We studied the activation of β2-adrenergic receptor（β2AR） by norepinephrine, epinephrine and isoprote- renol using docking and molecular dynamics（MD） simulation. The simulation was done on the assumption that β...We studied the activation of β2-adrenergic receptor（β2AR） by norepinephrine, epinephrine and isoprote- renol using docking and molecular dynamics（MD） simulation. The simulation was done on the assumption that β2AR was surrounded with explicit water and infinite lipid bilayer membrane at body temperature. So the result should be close to that under the physiological conditions. We calculated the structure of binding sites in β2AR for the three ac- tivators. We also simulated the change of the conformation ofβ2AR in the transmembrane regions（TMs）, in the mo- lecular switches, and in the conserved DRY（Aspartic acid, Arginine and Tyrosine） motif. This study provides detailed information concerning the structure ofβ2AR during activation process.展开更多
Primary lung graft dysfunction could significantly attribute to ischemia-reperfusion lung injury(IRLI)during transplantation surgery.β2-adrenergic agonists were one of the bronchodilators that had been well-establish...Primary lung graft dysfunction could significantly attribute to ischemia-reperfusion lung injury(IRLI)during transplantation surgery.β2-adrenergic agonists were one of the bronchodilators that had been well-established in the management of asthma and chronic obstructive pulmonary disease(COPD)with anti-inflammatory potency.By applying the model of isolated rat lung,we evaluated the efficacy of short-actingβ2-agonist inhalation to ameliorate ischemia-reperfusion damage.The experiment protocol was 180 min of global ischemia and then reperfusion for 60 min.In theβ2-agonist inhalation group,aerosolized albuterol was administrated prior ischemia procedure.Increased weight ratios of wet to dry lung and microvascular permeability were characterized in the IRLI group.In contrast,pre-inhaledβ2-agonist significantly mitigated the severity of pulmonary edema.Bronchoalveolar lavage from theβ2-agonist group presented decreased leukocyte counts and cytokines production,including interleukin-1β(IL-1β),tumor necrosis factor-α(TNF-α),and macrophage inflammatory protein 2(MIP-2).Devastating oxidative stress was widely recognized during the ischemia-reperfusion process,whileβ2-agonist pretreatment revealed subsided H2O2,myeloperoxidase(MPO),and the cleavage of caspase-3.Western blotting from lung homogenates identified the blockade of NF-κB and MAPK activation in theβ2-agonist inhalation group.Currently,there was no specific pharmacotherapy in IRLI management.Our results elucidated the protective effect ofβ2-agonist bronchodilator against ischemia-reperfusion induced oxidative stress,inflammation reaction,and pulmonary edema.展开更多
Adipose tissue is a promising target for treating obesity and metabolic diseases.However,pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient va...Adipose tissue is a promising target for treating obesity and metabolic diseases.However,pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient vascularization,especially in obese subjects.We have previously shown that during cold exposure,connexin43(Cx43)gap junctions are induced and activated to connect neighboring adipocytes to share limited sympathetic neuronal input amongst multiple cells.We reason the same mechanism may be leveraged to improve the efficacy of various pharmacological agents that target adipose tissue.Using an adipose tissue-specific Cx43 overexpression mouse model,we demonstrate effectiveness in connecting adipocytes to augment metabolic efficacy of theβ_(3)-adrenergic receptor agonist Mirabegron and FGF21.Additionally,combing those molecules with the Cx43 gap junction channel activator danegaptide shows a similar enhanced efficacy.In light of these findings,we propose a model in which connecting adipocytes via Cx43 gap junction channels primes adipose tissue to pharmacological agents designed to engage it.Thus,Cx43 gap junction activators hold great potential for combination with additional agents targeting adipose tissue.展开更多
基金Supported by the Young and Middle-Aged Scientists Research Awards Foundation of Shangdong Province,China(No.BS2011SW002)the Research Foundation for Advanced Talents of Ludong University,China(No.LY2011017)
文摘We studied the activation of β2-adrenergic receptor（β2AR） by norepinephrine, epinephrine and isoprote- renol using docking and molecular dynamics（MD） simulation. The simulation was done on the assumption that β2AR was surrounded with explicit water and infinite lipid bilayer membrane at body temperature. So the result should be close to that under the physiological conditions. We calculated the structure of binding sites in β2AR for the three ac- tivators. We also simulated the change of the conformation ofβ2AR in the transmembrane regions（TMs）, in the mo- lecular switches, and in the conserved DRY（Aspartic acid, Arginine and Tyrosine） motif. This study provides detailed information concerning the structure ofβ2AR during activation process.
