Q112414376
Dotaz
Zobrazit nápovědu
Význam peptidových terapeutik v posledních letech neustále roste. Peptidy jako potenciální léčiva mají mnoho příznivých chemických a farmakologických vlastností, počínaje jejich velkou rozmanitostí a konče vysokou afinitou k různým druhům přirozených receptorů. Přes tyto a další přínosy však mají i své nevýhody. Mají omezenou stabilitu v organismu v důsledku rychlé degradace a vylučování. Pro dosažení co nejlepšího farmakologického účinku je žádoucí hledat vhodné způsoby modifikace peptidů vedoucí k jejich vyšší stabilitě bez ztráty afinity k příslušným receptorům. Existuje mnoho různých způsobů modifikace peptidů. V této práci jsou shrnuty v současnosti používané syntetické přístupy potenciálně vedoucí ke zlepšení klíčových vlastností peptidů v roli nových perspektivních léčiv se zaměřením na lipidizaci. Tato práce zároveň nabízí přehled lipidizovaných peptidových léčiv, které jsou momentálně dostupné na trhu.
Peptide therapeutics are becoming increasingly important in the quest for effective compounds to treat various difficult-to-cure diseases. As potential therapeutics, peptides have many favorable chemical and pharmacological properties, ranging from their great diversity to their high affinity to various types of natural receptors. However, despite these and other advantages, they also have their pitfalls, such as a very limited stability in the organism. They have a short half-life and tend to be excreted from the body very quickly. In order to achieve a better pharmacological effect, it is desirable to find new means of modifying peptides to enable them to be used as effective drugs. There are many ways of altering the peptide structure. In this review, we summarize the approaches currently used to modify the peptide constitution with a focus on lipidization. Simultaneously this review summarizes all lipidized peptide-based therapeutics that are currently on the market.
Koletsky rats, the genetically obese strain of spontaneously hypertensive rats (SHROB), are the well-accepted animal model of human metabolic syndrome. They are characterized by early onset obesity, spontaneous hypertension, hyperinsulinemia, hyperlipidemia, proteinuria and shortened life-span. One of the factors in the pathogenesis of metabolic syndrome is oxidative stress. The aim of the present study was to compare two parameters related to oxidative stress: the levels of the main intracellular antioxidant, reduced glutathione as well as the indirect indicator of lipid peroxidation damage, thiobarbituric acid-reactive substances (TBARS) in heart, renal cortex and medulla and liver in male lean spontaneously hypertensive rats (SHR) and obese Koletsky rats. We did not find any significant differences in these markers in heart and kidneys. However, we found significantly lower glutathione level in Koletsky rat liver compared with SHR (5.03+/-0.23 vs. 5.83+/-0.14 μmol/g tissue, respectively). On the contrary, we observed significantly higher TBARS levels in Koletsky rat liver compared with SHR (28.56+/-2.15 vs. 21.83+/-1.60 nmol/mg protein, respectively). We conclude that the liver is the most sensitive tissue to oxidative damage with the significantly decreased concentration of glutathione and the significantly increased concentration of TBARS in obese Koletsky rats in comparison with lean control SHR.
- MeSH
- glutathion * metabolismus MeSH
- hypertenze metabolismus MeSH
- játra * metabolismus MeSH
- krysa rodu rattus MeSH
- látky reagující s kyselinou thiobarbiturovou metabolismus MeSH
- ledviny metabolismus MeSH
- myokard metabolismus MeSH
- obezita * metabolismus MeSH
- oxidační stres * fyziologie MeSH
- peroxidace lipidů * MeSH
- potkani inbrední SHR * MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Recent data suggest that the orexigenic peptide ghrelin and liver-expressed antimicrobial peptide 2 (LEAP2) have opposing effects on food intake regulation. Although circulating ghrelin is decreased in obesity, peripheral ghrelin administration does not induce food intake in obese mice. Limited information is available on ghrelin resistance in relation to LEAP2. In this study, the interplay between ghrelin and LEAP2 in obesity induced by a high-fat (HF) diet in mice was studied. First, the progression of obesity and intolerance to glucose together with plasma levels of active and total ghrelin, leptin, as well as liver LEAP2 mRNA expression at different time points of HF diet feeding was examined. In addition, the impact of switch from a HF diet to a standard diet on plasma ghrelin and LEAP2 production was studied. Second, sensitivity to the stable ghrelin analogue [Dpr3]Ghrelin or our novel LEAP2 analogue palm-LEAP2(1-14) during the progression of HF diet-induced obesity and after the switch for standard diet was investigated. Food intake was monitored after acute subcutaneous administration. HF diet feeding decreased both active and total plasma ghrelin and increased liver LEAP2 mRNA expression along with intolerance to glucose and the switch to a standard diet normalized liver LEAP2 mRNA expression and plasma level of active ghrelin, but not of total ghrelin. Additionally, our study demonstrates that a HF diet causes resistance to [Dpr3]Ghrelin, reversible by switch to St diet, followed by resistance to palm-LEAP2(1-14). Further studies are needed to determine the long-term effects of LEAP2 analogues on obesity-related ghrelin resistance.
