Serotoninový transportér 5-HTT hraje důležitou roli v serotonergní neurotransmisi a gen kódující tento protein patří mezi nejsledovanější geny v souvislosti s psychiatrickými onemocněními. Vyskytují se dvě základní varianty - krátká (S) a dlouhá (L), o jejichž délce rozhodují repetitivní sekvence v promotorové oblasti genu. Krátká varianta S je spojována s nižší transkripční činností genového promotoru a má souvislost s vyšší senzitivitou k podnětům vyvolávajícím úzkost a strach. Alela L je naopak spojována s nižším výskytem úzkostných a depresivních stavů, ale v souvislosti s některými poruchami pravděpodobně přispívá k projevům vyšší agresivity, psychomotorického neklidu a emoční nestability. Tyto souvislosti jsou v oblasti moderní genetiky a biologické psychiatrie předmětem intenzivního výzkumu a jejich objasnění může výrazným způsobem napomoci porozumění podstatě některých duševních onemocnění, které tak povede k efektivnější léčbě.
Serotonin transporter plays an important role in serotogenic transmisssion and the serotonin transporter gene is under investigation in connection with many psychiatric disorders. There are two main genetic variations in the promoter region of the gene - long (L) allele and a short (S). The S allele is associated with decreased transcriptional efficiency of the promoter leads to reduced serotonin re-uptake in comparison to the long allele which is associated with greater gene expression. The length of polymorphisms are considered to be important mediators of emotional instability and predisposition to mental illness, high trait anxiety, fear-related behavior, negative emotions. The serotonin transporter gene has received much attention in association with psychiatric disorders and its explication can improve understanding to its principles.
- MeSH
- Affective Disorders, Psychotic diagnosis etiology genetics MeSH
- Aggression MeSH
- Autistic Disorder diagnosis etiology genetics MeSH
- Mental Disorders diagnosis etiology genetics MeSH
- Financing, Organized MeSH
- Humans MeSH
- Evidence-Based Medicine MeSH
- Serotonin Plasma Membrane Transport Proteins diagnostic use genetics MeSH
- Polymorphism, Genetic genetics MeSH
- Feeding and Eating Disorders diagnosis etiology genetics MeSH
- Alcohol-Related Disorders diagnosis etiology genetics MeSH
- Self Mutilation diagnosis etiology genetics MeSH
- Check Tag
- Humans MeSH
Transportné proteíny z rodiny ABC (ATP-binding cassette) zabezpečujú transport rôznych substrátov cez biologické membrány. Zohrávajú esenciálnu úlohu v ochrane buniek pred toxickými zlúčeninami/metabolitmi. S nadexpresiou ABC transportných proteínov súvisí vznik mnohonásobnej rezistencie (MDR, multidrug resistance) buniek voči antimikróbnym zlúčeninám a protinádorovým chemoterapeutikám. Mutácie proteínov ABC-typu u ľudí sú príčinou viacerých genetických ochorení (cystická fibróza, adrenoleukodystrofia, defekty v transporte cholesterolu, žlče a pod.). Bunky mikroorganizmov obsahujú viaceré homológy klinicky významných ABC proteínov. Ich intenzívne molekulárne štúdium môže prispieť k návrhu nových postupov ako zvládnuť MDR resp. ochorenia, ktoré sú dôsledkom dysfunkcie ABC proteínov. Práca podáva prehľad súčasného stavu poznatkov o ABC transportných proteínoch v bunkách prokaryotických a eukaryotických mikroorganizmov.
The ABC (ATP binding cassette) transporter family includes membrane proteins that can transport a wide variety of substrates across biological membranes. These proteins play an essential role in the protection of cells from toxic compounds/metabolites. Their overexpression which leads to the development of multidrug resistance (MDR) in pathogens and enables cancer cells to survive chemotherapy is of major concern for human health. Mutations in ABC transporters are implicated in a number of Mendelian disorders such as cystic fibrosis, adrenoleukodystrophy and cholesterol and bile transport defects. In microbial cells, several homologues of human ABC transporters were identified. Their further molecular biological study can contribute to better understanding and treatment of MDR or diseases caused by dysfunction of ABC transporter proteins. A review is presented of the state of the art in ABC transporter proteins in both prokaryotic and eucaryotic cells. The role of microbial ABC transporters in the development of drug resistance is analyzed.
Předpokládá se, že kognitivní funkce mohou být v genetických studiích u psychiatrických poruch vhodnějším fenotypem než samotný klinický obraz, který je více ovlivněn faktory prostředí (Gottesman, 2003). U ADHD je přítomna porucha kognitivních funkcí z definice této poruchy. Od nehyperkinetické populace se skupina pacientů s ADHD odlišuje poruchou pozornosti a zvýšenou impulzivitou. Další poruchy existují v inhibici motoriky. Bylo zjištěno, že chybná inhibice odpovědi (která souvisí s impulzivitou) je vhodným endofenotypem ADHD a vyskytuje se i u příbuzných pacientů, kteří nevykazují klinické známky ADHD (Slaats-Willemse, 2003, Aron 2005). Vhodným endofenotypem je rovněž pozornost (Fan, 2001). Metodika: V naší práci jsme zkoumali korelace mezi genotypem a výsledky neuropsychologických testů (TDT, TE-NA-ZO a baterie NES2) u homogenní kavkazské populace 119 chlapců ve věku 7-13 let s dg. hyperkinetická porucha (F90.X dle MKN-10) - dále HKP. Byl stanoven genotyp pro "dopaminové" geny (DRD2, DRD4, DAT). Výsledky: V souboru jsme hledali korelaci mezi výsledky psychologických testů a genotypy jednotlivých genů. Korelační koeficienty pro žádnou kombinaci nebyly statisticky signifikantně odlišné od náhodného rozdělení. Závěr: V našem souboru jsme neprokázali korelace mezi polymorfismy "dopaminových" genů a výsledky neuropsychologických testů. Polymorfismus těchto genů v populaci českých hypekinetických chlapců neovlivňuje výkony v psychologických testech.
It is assumed that cognitive functions may be a better phenotype in genetic studies of psychiatric disorders than clinical picture itself as it is more influenced by the external factors (Gottesman, 2003). A cognitive deficit is present in ADHD patients as a matter of definition. The ADHD group differs from the non-ADHD population in terms of attention deficit and increased impulsivity. Other deficits exist in motor function inhibition. It has been found that incorrect response inhibition (which relates to impulsivity) is a suitable endophenotype of ADHD and is present as well in relatives of patients who themselves do not express clinical signs od ADHD (Slaats-Willemse, 2003, Aron, 2005). Attention is a suitable endophenotype as well (Fan, 2001). Method: In the present study the correlations between genotype and results of neuropsychological tests (TDT, TE-NA-ZO and NES2 battery) were studied in a homogenous Caucasian population of 119 boys in the age range 7-13 diagnosed with Hyperkinetic disorder (HKP - F90.X according to the ICD-10). The genotype for "dopaminergic" genes (DRD2, DRD4, DAT) was assessed. Results: Correlations between the results of psychological tests and genotypes of each gene were examined. The correlation coeficients for any combination were not significantly different from a random distribution. Conclusion: We did not prove any correlations between the "dopaminergic" genes polymorphisms and the results of neuropsychological tests in our sample. Polymorphisms of these genes do not influence the performance in psychological tests in the population of Czech hyperkinetic boys.
Alzheimer's disease (AD) is a devastating neurological disorder characterized by the pathological accumulation of macromolecular Aβ and tau leading to neuronal death. Drugs approved to treat AD may ameliorate disease symptoms, however, no curative treatment exists. Aβ peptides were discovered to be substrates of adenosine triphosphate-(ATP)-binding cassette (ABC) transporters. Activators of these membrane-bound efflux proteins that promote binding and/or translocation of Aβ could revolutionize AD medicine. The knowledge about ABC transporter activators is very scarce, however, the few molecules that were reported contain substructural features of multitarget (pan-)ABC transporter inhibitors. A cutting-edge strategy to obtain new drug candidates is to explore and potentially exploit the recently proposed multitarget binding site of pan-ABC transporter inhibitors as anchor point for the development of innovative activators to promote Aβ clearance from the brain. Molecular associations between functional bioactivities and physicochemical properties of small-molecules are key to understand these processes. This study provides an analysis of a recently reported unique multitarget dataset for the correlation between multitarget bioactivity and physicochemistry. Six novel pan-ABC transporter inhibitors were validated containing substructural features of ABC transporter activators, which underpins the relevance of the multitarget binding site for the targeted development of novel AD diagnostics and therapeutics.
- MeSH
- ATP Binding Cassette Transporter, Subfamily G, Member 2 metabolism MeSH
- ATP-Binding Cassette Transporters metabolism MeSH
- Alzheimer Disease * drug therapy metabolism MeSH
- Biological Transport MeSH
- Chemical Phenomena MeSH
- Humans MeSH
- Brain metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- MeSH
- Biological Transport MeSH
- Early Diagnosis MeSH
- Diet methods MeSH
- Epilepsy diagnosis etiology MeSH
- Glucose deficiency MeSH
- Infant MeSH
- Humans MeSH
- Brain Diseases, Metabolic, Inborn diagnosis MeSH
- Microcephaly diagnosis MeSH
- Psychomotor Disorders etiology MeSH
- Check Tag
- Infant MeSH
- Humans MeSH
- Male MeSH
- Publication type
- Case Reports MeSH
- Geographicals
- Slovakia MeSH