基金the Tri-Service General Hospital,National Defesnse Medical Center in Taiwan(TSGH-C108-109).
文摘Primary lung graft dysfunction could significantly attribute to ischemia-reperfusion lung injury(IRLI)during transplantation surgery.β2-adrenergic agonists were one of the bronchodilators that had been well-established in the management of asthma and chronic obstructive pulmonary disease(COPD)with anti-inflammatory potency.By applying the model of isolated rat lung,we evaluated the efficacy of short-actingβ2-agonist inhalation to ameliorate ischemia-reperfusion damage.The experiment protocol was 180 min of global ischemia and then reperfusion for 60 min.In theβ2-agonist inhalation group,aerosolized albuterol was administrated prior ischemia procedure.Increased weight ratios of wet to dry lung and microvascular permeability were characterized in the IRLI group.In contrast,pre-inhaledβ2-agonist significantly mitigated the severity of pulmonary edema.Bronchoalveolar lavage from theβ2-agonist group presented decreased leukocyte counts and cytokines production,including interleukin-1β(IL-1β),tumor necrosis factor-α(TNF-α),and macrophage inflammatory protein 2(MIP-2).Devastating oxidative stress was widely recognized during the ischemia-reperfusion process,whileβ2-agonist pretreatment revealed subsided H2O2,myeloperoxidase(MPO),and the cleavage of caspase-3.Western blotting from lung homogenates identified the blockade of NF-κB and MAPK activation in theβ2-agonist inhalation group.Currently,there was no specific pharmacotherapy in IRLI management.Our results elucidated the protective effect ofβ2-agonist bronchodilator against ischemia-reperfusion induced oxidative stress,inflammation reaction,and pulmonary edema.
基金supported in part by a research grant from Novo Nordsik(USA,to Philipp E.Scherer)by NIH Grants(USA)R01-DK55758,R01-DK099110,R01-DK127274,R01DK131537 and P01-AG051459 to Philipp E.Scherer,NIH Grant R00-DK114498+4 种基金NIH Grant K99-AG068239 to Shangang ZhaoNIH Grant K01-DK125447 to Yu A.AnNIH grants R01 DK119169 and P01 DK119130-5830 to Kevin W.WilliamsUSDA ARS(cooperative agreement 309251000-062)to Yi ZhuAHA Career Development Award 855170(USA)to Qingzhang Zhu。
文摘Adipose tissue is a promising target for treating obesity and metabolic diseases.However,pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient vascularization,especially in obese subjects.We have previously shown that during cold exposure,connexin43(Cx43)gap junctions are induced and activated to connect neighboring adipocytes to share limited sympathetic neuronal input amongst multiple cells.We reason the same mechanism may be leveraged to improve the efficacy of various pharmacological agents that target adipose tissue.Using an adipose tissue-specific Cx43 overexpression mouse model,we demonstrate effectiveness in connecting adipocytes to augment metabolic efficacy of theβ_(3)-adrenergic receptor agonist Mirabegron and FGF21.Additionally,combing those molecules with the Cx43 gap junction channel activator danegaptide shows a similar enhanced efficacy.In light of these findings,we propose a model in which connecting adipocytes via Cx43 gap junction channels primes adipose tissue to pharmacological agents designed to engage it.Thus,Cx43 gap junction activators hold great potential for combination with additional agents targeting adipose tissue.