- MeSH
- dieta s vysokým obsahem tuků * MeSH
- ghrelin * farmakologie MeSH
- glukosa MeSH
- messenger RNA MeSH
- myši MeSH
- obezita farmakoterapie MeSH
- receptory ghrelinu MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The worldwide increase in the incidence of obesity and cardiovascular and neurodegenerative diseases, e.g. Alzheimer's disease, is related to many factors, including an unhealthy lifestyle and aging populations. However, the interconnection between these diseases is not entirely clear, and it is unknown whether common mechanisms underlie these conditions. Moreover, there are currently no fully effective therapies for obesity and neurodegeneration. While there has been extensive research in preclinical models addressing these issues, the experimental findings have not been translated to the clinic. Another challenge relates to the time of onset of individual diseases, which may not be easily identified, since there are no specific indicators or biomarkers that define disease onset. Hence knowing when to commence preventive treatment is unclear. This is especially pertinent in neurodegenerative diseases, where the onset of the disease may be subtle and occur decades before the signs and symptoms manifest. In metabolic and cardiovascular disorders, the risk may occur in-utero, in line with the concept of fetal programming. This review provides a brief overview of the link between obesity, cardiovascular and neurodegenerative diseases and discusses potential common mechanisms including the role of the gut microbiome.
- MeSH
- Alzheimerova nemoc * metabolismus MeSH
- lidé MeSH
- neurodegenerativní nemoci * metabolismus MeSH
- obezita komplikace diagnóza epidemiologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Ačkoli jedinců s obezitou neustále přibývá, dostupnost účinné neinvazivní léčby je stále malá. Slibnými prostředky pro léčbu obezity jsou anorexigenní neuropeptidy s působností v mozku. Jejich dopravu do mozku ale komplikuje jejich malá stabilita a omezená schopnost překonat hematoencefalickou bariéru. Nedávno objevené anorexigenní neuropeptidy, jako peptid uvolňující prolaktin, představují nový směr ve vývoji antiobezitních látek. Neuropeptidy jsou uvolňovány a působí přímo v oblastech mozku regulujících příjem potravy, ale obecně neprocházejí hematoencefalickou bariérou po periferním podání. Nám se podařilo navrhnout a syntetizovat stabilní palmitoylované analogy tohoto neuropeptidu, které měly po periferním podání prodloužený akutní anorexigenní účinek v myších a potkanech. Opakované periferní podání palmitoylovaných analogů peptidu uvolňujícího prolaktin vedlo k dlouhodobému antiobezitnímu a antidiabetickému účinku u hlodavců s obezitou navozenou vysokotukovou dietou a s inzulinovou rezistencí. Dokázali jsme, že lipidizace by mohla být účinnou cestou, jak dosáhnout žádoucího centrálního účinku peptidu po jeho periferním podání pro léčbu obezity a vyplývajících komplikací, jako je diabetes 2. typu. Vedle vysokého věku jsou pro Alzheimerovu nemoc rizikovými faktory diabetes 2. typu a obezita. Proto látky snižující koncentraci glukosy v krvi a/nebo s anorexigenními účinky jsou potenciálně neuroprotektivní. Naše skupina sledovala vztah mezi obezitou, diabetem 2. typu a patologickými jevy při Alzheimerově nemoci a zkoumala, zda by originální palmitoylované analogy peptidu uvolňujícího prolaktin mohly působit prospěšně proti neurodegeneraci v několika myších modelech alzheimerovské patologie. Ukázali jsme, že tyto lipidizované analogy jsou potenciálně neuroprotektivní látky, které v myších modelech Alzheimerovy nemoci zlepšují prostorovou paměť, zvyšují neurogenezi, synaptogenezi a potlačují neuroinflamaci a dva hlavní znaky Alzheimerovy nemoci, hyperfosforylaci proteinu tau a vznik plaků amyloidního β‐peptidu.
