β2-Adrenergic activity of 6-methoxykaempferol-3-O-glucoside on rat uterus: In vitro and in silico studies

Ahmed, Aimun A. E.; Márki, Árpád; Gáspár, Róbert; Vasas, Andrea; Mudawi, Mahmoud M. E.; Verli, Judit; Jójárt, Balázs; Hohmann, Judit; Fekete, György

doi:10.1016/j.ejphar.2011.05.066

Cited by 8 publications

(4 citation statements)

References 23 publications

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“…Similarly, when compared to clenbuterol, the partial agonist of MB terbutaline had more contact interactions between its tert -butyl group (F8-F11) and F193 and hydrogen bond donor interactions between its 3,5-hydroxyl groups (F1) and S203, S207, and N293. Previous docking studies with terbutaline identified interactions between terbutaline and F193 but not between S203, S207, or N293 42 . However, those studies generated homology models of the rat β 2 AR from 2RH1, which represents an inactive conformation of the receptor 43 , while our study employed both active and inactive structures of the β 2 AR.…”

Section: Discussionmentioning

confidence: 94%

Structural and pharmacological basis for the induction of mitochondrial biogenesis by formoterol but not clenbuterol

Cameron

Peterson

Beeson

et al. 2017

Sci Rep

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Mitochondrial dysfunction is associated with numerous acute and chronic degenerative diseases. The beta-2 adrenergic receptor (β2AR) agonist formoterol induces mitochondrial biogenesis (MB), but other β2AR agonists, such as clenbuterol, do not. We sought to identify the MB signaling pathway of formoterol and the differences in signaling between these two ligands that result in the differential induction of MB. While formoterol and clenbuterol increased cAMP, only formoterol increased the phosphorylation of Akt and its downstream target eNOS. The increase in Akt phosphorylation was Gβγ- and PI3K-dependent, and the increase in eNOS phosphorylation was Gβγ- and Akt-dependent. Only formoterol increased cGMP. Formoterol induced MB as measured by increases in uncoupled cellular respiration and PGC-1α and NDUFS1 mRNA expression and was blocked by inhibitors of Gβγ, Akt, NOS, and soluble guanylate cyclase. To identify distinct receptor-ligand interactions leading to these differences in signaling, we docked formoterol and clenbuterol to six structures of the β2AR. Compared to clenbuterol, the methoxyphenyl group of formoterol interacted more frequently with V114 and F193, while its formamide group interacted more frequently with C191. These data indicate that the unique structural features of formoterol allow it to interact with the β2AR to activate the Gβγ-Akt-eNOS-sGC pathway to induce MB.

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Section: Discussionmentioning

confidence: 94%

Structural and pharmacological basis for the induction of mitochondrial biogenesis by formoterol but not clenbuterol

Cameron

Peterson

Beeson

et al. 2017

Sci Rep

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“…41,52,[58][59][60] The use of oral terbutaline was reported in a case study of an 11-year-old boy with erections lasting over 6 h. 61 After detumescence was achieved, the boy was given 3 mg oral terbutaline and observed for 12 h. He was discharged home with a protocol to take 1.5 mg oral terbutaline three times daily for 1 week. At 6-month follow-up, no further recurrences were reported.…”

Section: Hormonal Therapymentioning

confidence: 99%

Medical management of ischemic stuttering priapism: a contemporary review of the literature

Levey¹,

Kutlu²,

Bivalacqua³

2011

Asian J Androl

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Priapism is defined as a prolonged and persistent erection of the penis without sexual stimulation. This is a poorly understood disease process with little information on the pathophysiology of this erectile disorder. Complications from this disorder are devastating due to the irreversible erectile damage and resultant erectile dysfunction (ED). Stuttering priapism, though relatively rare, affects a high prevalence of men with sickle-cell disease (SCD) and presents a challenging problem with guidelines for treatment lacking or resulting in permanent ED. The mechanisms involved in the development of priapism in this cohort are poorly characterized; therefore, medical management of priapism represents a therapeutic challenge to urologists. Additional research is warranted, so we can effectively target treatments for these patients with prevention as the goal. This review gives an introduction to stuttering priapism and its clinical significance, specifically with regards to the patient with SCD. Additionally, the proposed mechanisms behind its pathophysiology and a summary of the current and future targets for medical management are discussed.

