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

Dopamine D₂-Receptor Antagonists Down-Regulate CYP1A1/2 and CYP1B1 in the Rat Liver

<div><p>Dopaminergic systems regulate the release of several hormones including growth hormone (GH), thyroid hormones, insulin, glucocorticoids and prolactin (PRL) that play significant roles in the regulation of various Cytochrome P450 (CYP) enzymes. The present study investigated the role of dopamine D₂-receptor-linked pathways in the regulation of CYP1A1, CYP1A2 and CYP1B1 that belong to a battery of genes controlled by the Aryl Hydrocarbon Receptor (AhR) and play a crucial role in the metabolism and toxicity of numerous environmental toxicants. Inhibition of dopamine D₂-receptors with sulpiride (SULP) significantly repressed the constitutive and benzo[a]pyrene (B[a]P)-induced <i>CYP1A1</i>, <i>CYP1A2</i> and <i>CYP1B</i> expression in the rat liver. The expression of <i>AhR</i>, heat shock protein 90 (<i>HSP90)</i> and AhR nuclear translocator <i>(ARNT)</i> was suppressed by SULP in B[a]P-treated livers, whereas the <i>AhRR</i> expression was increased by the drug suggesting that the SULP-mediated repression of the CYP1 inducibility is due to inactivation of the AhR regulatory system. At signal transduction level, the D₂-mediated down-regulation of constitutive <i>CYP1A1/2</i> and <i>CYP1B1</i> expression appears to be mediated by activation of the insulin/PI3K/AKT pathway. PRL-linked pathways exerting a negative control on various CYPs, and inactivation of the glucocorticoid-linked pathways that positively control the AhR-regulated CYP1 <i>genes</i>, may also participate in the SULP-mediated repression of both, the constitutive and induced <i>CYP1</i> expression. The present findings indicate that drugs acting as D₂-dopamine receptor antagonists can modify several hormone systems that regulate the expression of <i>CYP1A1</i>, <i>CYP1A2</i> and <i>CYP1B1</i>, and may affect the toxicity and carcinogenicity outcome of numerous toxicants and pre-carcinogenic substances. Therefore, these drugs could be considered as a part of the strategy to reduce the risk of exposure to environmental pollutants and pre-carcinogens.</p></div