Citrulline is a non-proteinogenic amino acid that forms as by-product in nitric oxide (NO) synthesis from arginine and may act in concert with NO as an independent signaling molecule that involves in the mechanism of vascular smooth muscle vasodilation. In this study we examined the effects of citrulline on pulmonary artery smooth muscles. Experimental design comprised outward potassium currents measurements in enzymatically isolated rat pulmonary artery smooth muscle (PASMc) cells using whole-cell patch clamp technique, isometric contractile force recordings on rat pulmonary artery rings and method of molecular docking simulation. Citrulline in a concentration 10-9-10-5 M relaxed phenylephrine (PHE)-preactivated SM of rat pulmonary artery in a dose-dependent manner (EC50 0,67 μM). This citrulline-induced relaxation was dependent on an intact endothelium. Bath application of citrulline (10-8-10-5 M) on isolated PASMc induced a significant increase in the amplitude of outward potassium current (Ik). The adenosine antagonist caffeine (10-6 M) effectively blocked both the citrulline-induced relaxation response and Ik increment. Molecular docking modeling suggests that caffeine blocking the potent activity of citrulline results from competitive interactions at the A2 adenosine receptor binding site. In summary, our data suggest that citrulline, released with NO at low concentrations, can effectively interact with adenosine receptors in smooth muscle cells, causing their relaxation, indicating surprising interaction between NO and adenosine pathways.

• MeSH
• arteria pulmonalis účinky léků   metabolismus   MeSH
• citrulin * farmakologie   metabolismus   MeSH
• krysa rodu rattus MeSH
• potkani Wistar MeSH
• purinergní receptory P1 metabolismus   MeSH
• simulace molekulového dockingu * MeSH
• svaly hladké cévní metabolismus   účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Caffeine, a simple purine alkaloid with the proper chemical name 1,3,7-trimethylpurine- 2,6-dione, is an abundant compound present in coffee, food and drugs. It interacts with various pathways of which antagonism of adenosine receptors is the most significant but the other physiological pathways can be influenced by caffeine as well. Interaction with glutamate and dopamine neurotransmission pathways, competition with other substrates on cytochrome P450, non-competitive inhibition of acetylcholinesterase, blocking of nicotinic acetylcholine receptor and competitive inhibition of cyclic nucleotide phosphodiesterase can be mentioned. Because of caffeine availability in foods, beverages and drugs, it has practical relevance even if the effect is weak. Intake of coffee containing edibles for a long period or even for a substantial part of life makes caffeine ́s impact significant. Low acute and chronic toxicity of caffeine is another important specification. The discoveries from the last few years point to the fact that caffeine would interfere with the progression of some age-related neurodegenerative disorders like Alzheimer's and Parkinson's diseases and dementia with Lewy bodies. In this review article, the recent findings about caffeine ́s impact on neurodegenerative diseases are presented and important facts about the caffeine effect, including the substantial discoveries, are described.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• alkaloidy * MeSH
• dopamin MeSH
• fosfodiesterasy metabolismus   MeSH
• glutamáty MeSH
• káva MeSH
• kofein metabolismus   farmakologie   MeSH
• lidé MeSH
• neurodegenerativní nemoci * farmakoterapie   MeSH
• nikotinové receptory * MeSH
• nukleotidy cyklické MeSH
• purinergní receptory P1 metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Multiple sclerosis (MS) is a highly disabling, progressive neurodegenerative disease with no curative treatment available. Although significant progress has been made in understanding how MS develops, there remain aspects of disease pathogenesis that are yet to be fully elucidated. In this regard, studies have shown that dysfunctional adenosinergic signaling plays a pivotal role, as patients with MS have altered levels adenosine (ADO), adenosine receptors and proteins involved in the generation and termination of ADO signaling, such as CD39 and adenosine deaminase (ADA). We have therefore performed a literature review regarding the involvement of the adenosinergic system in the development of MS and propose mechanisms by which the modulation of this system can support drug development and repurposing.

