Serum miR-181а and miR-25 Levels in Patients with Breast Cancer or Benign Breast Disease.

Circulating miR-181а and miR-25, which reflect regulation of the expression of carcinogenesis-related genes, were assayed in patients with invasive carcinoma of no specific type (ICNT) or benign breast diseases (BBDs) and in subjects without pathologies of the mammary gland (controls). miR-181а expression level proved to be higher compared to control in patients with fibroadenoma and adenosis with low, but not high, risk of malignant transformation, as well as in patients with luminal HER2-negative type B (Lum B HER2-), HER2-positive type (HER2+), and triple-negative breast cancer (TNBC) than in the controls and luminal-type (Lum A) breast cancer. MiR-25 expression level prevailed in patients with Lum B HER2- compared to control, Lum A, and TNBC patients compared to Lum A. Thus, miR-181а and miR-25 expression levels may be risk indicators of malignant transformation in some patients with BBD, whereas in patients with ICNT, these levels reflect pathological processes of different directions within the tumor.

Effects of prolonged subchronic benzo(α)pyrene exposure on rat liver morphology and CYP1A expression during treatment with menadione, quercetin, or tocopherol.

Arylamines and polycyclic aromatic hydrocarbons (PAHs) are hazardous anthropogenic pollutants in the environment. The toxicity of PAHs, which include benzo(α)pyrene (BP), is mediated by the activation of Р450 cytochromes of the 1А subfamily (CYP1A1 and CYP1A2). Previously, we have demonstrated that tocopherol, quercetin, and menadione inhibit the expression and activity of CYP1A in the liver of male Wistar rats after administration of a high BP dose to the rats for 3 days. Here, we confirmed the effects of tocopherol, quercetin, and menadione on the expression and activity of CYP1A and on rat liver morphology during prolonged administration (90 days) of a low BP dose. We revealed that subchronic oral administration of a low BP dose has no influence on CYP1A expression as compared to controls but can cause pathomorphological changes in rat liver tissue. These changes are abrogated by tocopherol, attenuated by quercetin, and enhanced by menadione.

Quercetin Attenuates Benzo(α)pyrene-induced CYP1A Expression.

We studied effects of nutrient quercetin on cytochromes' Р450 1А (CYP1A) activities (measured spectrofluorimetrically using 7-ethoxy-resorufin for CYP1A1 and 7-methoxy-resorufin for CYP1A2 as substrates), on mRNA levels (measured by RT-PCR), and on DNA-binding activities (evaluated by an electrophoretic mobility shift assay) of proteins regulating CYP1A expression in untreated and benzo(α)pyrene (BaP)-treated rats. Wistar rats received quercetin, BaP, or both once daily for 1-3 days. Quercetin did not influence CYP1A1 in untreated rats but inhibited BaP-mediated CYP1A induction on the transcriptional level decreasing positive input (AhR functional activity) and increasing negative input (AhRR/ARNT expression and Oct-1 and C/EBP functional activities).

The influence of changes in expression of redox-sensitive genes on the development of retinopathy in rats.

Age-related macular degeneration (AMD) is a complex multifactorial disease of the elderly, with unclear pathogenesis; AMD is the leading cause of blindness. One of the destructive processes in AMD is oxidative stress, which leads to an imbalance in the processes responsible for production and detoxification of reactive oxygen species. The aryl hydrocarbon receptor (AhR) signaling pathway can participate in the development of oxidative stress, but the main regulator of antioxidant defense is nuclear factor, erythroid derived 2 (Nrf2). AhR-dependent oxidative stress can be attenuated by activation of Nrf2, and defects in the Nrf2 signaling pathway can increase sensitivity of the cell to oxidative stress. Our aim was to determine the role of the pro-oxidant (AhR-dependent) and antioxidant (Nrf2-dependent) systems in the pathogenesis of AMD using rats of OXYS strain and of OXYSb substrain with signs of AMD-like retinopathy of varying severity. We compared the retinal levels of mRNA expression of Nrf2- and AhR-dependent redox-sensitive systems between 1-, 3-, and 12- month-old senescence-accelerated OXYS rats (have been shown to be a valid experimental model of AMD) and the rat substrain OXYSb, which shows low morbidity of AMD. We uncovered interstrain differences in the expression of Nrf2 and Nrf2-dependent genes (glutathione S-reductase [Gsr] and heme oxygenase 1 [Hmox1]), in the expression of AhR-dependent genes (cytochrome P450 1A2 [Cyp1a2] and cytochrome P450 1B1 [Cyp1b1]), and in the NADPH-quinone oxidoreductase (Nqo1) expression, which is controlled by both AhR and Nrf2. Binding of AhR and Nrf2 proteins to the regulatory regions of AhR and Nrf2 genes, respectively, was detected by chromatin immunoprecipitation in the retina of 1-, 3-, and 12-month-old OXYS, OXYSb, and Wistar (control) rats. We compared the strength of DNA-protein interactions of AhR and Nrf2 with regulatory sequences and found that the level of autoupregulation of the AhR gene was higher in the retina of 1-month-old OXYSb rats in comparison with OXYS rats. An imbalance between pro-oxidant (AhR-dependent) and antioxidant (Nrf2-dependent) systems may play a crucial role in the onset and/or progression of AMD.

[Effect of Hepatic P450 2e1 Activity Modulation on the Toxicity and Carcinogenicity of Diethylnitrosamine in Mice].

In this paper, the biological effects of diethylnitrosamine have been studied under controlled conditions of its metabolism in mice of different ages. The data presented indicate that diethylnitrosamine in a non-metabolized form exerts general toxic and hepatocarcinogenic effects while alkylating agents of this compound produce toxic liver injury. To our knowledge, the data presented impel to revise the general notion of an exceptional role of mutagenic activation in the carcinogenic effect of chemicals.

Rat hepatic CYP1A1 and CYP1A2 induction by menadione.

The effects of menadione on activities and expression of cytochrome P450 (CYP) 1A subfamily (CYP1A) isozymes in rat hepatic tissue were examined. When rats were treated orally with 15 mg/kg menadione for 4 days, the elevation of hepatic CYP1A1/1A2 specific activities in microsomal preparations was detected with approximately 5.4- and 2.5-fold increase over control values for ethoxyresorufin-O-deethylase (EROD, CYP1A1) and methoxyresorufin-O-demethylase (MROD, CYP1A2) activities, respectively. CYP1A1 and CYP1A2 mRNA levels in the liver of menadione-treated rats were approximately 11.8- and 1.8-fold higher than in controls, respectively, whereas the expression of the CYP1A regulatory proteins aryl hydrocarbon-receptor (AhR) and AhR nuclear translocator (Arnt) was not changed at the mRNA level. The result of this study demonstrates that menadione induces CYP1A1/1A2 expression in vivo through either transcriptional activation and/or mRNA stabilization.