Alzheimer's disease (AD) is the most common form of dementia. Characterized by progressive neurodegeneration, AD typically begins with mild cognitive decline escalating to severe impairment in communication and responsiveness. It primarily affects cerebral regions responsible for cognition, memory, and language processing, significantly impeding the functional independence of patients. With nearly 50 million dementia cases worldwide, a number expected to triple by 2050, the need for effective treatments is more urgent than ever. Recent insights into the association between obesity, type 2 diabetes mellitus, and neurodegenerative disorders have led to the development of promising treatments involving antidiabetic and anti-obesity agents. One such novel promising candidate for addressing AD pathology is a lipidized analogue of anorexigenic peptide called prolactin-releasing peptide (palm11-PrRP31). Interestingly, anorexigenic and orexigenic peptides have opposite effects on food intake regulation, however, both types exhibit neuroprotective properties. Recent studies have also identified ghrelin, an orexigenic peptide, as a potential neuroprotective agent. Hence, we employed both anorexigenic and orexigenic compounds to investigate the common mechanisms underpinning their neuroprotective effects in a triple transgenic mouse model of AD (3xTg-AD mouse model) combining amyloid-beta (Aβ) pathology and Tau pathology, two hallmarks of AD. We treated 3xTg-AD mice for 4 months with two stable lipidized anorexigenic peptide analogues - palm11-PrRP31, and liraglutide, a glucagon-like peptide 1 (GLP-1) analogue - as well as Dpr3-ghrelin, a stable analogue of the orexigenic peptide ghrelin, and using the method of immunohistochemistry and western blot demonstrate the effects of these compounds on the development of AD-like pathology in the brain. Palm11-PrRP31, Dpr3-ghrelin, and liraglutide reduced intraneuronal deposits of Aβ plaque load in the hippocampi and amygdalae of 3xTg-AD mice. Palm11-PrRP31 and Dpr3-ghrelin reduced microgliosis in the hippocampi, amygdalae, and cortices of 3xTg-AD mice. Palm11-PrRP31 and liraglutide reduced astrocytosis in the amygdalae of 3xTg-AD mice. We propose that these peptides are involved in reducing inflammation, a common mechanism underlying their therapeutic effects. This is the first study to demonstrate improvements in AD pathology following the administration of both orexigenic and anorexigenic compounds, highlighting the therapeutic potential of food intake-regulating peptides in neurodegenerative disorders.

• MeSH
• Alzheimerova nemoc * farmakoterapie   metabolismus   patologie   MeSH
• amyloidní beta-protein metabolismus   MeSH
• amyloidový prekurzorový protein beta genetika   metabolismus   MeSH
• ghrelin farmakologie   analogy a deriváty   terapeutické užití   metabolismus   MeSH
• hormon uvolňující prolaktin * analogy a deriváty   farmakologie   MeSH
• lidé MeSH
• liraglutid farmakologie   terapeutické užití   MeSH
• modely nemocí na zvířatech * MeSH
• myši inbrední C57BL MeSH
• myši transgenní * MeSH
• myši MeSH
• neuroprotektivní látky farmakologie   terapeutické užití   MeSH
• neurozánětlivé nemoci farmakoterapie   metabolismus   MeSH
• presenilin-1 genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Liver-enriched antimicrobial peptide 2 (LEAP2) is a natural antagonist/inverse agonist of ghrelin receptor GHSR. Its truncated palmitoylated analog palm-LEAP2(1-14) promised anti-obesity properties because it exhibited favourable stability and an acute anorexigenic effect in our previous studies. Here we demonstrate desirable palm-LEAP2(1-14) pharmacokinetics, with significant levels of the peptide persisting in mouse blood 3 h after its subcutaneous administration. Palm-LEAP2 (1-14) reduced ghrelin-induced c-Fos immunoreactivity in arcuate nucleus and area postrema, in line with previously described silencing of ghrelin orexigenic effect. In spite of this, anti-obesity effect was not reached by two-week palm-LEAP2(1-14) treatment in mice with diet-induced obesity. Similarly, palm-LEAP2(1-14) administered simultaneously with high-fat diet feeding for 8 weeks did not protect mice from development of obesity and related biochemical changes. However, palm-LEAP2(1-14) kept its ability to attenuate liver de novo lipogenesis, and prominently lowered liver gene expression of nuclear receptors PPARG, SREBF1 and PPARA, and also expression of lipogenic and lipolytic enzymes. In our recent study, we described a high-fat diet-induced ghrelin resistance, reversible by switch to standard diet, followed by resistance to the acute anorexigenic effects of palm-LEAP2(1-14). Here we conclude that this resistance to palm-LEAP2(1-14) in obesity is probably selective and does not concern its ability to inhibit liver lipid metabolism.

• MeSH
• dieta s vysokým obsahem tuků * škodlivé účinky   MeSH
• ghrelin * metabolismus   MeSH
• játra * metabolismus   účinky léků   MeSH
• kationické antimikrobiální peptidy metabolismus   MeSH
• lipogeneze účinky léků   genetika   MeSH
• metabolismus lipidů * účinky léků   MeSH
• myši inbrední C57BL * MeSH
• myši MeSH
• obezita * metabolismus   MeSH
• peptidové fragmenty MeSH
• protoonkogenní proteiny c-fos metabolismus   genetika   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

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.

• MeSH
• léčivé přípravky MeSH
• lidé MeSH
• lipopeptidy * farmakologie   terapeutické užití   MeSH
• peptidy chemie   farmakologie   terapeutické užití   MeSH
• stabilita léku MeSH
• Check Tag
• lidé MeSH

AIMS: This study investigates the neuroprotective effects of lipidized analogues of 2-SS-CART(61-102) derived from anorexigenic neuropeptide cocaine- and amphetamine-regulated transcript peptide (CARTp) in light of the link between obesity, its comorbidities, and the development of Alzheimer's disease. METHODS: We introduce novel lipidized analogues derived from 2-SS-CART(61-102), a specific analogue of natural CART(61-102), with two disulfide bridges. Using hypothermic PC12 cells, we tested the effect of the most potent analogues on Tau phosphorylation. We further described the anorexigenic and neuroprotective potential of subcutaneously (SC) injected lipidized CARTp analogue in a mouse model with prediabetes and obesity induced by neonatal monosodium glutamate (MSG) administration. RESULTS: Compared to the non-lipidized 2-SS-CART(61-102), all lipidized analogues exhibited a potent binding affinity to PC12 cells and enhanced in vitro stability in rat plasma. Two most potent lipidized analogues attenuated hypothermia-induced Tau hyperphosphorylation at multiple epitopes. Subsequently, chronic SC treatment with palm-2-SS-CART(61-102) significantly decreased body weight and food intake, improved metabolic parameters, decreased level of pTau and increased neurogenesis in hippocampi of obese MSG mice. CONCLUSION: Our unique CARTp analogue palm-2-SS-CART(61-102) shows promise as a potent anti-obesity and neuroprotective agent.

• MeSH
• anorektika farmakologie   MeSH
• buňky PC12 MeSH
• fosforylace účinky léků   MeSH
• glutamát sodný * MeSH
• krysa rodu rattus MeSH
• lipidy chemie   krev   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• neuroprotektivní látky * farmakologie   MeSH
• obezita * metabolismus   farmakoterapie   MeSH
• proteiny nervové tkáně * metabolismus   MeSH
• proteiny tau metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Since 1975, the incidence of obesity has increased to epidemic proportions, and the number of patients with obesity has quadrupled. Obesity is a major risk factor for developing other serious diseases, such as type 2 diabetes mellitus, hypertension, and cardiovascular diseases. Recent epidemiologic studies have defined obesity as a risk factor for the development of neurodegenerative diseases, such as Alzheimer's disease (AD) and other types of dementia. Despite all these serious comorbidities associated with obesity, there is still a lack of effective antiobesity treatment. Promising candidates for the treatment of obesity are anorexigenic neuropeptides, which are peptides produced by neurons in brain areas implicated in food intake regulation, such as the hypothalamus or the brainstem. These peptides efficiently reduce food intake and body weight. Moreover, because of the proven interconnection between obesity and the risk of developing AD, the potential neuroprotective effects of these two agents in animal models of neurodegeneration have been examined. The objective of this review was to explore anorexigenic neuropeptides produced and acting within the brain, emphasizing their potential not only for the treatment of obesity but also for the treatment of neurodegenerative disorders.

• MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   patologie   prevence a kontrola   MeSH
• hypothalamus účinky léků   metabolismus   patologie   MeSH
• látky proti obezitě * farmakologie   terapeutické užití   MeSH
• lidé MeSH
• mozek účinky léků   metabolismus   patologie   MeSH
• neurodegenerativní nemoci farmakoterapie   metabolismus   prevence a kontrola   MeSH
• neuropeptidy * metabolismus   farmakologie   terapeutické užití   MeSH
• neuroprotektivní látky * farmakologie   terapeutické užití   MeSH
• obezita * farmakoterapie   metabolismus   MeSH
• přijímání potravy účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

RF-amide peptides influence multiple physiological processes, including the regulation of appetite, stress responses, behavior, and reproductive and endocrine functions. In this study, we examined the roles of neuropeptide FF receptors (NPFFR1 and NPFFR2) by generating several lipidized analogs of neuropeptide AF (NPAF) and 1DMe, a stable analog of neuropeptide FF (NPFF). These analogs were administered peripherally for the first time to investigate their effects on food intake and other potential physiological outcomes. Lipidized NPAF and 1DMe analogs exhibited enhanced stability and increased pharmacokinetics. These analogs demonstrated preserved high affinity for NPFFR2 in the nanomolar range, while the binding affinity for NPFFR1 was tens of nanomoles. They activated the ERK and Akt signaling pathways in cells overexpressing the NPFFR1 and NPFFR2 receptors. Acute food intake in fasted mice decreased after the peripheral administration of oct-NPAF or oct-1DMe. However, this effect was not as pronounced as that observed after the injection of palm11-PrRP31, a potent anorexigenic compound used as a comparator that binds to GPR10 and the NPFFR2 receptor with high affinity. Neither oct-1DMe nor oct-NPAF decreased food intake or body weight in mice with diet-induced obesity during long-term treatment. In mice treated with oct-1DMe, we observed decreased activity in the central zone during the open field test and decreased activity in the open arms of the elevated plus maze. Furthermore, we observed a decrease in plasma noradrenaline levels and an increase in plasma corticosterone levels, as well as an increase in Crh expression in the hypothalamus. Moreover, neuronal activity in the hypothalamus was increased after treatment with oct-1DMe. In this study, we report that oct-1DMe did not have any long-term effects on the central regulation of food intake; however, it caused anxiety-like behavior.

• MeSH
• myši MeSH
• oligopeptidy * farmakologie   MeSH
• receptory neuropeptidů metabolismus   MeSH
• regulace chuti k jídlu * MeSH
• úzkost MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Peptides, as potential therapeutics continue to gain importance in the search for active substances for the treatment of numerous human diseases, some of which are, to this day, incurable. As potential therapeutic drugs, peptides have many favorable chemical and pharmacological properties, starting with their great diversity, through their high affinity for binding to all sort of natural receptors, and ending with the various pathways of their breakdown, which produces nothing but amino acids that are nontoxic to the body. Despite these and other advantages, however, they also have their pitfalls. One of these disadvantages is the very low stability of natural peptides. They have a short half-life and tend to be cleared from the organism very quickly. Their instability in the gastrointestinal tract, makes it impossible to administer peptidic drugs orally. To achieve the best pharmacologic effect, it is desirable to look for ways of modifying peptides that enable the use of these substances as pharmaceuticals. There are many ways to modify peptides. Herein we summarize the approaches that are currently in use, including lipidization, PEGylation, glycosylation and others, focusing on lipidization. We describe how individual types of lipidization are achieved and describe their advantages and drawbacks. Peptide modifications are performed with the goal of reaching a longer half-life, reducing immunogenicity and improving bioavailability. In the case of neuropeptides, lipidization aids their activity in the central nervous system after the peripheral administration. At the end of our review, we summarize all lipidized peptide-based drugs that are currently on the market.

• MeSH
• lipidy * chemie   MeSH
• peptidy * chemie   terapeutické užití   MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy 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

Alzheimer's disease (AD) is a progressive brain disorder characterized by extracellular amyloid-β (Aβ) plaques, intracellular neurofibrillary tangles formed by hyperphosphorylated Tau protein and neuroinflammation. Previous research has shown that obesity and type 2 diabetes mellitus, underlined by insulin resistance (IR), are risk factors for neurodegenerative disorders. In this study, obesity-induced peripheral and central IR and inflammation were studied in relation to AD-like pathology in the brains and periphery of APP/PS1 mice, a model of Aβ pathology, fed a high-fat diet (HFD). APP/PS1 mice and their wild-type controls fed either a standard diet or HFD were characterized at the ages of 3, 6 and 10 months by metabolic parameters related to obesity via mass spectroscopy, nuclear magnetic resonance, immunoblotting and immunohistochemistry to quantify how obesity affected AD pathology. The HFD induced substantial peripheral IR leading to central IR. APP/PS1-fed HFD mice had more pronounced IR, glucose intolerance and liver steatosis than their WT controls. The HFD worsened Aβ pathology in the hippocampi of APP/PS1 mice and significantly supported both peripheral and central inflammation. This study reveals a deleterious effect of obesity-related mild peripheral inflammation and prediabetes on the development of Aβ and Tau pathology and neuroinflammation in APP/PS1 mice.

• MeSH
• Alzheimerova nemoc * etiologie   MeSH
• amyloidní beta-protein MeSH
• diabetes mellitus 2. typu * MeSH
• dieta s vysokým obsahem tuků škodlivé účinky   MeSH
• inzulinová rezistence * MeSH
• myši MeSH
• neurozánětlivé nemoci MeSH
• zánět MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Zucker fatty (fa/fa) rats represent a well-established and widely used model of genetic obesity. Because previous metabolomic studies have only been published for young fa/fa rats up to 20 weeks of age, which can be considered early maturity in male fa/fa rats, the aim of our work was to extend the metabolomic characterization to significantly older animals. Therefore, the urinary profiles of obese fa/fa rats and their lean controls were monitored using untargeted NMR metabolomics between 12 and 40 weeks of age. At the end of the experiment, the rats were also characterized by NMR and LC-MS serum analysis, which was supplemented by a targeted LC-MS analysis of serum bile acids and neurotransmitters. The urine analysis showed that most of the characteristic differences detected in young obese fa/fa rats persisted throughout the experiment, primarily through a decrease in microbial co-metabolite levels, the upregulation of the citrate cycle, and changes in nicotinamide metabolism compared with the age-related controls. The serum of 40-week-old obese rats showed a reduction in several bile acid conjugates and an increase in serotonin. Our study demonstrated that the fa/fa model of genetic obesity is stable up to 40 weeks of age and is therefore suitable for long-term experiments.

• Publikační typ
• časopisecké články MeSH