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#31909494   2020/01/09 To Up

Hyperthermia-induced seizures produce long-term effects on the functionality of adenosine A receptor in rat cerebral cortex.

Febrile seizures are one of the most frequent childhood neurological disorders; they are classified into simple and prolonged, depending on their duration. Prolonged FS lasts more than 15 min and may evoke neurological sequelae in a process in which molecular alterations seem to play an important role. Adenosine is a purine nucleoside that exerts anticonvulsant effects through binding to adenosine A receptor (A R). This receptor belongs to the GPCR superfamily and is negatively coupled to adenylyl cyclase (AC) activity through Gi proteins. In the present study, we analyzed the functionality of A R, measured as the inhibition of forskolin-stimulated AC activity, 48 hr after hyperthermia-induced seizures (HIS). Surprisingly, the results obtained show that the activation of A R increased forskolin-stimulated cAMP production instead of decreasing it. This alteration was not accompanied by changes in αG protein levels. The functionality of A R remained altered two months after HIS. However, this alteration was abolished when AC assays were carried out in the presence of anti αGs subunit-specific antibody, suggesting that HIS can switch A R coupling from Gi to Gs proteins. Finally, radioligand binding assays revealed that density and affinity of A R were not significantly altered by HIS. In summary, the results obtained show that HIS induces long-term changes in the A R/AC signaling pathway in rat brain cortex.
María Crespo, David Agustín León-Navarro, María Ángeles Ruíz, Mairena Martín

2012 related Products with: Hyperthermia-induced seizures produce long-term effects on the functionality of adenosine A receptor in rat cerebral cortex.

100 μg100 μg100ul100 μg100ul100 μg100 μg100ug10 100ul100ug100ug Lyophilized

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#30822423   2019/02/26 To Up

Caffeine inhibits hypoxia-induced nuclear accumulation in HIF-1α and promotes neonatal neuronal survival.

Apnea of prematurity (AOP) defined as cessation of breathing for 15-20 s, is commonly seen in preterm infants. Caffeine is widely used to treat AOP due to its safety and effectiveness. Caffeine releases respiratory arrest by competing with adenosine for binding to adenosine A and A receptors (AR and AR). Long before its use in treating AOP, caffeine has been used as a psychostimulant in adult brains. However, the effect of caffeine on developing brains remains unclear. We found that AR proteins for caffeine binding were expressed in the brains of neonatal rodents and preterm infants (26-27 weeks). Neonatal AR proteins colocalized with PSD-95, suggesting its synaptic localization. In contrast, our finding on AR expression in neonatal neurons was restricted to the mRNA level as detected by single cell RT/PCR due to the lack of specific AR antibody. Furthermore, caffeine (200 μM) at a dose twice higher than the clinically relevant dose (36-130 μM) had minor or no effects on several basic neuronal functions, such as neurite outgrowth, synapse formation, expression of AR and transcription of CREB-1 and c-Fos, further supporting the safety of caffeine for clinical use. We found that treatment with CoCl (125 μM), a hypoxia mimetic agent, for 24 h triggered neuronal death and nuclear accumulation of HIF-1α in primary neuronal cultures. Subsequent treatment with caffeine at a concentration of 100 μM alleviated CoCl-induced cell death and prevented nuclear accumulation of HIF-1α. Consistently, caffeine treatment in early postnatal life of neonatal mice (P4-P7) also prevented subsequent hypoxia-induced nuclear increase of HIF-1α. Together, our data support the utility of caffeine in alleviating hypoxia-induced damages in developing neurons.
Hsiu-Ling Li, Nahla Zaghloul, Ijaz Ahmed, Anton Omelchenko, Bonnie L Firestein, Hai Huang, Latoya Collins

1446 related Products with: Caffeine inhibits hypoxia-induced nuclear accumulation in HIF-1α and promotes neonatal neuronal survival.

50 ul2ug1 mg50 ul96 assays5ug100 ul 100ul100ug400 ug

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#30679232   2019/01/24 To Up

Therapeutic FGF19 promotes HDL biogenesis and transhepatic cholesterol efflux to prevent atherosclerosis.

