ChemInform Abstract: 5-Oxo-1,4-dihydroindenopyridines: Calcium Modulators with Partial Calcium Agonistic Activity.

AbstractThe Ang–Tie signaling pathway is an important vascular signaling pathway regulating vascular growth and stability. Dysregulation in the pathway is associated with vascular dysfunction and numerous diseases that involve abnormal vascular permeability and endothelial cell inflammation. The understanding of the molecular mechanisms of the Ang–Tie pathway has been limited due to the complex reaction network formed by the ligands, receptors, and molecular regulatory mechanisms. In this study, we developed a mechanistic computational model of the Ang–Tie signaling pathway validated against experimental data. The model captures and reproduces the experimentally observed junctional localization and downstream signaling of the Ang–Tie signaling axis, as well as the time-dependent role of receptor Tie1. The model predicts that Tie1 modulates Tie2’s response to the context-dependent agonist Ang2 by junctional interactions. Furthermore, modulation of Tie1’s junctional localization, inhibition of Tie2 extracellular domain cleavage, and inhibition of VE-PTP are identified as potential molecular strategies for potentiating Ang2’s agonistic activity and rescuing Tie2 signaling in inflammatory endothelial cells.

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Two antibacterial and PPARα/γ-agonistic unsaturated keto fatty acids from a coral-associated actinomycete of the genus Micrococcus

Beilstein Journal of Organic Chemistry ◽

10.3762/bjoc.16.29 ◽

2020 ◽

Vol 16 ◽

pp. 297-304 ◽

Cited By ~ 1

Author(s):

Amit Raj Sharma ◽

Enjuro Harunari ◽

Naoya Oku ◽

Nobuyasu Matsuura ◽

Agus Trianto ◽

...

Keyword(s):

Fatty Acids ◽

Spectroscopic Analysis ◽

Culture Broth ◽

Peroxisome Proliferator ◽

Simulation Studies ◽

Fish Pathogen ◽

Chemical Structures ◽

Agonistic Activity ◽

Isoform Specificity ◽

Peroxisome Proliferator Activated Receptors

A pair of geometrically isomeric unsaturated keto fatty acids, (6E,8Z)- and (6E,8E)-5-oxo-6,8-tetradecadienoic acids (1 and 2), were isolated from the culture broth of an actinomycete of the genus Micrococcus, which was associated with a stony coral, Catalaphyllia sp. Their chemical structures were elucidated by spectroscopic analysis including NMR and MS, with special assistance of spin system simulation studies for the assignment of an E geometry at C8 in 2. As metabolites of microbes, compounds 1 and 2 are unprecedented in terms of bearing a 2,4-dienone system. Both 1 and 2 showed antibacterial activity against the plant pathogen Rhizobium radiobacter and the fish pathogen Tenacibaculum maritimum, with a contrasting preference that 1 is more effective to the former strain while 2 is so to the latter. In addition, compounds 1 and 2 displayed agonistic activity against peroxisome proliferator-activated receptors (PPARs) with an isoform specificity towards PPARα and PPARγ.

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Clonidine — Recurrent Apnea following Overdose

Drug Intelligence & Clinical Pharmacy ◽

10.1177/106002807901301207 ◽

1979 ◽

Vol 13 (12) ◽

pp. 778-780

Author(s):

Brian Grabert ◽

Christopher S. Conner ◽

Barry H. Rumack ◽

Robert G. Peterson

Keyword(s):

Respiratory Depression ◽

High Serum ◽

Serum Concentrations ◽

Mediated Effects ◽

Agonistic Activity

Recurrent episodes of apnea are described in two children following overdosage of clonidine. Respiratory depression and apnea requiring intubation may not occur for up to 2½ hours following ingestion of clonidine. Hypotension was absent in one case, suggesting opposition to centrally mediated effects by peripheral alpha-agonistic activity in the presence of high serum concentrations of clonidine. General symptoms and treatment of clonidine overdosage are discussed.

