CYP2E1 is an ethanol- and drug-metabolizing enzyme that can also activate procarcinogens and hepatotoxicants and generate reactive oxygen species; it has been implicated in the pathogenesis of liver ...diseases and cancer. Cigarette smoke increases CYP2E1 activity in rodents and in humans and we have shown that nicotine (0.1-1.0 mg/kg s.c. x 7 days) increases CYP2E1 protein and activity in the rat liver. In the current study, we have shown that the induction peaks at 4 h postnicotine (1 mg/kg s.c. x 7 days) treatment and recovers within 24 h. No induction was observed after a single injection, and 18 days of treatment did not increase the levels beyond that found at 7 days. We found that CYP2E1 is induced by very low doses of chronic (x 7 days) nicotine with an ED50 value of 0.01 mg/kg s.c.; 0.01 mg/kg in a rat model results in peak cotinine levels (nicotine metabolite) similar to those found in people exposed to environmental tobacco smoke (passive smokers; 2-7 ng/ml). Previously, we have shown no change in CYP2E1 mRNA, and our current mechanistic study indicates that nicotine does not regulate CYP2E1 expression by protein stabilization. We postulated that a nicotine metabolite could be causing the induction but found that cotinine (1 mg/kg x 7 days) did not increase CYP2E1. Our findings indicate that nicotine increases CYP2E1 at very low doses and may enhance CYP2E1-related toxicity in smokers, passive smokers, and people treated with nicotine (e.g., smokers, patients with Alzheimer's disease, ulcerative colitis or Parkinson's disease).
The use of ethanol and nicotine is strongly linked; 80 to 95% of heavy alcohol users are also smokers. In humans, cigarette smoking significantly enhances CYP2E1 activity, as measured by increased ...metabolism of chlorzoxazone in vivo. CYP2E1 metabolizes ethanol and can generate toxic intermediates. CYP2E1 also bioactivates tobacco smoke and other procarcinogens and several hepatotoxins. We hypothesized that, like ethanol, nicotine increases CYP2E1 activity. Rats were treated once daily with saline, ethanol (0.3, 1.0, and 3.0 g/kg p.o.), or nicotine bitartrate (0.1, 0.3, and 1.0 mg base/kg s.c.) for 7 days. After ethanol or nicotine administration, immunostaining for CYP2E1 was increased in the centrilobular regions of rat liver. Western blot analyses revealed that hepatic CYP2E1 levels were increased by ethanol (1.6-2.4-fold) and nicotine (1.3-1.7-fold). In vitro chlorzoxazone 6-hydroxylation analyses demonstrated elevated Vmax values (compared with saline-treated animals) by using hepatic microsomes from high-dose ethanol (2.27 +/- 0.12 versus 1.18 +/- 0.23 nmol/mg/min, p < 0.001) or nicotine-treated rats (2.35 +/- 0.04 versus 1.32 +/- 0.55 nmol/mg/min, p < 0.005), with no change in affinity. The magnitude of enhanced chlorzoxazone metabolism by microsomes from drug-treated animals is consistent with the observed increase in CYP2E1 protein by immunoblot. These data suggest that nicotine may increase CYP2E1-induced toxicity and contribute to cross-tolerance in smokers and people treated with nicotine (e.g., smokers, patients with Alzheimer's disease, ulcerative colitis, neuropsychiatric motor disorders).
Abstract
The PI3K pathway is involved in the regulation of cell growth, proliferation, metabolism and other functions. Aberrant signaling (PTEN loss of function, PIK3CA mutation, Akt amplification, ...etc.) from the PI3K pathway is observed in >50% of all tumors. Clinical evidence suggests that inhibiting the PI3K pathway is beneficial for the treatment of solid tumors and tumors of the hematopoietic system. Inhibition of p70S6K via rapalogs has been shown to block a negative feedback loop, thereby leading to the activation of Akt. The activation of this Akt feedback loop has been suggested to potentially compromise the clinical efficacy of selective mTORC1 inhibitors such as temsirolimus and everolimus. Dual p70S6K/Akt inhibition may promote improved pathway inhibition and also block the negative consequences of Akt activation through the negative feedback loop.
MSC2363318A is a highly kinase-selective, potent, adenosine triphosphate (ATP) competitive inhibitor of p70S6K, Akt1, and Akt3. In a cellular context, inhibition of p70S6K leads to potent inhibition of ribosomal protein S6 phosphorylation, while inhibition of Akt activity blocks the negative effects of a compensatory feedback loop. In addition, MSC2363318A exhibits potent anti-proliferative activity against many solid tumor cell lines in vitro, especially those with PI3K pathway genomic alterations. Further, MSC2363318A can also cross the blood-brain barrier, a unique characteristic that would allow for treating not only primary malignancies that are driven by PI3K pathway genomic alterations, but also indications with a high incidence of CNS metastases and primary malignancies of the central nervous system.
Oral treatment of mice with MSC2363318A resulted in significant inhibition of tumor growth in several subcutaneous human cancer xenograft models representing breast, pancreatic, glioblastoma and ovarian cancers. Of note, a breast cancer model possessing a PTEN loss of function showed tumor regression upon treatment with MSC2363318A. In addition, MSC2363318A exhibited increased exposure in tumors as compared to plasma, resulting in sustained inhibition of S6K phosphorylation for up to 24 hours. Key preclinical activities are being completed and first in human clinical studies are scheduled to be initiated in 2013.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A162.
Citation Format: Bayard R. Huck, Andreas Machl, Erik Wilker, Hui Tian, Sakeena Syed, Jing Lin, Jianguo Ma, Anderson Clark, Roseann Waterhouse, Remiguisz Kaleta, Alina Micu, Lynne Soughley, Long Li, Karin Groll, Sonja Kroesser, Frank Beier, Ursula Hering, Marc Lecomte, Katrin Wichert, Mauro D'Antonio, Paolo Di Eugenio. Identification of brain penetrant p70S6K/Akt inhibitor MSC2363318A. abstract. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A162.
Quality of sleep in students Micu, Alina; Cojocaru, Cristian; Luca, Gianina ...
Pneumologia (Bucharest, Romania),
2012 Jan-Mar, Letnik:
61, Številka:
1
Journal Article
Recenzirano
Sleep quality is an important factor involved in students' learning process. Using different methods, actual studies suggest that complaints about sleep problems are common in young medical students. ...The aim of this study was to evaluate if is any relation between factors like medium and lifestyle among students of the University of Medicine and Pharmacy "Grigore T Popa" from Iaşi. The study group included 30 students (2 of them were excluded) who performed a polisomnography, self reported Epworth questionnaire and two weeks sleep diary. Coffee, energy drinks, green and black tea and alcohol intake were recorded. In our evaluation it was used sleep disturbance index (SDI), for sleep quality description. In those two weeks, the mean sleep hours was 7.8 (95% CI 7.6-8), greater in female than in male. The results suggest a significant correlation between psychical excitants and sleep fragmentation. More, excessive daytime somnolence declared is not in concordance with sleep quality observed in sleep recorded with polysomnography. It looks to be in correlation with bad sleep habits and psychical excitants intake.
CYP2E1 is an ethanol and drug-metabolizing enzyme that can also bioactivate hepatotoxins and procarcinogens and generate reactive oxygen species; it has been implicated in the pathogenesis of liver ...diseases and cancer. Cigarette smoke increases CYP2E1 activity in rodents and in humans, and we have shown that nicotine increases CYP2E1 protein and activity in the rat liver. In the current studies we have shown that the induction peaks at 4 hours post nicotine treatment and requires multiple exposures to nicotine. We have found that CYP2E1 is induced by very low doses of nicotine with an ED50 of 0.01 mg/kg s.c. Our mechanistic studies indicate that nicotine does not regulate CYP2E1 expression by transcriptional mechanisms or by protein stabilization. Cotinine, the main nicotine metabolite is not involved in CYP2E1 induction in our rat model. Our findings indicate that nicotine may increase CYP2E1-induced toxicity in smokers, passive smokers and people treated with nicotine.
The digital revolution of the last decades has facilitated the intensive development of neuroscientific technologies, which can empirically support or reject previously developed sets of hypotheses ...and open avenues for the application of knowledge dynamics in management. This paper seeks to investigate the role of consulting services in the adoption of neuromanagement practices in Romanian organizations. The results presented in this paper are retrieved from a comprehensive neuroscience research, through which the emotional reaction of the investigated subjects to the stimuli was analyzed eye tracking (ET) technologies.
The results of a pilot-scale study on the influence of electric field use for stimulating the active sludge in the biological purification tank of a small capacity wastewater treatment plant (up to ...600 m3/day) are presented. Through specific comparative chemical tests (DO, COD, N-NH4, and Pt) it was found that, by applying a sinusoidal electric field of 5 Vrms/m at 49.9 Hz on the active sludge suspension, the overall pollutant denitrification process speed is doubled compared with the reference case when no stimulation is used. Also, under identical operating conditions, the residual pollutant content of the biological treatment tank outlet water is reduced approximately three times for COD and approximately two times for N-NH4 and Pt compared to the reference tank. These findings lead to the conclusion that, by stimulating the active sludge microbial activity of the wastewater treatment plants by a sinusoidal electric field of 5 Vrms/m at 49.9 Hz, the time of the biological purification treatment can be reduced by approx. 50%. This leads to a corresponding decrease in energy consumption, which usually represents more than 30% of a wastewater treatment plant’s specific electricity consumption.
Ovarian cancer is one of the most common causes of death in women as survival is highly dependent on the stage of the disease. Ovarian cancer is typically diagnosed in the late stage due to the fact ...that in the early phases is mostly asymptomatic. Genomic instability is one of the hallmarks of ovarian cancer. While ovarian cancer is stratified into different clinical subtypes, there still exists extensive genetic and progressive diversity within each subtype. Early detection of the disorder is one of the most important steps that facilitate a favorable prognosis and a good response to medical therapy for the patients. In targeted therapies, individual patients are treated by agents targeting the changes in tumor cells that help them grow, divide and spread. Currently, in gynecological malignancies, potential therapeutic targets include tumor-intrinsic signaling pathways, angiogenesis, homologous-recombination deficiency, hormone receptors, and immunologic factors. Ovarian cancer is usually diagnosed in the final stages, partially due to the absence of an effective screening strategy, although, over the times, numerous biomarkers have been studied and used to assess the status, progression, and efficacy of the drug therapy in this type of disorder.
Leather artefacts, archaeological, historical or modern, are prone to microbiological attack which could lead to irreversible degradation. Previous studies performed on new leather mock-ups indicated ...good resistance of leather at doses up to (25–50) kGy. The aim of this research is to improve our understanding about the changes in the thermal stability and structural order of collagen within vegetable-tanned leather exposed to gamma irradiation. Variously vegetable-tanned leather samples were therefore exposed to irradiation with Co-60 gamma-rays with increasing doses (10–100 kGy) and the dose-dependent effect on collagen-tannin matrix was investigated using micro-DSC, the best technique for determining proteins' thermal stability, coupled with FTIR-ATR and NMR MOUSE spectroscopy, to enhance the analytical coverage of the calorimetric profile. FTIR-ATR technique revealed the very subtle changes in collagen at the molecular (lower order) level by, which are reflected in the properties of the structures with a higher level of order, namely the hydrothermal stability of fibrils (measured by micro-DSC) and mobility of macromolecular chains (determined by NMR MOUSE). It was proved that a 10 kGy dose causes significant variation on collagen molecular structure, fibrils hydrothermal stability, and macromolecular chain's mobility when the collagen-tannin matrix is already thermally destabilized and present a wide distribution of collagen populations with distinct thermal stability. On the other hand, leathers characterized by high thermal stability and homogeneous distribution of collagen populations better withstood radiation up to either 25 kGy or 50 kGy, depending on the collagen-tannin interactions' strength. This protocol, with high analytical and diagnostic sensitivity, can thus be applied to characterize a broader range of collagen materials sterilized/crosslinked with gamma radiation.
•Effect of gamma irradiation on vegetable-tanned leather depends on dose.•Effect of gamma irradiation on leather depends on collagen thermal stability.•Thermally destabilized leather undergoes de-tanning at 10 kGy irradiation dose.•De-tanned collagen partially converts to gelatin at (50–100) kGy irradiation dose.•Highly stable leather withstand damage up to 100 kGy irradiation dose.
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