Fibroblast growth factor (FGF)19, an endocrine hormone produced in the gut, acts in the liver to control bile acid synthesis. NGM282, an engineered FGF19 analog, is currently in clinical development for treating nonalcoholic steatohepatitis. However, the molecular mechanisms that integrate FGF19 with cholesterol metabolic pathways are incompletely understood. Here, we report that FGF19 and NGM282 promote HDL biogenesis and cholesterol efflux from the liver by selectively modulating LXR signaling while ameliorating hepatic steatosis. We further identify ABCA1 and FGF receptor 4 as mediators of this effect, and that administration of a HMG-CoA reductase inhibitor or a blocking antibody against proprotein convertase subtilisin/kexin type 9 abolished FGF19-associated elevations in total cholesterol, HDL cholesterol (HDL-C), and LDL cholesterol in mice. Moreover, we show that a constitutively active MEK1, but not a constitutively active STAT3, mimics the effect of FGF19 and NGM282 on cholesterol change. In dyslipidemic mice fed a Western diet, treatment with NGM282 dramatically reduced atherosclerotic lesion area in aortas. Administration of NGM282 to healthy volunteers for 7 days resulted in a 26% increase in HDL-C levels compared with placebo. These findings outline a previously unrecognized role for FGF19 in the homeostatic control of cholesterol and may have direct impact on the clinical development of FGF19 analogs.
Mei Zhou, R Marc Learned, Stephen J Rossi, Hui Tian, Alex M DePaoli, Lei Ling

1495 related Products with: Therapeutic FGF19 promotes HDL biogenesis and transhepatic cholesterol efflux to prevent atherosclerosis.

1 mg 1 G1,000 tests1 module200ug 25 G

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#30002135   2018/08/06 To Up

Opposing effects of intracellular versus extracellular adenine nucleotides on autophagy: implications for β-cell function.

AMPK-mTORC1 signaling senses nutrient availability, thereby regulating autophagy. Surprisingly, we found that, in β-cells, the AMPK activator 5-amino-4-imidazolecarboxamide ribofuranoside (AICAR) inhibited, rather than stimulated, autophagy. AICAR is an intermediate in the generation of inosine monophosphate, with subsequent conversion to other purine nucleotides. Adenosine regulated autophagy in a concentration-dependent manner: at high concentrations, it mimicked the AICAR effect on autophagy, whereas at low concentrations it stimulated autophagy through its cognate A receptor. Adenosine regulation of autophagy was independent of AMPK or mTORC1 activity. Adenosine kinase (ADK) is the principal enzyme for metabolic adenosine clearance. ADK knockdown and pharmacological inhibition of the enzyme markedly stimulated autophagy in an adenosine A receptor-dependent manner. High-concentration adenosine increased insulin secretion in a manner sensitive to treatment with the autophagy inducer Tat-beclin1, and inhibition of autophagy augmented secretion. In conclusion, high concentrations of AICAR or adenosine inhibit autophagy, whereas physiological concentrations of adenosine or inhibition of adenosine clearance by ADK stimulate autophagy via the adenosine receptor. Adenosine might thus be an autocrine regulator of autophagy, independent of AMPK-mTORC1 signaling. Adenosine regulates insulin secretion, in part, through modulation of autophagy.
Tal Israeli, Yael Riahi, Ann Saada, Devorah Yefet, Erol Cerasi, Boaz Tirosh, Gil Leibowitz

1390 related Products with: Opposing effects of intracellular versus extracellular adenine nucleotides on autophagy: implications for β-cell function.

50 ml1 kit96 tests10 ml1 kit96 tests 5 lt96 tests

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#28775724   2017/07/20 To Up

Parasites Subvert the Host Inflammatory Response through the Adenosine A2 Receptor to Promote the Establishment of Infection.

Adenosine is an endogenously released purine nucleoside that signals through four widely expressed G protein-coupled receptors: A1, A2, A2, and A3. Of these, AR is recognized as mediating major adenosine anti-inflammatory activity. During cutaneous leishmaniasis, adenosine induces immunosuppression, which promotes the establishment of infection. Herein, we demonstrated that AR signaling is exploited by parasites, the etiologic agent that causes Visceral Leishmaniasis, to successfully colonize the vertebrate host. AR gene-deleted mice exhibited a well-developed cellular reaction with a strong Th1 immune response in the parasitized organs. An intense infiltration of activated neutrophils into the disease-target organs was observed in AR mice. These cells were characterized by high expression of CXCR2 and CD69 on their cell surfaces and increased expression. Interestingly, this phenotype was mediated by IFN-γ on the basis that a neutralizing antibody specific to this cytokine prevented neutrophilic influx into parasitized organs. In evaluating the immunosuppressive effects, we identified a decreased number of CD4 FOXP3 T cells and reduced expression in AR infected mice. During cell culture, AR splenocytes produced smaller amounts of IL-10. In conclusion, we demonstrated that the AR signaling pathway is detrimental to development of Th1-type adaptive immunity and that this pathway could be associated with the regulatory process. In particular, it promotes parasite surveillance.
Mikhael H F Lima, Lais A Sacramento, Gustavo F S Quirino, Marcela D Ferreira, Luciana Benevides, Alynne K M Santana, Fernando Q Cunha, Roque P Almeida, João S Silva, Vanessa Carregaro

2493 related Products with: Parasites Subvert the Host Inflammatory Response through the Adenosine A2 Receptor to Promote the Establishment of Infection.

1100.00 ul50 IU500 Units 100ul

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#27821588   2016/11/07 To Up

Smooth Muscle Cell Proangiogenic Phenotype Induced by Cyclopentenyl Cytosine Promotes Endothelial Cell Proliferation and Migration.

Vascular smooth muscle cells (SMCs) and endothelial cells (ECs) are in close contact with blood vessels. SMC phenotypes can be altered during pathological vascular remodeling. However, how SMC phenotypes affect EC properties remains largely unknown. In this study, we found that PDGF-BB-induced synthetic SMCs suppressed EC proliferation and migration while exhibiting increased expression of anti-angiogenic factors, such as endostatin, and decreased pro-angiogenic factors, including CXC motif ligand 1 (CXCL1). Cyclopentenyl cytosine (CPEC), a CTP synthase inhibitor that has been reported previously to inhibit SMC proliferation and injury-induced neointima formation, induced SMC redifferentiation. Interestingly, CPEC-conditioned SMC culture medium promoted EC proliferation and migration because of an increase in CXCL1 along with decreased endostatin production in SMCs. Addition of recombinant endostatin protein or blockade of CXCL1 with a neutralizing antibody suppressed the EC proliferation and migration induced by CPEC-conditioned SMC medium. Mechanistically, CPEC functions as a cytosine derivate to stimulate adenosine receptors A1 and A2a, which further activate downstream cAMP and Akt signaling, leading to the phosphorylation of cAMP response element binding protein and, consequently, SMC redifferentiation. These data provided proof of a novel concept that synthetic SMC exhibits an anti-angiogenic SMC phenotype, whereas contractile SMC shows a pro-angiogenic phenotype. CPEC appears to be a potent stimulator for switching the anti-angiogenic SMC phenotype to the pro-angiogenic phenotype, which may be essential for CPEC to accelerate re-endothelialization for vascular repair during injury-induced vascular wall remodeling.
Rui Tang, Gui Zhang, Shi-You Chen

2698 related Products with: Smooth Muscle Cell Proangiogenic Phenotype Induced by Cyclopentenyl Cytosine Promotes Endothelial Cell Proliferation and Migration.

1.00 flask0.5 ml1.00 flask100ul1.00 flask0.5 mg1 mg1.00 flask2500 assays

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#27671637   2016/09/26 To Up

Adenosine A1 receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280.

