Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 5 de 5
Filter
Add more filters










Database
Language
Publication year range
1.
Food Chem Toxicol ; 163: 112911, 2022 May.
Article in English | MEDLINE | ID: mdl-35292334

ABSTRACT

Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the USA. The short therapeutic window of the current antidote, N-acetylcysteine (NAC) highlights the need for novel late acting therapeutics. The neuronal guidance cue netrin-1 provides delayed protection against APAP hepatotoxicity through the adenosine A2B receptor (A2BAR). The clinical relevance of this mechanism was investigated here by administration of the A2BAR agonist BAY 60-6583, after an APAP overdose (300 or 600 mg/kg) in fasted male and female C57BL/6J mice with assessment of liver injury 6 or 24 h after APAP in comparison to NAC. BAY 60-6583 treatment 1.5 h after APAP overdose (600 mg/kg) protected against liver injury at 6 h by preserving mitochondrial function despite JNK activation and its mitochondrial translocation. Gender independent protection was sustained when BAY 60-6583 was given 6 h after APAP overdose (300 mg/kg), when NAC administration did not show benefit. This protection was accompanied by enhanced infiltration of macrophages with the reparative anti-inflammatory phenotype by 24 h, accompanied by a decrease in neutrophil infiltration. Thus, our data emphasize the remarkable therapeutic utility of using an A2BAR agonist, which provides delayed protection long after the standard of care NAC ceased to be effective.


Subject(s)
Chemical and Drug Induced Liver Injury , Drug Overdose , Acetaminophen/toxicity , Acetylcysteine/pharmacology , Animals , Chemical and Drug Induced Liver Injury/drug therapy , Chemical and Drug Induced Liver Injury/prevention & control , Drug Overdose/drug therapy , Female , Liver , Male , Mice , Mice, Inbred C57BL , Receptor, Adenosine A2B/therapeutic use
2.
Toxicol Lett ; 359: 84-95, 2022 Apr 15.
Article in English | MEDLINE | ID: mdl-35143882

ABSTRACT

Alcoholic hepatitis is a serious form of liver damage. Inflammation is a key factor in alcoholic hepatitis and plays a key role in the progression of alcoholic liver disease. Adenosine receptor A2B (A2BAR) is a member of the adenosine receptor family and generally considered to be a negative regulator of the inflammatory response. We found that A2BAR was the most highly expressed adenosine receptor in ETOH-fed mouse liver tissue and was also highly expressed in primary Kupffer cells and ETOH-induced RAW264.7 cells. In addition, injection of BAY 60-6583 stimulated A2BAR, induced upregulation of the expression levels of cAMP, and reduced ETOH-induced steatosis and inflammation in mice. At the same time, knockdown of A2BAR in vitro increased the inflammatory response in RAW264.7 cells triggered by ETOH. After knockdown of A2BAR in vitro, the release of the inflammatory cytokines IL-6, IL-1ß and TNF-α was increased. After overexpression of A2BAR in vitro, the cAMP level was significantly increased, PKA expression was increased, the expression of phosphorylated proteins in the NF-kB signal transduction pathway was significantly affected, and the expression of the key phosphorylated protein p-P65 was decreased. However, after the simultaneous overexpression of A2BAR and inhibition of PKA, the expression of the key phosphorylated protein p-P65 was still significantly decreased. In addition, after the expression of A2BAR increased or decreased in RAW264.7 cells, AML-12 cells were cultured in the supernatant of RAW264.7 cells stimulated by ETOH, and the apoptosis rate was significantly changed by flow cytometry. These results suggest that A2BAR can reduce alcoholic steatohepatitis by upregulating cAMP levels and negatively regulating the NF-kB pathway. Overall, these findings suggest the significance of A2BAR-mediated inflammation in alcoholic liver disease.


Subject(s)
Hepatitis, Alcoholic/drug therapy , Kupffer Cells/drug effects , NF-kappa B/drug effects , NF-kappa B/metabolism , Receptor, Adenosine A2B/therapeutic use , Receptors, Cyclic AMP/drug effects , Receptors, Cyclic AMP/metabolism , Animals , Disease Models, Animal , Female , Humans , Mice , Mice, Inbred C57BL
3.
J Neuroinflammation ; 9: 198, 2012 Aug 16.
Article in English | MEDLINE | ID: mdl-22894638

ABSTRACT

BACKGROUND: Neuroprotective and neurotrophic properties of leukemia inhibitory factor (LIF) have been widely reported. In the central nervous system (CNS), astrocytes are the major source for LIF, expression of which is enhanced following disturbances leading to neuronal damage. How astrocytic LIF expression is regulated, however, has remained an unanswered question. Since neuronal stress is associated with production of extracellular adenosine, we investigated whether LIF expression in astrocytes was mediated through adenosine receptor signaling. METHODS: Mouse cortical neuronal and astrocyte cultures from wild-type and adenosine A(2B) receptor knock-out animals, as well as adenosine receptor agonists/antagonists and various enzymatic inhibitors, were used to study LIF expression and release in astrocytes. When needed, a one-way analysis of variance (ANOVA) followed by Bonferroni post-hoc test was used for statistical analysis. RESULTS: We show here that glutamate-stressed cortical neurons induce LIF expression through activation of adenosine A(2B) receptor subtype in cultured astrocytes and require signaling of protein kinase C (PKC), mitogen-activated protein kinases (MAPKs: p38 and ERK1/2), and the nuclear transcription factor (NF)-κB. Moreover, LIF concentration in the supernatant in response to 5'-N-ethylcarboxamide (NECA) stimulation was directly correlated to de novo protein synthesis, suggesting that LIF release did not occur through a regulated release pathway. Immunocytochemistry experiments show that LIF-containing vesicles co-localize with clathrin and Rab11, but not with pHogrin, Chromogranin (Cg)A and CgB, suggesting that LIF might be secreted through recycling endosomes. We further show that pre-treatment with supernatants from NECA-treated astrocytes increased survival of cultured cortical neurons against glutamate, which was absent when the supernatants were pre-treated with an anti-LIF neutralizing antibody. CONCLUSIONS: Adenosine from glutamate-stressed neurons induces rapid LIF release in astrocytes. This rapid release of LIF promotes the survival of cortical neurons against excitotoxicity.


Subject(s)
Astrocytes/metabolism , Cerebral Cortex/metabolism , Excitatory Amino Acid Agents/toxicity , Leukemia Inhibitory Factor/metabolism , Neurons/metabolism , Receptor, Adenosine A2B/physiology , Animals , Cells, Cultured , Glutamic Acid/toxicity , Mice , Mice, Inbred C57BL , Mice, Knockout , Neuroprotective Agents/metabolism , Receptor, Adenosine A2B/therapeutic use
4.
Curr Top Med Chem ; 10(9): 923-40, 2010.
Article in English | MEDLINE | ID: mdl-20370659

ABSTRACT

A(2B) adenosine receptors have been investigated in recent years as potential target for the treatment of different pathologies. The involvement of this receptor in processes such as interleukins secretion, Ca(2+) mobilization, hepatic glucose regulation, tumor vascularisation, and cardioprotection have stimulated many researchers to develop specific agonists and antagonists. For many years, the lack of potent and selective A(2B) ligands precluded a deep exploration of their therapeutic prospective; at present, much progress in the field of antagonists led to preclinical studies for different compounds. Less populated is the universe of A(2B) agonists, but really promising for the involvement in ischemic preconditioning. A summary of the most significant advancements in the synthesis of new compounds and of the principal structure activity relationships is reported. The xanthine-based A(2B) antagonists currently show the better profile of affinity and selectivity, as CVT-6883 (CVT-Therapeutics: K(i(A2B))=22 nM, and selectivity higher than 50-fold over other subtypes), MRE-2029-F20 (Baraldi's group: K(i(A2B))=5.5 nM, selectivity >180 fold), LAS38096 (Almirall Prodesfarma: K(i(A2B))=17 nM, selectivity >60 fold), OSIP339391 (OSI Pharmaceuticals: K(i(A2B))=0.5 nM, selectivity >80 fold), PSB601 (Bonn University: K(i(A2B))=3.6 nM, selectivity >140 fold) and the deazaxanthine 32 of Carotti's group (K(i(A2B))=11 nM, selectivity >90 fold). Other recently emerging scaffolds with promising biological profiles are described. With regard to the agonists, many research groups are involved in the discovery of useful agonist radioligands, but the only example of potent and rather selective A(2B) agonists are compound 65, recently synthesized, and BAY-60-6583, that is under preclinical phase investigation.


Subject(s)
Receptor, Adenosine A2B/drug effects , Drug Design , Humans , Ligands , Protein Binding , Quantitative Structure-Activity Relationship , Receptor, Adenosine A2B/chemistry , Receptor, Adenosine A2B/therapeutic use
5.
Basic Res Cardiol ; 105(1): 129-37, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19730798

ABSTRACT

The mixed A1/A2a-adenosine agonist AMP579 given at reperfusion is protective in animal models of myocardial infarction. Receptor-blocking studies have indicated that the protection came from an adenosine receptor (AR), but neither A1- nor A2a-selective agonists could duplicate its protection. We recently found that A2b-selective agonists given at reperfusion are protective, and, therefore, tested whether AMP579 might also be an A2b agonist. We used human embryonic kidney cells overexpressing human A2b receptors as an assay system. In these cells, A2b receptor occupancy causes phosphorylation of ERK. AMP579 induced ERK phosphorylation with an EC50 of 250 nM and this phosphorylation could be blocked by MRS1754 or PSB1115, two highly selective blockers of human A2b receptors. We attempted to confirm our A2b hypothesis in a rabbit heart model of ischemia-reperfusion. AMP579 (500 nM) for 1 h starting at reperfusion reduced infarct size in isolated rabbit hearts exposed to 30 min of regional ischemia and 2 h of reperfusion (12.9 +/- 2.2% infarction of risk zone vs. 32.0 +/- 1.9% in untreated hearts). PSB1115 (500 nM) given for the first 15 min of reperfusion blocked AMP579's protection (32.2 +/- 3.1% infarction) which is consistent with an A2b mechanism. We conclude that AMP579 is a non-selective, but potent A2b-AR agonist, and that its protection against infarction is through that receptor.


Subject(s)
Adenosine A2 Receptor Agonists , Imidazoles/pharmacology , Myocardial Infarction/prevention & control , Myocardial Reperfusion Injury/prevention & control , Pyridines/pharmacology , Animals , Cell Line , Female , Hemodynamics , Humans , Imidazoles/therapeutic use , In Vitro Techniques , Male , Myocardial Infarction/pathology , Myocardial Infarction/physiopathology , Myocardial Reperfusion Injury/pathology , Myocardial Reperfusion Injury/physiopathology , Myocardium/pathology , Pyridines/therapeutic use , Rabbits , Receptor, Adenosine A2B/therapeutic use
SELECTION OF CITATIONS
SEARCH DETAIL
...