Classical nuclear hormone receptor activity as a mediator of complex concentration response relationships for endocrine active compounds

Cookman, Clifford J.; Belcher, Scott M.

doi:10.1016/j.coph.2014.09.013

Cited by 11 publications

(9 citation statements)

References 43 publications

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“…The analgesic effect evidently increased up to 75% at 0.2 mg/kg dose, whereas the peptide was significantly less effective at a 1 mg/kg. Many researchers have described this phenomenon [42,43]. This type of dose response was described for micronutrients, endocrine-disrupting chemicals, endogenous hormones, and other drugs.…”

Section: Discussionmentioning

confidence: 99%

Analgesic Activity of Acid-Sensing Ion Channel 3 (ASIС3) Inhibitors: Sea Anemones Peptides Ugr9-1 and APETx2 versus Low Molecular Weight Compounds

et al. 2018

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Acid-sensing ion channel 3 (ASIC3) makes an important contribution to the development and maintenance of inflammatory and acid-induced pain. We compared different ASIC3 inhibitors (peptides from sea anemones (APETx2 and Ugr9-1) and nonpeptide molecules (sevanol and diclofenac)) in anti-inflammatory action and analgesic effects. All tested compounds had distinct effects on pH-induced ASIC3 current. APETx2 inhibited only transient current, whereas Ugr9-1 and sevanol decreased transient and sustained components of the current. The effect on mice was evaluated after administering an intramuscular injection in the acetic acid writhing pain model and the complete Freund’s adjuvant-induced thermal hyperalgesia/inflammation test. The bell-shaped dependence of the analgesic effect was observed for APETx2 in the acetic acid-induced writhing test, as well as for sevanol and peptide Ugr9-1 in the thermal hyperalgesia test. This dependence could be evidence of the nonspecific action of compounds in high doses. Compounds reducing both components of ASIC3 current produced more significant pain relief than APETx2, which is an effective inhibitor of a transient current only. Therefore, the comparison of the efficacy of ASIC3 inhibitors revealed the importance of ASIC3-sustained currents’ inhibition for promotion of acidosis-related pain relief.

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Section: Discussionmentioning

confidence: 99%

Analgesic Activity of Acid-Sensing Ion Channel 3 (ASIС3) Inhibitors: Sea Anemones Peptides Ugr9-1 and APETx2 versus Low Molecular Weight Compounds

et al. 2018

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“…These complex dose-response relationships can be a result of several separate, yet simultaneously acting, mechanisms of action [89]. Estrogens and BPA are known to act with numerous receptor mediated pathways, either through classical nuclear receptor or rapid signaling mechanisms [90, 91]. While BPA has estrogen-like activity at ERα and ERβ at nM concentrations [92], it can also bind to and inhibit the androgen and thyroid hormone receptors at μM concentrations [93–96] to cause oppositional effects at low and high dose ranges.…”

Section: Discussionmentioning

confidence: 99%

Strain-specific induction of endometrial periglandular fibrosis in mice exposed during adulthood to the endocrine disrupting chemical bisphenol A

Kendziorski

Belcher

2015

Reproductive Toxicology

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The aim of this study was to compare effects of bisphenol A (BPA) on collagen accumulation in uteri of two mouse strains. Adult C57Bl/6N and CD-1 mice were exposed to dietary BPA (0.004–40 mg/kg/day) or 17α-ethinyl estradiol (0.00002–0.001 mg/kg/day) as effect control. An equine endometrosis-like phenotype with increased gland nesting and periglandular collagen accumulation was characteristic of unexposed C57Bl/6N, but not CD-1, endometrium. BPA non-monotonically increased gland nest density and periglandular collagen accumulation in both strains. Increased collagen I and III expression, decreased matrix metalloproteinase 2 (MMP2) and MMP14 expression, and increased immune response were associated with the endometrosis phenotype in the C57Bl/6N strain and the 30 ppm BPA CD-1 group. The association between the pro-collagen shift in increased collagen expression and decreased MMP2 expression and activity implies that strain differences and BPA exposure salter regulation of endometrial remodeling and contributes to increased fibrosis, a component of several human uterine diseases.

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“…They decreased CFA-induced paw edema only at one dose (0.072 mg/kg), showing a “bell-shaped” or “inverse U-shaped” dose response curve ( Figure 4 D). The most probable mechanism of this phenomenon in this case is the peptides’ action on different receptors/channels, depending on the concentration and the following competition between multiple signal pathways [ 34 , 35 , 36 ]. Taken together, data on peptides Ms 9a-2 and Ms 9a-3 show that these peptides can interact with TRPA1, but it is not their key target in vivo.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Structural Determinants of Peptide MS 9a-1 Essential for Potentiating of TRPA1 Channel

et al. 2022

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The TRPA1 channel is involved in a variety of physiological processes and its activation leads to pain perception and the development of inflammation. Peptide Ms 9a-1 from sea anemone Metridium senile is a positive modulator of TRPA1 and causes significant analgesic and anti-inflammatory effects by desensitization of TRPA1-expressing sensory neurons. For structural and functional analysis of Ms 9a-1, we produced four peptides—Ms 9a-1 without C-terminal domain (abbreviated as N-Ms), short C-terminal domain Ms 9a-1 alone (C-Ms), and two homologous peptides (Ms 9a-2 and Ms 9a-3). All tested peptides possessed a reduced potentiating effect on TRPA1 compared to Ms 9a-1 in vitro. None of the peptides reproduced analgesic and anti-inflammatory properties of Ms 9a-1 in vivo. Peptides N-Ms and C-Ms were able to reduce pain induced by AITC (selective TRPA1 agonist) but did not decrease AITC-induced paw edema development. Fragments of Ms 9a-1 did not effectively reverse CFA-induced thermal hyperalgesia and paw edema. Ms 9a-2 and Ms 9a-3 possessed significant effects and anti-inflammatory properties in some doses, but their unexpected efficacy and bell-shape dose–responses support the hypothesis of other targets involved in their effects in vivo. Therefore, activity comparison of Ms 9a-1 fragments and homologues peptides revealed structural determinants important for TRPA1 modulation, as well as analgesic and anti-inflammatory properties of Ms9a-1.

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Classical nuclear hormone receptor activity as a mediator of complex concentration response relationships for endocrine active compounds

Cited by 11 publications

References 43 publications

Analgesic Activity of Acid-Sensing Ion Channel 3 (ASIС3) Inhibitors: Sea Anemones Peptides Ugr9-1 and APETx2 versus Low Molecular Weight Compounds

Analgesic Activity of Acid-Sensing Ion Channel 3 (ASIС3) Inhibitors: Sea Anemones Peptides Ugr9-1 and APETx2 versus Low Molecular Weight Compounds

Strain-specific induction of endometrial periglandular fibrosis in mice exposed during adulthood to the endocrine disrupting chemical bisphenol A

Analysis of Structural Determinants of Peptide MS 9a-1 Essential for Potentiating of TRPA1 Channel

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