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Mahmoud M. El-mas – One of the best experts on this subject based on the ideXlab platform.

  • Oestrogen compromises the facilitatory effect of chronic nicotine on Adenosine A2B Receptor-K(+) channel-mediated renal vasodilation.
    Clinical and experimental pharmacology & physiology, 2014
    Co-Authors: Mahmoud M. El-mas, Sahar M. El-gowilly, Lamia K. Elsalakawy, Hanan M. El-gowelli
    Abstract:

    We have shown previously that the renal vasodilatory action of the Adenosine analogue 5′-N-ethylcarboxamidoAdenosine (NECA) in female rats is mediated via preferential activation of Adenosine A2B Receptor (A2B R)-K(+) channel signalling. In the present study, we tested the hypothesis that the renal vasodilatory effect of NECA and its A2B R/K(+) channel specificities are altered by chronic nicotine administration. The oestrogenic modulation of the nicotine-NECA renovascular interaction was also evaluated by determining the effect of ovariectomy (OVX) and oestrogen replacement (OVXE2) on the evoked responses. In isolated phenylephrine-preconstricted perfused kidneys obtained from sham-operated rats, vasodilation in response to cumulative bolus injections of NECA (1.6-50 nmol) or papaverine (1-243 nmol) were not affected by nicotine (1-8 mg/kg per day, i.p., 2 weeks). However, vasodilator responses to NECA, but not papaverine, were reduced in kidneys of OVX rats and restored to near-sham values after E2 replacement. Further, nicotine increased NECA-induced vasodilation in perfused kidneys from OVX rats, but failed to do so in OVXE2 preparations. The enhanced NECA responsiveness in nicotine-treated OVX preparations was abolished after infusion (into isolated kidneys) of 10 μmol/L alloxazine (A2B R antagonist) or BaCl2 plus glibenclamide (blockers of inward rectifier and ATP-sensitive K(+) channels, respectively). Vasodilator responses to 0.05-1.6 μmol minoxidil (a K(+) channel opener) were increased by nicotine in OVX, but not OVXE2, preparations and this increase was abolished after infusion of BaCl2  + glibenclamide. Together, the data suggest that chronic nicotine enhances A2B R/K(+) channel-mediated renal vasodilation in oestrogen-depleted rats.

  • Nitric oxide synthase/K+ channel cascade triggers the Adenosine A2B Receptor-sensitive renal vasodilation in female rats
    European Journal of Pharmacology, 2013
    Co-Authors: Hanan M. El-gowelli, Sahar M. El-gowilly, Lamia K. Elsalakawy, Mahmoud M. El-mas
    Abstract:

    Abstract Adenosine A2BReceptors mediate the Adenosine-evoked renal vasodilations in male rats. Here, we tested whether this finding could be replicated in female renal vasculature and whether K+ hyperpolarization induced by nitric oxide synthase (NOS) and/or heme oxygenase (HO) accounts for Adenosine A2B Receptor-sensitive renal vasodilations. In phenylephrine-preconstricted perfused kidneys, vasodilations caused by the Adenosine analog 5′-N-ethylcarboxamidoAdenosine (NECA, 1.6–50 nmol) were attenuated after blockade of Adenosine A2B (alloxazine) but not A2A [8-(3-Chlorostyryl) caffeine, CSC] or A3 Receptors (N-(2-methoxyphenyl)-N′-[2-(3-pyridinyl)-4-quinazolinyl]-urea, VUF 5574), confirming the preferential involvement of A2B Receptors in NECA responses. NOS activation mediated the A2B Receptor-mediated NECA response because: (i) NOS inhibition (Nω-nitro- l -arginine-methyl ester, l -NAME) attenuated NECA vasodilations, (ii) concurrent l -NAME/alloxazine exposure caused more inhibition of NECA responses, and (iii) inhibition of NECA responses by alloxazine disappeared in l -arginine-supplemented preparations. Although HO inhibition (zinc protoporphyrin) failed to modify NECA responses, the attenuation of these responses by alloxazine disappeared in hemin (HO inducer)-treated preparations. NECA vasodilations were also attenuated after exposure to BaCl2, glibenclamide but not tetraethylammonium (blockers of inward rectifier, ATP-sensitive, and Ca2+-dependent K+-channels, respectively). The combined alloxazine/BaCl2/glibenclamide infusion caused no additional attenuation of NECA vasodilations. Vasodilations caused by minoxidil (K+-channel opener) were reduced by l -NAME or BaCl2/glibenclamide, supporting the importance of NOS signaling in K+ hyperpolarization. NECA or minoxidil vasodilations were attenuated by ouabain, Na+/K+-ATPase inhibitor, and in KCl-preconstricted preparations. Overall, facilitation of Adenosine A2B Receptor/NOS/K+ channel/Na+/K+-ATPase cascade underlies NECA vasodilations in female rats. Enhancing HO activity, albeit not causally related to NECA vasodilations, improves the pharmacologically compromised (alloxazine) NECA response.