• MeSH
• adenosin imunologie   MeSH
• adenosindeaminasa imunologie   MeSH
• apyrasa imunologie   MeSH
• lidé MeSH
• neurodegenerativní nemoci * etiologie   imunologie   terapie   MeSH
• purinergní receptory P1 * imunologie   MeSH
• roztroušená skleróza * etiologie   imunologie   terapie   MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

A key objective in immuno-oncology is to reactivate the dormant immune system and increase tumour immunogenicity. Adenosine is an omnipresent purine that is formed in response to stress stimuli in order to restore physiological balance, mainly via anti-inflammatory, tissue-protective, and anti-nociceptive mechanisms. Adenosine overproduction occurs in all stages of tumorigenesis, from the initial inflammation/local tissue damage to the precancerous niche and the developed tumour, making the adenosinergic pathway an attractive but challenging therapeutic target. Many current efforts in immuno-oncology are focused on restoring immunosurveillance, largely by blocking adenosine-producing enzymes in the tumour microenvironment (TME) and adenosine receptors on immune cells either alone or combined with chemotherapy and/or immunotherapy. However, the effects of adenosinergic immunotherapy are not restricted to immune cells; other cells in the TME including cancer and stromal cells are also affected. Here we summarise recent advancements in the understanding of the tumour adenosinergic system and highlight the impact of current and prospective immunomodulatory therapies on other cell types within the TME, focusing on adenosine receptors in tumour cells. In addition, we evaluate the structure- and context-related limitations of targeting this pathway and highlight avenues that could possibly be exploited in future adenosinergic therapies.

• MeSH
• adenosin biosyntéza   genetika   imunologie   terapeutické užití   MeSH
• cílená molekulární terapie * MeSH
• imunoterapie trendy   MeSH
• karcinogeneze účinky léků   imunologie   MeSH
• lidé MeSH
• nádorové mikroprostředí účinky léků   imunologie   MeSH
• nádory genetika   imunologie   terapie   MeSH
• purinergní receptory P1 imunologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Aim: We studied the influence of coffee consumption on the therapeutic effect of methotrexate (MTX) in patients with rheumatoid arthritis (RA) sorted according to ADORA2A genotypes. Patients & methods: 82 RA patients were dichotomized according to caffeine intake with a threshold of 700 mg/week. Disease activity score 28 (DAS28) was applied (>3.2: high; <3.2: low or remission). Patients were genotyped using quantitative PCR allelic discrimination. Results: We found significantly higher risk of RA in patients with higher caffeine intake and the CT genotype of ADOARA2A rs2298383, rs3761422 and rs2267076 SNPs. The CC genotype of ADORA2A rs2236624 SNP in patients with lower caffeine intake treated with MTX is significantly protective. Conclusion:ADORA2A genotypes and coffee intake influence risk of RA and efficacy of it MTX treatment.

• MeSH
• adenosin genetika   metabolismus   MeSH
• antirevmatika metabolismus   terapeutické užití   MeSH
• dospělí MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• káva škodlivé účinky   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• methotrexát metabolismus   terapeutické užití   MeSH
• průřezové studie MeSH
• receptor adenosinový A2A genetika   MeSH
• revmatoidní artritida farmakoterapie   genetika   metabolismus   MeSH
• signální transdukce účinky léků   fyziologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Although the modulation of host physiology has been interpreted as an essential process supporting baculovirus propagation, the requirement of energy supply for host antivirus reactions could not be ruled out. Our present study showed that metabolic induction upon AcMNPV (budded virus) infection of Bombyx mori stimulated virus clearance and production of the antivirus protein, gloverin. In addition, we demonstrated that adenosine receptor signaling (AdoR) played an important role in regulating such metabolic reprogramming upon baculovirus infection. By using a second lepidopteran model, Spodoptera frugiperda Sf-21 cells, we demonstrated that the glycolytic induction regulated by adenosine signaling was a conservative mechanism modulating the permissiveness of baculovirus infection. Another interesting finding in our present study is that both BmNPV and AcMNPV infection cause metabolic activation, but it appears that BmNPV infection moderates the level of ATP production, which is in contrast to a dramatic increase upon AcMNPV infection. We identified potential AdoR miRNAs induced by BmNPV infection and concluded that BmNPV may attempt to minimize metabolic activation by suppressing adenosine signaling and further decreasing the host's anti-baculovirus response. Our present study shows that activation of energy synthesis by adenosine signaling upon baculovirus infection is a host physiological response that is essential for supporting the innate immune response against infection.

• MeSH
• adenosin metabolismus   MeSH
• adenosintrifosfát biosyntéza   MeSH
• bourec metabolismus   virologie   MeSH
• deoxyglukosa farmakologie   MeSH
• energetický metabolismus MeSH
• glykolýza účinky léků   genetika   MeSH
• hmyzí proteiny metabolismus   MeSH
• infekce DNA virem metabolismus   virologie   MeSH
• interakce hostitele a patogenu imunologie   MeSH
• mezibuněčné signální peptidy a proteiny metabolismus   MeSH
• nukleopolyhedroviry fyziologie   MeSH
• purinergní receptory P1 genetika   metabolismus   MeSH
• replikace viru účinky léků   MeSH
• Sf9 buňky MeSH
• Spodoptera MeSH
• transfekce MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Epilepsy is a multifactorial disorder associated with neuronal hyperexcitability that affects more than 1% of the human population. It has long been known that adenosine can reduce seizure generation in animal models of epilepsies. However, in addition to various side effects, the instability of adenosine has precluded its use as an anticonvulsant treatment. Here we report that a stable analogue of diadenosine-tetraphosphate: AppCH2ppA effectively suppresses spontaneous epileptiform activity in vitro and in vivo in a Tuberous Sclerosis Complex (TSC) mouse model (Tsc1+/-), and in postsurgery cortical samples from TSC human patients. These effects are mediated by enhanced adenosine signaling in the cortex post local neuronal adenosine release. The released adenosine induces A1 receptor-dependent activation of potassium channels thereby reducing neuronal excitability, temporal summation, and hypersynchronicity. AppCH2ppA does not cause any disturbances of the main vital autonomous functions of Tsc1+/- mice in vivo. Therefore, we propose this compound to be a potent new candidate for adenosine-related treatment strategies to suppress intractable epilepsies.

• MeSH
• adenosin fyziologie   MeSH
• antikonvulziva aplikace a dávkování   MeSH
• dinukleosidfosfáty aplikace a dávkování   MeSH
• draslíkové kanály fyziologie   MeSH
• hamartin genetika   MeSH
• lidé MeSH
• membránové potenciály účinky léků   MeSH
• myši transgenní MeSH
• myši MeSH
• neokortex účinky léků   patofyziologie   MeSH
• neurony účinky léků   fyziologie   MeSH
• receptor adenosinový A1 fyziologie   MeSH
• signální transdukce účinky léků   MeSH
• záchvaty patofyziologie   prevence a kontrola   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

G protein-coupled receptors (GPCRs) control cellular signaling and responses. Many of these GPCRs are modulated by cholesterol and polyunsaturated fatty acids (PUFAs) which have been shown to co-exist with saturated lipids in ordered membrane domains. However, the lipid compositions of such domains extracted from the brain cortex tissue of individuals suffering from GPCR-associated neurological disorders show drastically lowered levels of PUFAs. Here, using free energy techniques and multiscale simulations of numerous membrane proteins, we show that the presence of the PUFA DHA helps helical multi-pass proteins such as GPCRs partition into ordered membrane domains. The mechanism is based on hybrid lipids, whose PUFA chains coat the rough protein surface, while the saturated chains face the raft environment, thus minimizing perturbations therein. Our findings suggest that the reduction of GPCR partitioning to their native ordered environments due to PUFA depletion might affect the function of these receptors in numerous neurodegenerative diseases, where the membrane PUFA levels in the brain are decreased. We hope that this work inspires experimental studies on the connection between membrane PUFA levels and GPCR signaling.

• MeSH
• cholesterol metabolismus   MeSH
• konformace proteinů MeSH
• kyseliny dokosahexaenové chemie   metabolismus   MeSH
• lidé MeSH
• membránové mikrodomény chemie   metabolismus   MeSH
• membránové proteiny chemie   metabolismus   MeSH
• modely neurologické MeSH
• molekulární modely MeSH
• mozek metabolismus   MeSH
• nenasycené mastné kyseliny metabolismus   MeSH
• nervové receptory chemie   metabolismus   MeSH
• počítačová simulace MeSH
• receptor adenosinový A2A chemie   metabolismus   MeSH
• receptory spřažené s G-proteiny chemie   metabolismus   MeSH
• signální transdukce MeSH
• termodynamika MeSH
• výpočetní biologie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Prenatal exposure to caffeine can cause developmental problems. This study determined chronic influence of prenatal caffeine at relatively higher doses on cognitive functions in the rat offspring. Pregnant Sprague-Dawley rats (4-month-old) were exposed to caffeine (20 mg/kg, twice a day) for whole pregnancy from gestational day 4. Fetal and offspring body and brain weight was measured. Learning and memory were tested in adult offspring with Morris water maze. Learning and memory-related receptors were measured. The exposure to prenatal caffeine not only caused fetal growth restriction, but also showed long-term effects on learning and memory in the offspring. The caffeine offspring exhibited longer escape latency and path length in navigation testing. The number of passing the target was significantly reduced in those offspring. The expression of adenosine A(1) and A(2A) receptors, nuclear PKA C(alpha), C(beta) subunits, and pCREB were significantly increased in the fetal and neonatal brain, and suppressed in the hippocampus of the adult offspring. The expression of BDNF and TrkB were reduced regardless of various ages. The results suggest that intrauterine programming dysfunction of adenosine receptors and the down-stream of cAMP/PKA/pCREB system may play an important role in prenatal caffeine induced cognition disorders in the adult offspring.

• MeSH
• bludiště - učení účinky léků   fyziologie   MeSH
• kofein toxicita   MeSH
• krysa rodu rattus MeSH
• mozkový neurotrofický faktor metabolismus   MeSH
• paměť účinky léků   fyziologie   MeSH
• poruchy paměti chemicky indukované   diagnóza   metabolismus   MeSH
• potkani Sprague-Dawley MeSH
• protein vázající element responzivní pro cyklický AMP metabolismus   MeSH
• proteinkinasy závislé na cyklickém AMP metabolismus   MeSH
• purinergní receptory P1 metabolismus   MeSH
• signální transdukce účinky léků   fyziologie   MeSH
• těhotenství MeSH
• zpožděný efekt prenatální expozice chemicky indukované   diagnóza   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVE: The treatment of rheumatoid arthritis (RA) patients with methotrexate (MTX) is linked to the development or progression of rheumatoid nodules. The aim of this study was to determine whether folate and adenosine pathways-related single nucleotide polymorphisms might be predictive of increased nodule formation in RA patients treated with oral MTX. METHODS: A total of 185 Caucasian RA patients were enrolled in this cross-sectional study, all of whom fulfilled the 1987 RA criteria of the American College of Rheumatology; each patient had a history of MTX treatment. RESULTS: A higher frequency of the MTHFR 1298AA genotype was found in 17 (70.8%) of 24 patients with general nodules [odds ratio (OR)=3.08, 95% confidence interval (CI): 1.20-7.69] and in 14 (73.7%) of 19 patients who developed nodules during MTX treatment (OR=3.55, 95% CI: 1.22-10.32). In contrast, a negative association with nodules during MTX treatment (OR=0.29, 95% CI: 0.08-1.10) was found for 19 (79.2%) patients with the TT genotype (rs2298383) in the adenosine A2a receptor gene (ADORA2A). However, the significance did not remain upon correction for multiple testing. The combination of MTHFR 1298AA along with ADORA2A rs2298383 CC or CT genotypes occurring in one-third of RA patients showed a higher frequency of general nodules 15/59 (25.4%) as well as developing nodules during MTX treatment 13/59 (22.0%) in comparison with the overall studied group: 24/185 (13.0%) and 19/185 (10.3%), respectively. CONCLUSION: This exploratory study indicates for the first time a plausible association of adenosine and folate pathways single nucleotide polymorphisms in nodules' etiopathogenesis.

• MeSH
• antirevmatika aplikace a dávkování   škodlivé účinky   MeSH
• dospělí MeSH
• genetická predispozice k nemoci MeSH
• genetické asociační studie MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé středního věku MeSH
• lidé MeSH
• methotrexát aplikace a dávkování   škodlivé účinky   MeSH
• methylentetrahydrofolátreduktasa (NADPH2) genetika   MeSH
• průřezové studie MeSH
• receptor adenosinový A2A genetika   MeSH
• revmatoidní artritida farmakoterapie   MeSH
• revmatoidní uzlíky chemicky indukované   genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH