Numbers of pathogenic bacteria can induce apoptosis in human host cells and modulate the cellular pathways responsible for inducing or inhibiting apoptosis. These pathogens are significantly recognized by host proteins and provoke the multitude of several signaling pathways and alter the cellular apoptotic stimuli. This process leads the bacterial entry into the mammalian cells and evokes a variety of responses like phagocytosis, release of mitochondrial cytochrome c, secretion of bacterial effectors, release of both apoptotic and inflammatory cytokines, and the triggering of apoptosis. Several mechanisms are involved in bacteria-induced apoptosis including, initiation of the endogenous death machinery, pore-forming proteins, and secretion of superantigens. Either small molecules or proteins may act as a binding partner responsible for forming the protein complexes and regulate enzymatic activity via protein-protein interactions. The bacteria induce apoptosis, attack the human cell and gain control over various types of cells and tissue. Since these processes are intricate in the defense mechanisms of host organisms against pathogenic bacteria and play an important function in host-pathogen interactions. In this chapter, we focus on the various bacterial-induced apoptosis mechanisms in host cells and discuss the important proteins and bacterial effectors that trigger the host cell apoptosis. The structural characterization of bacterial effector proteins and their interaction with human host cells are also considered.
- Klíčová slova
- Apoptosis, Bcl-2, CagA, Caspase, Cytochrome c, Hemolysin, Nf-kB, Pathogenic bacteria, TLR,
- MeSH
- apoptóza imunologie MeSH
- Bacteria * imunologie patogenita MeSH
- bakteriální infekce imunologie MeSH
- bakteriální proteiny * chemie imunologie MeSH
- faktory virulence * chemie imunologie MeSH
- lidé MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- bakteriální proteiny * MeSH
- faktory virulence * MeSH
The insect cuticle is the interface between internal homeostasis and the often harsh external environment. Cuticular hydrocarbons (CHCs) are key constituents of this hard cuticle and are associated with a variety of functions including stress response and communication. CHC production and deposition on the insect cuticle vary among natural populations and are affected by developmental temperature; however, little is known about CHC plasticity in response to the environment experienced following eclosion, during which time the insect cuticle undergoes several crucial changes. We targeted this crucial to important phase and studied post-eclosion temperature effects on CHC profiles in two natural populations of Drosophila melanogaster. A forty-eight hour post-eclosion exposure to three different temperatures (18, 25, and 30°C) significantly affected CHCs in both ancestral African and more recently derived North American populations of D. melanogaster. A clear shift from shorter to longer CHCs chain length was observed with increasing temperature, and the effects of post-eclosion temperature varied across populations and between sexes. The quantitative differences in CHCs were associated with variation in desiccation tolerance among populations. Surprisingly, we did not detect any significant differences in water loss rate between African and North American populations. Overall, our results demonstrate strong genetic and plasticity effects in CHC profiles in response to environmental temperatures experienced at the adult stage as well as associations with desiccation tolerance, which is crucial in understanding holometabolan responses to stress.
- Klíčová slova
- Drosophila melanogaster, cuticular hydrocarbons, desiccation tolerance, eclosion, natural populations, phenotypic plasticity, water loss rate,
- Publikační typ
- časopisecké články MeSH
DFTB+ is a versatile community developed open source software package offering fast and efficient methods for carrying out atomistic quantum mechanical simulations. By implementing various methods approximating density functional theory (DFT), such as the density functional based tight binding (DFTB) and the extended tight binding method, it enables simulations of large systems and long timescales with reasonable accuracy while being considerably faster for typical simulations than the respective ab initio methods. Based on the DFTB framework, it additionally offers approximated versions of various DFT extensions including hybrid functionals, time dependent formalism for treating excited systems, electron transport using non-equilibrium Green's functions, and many more. DFTB+ can be used as a user-friendly standalone application in addition to being embedded into other software packages as a library or acting as a calculation-server accessed by socket communication. We give an overview of the recently developed capabilities of the DFTB+ code, demonstrating with a few use case examples, discuss the strengths and weaknesses of the various features, and also discuss on-going developments and possible future perspectives.
- Publikační typ
- časopisecké články MeSH
Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases, characterized by the accumulation of extracellular amyloid plaques and intraneuronal neurofibrillary tangles. These tangles mainly consist of hyperphosphorylated tau protein. As it induces tau hyperphosphorylation in vitro and in vivo, hypothermia is a useful tool for screening potential neuroprotective compounds that ameliorate tau pathology. In this study, we examined the effect of prolactin-releasing peptide (PrRP), its lipidized analog palm11-PrRP31 and glucagon-like-peptide-1 agonist liraglutide, substances with anorexigenic and antidiabetic properties, on tau phosphorylation and on the main kinases and phosphatases involved in AD development. Our study was conducted in a neuroblastoma cell line SH-SY5Y and rat primary neuronal cultures under normothermic and hypothermic conditions. Hypothermia induced a significant increase in tau phosphorylation at the pThr212 and pSer396/pSer404 epitopes. The palmitoylated analogs liraglutide and palm11-PrRP31 attenuated tau hyperphosphorylation, suggesting their potential use in the treatment of neurodegenerative diseases.
- Klíčová slova
- Hypothermia, SH-SY5Y, lipidization, primary neuronal culture, prolactin-releasing peptide, tau phosphorylation,
- MeSH
- buněčné linie MeSH
- fosforylace účinky léků MeSH
- glukagonu podobný peptid 1 agonisté MeSH
- hormon uvolňující prolaktin analogy a deriváty farmakologie MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- liraglutid farmakologie MeSH
- neurodegenerativní nemoci farmakoterapie metabolismus MeSH
- neurony * účinky léků metabolismus MeSH
- neuroprotektivní látky farmakologie MeSH
- proteiny tau metabolismus MeSH
- terapeutická hypotermie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- glukagonu podobný peptid 1 MeSH
- hormon uvolňující prolaktin MeSH
- liraglutid MeSH
- neuroprotektivní látky MeSH
- palm11-PrRP31 MeSH Prohlížeč
- proteiny tau MeSH
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the elderly population. Numerous epidemiological and experimental studies have demonstrated that patients who suffer from obesity or type 2 diabetes mellitus have a higher risk of cognitive dysfunction and AD. Several recent studies demonstrated that food intake-lowering (anorexigenic) peptides have the potential to improve metabolic disorders and that they may also potentially be useful in the treatment of neurodegenerative diseases. In this review, the neuroprotective effects of anorexigenic peptides of both peripheral and central origins are discussed. Moreover, the role of leptin as a key modulator of energy homeostasis is discussed in relation to its interaction with anorexigenic peptides and their analogs in AD-like pathology. Although there is no perfect experimental model of human AD pathology, animal studies have already proven that anorexigenic peptides exhibit neuroprotective properties. This phenomenon is extremely important for the potential development of new drugs in view of the aging of the human population and of the significantly increasing incidence of AD.
- Klíčová slova
- Alzheimer’s disease pathology, anorexigenic neuropeptides, experimental rodent models, leptin,
- MeSH
- Alzheimerova nemoc metabolismus prevence a kontrola MeSH
- anorektika metabolismus farmakologie MeSH
- energetický metabolismus účinky léků MeSH
- homeostáza účinky léků MeSH
- kyselina pyrrolidonkarboxylová analogy a deriváty metabolismus farmakologie MeSH
- leptin metabolismus MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- neuroprotektivní látky farmakologie MeSH
- oligopeptidy metabolismus farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- anorektika MeSH
- kyselina pyrrolidonkarboxylová MeSH
- leptin MeSH
- neuroprotektivní látky MeSH
- oligopeptidy MeSH
- pyroglutamyl-histidyl-glycine MeSH Prohlížeč
Obesity and type 2 diabetes mellitus (T2DM) were characterized as risk factors for Alzheimer's disease (AD) development. Subsequently, T2DM drugs, such as liraglutide, were proven to be neuroprotective compounds attenuating levels of amyloid deposits, and tau hyperphosphorylation, both hallmarks of AD. The central anorexigenic effects of liraglutide inspired us to examine the potential neuroprotective effects of palm11-PrRP31, a strong anorexigenic analog with glucose-lowering properties, in THY-Tau22 mice overexpressing mutated human tau, a model of AD-like tau pathology. Seven-month-old THY-Tau22 mice were subcutaneously infused with palm11-PrRP31 for 2 months. Spatial memory was tested before and after the treatment, using a Y-maze. At the end of the treatment, mice were sacrificed by decapitation and hippocampi were dissected and analyzed by immunoblotting with specific antibodies. Treatment with palm11-PrRP31 resulted in significantly improved spatial memory. In the hippocampi of palm11-PrRP31-treated THY-Tau22 mice, tau protein phosphorylation was attenuated at Thr231, Ser396, and Ser404, the epitopes linked to AD progression. The mechanism of this attenuation remains unclear, since the activation of those kinases most implicated in tau hyperphosphorylation, such as GSK-3β, JNK, or MAPK/ERK1/2, remained unchanged by palm11-PrRP31 treatment. Furthermore, we observed a significant increase in the amount of postsynaptic density protein PSD95, and a non-significant increase of synaptophysin, both markers of increased synaptic plasticity, which could also result in improved spatial memory of THY-Tau22 mice treated with palm11-PrRP31. Palm11-PrRP31 seems to be a potential tool for the attenuation of neurodegenerative disorders in the brain. However, the exact mechanism of its action must be elucidated.
- Klíčová slova
- Alzheimer’s disease, THY-Tau22 mice, palm11-PrRP31, spatial memory, synaptic plasticity, tau hyperphosphorylation,
- MeSH
- bludiště - učení účinky léků fyziologie MeSH
- fosforylace účinky léků MeSH
- hipokampus účinky léků metabolismus patologie MeSH
- hormon uvolňující prolaktin analogy a deriváty farmakologie terapeutické užití MeSH
- krátkodobá paměť účinky léků fyziologie MeSH
- modely nemocí na zvířatech MeSH
- myši transgenní MeSH
- neuroprotektivní látky farmakologie MeSH
- poruchy paměti farmakoterapie metabolismus patologie MeSH
- prostorová paměť účinky léků fyziologie MeSH
- proteiny tau metabolismus MeSH
- tauopatie farmakoterapie metabolismus patologie psychologie MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- hormon uvolňující prolaktin MeSH
- Mapt protein, mouse MeSH Prohlížeč
- neuroprotektivní látky MeSH
- palm11-PrRP31 MeSH Prohlížeč
- proteiny tau MeSH
Previous studies indicate that hypothalamic prolactin-releasing peptide (PrRP), signaling via GPR10 and neuropeptide FF2 receptor, is involved in energy homeostasis, stress responses, and cardiovascular regulation. Energy homeostasis depends on the balance between food intake regulation and energy expenditure, in which the hypothalamus plays a key role. The lipidization of PrRP31 with palmitoyl acid allows it to produce its anorexigenic effect after repeated peripheral administration and to reduce body weight and improve metabolic parameters in diet-induced obese (DIO) mice. The aim of this study was to reveal the transient and long-lasting changes in neuronal activity via c-Fos and FosB immunohistochemistry in brain nuclei related to food intake regulation and energy homeostasis during the first days of treatment with a newly designed lipidized analog of PrRP31 (palm11-PrRP31) with promising antiobesity effects. The data revealed that the anorexigenic effect of repeated application of palm11-PrRP31 was associated with delayed but gradually significantly reduced cumulative food intake in mice as well as with a significant reduction in their body weight. Moreover, while the repeated application of palm11-PrRP31 was associated with a significant reduction in acute cell activity in the paraventricular hypothalamic nucleus (PVN) and nucleus of the solitary tract (NTS) compare to its acute treatment, both acute and long-lasting cell activity in the dorsomedial hypothalamic nucleus (DMN) were increased. The data indicate that DMN neurons might be tonically activated after repeated administration of lipidized PrRP analogs that may be associated with the process of long-term adaptation to modified energy homeostasis.
- Klíčová slova
- Dorsomedial hypothalamic nucleus, FosB, Lipidization, Mice, Prolactin-releasing peptide, c-Fos,
- MeSH
- energetický metabolismus MeSH
- hormon uvolňující prolaktin metabolismus farmakologie MeSH
- hypothalamus účinky léků metabolismus MeSH
- lipidy farmakologie MeSH
- myši inbrední C57BL MeSH
- neurony metabolismus MeSH
- nucleus dorsomedialis hypothalami účinky léků metabolismus MeSH
- obezita farmakoterapie MeSH
- přijímání potravy účinky léků MeSH
- protoonkogenní proteiny c-fos metabolismus MeSH
- tělesná hmotnost účinky léků MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- Fosb protein, mouse MeSH Prohlížeč
- hormon uvolňující prolaktin MeSH
- lipidy MeSH
- protoonkogenní proteiny c-fos MeSH
BACKGROUND/OBJECTIVES: Prolactin-releasing peptide (PrRP) has a potential to decrease food intake and ameliorate obesity, but is ineffective after peripheral administration. We have previously shown that our novel lipidized analogs PrRP enhances its stability in the circulation and enables its central effect after peripheral application. The purpose of this study was to explore if sub-chronic administration of novel PrRP analog palmitoylated in position 11 (palm11-PrRP31) to Koletsky-spontaneously hypertensive obese rats (SHROB) could lower body weight and glucose intolerance as well as other metabolic parameters. SUBJECTS/METHODS: The SHROB rats (n = 16) were used for this study and age-matched hypertensive lean SHR littermates (n = 16) served as controls. Palm11-PrRP31 was administered intraperitoneally to SHR and SHROB (n = 8) at a dose of 5 mg/kg once-daily for 3 weeks. During the dosing period food intake and body weight were monitored. At the end of the experiment the oral glucose tolerance test was performed; plasma and tissue samples were collected. Thereafter, arterial blood pressure was measured. RESULTS: At the end of the experiment, vehicle-treated SHROB rats showed typical metabolic syndrome parameters, including obesity, glucose intolerance, dyslipidemia, and hypertension. Peripheral treatment with palm11-PrRP31 progressively decreased the body weight of SHR rats but not SHROB rats, though glucose tolerance was markedly improved in both strains. Moreover, in SHROB palm11-PrRP31 ameliorated the HOMA index, insulin/glucagon ratio, and increased insulin receptor substrate 1 and 2 expression in fat and insulin signaling in the hypothalamus, while it had no effect on blood pressure. CONCLUSIONS: We demonstrated that our new lipidized PrRP analog is capable of improving glucose tolerance in obese SHROB rats after peripheral application, suggesting that its effect on glucose metabolism is independent of leptin signaling and body weight lowering. These data suggest that this analog has the potential to be a compound with both anti-obesity and glucose-lowering properties.
- MeSH
- glukagon krev MeSH
- glukózový toleranční test MeSH
- hormon uvolňující prolaktin aplikace a dávkování analogy a deriváty farmakologie terapeutické užití MeSH
- hypertenze krev farmakoterapie MeSH
- inzulin krev metabolismus MeSH
- inzulinová rezistence MeSH
- krevní glukóza metabolismus MeSH
- krevní tlak účinky léků MeSH
- lipidy krev MeSH
- metabolický syndrom * krev farmakoterapie metabolismus MeSH
- mozek účinky léků metabolismus MeSH
- obezita * krev farmakoterapie MeSH
- porucha glukózové tolerance * krev farmakoterapie MeSH
- potkani inbrední SHR MeSH
- proteiny insulinového receptorového substrátu metabolismus MeSH
- tělesná hmotnost účinky léků MeSH
- tuková tkáň účinky léků metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- glukagon MeSH
- hormon uvolňující prolaktin MeSH
- inzulin MeSH
- krevní glukóza MeSH
- lipidy MeSH
- proteiny insulinového receptorového substrátu MeSH
In our project, ghrelin analogs possessing enhanced stability and potential to significantly increase food intake were used. Three newly synthesized ghrelin analogs with fatty acid residues consisting of 8, 10, and 14 carbon atoms were studied. The main goal of this work was to develop a suitable analytical method for the determination of the stability of the novel ghrelin analogs in plasma. An appropriate liquid chromatography-mass spectrometry method was developed and optimized. The results obtained were compared with the data measured by using a commercial enzyme-linked immunosorbent assay kit, and a good correlation was found. A preparation strategy for plasma samples was optimized and consisted of simple dilution of the plasma samples followed by direct injection onto a very short monolithic column in combination with mass spectrometric detection. The developed analytical method was utilized for the determination of the stability of the prepared lipopeptides in plasma and for the quantification of the lipopeptides in a preliminary pharmacokinetic study. The feasibility of the developed separation method was clearly demonstrated. Accuracy and precision were within 80-120% and ±20% limits, respectively. Calibration curves were constructed in the range of 1-250 μg/mL.
- Klíčová slova
- enzyme-linked immunosorbent assay, ghrelin, lipopeptides, liquid chromatography mass spectrometry, monolithic columns,
- MeSH
- chromatografie kapalinová * MeSH
- ghrelin analogy a deriváty MeSH
- kalibrace MeSH
- lipopeptidy krev MeSH
- reprodukovatelnost výsledků MeSH
- tandemová hmotnostní spektrometrie * MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- ghrelin MeSH
- lipopeptidy MeSH
