Oleuropein-induced acceleration of cytochrome p450-catalyzed drug metabolism: Central role for nuclear receptor peroxisome proliferator-activated receptor a

Oleuropein (OLE), the main constituent of Olea europaea, displays pleiotropic beneficial effects in health and disease, which are mainly attributed to its anti-inflammatory and cardioprotective properties. Several food supplements and herbal medicines contain OLE and are available without a prescription. This study investigated the effects of OLE on the main cytochrome P450s (P450s) catalyzing the metabolism of many prescribed drugs. Emphasis was given to the role of peroxisome proliferator-activated receptor a (PPARa), a nuclear transcription factor regulating numerous genes including P450s. 129/Sv wild-type and Ppara-null mice were treated with OLE for 6 weeks. OLE induced Cyp1a1, Cyp1a2, Cyp1b1, Cyp3a14, Cyp3a25, Cyp2c29, Cyp2c44, Cyp2d22, and Cyp2e1 mRNAs in liver of wild-type mice, whereas no similar effects were observed in Ppara-null mice, indicating that the OLEinduced effect on these P450s is mediated by PPARa. Activation of the pathways related to phosphoinositide 3-kinase/protein kinase B (AKT)/forkhead box protein O1, c-Jun N-terminal kinase, AKT/ p70, and extracellular signal-regulated kinase participates in P450 induction by OLE. These data indicate that consumption of herbal medicines and food supplements containing OLE could accelerate the metabolism of drug substrates of the above-mentioned P450s, thus reducing their efficacy and the outcome of pharmacotherapy. Therefore, OLE-induced activation of PPARa could modify the effects of drugs due to their increased metabolism and clearance, which should be taken into account when consuming OLE-containing products with certain drugs, in particular those of narrow therapeutic window. © 2021 American Society for Pharmacology and Experimental Therapy. All rights reserved

Balance training programs for soccer injuries prevention

The purpose of the study was to compare 2 different balance training programs, based on distinct exercise frequencies, with the aim of improving proprioceptive ability. Thirty eight professional soccer players, were randomly assigned into 3 groups: the A group, exercised with a frequency of 6 times per week, for 3 weeks, the B group exercised with a frequency of 3 times per week, for 6 weeks and the C group (control) did not follow a highly specific balance training, but only a standard soccer training. All participants were evaluated with the use of an electronic stability system (indices-deviations) and of a wooden balance board (time on balance) before (pre test) and after the training period (post test). Analyses of variance (ANOVAs), with repeated measures on the last factor, were conducted to determine effect of training programs and measures (pre-test, post-test) on balance test indices (SI, API, and MLI) and time on balance board. The results showed that both training groups improved their balance ability similarly (p<0.05) despite the different frequency of the balance training program. The authors proposed that balance training program can be applied in soccer players on a daily basis or at least 3 times per week, according to the demands of the training period

The olive constituent oleuropein, as a PPARα agonist, markedly reduces serum triglycerides

Oleuropein (OLE), a main constituent of olive, exhibits antioxidant and hypolipidemic effects, while it reduces the infarct size in chow- and cholesterol-fed rabbits. Peroxisome proliferator-activated receptor α (PPARα) has essential roles in the control of lipid metabolism and energy homeostasis. This study focused on the mechanisms underlying the hypolipidemic activity of OLE and, specifically, on the role of PPARα activation in the OLE-induced effect. Theoretical approach using Molecular Docking Simulations and luciferase reporter gene assay indicated that OLE is a ligand of PPARα. The effect of OLE (100 mg/kg, p.o., per day, ×6 weeks) on serum triglyceride (TG) and cholesterol levels was also assessed in adult male wild-type and Ppara-null mice. Molecular Docking Simulations, Luciferase reporter gene assay and gene expression analysis indicated that OLE is a PPARα agonist that up-regulates several PPARα target genes in the liver. This effect was associated with a significant reduction of serum TG and cholesterol levels. In contrast, OLE had no effect in Ppara-null mice, indicating a direct involvement of PPARα in the OLE-induced serum TG and cholesterol reduction. Activation of hormone-sensitive lipase in the white adipose tissue (WAT) and the liver of wild-type mice and up-regulation of several hepatic factors involved in TG uptake, transport, metabolism and clearance may also contribute in the OLE-induced TG reduction. In summary, OLE has a beneficial effect on TG homeostasis via PPARα activation. OLE also activates the hormone sensitive lipase in the WAT and liver and up-regulates several hepatic genes with essential roles in TG homeostasis. © 2018 Elsevier Inc

<i>In vivo</i> assessment of the effect of D₂-receptor blockade on the activation of GH/STAT5b signalling pathway.

<p>Western blotting showing the SULP-mediated suppression of STAT5b phosphorylation. Numbers in the western blot captures indicate the STAT5b phoshorylation level following treatment compared to the control level that was set at 1. Lanes C: control; SULP: sulpiride (selective dopamine D₂-antagonist); B[a]P: benzo[a]pyrene; OIL: olive oil.</p

Sulpiride-induced effect on rat hormonal state.

<p>C; controls treated with normal saline; SULP: sulpiride (dopamine D₂-antagonist); B[a]P: benzo[a]pyrene; OIL: olive oil; T3: triiodothyronin expressed in ng/dl; T4: thyroxin expressed in μg/dl; TSH: thyroid-stimulating hormone expressed in ng/ml; GH: growth hormone expressed in ng/ml; PRL: prolactin expressed in ng/ml; Corticosterone expressed in mg/ml; Insulin expressed in pg/ml. Values are expressed as mean ± SE (n = 10). The asterisks indicate the significance of the differences between SULP-treated rats and controls, and between B[a]P-exposed rats with and without concomitant treatment with SULP</p><p>*P<0.05</p><p>**P<0.005</p><p>***P<0.001</p><p>Sulpiride-induced effect on rat hormonal state.</p

D₂-dopaminergic receptor-mediated effect on hepatic total P450 content and CYP1B1.

<p>(A) Assessment of sulpiride effect on total P450 content in the liver of rats treated with either normal saline or benzo[a]pyrene. (B) Assessment of sulpiride effect on hepatic CYP1B1 mRNA expression following treatment with either normal saline or benzo[a]pyrene. Bonferroni’s correction and Tukey post-hoc tests took place in the comparisons of the data presented here. (C vs SULP, C vs B[a]P and B[a]P vs (B[a]P+SULP)). C: controls treated with normal saline; SULP: sulpiride (dopamine D₂-antagonist); B[a]P: benzo[a]pyrene; OIL: olive oil; *P<0.05, **P<0.01, #P<0.005, ***P<0.001.</p

The dopamine D₂-receptor-mediated control of the insulin/PI3K/AKT/FOXO1 signalling pathway activation.

<p>Dopamine stimulates D₂-ARs on pancreatic β-cells and restricts the release of insulin in response to increased plasma glucose levels [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0128708#pone.0128708.ref061" target="_blank">61</a>]. In contrast, blockade of D₂-dopaminergic receptors by sulpiride, increases insulin release [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0128708#pone.0128708.ref022" target="_blank">22</a>], which in turn, stimulates insulin receptors (IR) in hepatocyte plasma membranes, an effect resulting in the phosphorylation of the Insulin Receptor Substrate (IRS) at different docking sites, where the phosphatidylinositol 3-kinase (PI3K) binds. Activated PI3K converts phosphatidylinositol biphosphate to phosphatidylinositol triphosphate, which subsequently activates protein kinase B (AKT). Upon activation AKT phosphorylates the transcription factor forkhead box O1 (FOXO1), which then translocates into the cytoplasm thus terminating <i>CYP1A1</i>, <i>CYP1A2</i> and <i>CYP1B1</i> gene transcription [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0128708#pone.0128708.ref022" target="_blank">22</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0128708#pone.0128708.ref075" target="_blank">75</a>].</p