  • Nitric oxide synthase/K+ channel cascade triggers the Adenosine A(2B) Receptor-sensitive renal vasodilation in female rats.
    European journal of pharmacology, 2013
    Co-Authors: Hanan M. El-gowelli, Sahar M. El-gowilly, Lamia K. Elsalakawy, Mahmoud M. El-mas
    Abstract:

    Adenosine A2BReceptors mediate the Adenosine-evoked renal vasodilations in male rats. Here, we tested whether this finding could be replicated in female renal vasculature and whether K(+) hyperpolarization induced by nitric oxide synthase (NOS) and/or heme oxygenase (HO) accounts for Adenosine A2B Receptor-sensitive renal vasodilations. In phenylephrine-preconstricted perfused kidneys, vasodilations caused by the Adenosine analog 5′-N-ethylcarboxamidoAdenosine (NECA, 1.6-50 nmol) were attenuated after blockade of Adenosine A2B (alloxazine) but not A2A [8-(3-Chlorostyryl) caffeine, CSC] or A3 Receptors (N-(2-methoxyphenyl)-N’-[2-(3-pyridinyl)-4-quinazolinyl]-urea, VUF 5574), confirming the preferential involvement of A2B Receptors in NECA responses. NOS activation mediated the A2B Receptor-mediated NECA response because: (i) NOS inhibition (N(ω)-nitro-L-arginine-methyl ester, L-NAME) attenuated NECA vasodilations, (ii) concurrent L-NAME/alloxazine exposure caused more inhibition of NECA responses, and (iii) inhibition of NECA responses by alloxazine disappeared in L-arginine-supplemented preparations. Although HO inhibition (zinc protoporphyrin) failed to modify NECA responses, the attenuation of these responses by alloxazine disappeared in hemin (HO inducer)-treated preparations. NECA vasodilations were also attenuated after exposure to BaCl2, glibenclamide but not tetraethylammonium (blockers of inward rectifier, ATP-sensitive, and Ca(2+)-dependent K(+)-channels, respectively). The combined alloxazine/BaCl2/glibenclamide infusion caused no additional attenuation of NECA vasodilations. Vasodilations caused by minoxidil (K(+)-channel opener) were reduced by L-NAME or BaCl2/glibenclamide, supporting the importance of NOS signaling in K(+) hyperpolarization. NECA or minoxidil vasodilations were attenuated by ouabain, Na(+)/K(+)-ATPase inhibitor, and in KCl-preconstricted preparations. Overall, facilitation of Adenosine A2B Receptor/NOS/K(+) channel/Na(+)/K(+)-ATPase cascade underlies NECA vasodilations in female rats. Enhancing HO activity, albeit not causally related to NECA vasodilations, improves the pharmacologically compromised (alloxazine) NECA response.

Hanan M. El-gowelli – One of the best experts on this subject based on the ideXlab platform.

