zmena životného štýlu a diétne opatrenia majú na hladiny Lp(a) len minimálny alebo žiadny vplyv. V súčasnosti je lipoproteínová aferéza jedinou schválenou liečbou zvýšených hladín Lp(a). Táto metóda je však pre pacienta časovo náročná a jej účinnosť je len mierna. Napriek veľkej snahe vyvinúť optimálnu farmakologickú intervenciu za účelom zníženia hladín Lp(a) a s tým súvisiaceho kardiovaskulárneho (KV) rizika, majú existujúce liečivá len obmedzenú účinnosť pri redukcii Lp(a). Hoci statíny zostávajú na účely zníženia hladín LDL-cholesterolu metódou prvej voľby, nepreukázali zníženie rizika ASKVO spojeného s Lp(a). Lieky ako alirokumab, evolokumab a inklisiran dokážu znížiť hladiny Lp(a) o 20–25 %, ale nie je jasné, ako sa tento pokles premieta do zníženia rizika ASKVO sprostredkovaného Lp(a). Niacín taktiež znižuje hladiny Lp(a), avšak jeho účinnosť v redukcii súvisiacich rizík je nejasná a jeho vedľajšie účinky obmedzujú jeho široké používanie. Odporúčania na skríning a manažment vysokých hladín Lp(a) sa značne líšia naprieč národnými a medzinárodnými odporúčaniami. Medzi nové liečby zamerané na Lp(a) patria 3 skúmané zlúčeniny: malé interferujúce RNA agens (olpasiran a SLN360) a antisense oligonukleotid (pelacarsen/pelakarsen). Tieto lieky fungujú tak, že blokujú transláciu mediátorovej RNA pre apo(a), ktorý je kľúčovou súčasťou Lp(a), a tým výrazne znižujú jeho produkciu v pečeni. Táto prehľadová práca si kladie za cieľ opísať súčasné odporúčania pre skríning a manažment zvýšenej hladiny Lp(a), zhodnotiť účinky dostupných liekov na zníženie jeho hladín a preskúmať potenciál nových liečebných postupov zameraných na Lp(a).

Lipoprotein(a), or Lp(a), shares structural similarities with low-density lipoprotein (LDL) but is distinct because it includes the glycoprotein apolipoprotein(a) [apo(a)]. Due to its roles in promoting thrombosis and inflammation, Lp(a) is recognized as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis. Lp(a) levels are predominantly determined by genetics, with approximately 20%–25% of the global population having levels ≥ 50 mg/dL (or ≥ 125 nmol/L). Lifestyle and dietary changes have minimal or no impact on Lp(a) levels. Currently, lipoprotein apheresis is the only approved treatment for elevated Lp(a). However, this approach is time-consuming for patients and provides only moderate efficacy. While there is considerable interest in pharmacological strategies to lower Lp(a) levels and mitigate associated risks, existing lipid-lowering treatments show limited success in reducing Lp(a). Although statins remain the first-line therapy for lowering LDL cholesterol, they have not demonstrated a reduction in Lp(a)-related ASCVD risk. Medications like alirocumab, evolocumab, and inclisiran can reduce Lp(a) levels by 20–25%, but it is unclear how these reductions translate into lower Lp(a)-mediated ASCVD risk. Niacin also lowers Lp(a) levels, though its role in reducing associated risks is uncertain, and side effects limit its widespread use. Guidelines for screening and managing high Lp(a) levels vary significantly across national and international recommendations. Emerging therapies targeting Lp(a) include three investigational compounds: small interfering RNA (siRNA) agents (olpasiran, SLN360) and an antisense oligonucleotide (pelacarsen). These treatments work by blocking the translation of messenger RNA (mRNA) for apo(a), a critical component of Lp(a), thus significantly reducing its production in the liver. This review aims to outline current screening and management recommendations for elevated Lp(a), evaluate the impact of existing lipid-lowering therapies on Lp(a), and explore the potential of new treatments targeting Lp(a).