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“…In this regard, the approach of PK/PD modeling is adopted to investigate the dose-response relationship for some drugs in vivo 7–9. However, for other drugs, a simpler relationship between the concentration and effect is modeled mathematically to conceptualize receptor occupancy and drug response in an idealized in vitro system 10–12…”

Section: Introductionmentioning

confidence: 99%

Time and dose relationships between schisandrin B- and schisandrae fructus oil-induced hepatotoxicity and the associated elevations in hepatic and serum triglyceride levels in mice

Zhang¹,

Pan²,

Zhou³

et al. 2014

DDDT

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BackgroundSchisandrin B (Sch B), a dibenzocyclooctadiene compound, is isolated from schisandrae fructus (SF). This study was conducted to compare the time- and dose-response between Sch B- and SF oil (SFO)-induced changes in hepatic and serum parameters in mice.MethodsInstitute of Cancer Research (ICR) mice were given a single oral dose of Sch B (0.125–2 g/kg) or SFO (0.3–5 g/kg). Serum alanine aminotransferase (ALT) activity, hepatic malondialdehyde, and triglyceride (TG) levels were measured at increasing time intervals within 6–120 hours postdosing.ResultsSerum ALT activity was elevated by 60%, with maximum effect (Emax) =45.77 U/L and affinity (KD) =1.25 g/kg at 48–96 hours following Sch B, but not SFO, treatment. Sch B and SFO treatments increased hepatic malondialdehyde level by 70% (Emax =2.30 nmol/mg protein and KD =0.41 g/kg) and 22% (Emax =1.42 nmol/mg protein and KD =2.56 g/kg) at 72 hours postdosing, respectively. Hepatic index was increased by 16%–60% (Emax =11.01, KD =0.68 g/kg) and 8%–32% (Emax =9.88, KD =4.47 g/kg) at 12–120 hours and 24–120 hours after the administration of Sch B and SFO, respectively. Hepatic TG level was increased by 40%–158% and 35%–85%, respectively, at 12–96 hours and 6–48 hours after Sch B and SFO treatment, respectively. The values of Emax and KD for Sch B/SFO-induced increase in hepatic TG were estimated to be 22.94/15.02 μmol/g and 0.78/3.03 g/kg, respectively. Both Sch B and SFO increased serum TG (up to 427% and 123%, respectively), with the values of Emax =5.50/4.60 mmol/L and KD =0.43/2.84 g/kg, respectively.ConclusionThe findings indicated that Sch B/SFO-induced increases in serum/hepatic parameters occurred in a time-dependent manner, with the time of onset being serum TG level < hepatic TG level < hepatic index < serum ALT activity. However, the time of recovery of these parameters to normal values varied as follow: serum TG level < hepatic TG level and liver injury < hepatic index. The Emax and affinity of Sch B on tissue/enzyme/receptor were larger than those of SFO.

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β2-Adrenergic activity of 6-methoxykaempferol-3-O-glucoside on rat uterus: In vitro and in silico studies

Cited by 8 publications

References 23 publications

Structural and pharmacological basis for the induction of mitochondrial biogenesis by formoterol but not clenbuterol

Structural and pharmacological basis for the induction of mitochondrial biogenesis by formoterol but not clenbuterol

Medical management of ischemic stuttering priapism: a contemporary review of the literature

Time and dose relationships between schisandrin B- and schisandrae fructus oil-induced hepatotoxicity and the associated elevations in hepatic and serum triglyceride levels in mice

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