Accumulation of Tau is a characteristic hallmark of several neurodegenerative diseases but the mode of toxic action of Tau is poorly understood. Here, we show that the Tau protein is toxic due to its aggregation propensity, whereas phosphorylation and/or missorting is not sufficient to cause neuronal dysfunction. Aggregate-prone Tau accumulates, when expressed in vitro at near-endogenous levels, in axons as spindle-shaped grains. These axonal grains contain Tau that is folded in a pathological (MC-1) conformation. Proaggregant Tau induces a reduction of neuronal ATP, concomitant with loss of dendritic spines. Counterintuitively, axonal grains of Tau are not targeted for degradation and do not induce a molecular stress response. Proaggregant Tau causes neuronal and astrocytic hypoactivity and presynaptic dysfunction instead. Here, we show that the adenosine A receptor antagonist rolofylline (KW-3902) is alleviating the presynaptic dysfunction and restores neuronal activity as well as dendritic spine levels in vitro. Oral administration of rolofylline for 2-wk to 14-mo-old proaggregant Tau transgenic mice restores the spatial memory deficits and normalizes the basic synaptic transmission. These findings make rolofylline an interesting candidate to combat the hypometabolism and neuronal dysfunction associated with Tau-induced neurodegenerative diseases.
Frank J A Dennissen, Marta Anglada-Huguet, Astrid Sydow, Eckhard Mandelkow, Eva-Maria Mandelkow

1227 related Products with: Adenosine A1 receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280.

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#27566294   2016/08/26 To Up

A2A adenosine receptor upregulation correlates with disease activity in patients with systemic lupus erythematosus.

Adenosine is a purine nucleoside implicated in the regulation of the innate and adaptive immune systems, acting through its interaction with four cell surface receptors: A1, A2A, A2B, and A3. There is intense interest in understanding how adenosine functions in health and during disease, but surprisingly little is known about the actual role of adenosine-mediated mechanisms in systemic lupus erythematosus (SLE). With this background, the aim of the present study was to test the hypothesis that dysregulation of A1, A2A, A2B, and A3 adenosine receptors (ARs) in lymphocytes of patients with SLE may be involved in the pathogenesis of the disease and to examine the correlations between the status of the ARs and the clinical parameters of SLE.
Alessandra Bortoluzzi, Fabrizio Vincenzi, Marcello Govoni, Melissa Padovan, Annalisa Ravani, Pier Andrea Borea, Katia Varani

2362 related Products with: A2A adenosine receptor upregulation correlates with disease activity in patients with systemic lupus erythematosus.

50μl200ul200ul500 tests100ug100 μg100ug48 assays100ul96 tests250 Tests / Kit

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#27339059   2016/06/23 To Up

Presynaptic muscarinic acetylcholine autoreceptors (M1, M2 and M4 subtypes), adenosine receptors (A1 and A2A) and tropomyosin-related kinase B receptor (TrkB) modulate the developmental synapse elimination process at the neuromuscular junction.

The development of the nervous system involves an initially exuberant production of neurons that make an excessive number of synaptic contacts. The initial overproduction of synapses promotes connectivity. Hebbian competition between axons with different activities (the least active are punished) leads to the loss of roughly half of the overproduced elements and this refines connectivity and increases specificity. The neuromuscular junction is innervated by a single axon at the end of the synapse elimination process and, because of its relative simplicity, has long been used as a model for studying the general principles of synapse development. The involvement of the presynaptic muscarinic ACh autoreceptors may allow for the direct competitive interaction between nerve endings through differential activity-dependent acetylcholine release in the synaptic cleft. Then, the most active ending may directly punish the less active ones. Our previous results indicate the existence in the weakest axons on the polyinnervated neonatal NMJ of an ACh release inhibition mechanism based on mAChR coupled to protein kinase C and voltage-dependent calcium channels. We suggest that this mechanism plays a role in the elimination of redundant neonatal synapses.
Laura Nadal, Neus Garcia, Erica Hurtado, Anna Simó, Marta Tomàs, Maria A Lanuza, Manel Santafé, Josep Tomàs

1515 related Products with: Presynaptic muscarinic acetylcholine autoreceptors (M1, M2 and M4 subtypes), adenosine receptors (A1 and A2A) and tropomyosin-related kinase B receptor (TrkB) modulate the developmental synapse elimination process at the neuromuscular junction.

100 mg25 mg100ug50 ug 100ug1000 TESTS/0.65ml100ug100ul100ug 5 G100ug200

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