• MeSH
• hypolipidemika aplikace a dávkování   farmakologie   klasifikace   MeSH
• kardiovaskulární nemoci * farmakoterapie   prevence a kontrola   MeSH
• LDL-cholesterol krev   účinky léků   MeSH
• lidé MeSH
• lipoprotein (a) * farmakologie   krev   účinky léků   MeSH
• rizikové faktory kardiovaskulárních chorob MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Creatine is a nitrogen-containing carboxylic acid and a main component of phosphocreatine. In recent years, creatine is considered as a component of dietary nutrition, to improve the efficiency of physical activity and increase muscle mass of athletes and older people. Creatine has been shown to be able restore cardiac contractility impairment after myocardial infarction. However, as muscle cells do not synthesise creatine, the efficiency of creatine depends on its transmembrane transport. In our study, we evaluated the effect of «ProCreatine» (ProCr), a novel membrane transporter-independent creatine modification on fatigability of the rat gastrocnemius muscle and portal vein smooth muscle using fatigue stimulation pools. Mechanokinetic and biomechanical markers of fatigue in muscles to maintain the level of isometric tension induced by field electrical stimulation were examined. The results indicate that administration of ProCr to skeletal muscle significantly increases maximal force output, integrated muscle contractile force and significantly increases muscle productivity. We observed positive changes in all studied biochemical indices of fatigue. In addition, ProCr increases the duration of sustaining a constant level of isometric contraction in portal vein smooth muscle caused by electrical stimulation by 6 fold. Regular creatine in the same dose had no significant effect on these parameters neither in skeletal nor in smooth muscles. The data obtained suggest the possibility of using ProCr as a therapeutic agent capable of reducing and correcting pathological conditions of the muscular system that arise during the processes of fatigue in skeletal muscles and smooth muscles of hollow organs.

• Publikační typ
• časopisecké články MeSH

Due to the bio-inert nature of titanium (Ti) and subsequent accompanying chronic inflammatory response, an implant's stability and function can be significantly affected, which is why various surface modifications have been employed, including the deposition of titanium oxide (TiO2) nanotubes (TNTs) onto the native surface through the anodic oxidation method. While the influence of nanotube diameter on cell behaviour and osteogenesis is very well documented, information regarding the effects of nanotube lateral spacing on the in vivo new bone formation process is insufficient and hard to find. Considering this, the present study's aim was to evaluate the mechanical properties and the osteogenic ability of two types of TNTs-based pins with different lateral spacing, e.g., 25 nm (TNTs) and 92 nm (spTNTs). The mechanical properties of the TNT-coated implants were characterised from a morphological point of view (tube diameter, spacing, and tube length) using scanning electron microscopy (SEM). In addition, the chemical composition of the implants was evaluated using X-ray photoelectron spectroscopy, while surface roughness and topography were characterised using atomic force microscopy (AFM). Finally, the implants' hardness and elastic modulus were investigated using nanoindentation measurements. The in vivo new bone formation was histologically evaluated (haematoxylin and eosin-HE staining) at 6 and 30 days post-implantation in a rat model. Mechanical characterisation revealed that the two morphologies presented a similar chemical composition and mechanical strength, but, in terms of surface roughness, the spTNTs exhibited a higher average roughness. The microscopic examination at 1 month post-implantation revealed that spTNTs pins (57.21 ± 34.93) were capable of promoting early new bone tissue formation to a greater extent than the TNTs-coated implants (24.37 ± 6.5), with a difference in the average thickness of the newly formed bone tissue of ~32.84 μm, thus highlighting the importance of this parameter when designing future dental/orthopaedic implants.

• Publikační typ
• časopisecké články MeSH

Úvod: Zdraví žen je často přehlíženo a nedostatečně zkoumáno v minulosti i současnosti. Dysmenorea, známá jako bolestivá menstruace, je běžný gynekologický stav způsobující intenzivní bolest a dysfunkci u žen v reprodukčním věku. Cíl: Obecným cílem studie bylo určit prevalenci dysmenorey u žen ve věku 18–50 let v Malajsii. Zkoumali jsme dysmenoreu, její vliv na každodenní aktivity ve srovnání se ženami bez dysmenorey, faktory, které bolest při menstruaci zhoršují, příznaky, životní návyky a způsoby zvládání dysmenorey. Metody: Průřezová studie byla provedena během roku 2024 po dobu tří měsíců. Cílovou skupinou byly ženy ve věku 18–50 let žijící v Malajsii. Použito bylo nepravděpodobnostní výběrové šetření (non-probability convenient sampling), přičemž dotazníky byly distribuovány prostřednictvím Google formulářů za účelem sběru dat. Ke statistické analýze a měření asociací byl využit software SPSS a chí-kvadrát test. Výsledky: Studie ukázala, že prevalence dysmenorey činila 92,8 %. Byl zjištěn významný vztah mezi závažností dysmenorey a různými sociodemografickými faktory, zejména věkem a indexem tělesné hmotnosti (BMI) s hodnotou p < 0,05. Nebyl však nalezen žádný významný vztah mezi věkovými skupinami a intenzitou dysmenorey, což naznačuje, že věk silně neovlivňuje závažnost dysmenorey. Situace, jako bolest při stolici nebo při chůzi, byly spojeny se zvýšenou závažností dysmenorey (p < 0,001). Mezi strategie zvládání patřilo časté užívání analgetik u žen s těžkou dysmenoreou (p < 0,001). Závěr: Studie ukázala, že dysmenorea má významný dopad na kvalitu života většiny žen, které zažívají střední až silné bolesti trvající 1 až 3 dny. Implementace účinných strategií, jako je úprava životního stylu, poskytování informací a činnost podpůrných skupin, může ženám pomoci zvládat dysmenoreu. Tyto strategie mají potenciál výrazně zlepšit celkovou pohodu postižených žen a snížit zátěž, kterou tento stav představuje.