  • Oestrogen compromises the facilitatory effect of chronic nicotine on Adenosine A2B Receptor-K(+) channel-mediated renal vasodilation.
    Clinical and experimental pharmacology & physiology, 2014
    Co-Authors: Mahmoud M. El-mas, Sahar M. El-gowilly, Lamia K. Elsalakawy, Hanan M. El-gowelli
    Abstract:

    We have shown previously that the renal vasodilatory action of the Adenosine analogue 5′-N-ethylcarboxamidoAdenosine (NECA) in female rats is mediated via preferential activation of Adenosine A2B Receptor (A2B R)-K(+) channel signalling. In the present study, we tested the hypothesis that the renal vasodilatory effect of NECA and its A2B R/K(+) channel specificities are altered by chronic nicotine administration. The oestrogenic modulation of the nicotine-NECA renovascular interaction was also evaluated by determining the effect of ovariectomy (OVX) and oestrogen replacement (OVXE2) on the evoked responses. In isolated phenylephrine-preconstricted perfused kidneys obtained from sham-operated rats, vasodilation in response to cumulative bolus injections of NECA (1.6-50 nmol) or papaverine (1-243 nmol) were not affected by nicotine (1-8 mg/kg per day, i.p., 2 weeks). However, vasodilator responses to NECA, but not papaverine, were reduced in kidneys of OVX rats and restored to near-sham values after E2 replacement. Further, nicotine increased NECA-induced vasodilation in perfused kidneys from OVX rats, but failed to do so in OVXE2 preparations. The enhanced NECA responsiveness in nicotine-treated OVX preparations was abolished after infusion (into isolated kidneys) of 10 μmol/L alloxazine (A2B R antagonist) or BaCl2 plus glibenclamide (blockers of inward rectifier and ATP-sensitive K(+) channels, respectively). Vasodilator responses to 0.05-1.6 μmol minoxidil (a K(+) channel opener) were increased by nicotine in OVX, but not OVXE2, preparations and this increase was abolished after infusion of BaCl2  + glibenclamide. Together, the data suggest that chronic nicotine enhances A2B R/K(+) channel-mediated renal vasodilation in oestrogen-depleted rats.

  • Nitric oxide synthase/K+ channel cascade triggers the Adenosine A2B Receptor-sensitive renal vasodilation in female rats
    European Journal of Pharmacology, 2013
    Co-Authors: Hanan M. El-gowelli, Sahar M. El-gowilly, Lamia K. Elsalakawy, Mahmoud M. El-mas
    Abstract:

    Abstract Adenosine A2BReceptors mediate the Adenosine-evoked renal vasodilations in male rats. Here, we tested whether this finding could be replicated in female renal vasculature and whether K+ hyperpolarization induced by nitric oxide synthase (NOS) and/or heme oxygenase (HO) accounts for Adenosine A2B Receptor-sensitive renal vasodilations. In phenylephrine-preconstricted perfused kidneys, vasodilations caused by the Adenosine analog 5′-N-ethylcarboxamidoAdenosine (NECA, 1.6–50 nmol) were attenuated after blockade of Adenosine A2B (alloxazine) but not A2A [8-(3-Chlorostyryl) caffeine, CSC] or A3 Receptors (N-(2-methoxyphenyl)-N′-[2-(3-pyridinyl)-4-quinazolinyl]-urea, VUF 5574), confirming the preferential involvement of A2B Receptors in NECA responses. NOS activation mediated the A2B Receptor-mediated NECA response because: (i) NOS inhibition (Nω-nitro- l -arginine-methyl ester, l -NAME) attenuated NECA vasodilations, (ii) concurrent l -NAME/alloxazine exposure caused more inhibition of NECA responses, and (iii) inhibition of NECA responses by alloxazine disappeared in l -arginine-supplemented preparations. Although HO inhibition (zinc protoporphyrin) failed to modify NECA responses, the attenuation of these responses by alloxazine disappeared in hemin (HO inducer)-treated preparations. NECA vasodilations were also attenuated after exposure to BaCl2, glibenclamide but not tetraethylammonium (blockers of inward rectifier, ATP-sensitive, and Ca2+-dependent K+-channels, respectively). The combined alloxazine/BaCl2/glibenclamide infusion caused no additional attenuation of NECA vasodilations. Vasodilations caused by minoxidil (K+-channel opener) were reduced by l -NAME or BaCl2/glibenclamide, supporting the importance of NOS signaling in K+ hyperpolarization. NECA or minoxidil vasodilations were attenuated by ouabain, Na+/K+-ATPase inhibitor, and in KCl-preconstricted preparations. Overall, facilitation of Adenosine A2B Receptor/NOS/K+ channel/Na+/K+-ATPase cascade underlies NECA vasodilations in female rats. Enhancing HO activity, albeit not causally related to NECA vasodilations, improves the pharmacologically compromised (alloxazine) NECA response.

  • Nitric oxide synthase/K+ channel cascade triggers the Adenosine A(2B) Receptor-sensitive renal vasodilation in female rats.
    European journal of pharmacology, 2013
    Co-Authors: Hanan M. El-gowelli, Sahar M. El-gowilly, Lamia K. Elsalakawy, Mahmoud M. El-mas
    Abstract:

    Adenosine A2BReceptors mediate the Adenosine-evoked renal vasodilations in male rats. Here, we tested whether this finding could be replicated in female renal vasculature and whether K(+) hyperpolarization induced by nitric oxide synthase (NOS) and/or heme oxygenase (HO) accounts for Adenosine A2B Receptor-sensitive renal vasodilations. In phenylephrine-preconstricted perfused kidneys, vasodilations caused by the Adenosine analog 5′-N-ethylcarboxamidoAdenosine (NECA, 1.6-50 nmol) were attenuated after blockade of Adenosine A2B (alloxazine) but not A2A [8-(3-Chlorostyryl) caffeine, CSC] or A3 Receptors (N-(2-methoxyphenyl)-N’-[2-(3-pyridinyl)-4-quinazolinyl]-urea, VUF 5574), confirming the preferential involvement of A2B Receptors in NECA responses. NOS activation mediated the A2B Receptor-mediated NECA response because: (i) NOS inhibition (N(ω)-nitro-L-arginine-methyl ester, L-NAME) attenuated NECA vasodilations, (ii) concurrent L-NAME/alloxazine exposure caused more inhibition of NECA responses, and (iii) inhibition of NECA responses by alloxazine disappeared in L-arginine-supplemented preparations. Although HO inhibition (zinc protoporphyrin) failed to modify NECA responses, the attenuation of these responses by alloxazine disappeared in hemin (HO inducer)-treated preparations. NECA vasodilations were also attenuated after exposure to BaCl2, glibenclamide but not tetraethylammonium (blockers of inward rectifier, ATP-sensitive, and Ca(2+)-dependent K(+)-channels, respectively). The combined alloxazine/BaCl2/glibenclamide infusion caused no additional attenuation of NECA vasodilations. Vasodilations caused by minoxidil (K(+)-channel opener) were reduced by L-NAME or BaCl2/glibenclamide, supporting the importance of NOS signaling in K(+) hyperpolarization. NECA or minoxidil vasodilations were attenuated by ouabain, Na(+)/K(+)-ATPase inhibitor, and in KCl-preconstricted preparations. Overall, facilitation of Adenosine A2B Receptor/NOS/K(+) channel/Na(+)/K(+)-ATPase cascade underlies NECA vasodilations in female rats. Enhancing HO activity, albeit not causally related to NECA vasodilations, improves the pharmacologically compromised (alloxazine) NECA response.

Christa E. Müller – One of the best experts on this subject based on the ideXlab platform.