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Agonistic and antagonistic properties of progesterone metabolites at the human mineralocorticoid receptor

Acta Endocrinologica ◽

10.1530/eje.0.1460789 ◽

2002 ◽

pp. 789-799 ◽

Cited By ~ 71

Author(s):

M Quinkler ◽

B Meyer ◽

C Bumke-Vogt ◽

C Grossmann ◽

U Gruber ◽

...

Keyword(s):

Binding Affinity ◽

Mineralocorticoid Receptor ◽

Antagonistic Activity ◽

Luciferase Reporter ◽

Protective Mechanism ◽

Luciferase Reporter Gene ◽

Binding Characteristics ◽

Rabbit Reticulocyte Lysate System ◽

Progesterone Metabolites ◽

Agonistic Activity

OBJECTIVE: Progesterone binds to the human mineralocorticoid receptor (hMR) with nearly the same affinity as do aldosterone and cortisol, but confers only low agonistic activity. It is still unclear how aldosterone can act as a mineralocorticoid in situations with high progesterone concentrations, e.g. pregnancy. One mechanism could be conversion of progesterone to inactive compounds in hMR target tissues. DESIGN: We analyzed the agonist and antagonist activities of 16 progesterone metabolites by their binding characteristics for hMR as well as functional studies assessing transactivation. METHODS: We studied binding affinity using hMR expressed in a T7-coupled rabbit reticulocyte lysate system. We used co-transfection of an hMR expression vector together with a luciferase reporter gene in CV-1 cells to investigate agonistic and antagonistic properties. RESULTS: Progesterone and 11beta-OH-progesterone (11beta-OH-P) showed a slightly higher binding affinity than cortisol, deoxycorticosterone and aldosterone. 20alpha-dihydro(DH)-P, 5alpha-DH-P and 17alpha-OH-P had a 3- to 10-fold lower binding potency. All other progesterone metabolites showed a weak affinity for hMR. 20alpha-DH-P exhibited the strongest agonistic potency among the metabolites tested, reaching 11.5% of aldosterone transactivation. The agonistic activity of 11beta-OH-P, 11alpha-OH-P and 17alpha-OH-P was 9, 5.1 and 4.1% respectively. At a concentration of 100 nmol/l, progesterone, 17alpha-OH-P and 20alpha-DH-P inhibit nearly 75, 40 and 35% of the transactivation by aldosterone respectively. All other progesterone metabolites tested demonstrate weaker affinity, and agonistic and antagonistic potency. CONCLUSIONS: The binding affinity for hMR and the agonistic and antagonistic activity diminish with increasing reduction of the progesterone molecule at C20, C17 and at ring A. We assume that progesterone metabolism to these compounds is a possible protective mechanism for hMR. 17alpha-OH-P is a strong hMR antagonist and could exacerbate mineralocorticoid deficiency in patients with congenital adrenal hyperplasia.

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Identification of Human Toll-like Receptor 2-Agonistic Activity in Dihydropyridine–Quinolone Carboxamides

ACS Medicinal Chemistry Letters ◽

10.1021/acsmedchemlett.8b00540 ◽

2018 ◽

Vol 10 (1) ◽

pp. 132-136 ◽

Cited By ~ 4

Author(s):

Ziwei Hu ◽

Janardhan Banothu ◽

Mallesh Beesu ◽

Collin J. Gustafson ◽

Michael J. H. Brush ◽

...

Keyword(s):

Toll Like Receptor ◽

Toll Like Receptor 2 ◽

Agonistic Activity

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Foraging and agonistic activity co-occur in free-ranging blue crabs (Callinectes sapidus): observation of animals by ultrasonic telemetry

Journal of Experimental Marine Biology and Ecology ◽

10.1016/s0022-0981(98)00129-4 ◽

1999 ◽

Vol 233 (1) ◽

pp. 143-160 ◽

Cited By ~ 51

Author(s):

Mary E Clark ◽

Thomas G Wolcott ◽

Donna L Wolcott ◽

Anson H Hines

Keyword(s):

Callinectes Sapidus ◽

Blue Crabs ◽

Ultrasonic Telemetry ◽

Agonistic Activity ◽

Free Ranging

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Alterbrassicicene A, a Highly Transformed Fusicoccane-Derived Diterpenoid with Potent PPAR-γ Agonistic Activity from Alternaria brassicicola

Organic Letters ◽

10.1021/acs.orglett.8b03553 ◽

2018 ◽

Vol 20 (24) ◽

pp. 7982-7986 ◽

Cited By ~ 19

Author(s):

Fengli Li ◽

Weiguang Sun ◽

Jiankun Guan ◽

Yuanyuan Lu ◽

Sitian Zhang ◽

...

Keyword(s):

Alternaria Brassicicola ◽

Ppar Γ ◽

Agonistic Activity

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Evidence that tumor necrosis factor alpha (TNF)-induced activation of neutrophil respiratory burst on biologic surfaces is mediated by the p55 TNF receptor

Blood ◽

10.1182/blood.v84.1.287.bloodjournal841287 ◽

1994 ◽

Vol 84 (1) ◽

pp. 287-293

Author(s):

R Menegazzi ◽

R Cramer ◽

P Patriarca ◽

P Scheurich ◽

P Dri

Keyword(s):

Respiratory Burst ◽

Tumor Necrosis ◽

Tnf Receptor ◽

Necrosis Factor Alpha ◽

Agonistic Activity ◽

Factor Alpha ◽

Coated Surfaces ◽

O2 Production ◽

Agonistic Effect ◽

Necrosis Factor

Polymorphonuclear leukocytes (PMN) residing on biologic surfaces respond with a vigorous respiratory burst when exposed to tumor necrosis factor alpha (TNF). PMN possess both the p55 and the p75 TNF receptors, but their role in the elicitation of the respiratory burst is not known. We addressed this problem by studying the effect of monoclonal antibodies (MoAbs) directed against the p55 TNF receptor (MoAb H398 and MoAb htr-9) and the p75 TNF receptor (MoAb utr-1) on TNF- induced production of O2- by PMN residing on fibronectin-coated surfaces. Neither the anti-p55 nor the anti-p75 MoAbs affected TNF- induced O2- production despite their known ability to competitively inhibit TNF binding to the corresponding receptor. Experiments with the antibodies alone showed that the anti-p55 MoAbs directly triggered PMN O2- production, whereas no response was elicited by the anti-p75 MoAb. PMN unresponsiveness to the anti-p75 MoAb could not be ascribed to low expression of p75 receptor, because binding of the anti-p75 MoAb utr-1 to PMN was, indeed, even higher than binding of the anti-p55 MoAb htr- 9. The agonistic activity of the anti-p55 MoAbs was comparable with that of TNF and was not or only minimally modified by the simultaneous presence of TNF. Triggering of the respiratory burst by TNF was completely prevented by Fab fragments of the anti-p55 MoAb H398. Moreover, the monovalent Fab fragments, which lacked any stimulatory effect on PMN O2- production, acquired strong agonistic activity on cross-linking with anti Fab antibodies, suggesting that the ability of the anti-p55 antibodies to stimulate PMN O2- production depends on their ability to cross-link the TNF receptors. The agonistic effect of the anti-p55 MoAbs was only observed with cells residing on fibronectin- coated surfaces and not with cells in suspension, and in terms of kinetics, dependence on beta 2 integrin-mediated adherence, microfilament integrity, and sensitivity to elevations of intracellular levels of cAMP, it was virtually indistinguishable from the agonistic effect of TNF. Taken together, these results suggest that the p55 receptor is responsible for TNF-induced triggering of the respiratory burst of PMN residing on biologic surfaces.

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