Background: Women‘s health is often overlooked and under-studied in the past and present. Dysmenorrhea is known as painful menstruation which is a common gynaecological condition that causes intense pain and dysfunction in women of reproductive age. Objective: The general objective is to determine the prevalence of dysmenorrhea among females aged 18 to 50 years old in Malaysia. We studied dysmenorrhea and how it affects daily activities compared to females without dysmenorrhea, factors that aggravate the menstrual pain, symptoms, lifestyle habits and coping mechanisms associated with dysmenorrhea. Methods: A cross-sectional study conducted during 2024 for a period of 3 months. Our targeted population was females aged 18-50 years old in Malaysia. Non-probability convenient sampling was used and distributed via google form questionnaires to collect data. Statistical software SPSS and chi-square test was used to analyse the data to measure the associations. Results: The study showed that prevalence of dysmenorrhea was 92.8% and there was a significant relationship between dysmenorrhea severity and various sociodemographic factors, particularly age and body mass index (BMI) with p < 0.05. There was no significant association between age groups and dysmenorrhea intensity, thus indicating that age does not strongly influence severity of dysmenorrhea. Situational factors such as pain during bowel movements or while walking are associated with increased severity of dysmenorrhea (p < 0.001). Coping strategies show analgesic use is common among women with severe dysmenorrhea (p < 0.001). Conclusion: This study showed that dysmenorrhea has a significant impact on the quality of life of the majority of women experiencing moderate to severe pain lasting 1 to 3 days. The implementation of effective strategies such as lifestyle modification, providing information and support groups can empower individuals to manage dysmenorrhea should be done as they have the potential to significantly enhance the overall well-being of those affected, ultimately reducing the burden of this condition on women.

Daunorubicin (DNR) is an anthracycline antibiotic originating from soil-dwelling actinobacteria extensively used to treat malignant tumors. Over the decades, extensive attempts were made to enhance the production of anthracyclines by introducing genetic modifications and mutations in combination with media optimization, but the target production levels remain comparatively low. Developing an appropriate culture medium to maximize the yield of DNR and preventing autotoxicity for the producing organism remains a challenge. Our prospective review sheds light on a method involving perturbation that enhances the precursors to regulate the type II PKS pathway, enhancing cells' capacity to increase secondary metabolite production. The suggested method also entails the preparation of culture media for the cultivation of Streptomyces sp. and enhanced yield of DNR, as well as making it inactive with iron or its reduced forms following efflux from the producer. The iron or iron-DNR complex is encapsulated by oleic acid or lipid micelle layers in the culture media, finally resulting in the generated inactive DNR and the DNR-iron-oil complex. This idea has the potential to protect the producer organism from autotoxicity and prevent the inhibition of metabolite production. The approach of substituting sugar with oil in culture media has a dual role wherein it promotes Streptomyces growth by utilizing lipids as an energy source and encapsulating the generated DNR-iron complex in the medium. In this review, we discussed aspects like anthracycline producers, biosynthesis pathways, and gene regulation; side effects of DNR; mechanisms for autotoxicity evasion; and culture media components for the enhancement of DNR production in Streptomyces sp. We anticipate that our work will help researchers working with secondary metabolites production and decipher a methodology that would enhance DNR yield and facilitate the extraction of the resulting DNR by lowering costs in large-scale fermentation.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The increase in extreme climate events associated with global warming is a great menace to crop productivity nowadays. In addition to abiotic stresses, warmer conditions favor the spread of infectious diseases affecting plant performance. Within this context, beneficial microbes constitute a sustainable alternative for the mitigation of the effects of climate change on plant growth and productivity. Used as biostimulants to improve plant growth, they also increase plant resistance to abiotic and biotic stresses through the generation of a primed status in the plant, leading to a better and faster response to stress. In this review, we have focused on the importance of a balanced redox status for the adequate performance of the plant and revisited the different antioxidant mechanisms supporting the biocontrol effect of beneficial microbes through the adjustment of the levels of reactive oxygen species (ROS). In addition, the different tools for the analysis of antioxidant responses and redox regulation have been evaluated. The importance of redox regulation in the activation of the immune responses through different mechanisms, such as transcriptional regulation, retrograde signaling, and post-translational modification of proteins, emerges as an important research goal for understanding the biocontrol activity of the beneficial microbes.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