  • PSB 603 – a known selective Adenosine A2B Receptor antagonist – has anti-inflammatory activity in mice.
    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2020
    Co-Authors: Magdalena Kotańska, Małgorzata Szafarz, Kamil Mika, Anna Dziubina, Marek Bednarski, Christa E. Müller, Jacek Sapa, Katarzyna Kieć-kononowicz
    Abstract:

    Abstract A2B Adenosine Receptors are present in a wide spectrum of tissues, especially on cells of the immune system. Since these particular Receptors have the lowest, of all Adenosine Receptor subtypes, affinity for Adenosine they are believed to play a special role in immunological processes associated with elevated Adenosine levels such as inflammation. The aim of this preliminary study was to determine the potential anti-inflammatory properties of compound PSB-603, a potent and selective Adenosine A2B Receptor antagonist, in two different experimental models of local and systemic inflammation. In a model of inflammation induced by local carrageenan administration paw edema was measured using a pletysmometer. Additionally, levels of C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrnecrosistor alpha (TNF-α) and reactive oxygen species (ROS) were determined in the inflamed paw. Using the mouse model of peripheral inflammation induced by intraperitoneal (ip) administration of zymosan A, the influence of the A2B antagonist on the infiltration of neutrophils into the peritoneum and its effect on the plasma levels of CRP, TNF-α, and IL-6 were investigated. The results showed that PSB-603 administered at a dose of 5 mg/kg b.w. ip significantly reduced inflammation in both tested models. Particularly, it significantly decreased levels of the inflammatory cytokines IL-6, TNF-α and of ROS in the inflamed paw and reduced inflammation of the peritoneum by significantly decreasing the infiltration of leukocytes. Additionally, in the latter model, no statistically significant difference was observed in the CRP level between the control group without inflammation and the group which has been treated with the PSB-603 compound. Thus, the results may indicate the anti-inflammatory activity of Adenosine A2B Receptor antagonists in two different models of inflammation.

  • fluorescent labeled selective Adenosine A2B Receptor antagonist enables competition binding assay by flow cytometry
    Journal of Medicinal Chemistry, 2018
    Co-Authors: Meryem Kose, Sabrina Gollos, Tadeusz Karcz, Amelie Fiene, Fabian Heisig, Andrea Behrenswerth, Vigneshwaran Namasivayam, Katarzyna Kieckononowicz, Christa E. Müller
    Abstract:

    Fluorescent ligands represent powerful tools for biological studies and are considered attractive alternatives to radioligands. In this study, we developed fluorescent antagonists for A2B Adenosine Receptors (A2BARs), which are targeted by antiasthmatic xanthines and were proposed as novel targets in immuno-oncology. Our approach was to merge a small borondipyrromethene (BODIPY) derivative with the pharmacophore of 8-substituted xanthine derivatives. On the basis of the design, synthesis, and evaluation of model compounds, several fluorescent ligands were synthesized. Compound 29 (PSB-12105), which displayed high affinity for human, rat, and mouse A2BARs (Ki = 0.2–2 nM) and high selectivity for this AR subtype, was selected for further studies. A homology model of the human A2BAR was generated, and docking studies were performed. Moreover, 29 allowed us to establish a homogeneous Receptor–ligand binding assay using flow cytometry. These compounds constitute the first potent, selective fluorescent A2BAR li…

  • Domains for activation and inactivation in G protein-coupled Receptors–a mutational analysis of constitutive activity of the Adenosine A2B Receptor.
    Biochemical pharmacology, 2014
    Co-Authors: Miriam C. Peeters, Christa E. Müller, Rachel J. J. Elands, Gerard J. P. Van Westen, Eelke B. Lenselink, Adriaan P. Ijzerman
    Abstract:

    G protprotein-coupled Receptors (GPCRs) are a major drug target and can be activated by a range of stimuli, from photons to proteins. Most, if not all, GPCRs also display a basal level of biological response in the absence of such a stimulus. This level of so-called constitutive activity results from a delicate energy equilibrium that exists between the active and the inactive state of the Receptor and is the first determinant in the GPCR activation mechanism. Here we describe new insights in specific regions of the Adenosine A2B Receptor that are essential in activation and inactivation. We developed a new screening method using the MMY24 S. Cerevisiae strain by which we were able to screen for constitutively inactive mutants Receptors (CIMs). We applied this screening method on a mutagenic library of the Adenosine A2B Receptor, where random mutations were introduced in transmembrane domains four and five (TM4 and TM5) linked by extracellular loop 2 (EL2). The screen resulted in the identification of 22 single and double mutant Receptors, all showing a decrease in constitutive activity as well as in agonist potency. By comparing these results with a previous screen of the same mutagenic library for constitutively active mutant Receptors (CAMs), we discovered specific regions in this G protprotein-coupled Receptor involved in either inactivation or activation or both. The results suggest the activation mechanism of GPCRs to be much less restricted to sites of high conservation or direct interaction with the ligand or G protprotein and illustrate how dynamic the activation process of GPCRs is.

Adriaan P. Ijzerman – One of the best experts on this subject based on the ideXlab platform.

  • Domains for activation and inactivation in G protein-coupled Receptors–a mutational analysis of constitutive activity of the Adenosine A2B Receptor.
    Biochemical pharmacology, 2014
    Co-Authors: Miriam C. Peeters, Christa E. Müller, Rachel J. J. Elands, Gerard J. P. Van Westen, Eelke B. Lenselink, Adriaan P. Ijzerman
    Abstract:

    G protein-coupled Receptors (GPCRs) are a major drug target and can be activated by a range of stimuli, from photons to proteins. Most, if not all, GPCRs also display a basal level of biological response in the absence of such a stimulus. This level of so-called constitutive activity results from a delicate energy equilibrium that exists between the active and the inactive state of the Receptor and is the first determinant in the GPCR activation mechanism. Here we describe new insights in specific regions of the Adenosine A2B Receptor that are essential in activation and inactivation. We developed a new screening method using the MMY24 S. Cerevisiae strain by which we were able to screen for constitutively inactive mutants Receptors (CIMs). We applied this screening method on a mutagenic library of the Adenosine A2B Receptor, where random mutations were introduced in transmembrane domains four and five (TM4 and TM5) linked by extracellular loop 2 (EL2). The screen resulted in the identification of 22 single and double mutant Receptors, all showing a decrease in constitutive activity as well as in agonist potency. By comparing these results with a previous screen of the same mutagenic library for constitutively active mutant Receptors (CAMs), we discovered specific regions in this G protein-coupled Receptor involved in either inactivation or activation or both. The results suggest the activation mechanism of GPCRs to be much less restricted to sites of high conservation or direct interaction with the ligand or G protein and illustrate how dynamic the activation process of GPCRs is.

  • gpcr structure and activation an essential role for the first extracellular loop in activating the Adenosine A2B Receptor
    The FASEB Journal, 2011
    Co-Authors: Miriam C. Peeters, Margot W. Beukers, Christa E. Müller, Gerard J. P. Van Westen, Dong Guo, Lisanne E Wisse, Adriaan P. Ijzerman
    Abstract:

    The highly variable extracellular loops in G protprotein-coupled Receptors (GPCRs) have been implicated in Receptor activation, the mechanism of which is poorly understood. In a random mutagenesis screen on the human Adenosine A(2B) Receptor (A(2B)R) using the MMY24 Saccharomyces cerevisiae strain as a read-out system, we found that two residues in the first extracellular loop, a phenylalanine and an aspartic acid at positions 71 and 74, respectively, are involved in Receptor activation. We subsequently performed further site-directed and site-saturation mutagenesis. These experiments revealed that the introduction of mutations at either of the identified positions results in a wide variety of Receptor activation profiles, with changes in agonist potency, constitutive activity, and intrinsic activity. Radioligand binding studies showed that the changes in activation were not due to changes in Receptor expression. We interpret these data in the light of the recently revealed structure of the Adenosine A(2A)R, the closest homologue of the A(2B)R. The two residues are suggested to be vital in maintaining the tertiary structure of a β sheet in the extracellular domain of the A(2B)R. We hypothesize that deterioration of structure in the extracellular domains of GPCRs compromises overall Receptor structure with profound consequences for Receptor activation and constitutive activity.

  • Structure-affinity relationships of Adenosine A2B Receptor ligands.
    Medicinal research reviews, 2006
    Co-Authors: Margot W. Beukers, Illiana Meurs, Adriaan P. Ijzerman
    Abstract:

    Many selective and high affinity agonists and antagonists have been developed for the Adenosine A1, A2A, and A3 Receptors. Very recently such compounds have been identified for the Adenosine A2B Receptors. This review presents an overview of the structure-affinity relationships of antagonists and agonists for this Receptor subtype as published in the scientific and patent literature. To date the most selective >370-fold, high affinity Adenosine A2B Receptor antagonist is the xanthine analog, compound 16 (8-(1-(3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrazol-4-yl)-1,3-dipropyl-1H-purine-2,6(3H,7H)-dione). The pyrrolopyrimidine analog OSIP339391 (73) is slightly less selective, 70-fold, but has a higher affinity 0.41 nM compared to 1 nM for compound 16. Other promising classes of compounds with selectivities ranging from 10- to 160-fold and affinities ranging from 3 to 112 nM include triazolo, aminothiazole, quinazoline, and pyrimidin-2-amine analogs. Progress has also been achieved concerning the development of selective high affinity agonists for the Adenosine A2B Receptor. For years the most potent, albeit non-selective Adenosine A2B Receptor agonist was (S)PHPNECA (88). Last year, a new class of non-ribose ligands was reported. Several compounds displayed selectivity with respect to Adenosine A2A and A3 Receptors. In addition, full and partial agonists for the Adenosine A2B Receptor were identified with EC50 values of 10 nM (LUF5835, 103) and 9 nM (LUF5845, 105), respectively. © 2006 Wiley Periodicals, Inc. Med Res Rev, 26, No. 5, 667–698, 2006

Yang Xia – One of the best experts on this subject based on the ideXlab platform.

  • Adenosine A2B Receptor a pathogenic factor and a therapeutic target for sensorineural hearing loss
    The FASEB Journal, 2020
    Co-Authors: Jeanne M Manalo, Hong Liu, Hong Sun, Rodney E. Kellems, Dalian Ding, John Hicks, Richard Salvi, Fred A Pereira, Yang Xia
    Abstract:

    Over 466 million people worldwide are diagnosed with hearing loss (HL). About 90% of HL cases are sensorineural HL (SNHL) with treatments limited to hearing aids and cochlear implants with no FDA-approved drugs. Intriguingly, ADA-deficient patients have been reported to have bilateral SNHL, however, its underlying cellular and molecular basis remain unknown. We report that Ada-/- mice, phenocopying ADA-deficient humans, displayed SNHL. Ada-/- mice cochlea with elevated Adenosine caused substantial nerve fiber demyelination and mild hair cell loss. ADA enzyme therapy in these mice normalized cochlear Adenosine levels, attenuated SNHL, and prevented demyelination. Additionally, ADA enzyme therapy rescued SNHL by restoring nerve fiber structure in Ada-/- mice post two-week drug withdrawal. Moreover, elevated cochlear Adenosine in untreated mice was associated with enhanced AdorA2B gene expression. Preclinically, ADORA2B-specific antagonist treatment in Ada-/- mice significantly improved HL, nerve fiber density, and myelin compaction. We also provided genetic evidence that ADORA2B is detrimental for age-related SNHL by impairing cochlear myelination in WT aged mice. Overall, understanding purinergic molecular signaling in SNHL in Ada-/- mice allows us to further discover that ADORA2B is also a pathogenic factor underlying aged-related SNHL by impairing cochlear myelination and lowering cochlear Adenosine levels or blocking ADORA2B signaling are effective therapies for SNHL.

  • abstract 17080 Adenosine A2B Receptor mediated erythrocyte oxygen release counteracts renal hypoxia and its progression
    Circulation, 2017
    Co-Authors: Zhangzhe Peng, Weiru Zhang, Rodney E. Kellems, Renna Luo, Lijian Tao, Yang Xia
    Abstract:

    Introduction: Insufficient tissue oxygen (O2) availability (hypoxia) is commonly seen in patients with cardiovascular diseases (CVD) ,chronic kidney diseases (CKD), respiratory diseases and certain cancers. Although erythrocyte is the only cell type responsible for delivering and sensoring O2, its function in pathological tissue hypoxia remains largely unknown. Hypothesis: Erythrocyte A2B Adenosine Receptor (ADORA2B) plays a key protective role in Ang II-induced tissue damage by increasing 2,3-biphosphoglycerate(2, 3-BPG) and oxygen release to counteract tissue hypoxia. Methods: We infused angiotensin II (Ang II, 140ng/kg/min) to mice with specific deletion of ADORA2B in erythrocytes (ADORA2B f/f /EpoR-Cre + ) for 14 days and measured the levels of 2,3-BPG,P50,p-AMPK in erythrocytes of mild and severe CKD patients. Results: We found that 2,3-BPG, an erythrocyte-specific metabolite enhancing O2 delivery, was significantly induced in the erythrocytes of mice infused with Ang II. Mouse genetic studies demonstrated that Ang II induced local tissue accumulation of Adenosine and that elevated Adenosine-mediated erythrocyte ADORA2B activation was beneficial by inducing 2,3-BPG production, triggering O2 release to counteract tissue hypoxia, heart and kidney damage including proteinuria along with the mRNA levels of collagen I, fibronectin, prepro-ET-1 and endothelin Receptor type A, which are known tissue damage associated genes. Mechanistically, we revealed that AMPK is an intracellular signaling molecular functioning downstream of ADORA2B underlying elevated 2,3-BPG production by inducing BPG mutase activity and protects tissue hypoxia, kidney dysfunction and renal fibrosis. Finally, we translated our mouse study to human and confirmed that the levels of 2,3-BPG, P50 and p-AMPK were elevated in erythrocytes of hypertensive CKD patients compared to healthy individuals and correlated to disease severity. Conclusions: We demonstrate that erythrocyte ADORA2B-mediated AMPK activation plays a key protective role in Ang II-induced tissue damage by increasing 2, 3-BPG and oxygen release to counteract tissue hypoxia and immediately suggest novel therapies for hypertension and CKD.

  • The Adenosine A2B Receptor promotes tumor progression of bladder urothelial carcinoma by enhancing MAPK signaling pathway
    Oncotarget, 2017
    Co-Authors: Yihong Zhou, Xi Chu, Fei Deng, Liang Tong, Guoxiong Tong, Jianye Liu, Jin Tang, Yuxin Tang, Yang Xia
    Abstract:

    // Yihong Zhou 1 , Xi Chu 1 , Fei Deng 1 , Liang Tong 1 , Guoxiong Tong 1 , Ye Yi 1 , Jianye Liu 1 , Jin Tang 1 , Yuxin Tang 1 , Yang Xia 2 and Yingbo Dai 1 1 Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, China 2 Department of Biochemistry and Molecular Biology, University of Texas Medical School, Houston, Texas, USA Correspondence to: Yingbo Dai, email: // Keywords : Adenosine A2B Receptor, bladder urothelial carcinoma, prognosis, MAPK signaling Received : March 14, 2017 Accepted : May 01, 2017 Published : May 12, 2017 Abstract The Adenosine A2B Receptor (A2BR) was considered to play an oncogenic role in many human malignancies. However, the expression and molecular function of A2BR in bladder urothelial carcinoma (BUC) have not been well elucidated. Herein, we found that the expression of A2BR was higher than other Adenosine Receptors in BUC tissues and cells, and it was upregulated in BUC tissues compared with matched normal bladder tissues. Furthermore, high expression of A2BR was associated with poor prognosis of patients with BUC. In addition, suppression of A2BR inhibited the proliferation, migration and invasion of BUC cells and arrested the cell cycle at the G1 phase. Finally, we demonstrated that downregulation of A2BR inhibited the proliferation, migration and invasion of BUC in part via the MAPK signaling pathway, increasing the levels of P21 but decreasing the levels of cyclin B1, D, E1, MMP-2 and MMP-9. Overexpression of MMP-2 could rescue BUC cells migration and invasion. Thus, the present study indicates that A2BR may play a potential oncogenic role in BUC progression and act as a potential biomarker to identify BUC patients with poor clinical outcomes.