Obesity is an escalating epidemic, but an effective non-invasive therapy is still scarce. For the obesity treatment, anorexigenic neuropeptides represent promising tools, but their delivery from the periphery to the brain is complicated because peptides have a low stability and limited ability to cross the blood-brain barrier. Recently discovered anorexigenic neuropeptides, such as prolactin-releasing peptide, represent new trends in development of anti-obesity agents. They are released and acting directly in brain areas regulating food intake, but generally do not cross the blood-brain barrier if administered peripherally. We succeeded to design stable palmitoylated analogs of this neuropeptide with a prolonged acute anorexigenic effect after peripheral administration as shown in mice and rats. Repeated peripheral administration of the lipidized prolactin-releasing peptide analogs resulted in long-lasting anti-obesity and antidiabetic effects in rodent models of diet-induced obesity and insulin resistance. We proved that lipidation might be an effective way to transmit the desired effect to the central nervous system after peripheral administration, for a potential treatment of obesity and related complications such as type-2 diabetes. Besides the advanced age, type-2 diabetes and obesity were shown to be risk factors for Alzheimer's disease; therefore, compounds with glucose-lowering and/or anorexigenic properties were proposed to be neuroprotective. In our group, we studied a possible crosstalk between obesity, type-2 diabetes and Alzheimer's-like pathology. We also investigated if our novel palmitoylated analogs of prolactin-releasing peptide could have beneficial effect on neurodegeneration in several mouse models of Alzheimer's-like pathology and their age-matched wild type controls. We demonstrated that these lipidized analogs are potentially neuroprotective substances improving spatial memory, neurogenesis, synaptogenesis and attenuating neuroinflammation and two hallmarks of Alzheimer's disease, i.e., tau hyper-phosphorylation and β-amyloid plaques in different mouse models of Alzheimer's-like neurodegeneration.
- MeSH
- Alzheimerova nemoc farmakoterapie MeSH
- hormon uvolňující prolaktin * farmakologie terapeutické užití MeSH
- inzulinová rezistence MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- obezita farmakoterapie MeSH
- objevování léků MeSH
- prediabetes farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
Prolactin-releasing peptide (PrRP) has been proposed to mediate the central satiating effects of cholecystokinin (CCK) through the vagal CCK1 receptor. PrRP acts as an endogenous ligand of G protein-coupled receptor 10 (GPR10), which is expressed at the highest levels in brain areas related to food intake regulation, e.g., the paraventricular hypothalamic nucleus (PVN) and nucleus of the solitary tract (NTS). The NTS and PVN are also significantly activated after peripheral CCK administration. The aim of this study was to determine whether the endogenous PrRP neuronal system in the brain is involved in the central anorexigenic effect of the peripherally administered CCK agonist JMV236 or the CCK1 antagonist devazepide and whether the CCK system is involved in the central anorexigenic effect of the peripherally applied lipidized PrRP analog palm-PrRP31 in fasted lean mice. The effect of devazepide and JMV236 on the anorexigenic effects of palm-PrRP31 as well as devazepide combined with JMV236 and palm-PrRP31 on food intake and Fos cell activation in the PVN and caudal NTS was examined. Our results suggest that the anorexigenic effect of JMV236 is accompanied by activation of PrRP neurons of the NTS in a CCK1 receptor-dependent manner. Moreover, while the anorexigenic effect of palm-PrRP31 was not affected by JMV236, it was partially attenuated by devazepide in fasted mice. The present findings indicate that the exogenously influenced CCK system may be involved in the central anorexigenic effect of peripherally applied palm-PrRP31, which possibly indicates some interaction between the CCK and PrRP neuronal systems.