This work aims to describe the effect of the surface modification of TiO2 nanotube (TNT) layers on Ti-6Al-4V (TiAlV) alloy by ultrathin TiO2 coatings prepared via Atomic Layer Deposition (ALD) on the growth of MG-63 osteoblastic cells. The TNT layers with two distinctly different inner diameters, namely ∼15 nm and ∼50 nm, were prepared via anodic oxidation of the TiAlV alloy. Flat, i.e., non-anodized, TiAlV alloy foils were used as reference substrates. Additionally, a part of the TNT layers and alloy foils was coated with ultrathin coatings of TiO2 by ALD. The number of TiO2 ALD cycles used was 1 and 5 leading to a nominal TiO2 thickness of ∼0.055 and ∼0.3 nm, respectively. The ultrathin TiO2 coating by ALD enabled to optimize the surface hydrophilicity for optimal cell growth. In addition, coatings shaded impurities of V- and F-based species (stemming from the alloy and the anodization electrolyte) that affect the biocompatibility of the tested materials while preserving the original structure and morphology. The evaluation of the biocompatibility before and after TiO2 ALD coating on TiAlV flat surfaces and TNT layers was carried out using MG-63 osteoblastic cells and compared after incubation for up to 96 h. The cell growth, adhesion, and proliferation of the MG-63 on TiAlV foils and TNT layers showed significant enhancement after the surface modification by TiO2 ALD.

• Publikační typ
• časopisecké články MeSH

High-risk human papillomaviruses (HPVs) cause various cancers. While type-specific prophylactic vaccines are available, additional anti-viral strategies are highly desirable. Initial HPV cell entry involves receptor-switching induced by structural capsid modifications. These modifications are initiated by interactions with cellular heparan sulphates (HS), however, their molecular nature and functional consequences remain elusive. Combining virological assays with hydrogen/deuterium exchange mass spectrometry, and atomic force microscopy, we investigate the effect of capsid-HS binding and structural activation. We show how HS-induced structural activation requires a minimal HS-chain length and simultaneous engagement of several binding sites by a single HS molecule. This engagement introduces a pincer-like force that stabilizes the capsid in a conformation with extended capsomer linkers. It results in capsid enlargement and softening, thereby likely facilitating L1 proteolytic cleavage and subsequent L2-externalization, as needed for cell entry. Our data supports the further devising of prophylactic strategies against HPV infections.

• MeSH
• heparitinsulfát * metabolismus   chemie   MeSH
• infekce papilomavirem virologie   MeSH
• internalizace viru * MeSH
• kapsida * metabolismus   chemie   MeSH
• lidé MeSH
• lidské papilomaviry MeSH
• lidský papilomavirus 16 metabolismus   fyziologie   MeSH
• mikroskopie atomárních sil * MeSH
• Papillomaviridae fyziologie   MeSH
• polysacharidy metabolismus   chemie   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• virové plášťové proteiny * metabolismus   chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Dietary polyphenols have been associated with many beneficial cardiovascular effects. However, these effects are rather attributed to small phenolic metabolites formed by the gut microbiota, which reach sufficient concentrations in systemic circulation. 4-Methylcatechol (4-MC) is one such metabolite. As it is shown to possess considerable vasorelaxant effects, this study aimed to unravel its mechanism of action. To this end, experimental in vitro and in silico approaches were employed. In the first step, isometric tension recordings were performed on rat aortic rings. 4-MC potentiated the effect of cyclic nucleotides, but the effect was not mediated by either soluble guanylyl cyclase (sGC), modification of cyclic adenosine monophosphate levels, or protein kinase G. Hence, downstream targets such as calcium or potassium channels were considered. Inhibition of voltage-gated K+ channels (KV) markedly decreased the effect of 4-MC, and vasodilation was partly decreased by inhibition of the KV7 isoform. Contrarily, other types of K+ channels or L-type Ca2+ channels were not involved. In silico reverse docking confirmed that 4-MC binds to KV7.4 through hydrogen bonding and hydrophobic interactions. In particular, it interacts with two crucial residues for KV7.4 activation: Trp242 and Phe246. In summary, our findings suggested that 4-MC exerts vasorelaxation by opening KV channels with the involvement of KV7.4.

• MeSH
• aorta účinky léků   metabolismus   MeSH
• draslíkové kanály řízené napětím * metabolismus   MeSH
• katecholy * farmakologie   MeSH
• krysa rodu rattus MeSH
• potkani Wistar MeSH
• quercetin * farmakologie   MeSH
• simulace molekulového dockingu MeSH
• vazodilatace * účinky léků   MeSH
• vazodilatancia farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH