BACKGROUND: Understanding population health trends and their key determinants is essential for planning health services and implementing effective interventions. One of these determinants may be national cultural characteristics that are related to various health outcomes and health-related behaviours. However, little is known about their potential association to overall burden of disease. Thus, this study examined whether cultural characteristics expressed by Hofstede indexes are associated with the burden of disease. METHODS: We used data from open-source databases - Hofstede's Cultural Index, the Global Burden of Diseases (GBD) and the Human Development Index (HDI). The final sample comprised 69 countries covering all the continents. The burden of disease was measured using disability-adjusted life years (DALYs), years lived with disabilities (YLD), and years of life lost (YLL). National cultural characteristics were measured using Hofstede's dimensions. Bayesian correlation analyses were conducted to assess the relationships between cultural dimensions and health outcomes, stratified by countries' HDI levels. RESULTS: In countries with a very high HDI, there was strong evidence (Bayes Factor > 10) of a positive correlation of Power distance with the total disability-adjusted life years (r = 0.448) and years of life lost (r = 0.528), and Individualism (r = 0.667) and Indulgence (r = 0.494) with years lived with disabilities. In contrast, Long-term orientation negatively correlated of with years lived with disabilities (r = -0.527) and Indulgence with disability-adjusted life years (r = -0.437) and years of life lost (r = -0.537). Further, Power distance and Indulgence were correlated with the majority of the GBD indicators and Individualism with a few GBD indicators. In countries with a high and medium HDI, strong evidence of the associations was found in only a few cases. CONCLUSION: We found a correlation between national cultural characteristics and burden of disease. Policy-makers should consider integrating cultural factors into public health strategies to better align healthcare interventions with the local population's values and behaviours. Moreover, cross-cultural research and collaboration should increase to understand how cultural influences can be used to mitigate disease burdens and improve health outcomes globally. This study also opens a potentially new research area within population health research.
Kynurenic acid is a neuroprotective metabolite of tryptophan formed by kynurenine aminotransferase (KAT) catalyzed transformation of kynurenine. However, its high brain levels are associated with cognitive deficit and with the pathophysiology of schizophrenia. Although several classes of KAT inhibitors have been published, the search for new inhibitor chemotypes is crucial for the process of finding suitable clinical candidates. Therefore, we used pharmacophore modeling and molecular docking, which predicted derivatives of heterocyclic amino ketones as new potential irreversible inhibitors of kynurenine aminotransferase II. Thiazole and triazole-based amino ketones were synthesized within a SAR study and their inhibitory activities were evaluated in vitro. The observed activities confirmed our computational model and, moreover, the best compounds showed sub-micromolar inhibitory activity with 2-alaninoyl-5-(4-fluorophenyl)thiazole having IC50 = 0.097 µM.
- Publikační typ
- časopisecké články MeSH
Ovarian cancer is one of the most common causes of death among gynecological malignancies. Molecular changes occurring in the primary tumor lead to metastatic spread into the peritoneum and the formation of distant metastases. Identification of these changes helps to reveal the nature of metastases development and decipher early biomarkers of prognosis and disease progression. Comparing differences in gene expression profiles between primary tumors and metastases, together with disclosing their epigenetic regulation, provides interesting associations with progression and metastasizing. Regulatory elements from the non-coding RNA families such as microRNAs and long non-coding RNAs seem to participate in these processes and represent potential molecular biomarkers of patient prognosis. Progress in therapy individualization and its proper targeting also rely upon a better understanding of interactions among the above-listed factors. This review aims to summarize currently available findings of microRNAs and long non-coding RNAs linked with tumor progression and metastatic process in ovarian cancer. These biomolecules provide promising tools for monitoring the patient's response to treatment, and further they serve as potential therapeutic targets of this deadly disease.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The GluN2A subunit of N-methyl-D-aspartate (NMDA) receptors becomes dominant during postnatal development, overgrowing the originally dominant GluN2B subunit. The aim of our study was to show changes of anticonvulsant action of the GluN2A subunit-preferring antagonist during postnatal development of rats. Possible anticonvulsant action of GluN2A-preferring antagonist of NMDA receptors P = [[[(1S)-1-(4-bromophenyl)ethyl]amino](1,2,3,4-tetrahydro-2,3-dioxo-5-quinoxalinyl)methyl]phosphonic acid tetrasodium salt (PEAQX) (5, 10, 20 mg/kg s.c.) was tested in 12-, 18-, and 25-day-old rats in three models of convulsive seizures. Pentylenetetrazol-induced generalized seizures with a loss of righting reflexes generated in the brainstem were suppressed in all three age groups in a dose-dependent manner. Minimal clonic seizures with preserved righting ability exhibited only moderately prolonged latency after the highest dose of PEAQX. Anticonvulsant action of all three doses of PEAQX against cortical epileptic afterdischarges (generated in the forebrain) was found in the 25-day-old animals. The highest dose (20 mg/kg) was efficient also in the two younger groups, which might be due to lower specificity of PEAQX and its partial affinity to the GluN2B subunit. Our results are in agreement with the postero-anterior maturation gradient of subunit composition of NMDA receptors (i.e., an increase of GluN2A representation). In spite of the lower selectivity of PEAQX, our data demonstrate, for the first time, developmental differences in comparison with an antagonist of NMDA receptors with a dominant GluN2B subunit.
- Publikační typ
- časopisecké články MeSH
The effect of venlafaxine, a pharmaceutical commonly found in aquatic environment, was analyzed on non-target organism, Danio rerio (Hamilton, 1822). D. rerio embryos were treated by two different concentrations of venlafaxine: either concentration relevant in aquatic environment (0.3 μg/L) or concentration that was two orders of magnitude higher (30 μg/L) for the evaluation of dose-dependent effect. Time-dependent effect was rated at 24, 96, and 144 h post-fertilization (hpf). For gene expression, genes representing one of the phases of xenobiotic biotransformation (0 to III) were selected. The results of this study showed that the effect of venlafaxine on the zebrafish embryos is the most evident at hatching (96 hpf). At this time, the results showed a downregulation of gene expression in each phase of biotransformation and in both tested concentrations. In contrast, an upregulation of most of the genes was observed 144 hpf for both tested venlafaxine concentrations. The study shows that venlafaxine can affect the gene expression of biotransformation enzymes in D. rerio embryos even in the environmentally relevant concentration and thus disrupt the process of biotransformation. Moreover, the pxr regulation of genes seems to be disrupted after venlafaxine exposure in dose- and time-dependent manner.
- MeSH
- antidepresiva farmakologie MeSH
- biotransformace MeSH
- chemické látky znečišťující vodu farmakologie MeSH
- dánio pruhované * MeSH
- embryo nesavčí účinky léků enzymologie MeSH
- regulace genové exprese enzymů * MeSH
- venlafaxin hydrochlorid farmakologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
In this communication, we report the synthesis and cholinesterase (ChE)/monoamine oxidase (MAO) inhibition of 19 quinolinones (QN1-19) and 13 dihydroquinolinones (DQN1-13) designed as potential multitarget small molecules (MSM) for Alzheimer's disease therapy. Contrary to our expectations, none of them showed significant human recombinant MAO inhibition, but compounds QN8, QN9, and DQN7 displayed promising human recombinant acetylcholinesterase (hrAChE) and butyrylcholinesterase (hrBuChE) inhibition. In particular, molecule QN8 was found to be a potent and quite selective non-competitive inhibitor of hrAChE (IC50 = 0.29 μM), with Ki value in nanomolar range (79 nM). Pertinent docking analysis confirmed this result, suggesting that this ligand is an interesting hit for further investigation.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- Alzheimerova nemoc farmakoterapie MeSH
- chinolony farmakologie MeSH
- cholinesterasové inhibitory farmakologie MeSH
- inhibiční koncentrace 50 MeSH
- inhibitory MAO farmakologie MeSH
- kinetika MeSH
- lidé MeSH
- ligandy MeSH
- magnetická rezonanční spektroskopie MeSH
- monoaminoxidasa metabolismus MeSH
- preklinické hodnocení léčiv MeSH
- racionální návrh léčiv MeSH
- rekombinantní proteiny metabolismus MeSH
- simulace molekulového dockingu MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Although multiprotein membrane complexes play crucial roles in bacterial physiology and virulence, the mechanisms governing their quality control remain incompletely understood. In particular, it is not known how unincorporated, orphan components of protein complexes are recognised and eliminated from membranes. Rhomboids, the most widespread and largest superfamily of intramembrane proteases, are known to play key roles in eukaryotes. In contrast, the function of prokaryotic rhomboids has remained enigmatic. Here, we show that the Shigella sonnei rhomboid proteases GlpG and the newly identified Rhom7 are involved in membrane protein quality control by specifically targeting components of respiratory complexes, with the metastable transmembrane domains (TMDs) of rhomboid substrates protected when they are incorporated into a functional complex. Initial cleavage by GlpG or Rhom7 allows subsequent degradation of the orphan substrate. Given the occurrence of this strategy in an evolutionary ancient organism and the presence of rhomboids in all domains of life, it is likely that this form of quality control also mediates critical events in eukaryotes and protects cells from the damaging effects of orphan proteins.
- MeSH
- bakteriální proteiny chemie metabolismus MeSH
- endopeptidasy chemie metabolismus MeSH
- membránové proteiny metabolismus MeSH
- proteinové domény MeSH
- proteolýza MeSH
- Shigella sonnei enzymologie metabolismus MeSH
- substrátová specifita MeSH
- transport elektronů MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH