Obezita je závažné chronické onemocnění, jehož léčba vyžaduje komplexní přístup. Základními pilíři léčby obezity jsou zdravé jídelní zvyklosti a návyky, dostatek pohybové aktivity a pravidelného spánku. Nadměrná tělesná hmotnost je často spojena s psychopatologickým chováním. Děti vykazují smutek, depresi, nízký stupeň sebehodnocení, a proto role psychoterapie či kognitivně-behaviorální terapie je v přístupu k obéznímu jedinci velmi důležitá. V posledních letech se významně rozšiřují možnosti využití farmakoterapie, a to jak cílené u léčby některých genetických poruch, tak i pro léčbu polygenně podmíněné obezity. V současnosti jsou pro použití u dětí schváleny tři léky – metreleptin, setmelanotid a liraglutid. Metreleptin je určen pro léčbu geneticky potvrzeného deficitu leptinu. Setmelanotid je indikován při patogenních variantách genů pro leptinový receptor, proopiomelanokortin či proprotein- -konvertázu a u pacientů s Bardetovým–Biedlovým syndromem. U jiných typů obezity lze využít léčbu liraglutidem, jenž je analogem glukagon-like peptidu 1. Výzkum stále pokračuje a další nové molekuly a jejich kombinace, které mohou být doplňkem v komplexním přístupu v léčbě obezity, lze očekávat.
Obesity is a serious chronic condition that requires a comprehensive multidisciplinary approach. The main components of obesity treatment are education towards healthy eating habits, increased physical activity, decreased sedentarism and regular sleep pattern. Excess body weight is often associated with psychopathological behavior. Children often present with sadness, depression, low self-esteem, and therefore the role of psychotherapy or cognitive behavioral therapy is highly important in the complex approach to the treatment of childhood obesity. In recent years, the use of pharmacotherapy, both targeted for the treatment of certain genetic disorders and for the treatment of polygenic obesity, has significantly expanded. Three drugs are currently approved for use in children. These are metreleptin for genetically confirmed leptin deficiency, and setmelanotide, which is used in individuals with pathogenic variants of genes encoding leptin receptor, proopiomelanocortin or proprotein convertase genes, and in patients with Bardet-Biedl syndrome. Other types of obesity may benefit from treatment with liraglutide, which is a glucagon-like peptide 1 analogue. Obesity research is ongoing, and new molecules and their combinations that may be complementary in a comprehensive approach to obesity treatment can be expected.
- Klíčová slova
- metreleptin, setmelanotid,
- MeSH
- alfa-MSH analogy a deriváty farmakologie terapeutické užití MeSH
- dítě MeSH
- glukagonu podobný peptid 1 analogy a deriváty farmakologie terapeutické užití MeSH
- látky proti obezitě terapeutické užití MeSH
- leptin analogy a deriváty farmakologie terapeutické užití MeSH
- lidé MeSH
- obezita dětí a dospívajících * farmakoterapie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
The equilibrium and reciprocal actions among appetite-stimulating (orexigenic) and appetite-suppressing (anorexigenic) signals synthesized in the gut, brain, microbiome and adipose tissue (AT), seems to play a pivotal role in the regulation of food intake and feeding behavior, anxiety, and depression. A dysregulation of mechanisms controlling the energy balance may result in eating disorders such as anorexia nervosa (AN) and bulimia nervosa (BN). AN is a psychiatric disease defined by chronic self-induced extreme dietary restriction leading to an extremely low body weight and adiposity. BN is defined as out-of-control binge eating, which is compensated by self-induced vomiting, fasting, or excessive exercise. Certain gut microbiota-related compounds, like bacterial chaperone protein Escherichia coli caseinolytic protease B (ClpB) and food-derived antigens were recently described to trigger the production of autoantibodies cross-reacting with appetite-regulating hormones and neurotransmitters. Gut microbiome may be a potential manipulator for AT and energy homeostasis. Thus, the regulation of appetite, emotion, mood, and nutritional status is also under the control of neuroimmunoendocrine mechanisms by secretion of autoantibodies directed against neuropeptides, neuroactive metabolites, and peptides. In AN and BN, altered cholinergic, dopaminergic, adrenergic, and serotonergic relays may lead to abnormal AT, gut, and brain hormone secretion. The present review summarizes updated knowledge regarding the gut dysbiosis, gut-barrier permeability, short-chain fatty acids (SCFA), fecal microbial transplantation (FMT), blood-brain barrier permeability, and autoantibodies within the ghrelin and melanocortin systems in eating disorders. We expect that the new knowledge may be used for the development of a novel preventive and therapeutic approach for treatment of AN and BN.
- MeSH
- autoprotilátky * MeSH
- ghrelin imunologie MeSH
- inzulin imunologie MeSH
- leptin imunologie MeSH
- lidé MeSH
- melanocyty stimulující hormony imunologie MeSH
- neuropeptid Y imunologie MeSH
- poruchy příjmu potravy imunologie mikrobiologie MeSH
- střevní mikroflóra imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Leptin-melanocortin pathway plays an essential role in the body weight regulation. Enhanced melanocortin signaling in the hypothalamus results in both decreased food intake and increased energy expenditure. The discovery of monogenic obesities with dysfunction of melanocortin-4 receptor (MC4R) greatly contributed to understanding of energy balance regulation. This review presents phenotypical characterization and prevalence of the MC4R gene mutations. Genome-wide association studies revealed that MC4R gene is significantly related not only to monogenic obesities but also to common obesity. An interaction of variants in the MC4R gene with fat mass and obesity associated (FTO) gene significantly increases the risk for obesity, particularly in adolescence. On the other hand, about 15 % of the MC4R gene variants result in a gain of function that protects against obesity and is associated with favorable metabolic profile. Long-term attempts to activate the MC4R have recently been finalized by a discovery of setmelanotide, a novel specific MC4R agonist that is devoid of untoward cardiovascular side-effects. The employment of specific MC4R agonists may open new horizons not only in the treatment of rare monogenic obesities but also in some common obesities where stimulation of MC4R could be achieved.
- MeSH
- alfa-MSH farmakologie MeSH
- celogenomová asociační studie MeSH
- cílená molekulární terapie MeSH
- látky proti obezitě farmakologie MeSH
- lidé MeSH
- mutace * MeSH
- obezita farmakoterapie genetika metabolismus MeSH
- receptor melanokortinový typ 4 genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND: Nanoparticle-based systems are promising for the development of imaging and therapeutic agents. The main advantage of nanoparticles over traditional systems lies in the possibility of loading multiple functionalities onto a single molecule, which are useful for therapeutic and/or diagnostic purposes. These functionalities include targeting moieties which are able to recognize receptors overexpressed by specific cells and tissues. However, targeted delivery of nanoparticles requires an accurate system design. We present here a rationally designed, genetically engineered, and chemically modified protein-based nanoplatform for cell/tissue-specific targeting. METHODS: Our nanoparticle constructs were based on the heavy chain of the human protein ferritin (HFt), a highly symmetrical assembly of 24 subunits enclosing a hollow cavity. HFt-based nanoparticles were produced using both genetic engineering and chemical functionalization methods to impart several functionalities, ie, the α-melanocyte-stimulating hormone peptide as a melanoma-targeting moiety, stabilizing and HFt-masking polyethylene glycol molecules, rhodamine fluorophores, and magnetic resonance imaging agents. The constructs produced were extensively characterized by a number of physicochemical techniques, and assayed for selective melanoma-targeting in vitro and in vivo. RESULTS: Our HFt-based nanoparticle constructs functionalized with the α-melanocyte-stimulating hormone peptide moiety and polyethylene glycol molecules were specifically taken up by melanoma cells but not by other cancer cell types in vitro. Moreover, experiments in melanoma-bearing mice indicate that these constructs have an excellent tumor-targeting profile and a long circulation time in vivo. CONCLUSION: By masking human HFt with polyethylene glycol and targeting it with an α-melanocyte-stimulating hormone peptide, we developed an HFt-based melanoma-targeting nanoplatform for application in melanoma diagnosis and treatment. These results could be of general interest, because the same strategy can be exploited to develop ad hoc nanoplatforms for specific delivery towards any cell/tissue type for which a suitable targeting moiety is available.
- MeSH
- alfa-MSH chemie diagnostické užití MeSH
- apoferritiny chemie MeSH
- buňky HT-29 MeSH
- fluorescenční barviva chemie diagnostické užití MeSH
- konfokální mikroskopie MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- magnetické nanočástice chemie diagnostické užití ultrastruktura MeSH
- melanom experimentální diagnóza MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nanomedicína MeSH
- nanotechnologie MeSH
- polyethylenglykoly chemie MeSH
- rekombinantní proteiny chemie MeSH
- stabilita proteinů MeSH
- systémy cílené aplikace léků MeSH
- transmisní elektronová mikroskopie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
2mg/kg melanotan II (MTII, administered i.p.), a cyclic peptide analog of alpha-melanocyte stimulating hormone, at a single dose increased grooming in naive rats placed in an unfamiliar open-field device without changing locomotion or rearing. Male rats exposed to restraint/immobilization stress (IS) for 1h on three consecutive days displayed increased grooming after the second stressor exposure, compared to pre-stress levels. MTII, administered to the rats after IS, enhanced the grooming response compared both to the pre- and post-stress values. The increase was greatest after the first dose and declined over the following two applications. As to the locomotion of rats in the entire experimental space, IS reduced the distance moved only after the first two stressor exposures; MTII did not influence these alterations. Locomotion in the central part of arena was not reduced by the stressor or by MTII, on the contrary, there was an increase in both groups after the third intervention. The only observed change in rearing was an increase in the MTII group after the third restraint exposure. Thus, MTII selectively increased grooming without markedly affecting the spatio-temporal structure of locomotor behavior in the open-field. The decline of MTII enhanced grooming over the three test days may be interpreted in terms of adaptation to the stressor and of the developing tolerance to the peptide.
- MeSH
- alfa-MSH analogy a deriváty farmakologie MeSH
- chování zvířat MeSH
- cyklické peptidy farmakologie MeSH
- fyzické omezení MeSH
- krysa rodu rattus MeSH
- melanokortiny antagonisté a inhibitory MeSH
- pátrací chování fyziologie účinky léků MeSH
- péče o zevnějšek u zvířat fyziologie účinky léků MeSH
- pohybová aktivita účinky léků MeSH
- potkani Wistar MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
Skin, the largest organ of our body, is often plagued by cancer because of exposure to ultraviolet radiation from the sun. A report by Cui et al. (2007) in this issue of Cell explains how the tumor suppressor p53 protects the skin by stimulating the suntan response.
- MeSH
- alfa-MSH genetika MeSH
- geny p53 MeSH
- keratinocyty metabolismus účinky záření MeSH
- kůže * metabolismus účinky záření MeSH
- lidé MeSH
- melaniny biosyntéza MeSH
- melanocyty metabolismus účinky záření MeSH
- myši MeSH
- nádorový supresorový protein p53 * metabolismus MeSH
- nádory kůže genetika MeSH
- pigmentace kůže MeSH
- poškození DNA MeSH
- pro-opiomelanokortin genetika metabolismus MeSH
- ultrafialové záření * škodlivé účinky MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- MeSH
- experimenty na zvířatech statistika a číselné údaje MeSH
- financování organizované MeSH
- fluorescenční protilátková technika metody statistika a číselné údaje využití MeSH
- imunohistochemie metody statistika a číselné údaje MeSH
- infarkt myokardu farmakoterapie genetika prevence a kontrola MeSH
- krysa rodu rattus MeSH
- melanocyty stimulující hormony analýza diagnostické užití MeSH
- myši chirurgie MeSH
- receptory kalcitoninu krev metabolismus účinky léků MeSH
- srdce účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- myši chirurgie MeSH
- zvířata MeSH