- MeSH
- anorektika aplikace a dávkování MeSH
- antagonisté hormonů aplikace a dávkování MeSH
- chemokiny CC účinky léků metabolismus MeSH
- cholecystokinin metabolismus MeSH
- devazepid aplikace a dávkování MeSH
- hormon uvolňující prolaktin aplikace a dávkování analogy a deriváty MeSH
- injekce intraperitoneální MeSH
- injekce subkutánní MeSH
- myši inbrední C57BL MeSH
- nucleus paraventricularis hypothalami účinky léků metabolismus MeSH
- nucleus solitarius účinky léků metabolismus MeSH
- omezení příjmu potravy MeSH
- peptidové fragmenty aplikace a dávkování MeSH
- přijímání potravy účinky léků MeSH
- protoonkogenní proteiny c-fos metabolismus MeSH
- signální transdukce MeSH
- sinkalid aplikace a dávkování analogy a deriváty MeSH
- stravovací zvyklosti účinky léků MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are increasing in prevalence. Currently, there are no effective and specific treatments for these disorders. Recently, positive effects of the orexigenic hormone ghrelin on memory and learning were demonstrated in mouse models of AD and PD. In this study, we tested the potential neuroprotective properties of a stable and long-lasting ghrelin analog, Dpr(3)ghrelin (Dpr(3)ghr), in SH-SY5Y neuroblastoma cells stressed with 1.2 mM methylglyoxal (MG), a toxic endogenous by-product of glycolysis, and we examined the impact of Dpr(3)ghr on apoptosis. Pre-treatment with both 10(-5) and 10(-7) M Dpr(3)ghr resulted in increased viability in SH-SY5Y cells (determined by MTT staining), as well as reduced cytotoxicity of MG in these cells (determined by LDH assay). Dpr(3)ghr increased viability by altering pro-apoptotic and viability markers: Bax was decreased, Bcl-2 was increased, and the Bax/Bcl-2 ratio was attenuated. The ghrelin receptor GHS-R1 and Dpr(3)ghr-induced activation of PBK/Akt were immuno-detected in SH-SY5Y cells to demonstrate the presence of GHS-R1 and GHS-R1 activation, respectively. We demonstrated that Dpr(3)ghr protected SH-SY5Y cells against MG-induced neurotoxicity and apoptosis. Our data suggest that stable ghrelin analogs may be candidates for the effective treatment of neurodegenerative disorders.
- MeSH
- apoptóza účinky léků MeSH
- ghrelin analogy a deriváty farmakologie MeSH
- glykolýza účinky léků MeSH
- L-laktátdehydrogenasa metabolismus MeSH
- lidé MeSH
- MAP kinasový signální systém účinky léků MeSH
- membránový potenciál mitochondrií účinky léků MeSH
- nádorové buněčné linie MeSH
- neuroprotektivní látky farmakologie MeSH
- neurotoxické syndromy prevence a kontrola MeSH
- proteiny regulující apoptózu biosyntéza genetika MeSH
- pyruvaldehyd toxicita MeSH
- receptory ghrelinu biosyntéza MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The incidence of metabolic syndrome increases in the developed countries, therefore biomedical research is focused on the understanding of its etiology. The study of exact mechanisms is very complicated because both genetic and environmental factors contribute to this complex disease. The ability of environmental factors to promote phenotype changes by epigenetic DNA modifications (i.e. DNA methylation, histone modifications) was demonstrated to play an important role in the development and predisposition to particular symptoms of metabolic syndrome. There is no doubt that the early life, such as the fetal and perinatal periods, is critical for metabolic syndrome development and therefore critical for prevention of this disease. Moreover, these changes are visible not only in individuals exposed to environmental factors but also in the subsequent progeny for multiple generations and this phenomenon is called transgenerational inheritance. The knowledge of molecular mechanisms, by which early minor environmental stimuli modify the expression of genetic information, might be the desired key for the understanding of mechanisms leading to the change of phenotype in adulthood. This review provides a short overview of metabolic syndrome epigenetics.
