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Obesity is associated with an increased incidence of high-grade prostate cancer (PC) and worse prognosis for PC patients. Recently, we showed in men that obesity-related periprostatic white adipose tissue (WAT) inflammation, characterized by macrophages surrounding dead or dying adipocytes forming crown-like structures, was associated with high-grade PC. Possibly, interventions that suppress periprostatic WAT inflammation will improve outcomes for men with PC. Here, we tested the hypothesis that supplemental 17β-estradiol (E2) could decrease periprostatic WAT inflammation in obese male mice. Mice were fed a high-fat diet to induce periprostatic WAT inflammation before being treated with supplemental E2. E2 supplementation suppressed caloric intake, induced weight loss, decreased periprostatic WAT inflammation and downregulated the expression of genes linked to inflammation including Cd68, Mcp1 and Tnf. Similar to the effects of E2 supplementation, treatment with diethylstilbestrol, a synthetic estrogen, also suppressed caloric intake and reduced periprostatic WAT inflammation. To determine whether the observed effects of supplemental estrogen could be reproduced by caloric restriction (CR) alone, obese mice were put on a 30% CR diet. Like estrogen treatment, CR was effective in reducing body weight, periprostatic WAT inflammation and the expression of pro-inflammatory genes. Transcriptomic analyses of periprostatic fat showed that obesity was associated with enrichment in inflammatory response pathways, which were normalized by both supplemental E2 and CR. Taken together, these findings strengthen the rationale for future efforts to determine whether either CR or supplemental estrogen will decrease periprostatic WAT inflammation and thereby improve outcomes for men with PC., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Context: Most estrogen-dependent breast cancers occur after menopause, despite low levels of circulating estrogens. Breast expression of the estrogen-biosynthetic enzyme, aromatase, is proposed to drive breast cancer development after menopause. However, the effects of menopause on breast aromatase expression are unknown., Objective: To determine the effect of menopause on breast aromatase expression in relation to body mass index (BMI), white adipose tissue inflammation (WATi), and systemic markers of metabolic dysfunction., Design, Setting, and Participants: Cross-sectional study of 102 premenopausal (age 27 to 56) and 59 postmenopausal (age 45 to 74) women who underwent mastectomy for breast cancer treatment/prevention., Outcome: Breast tissue was assessed for the presence of crown-like structures and the expression and activity of aromatase. Systemic markers examined include interleukin (IL)-6, insulin, glucose, leptin, adiponectin, high-sensitivity C-reactive protein (hsCRP), cholesterol, and triglycerides. Multivariable analysis was performed for aromatase messenger RNA (mRNA) in relation to BMI, WATi, and blood markers., Results: Postmenopausal women had higher BMI and more breast WATi than premenopausal women. Fasting levels of IL-6, glucose, leptin, hsCRP, and homeostatic model assessment 2 insulin resistance score were higher in the postmenopausal group. BMI was positively correlated with aromatase mRNA in both pre- and postmenopausal women. Aromatase levels were higher in breast tissue of postmenopausal women, with levels being higher in inflamed vs noninflamed, independent of BMI. Adipocyte diameter and levels of leptin, hsCRP, adiponectin, and high-density lipoprotein cholesterol were more strongly correlated with aromatase in postmenopausal than premenopausal women., Conclusions: Elevated aromatase in the setting of adipose dysfunction provides a possible mechanism for the higher incidence of hormone-dependent breast cancer in obese women after menopause., (Copyright © 2017 Endocrine Society)

Obesity is associated with breast white adipose tissue (WAT) inflammation, elevated levels of the estrogen biosynthetic enzyme, aromatase, and systemic changes that have been linked to the pathogenesis of breast cancer. Here, we determined whether metabolic obesity, including changes in breast biology and systemic effects, occurs in a subset of women with normal body mass index (BMI). Breast WAT and fasting blood were collected from 72 women with normal BMI (<25 kg/m 2 ) undergoing mastectomy for breast cancer risk reduction or treatment. WAT inflammation was defined by the presence of crown-like structures of the breast (CLS-B) which are composed of dead or dying adipocytes surrounded by macrophages. Severity of inflammation was measured as CLS-B/cm 2 The primary objective was to determine whether breast WAT inflammation is associated with aromatase expression and activity. Secondary objectives included assessment of circulating factors and breast adipocyte size. Breast WAT inflammation was present in 39% of women. Median BMI was 23.0 kg/m 2 (range, 18.4-24.9 kg/m 2 ) in women with breast WAT inflammation versus 21.8 kg/m 2 (range, 17.3-24.6 kg/m 2 ) in those without inflammation ( P = 0.04). Breast WAT inflammation was associated with elevated aromatase expression and activity, which increased with severity of inflammation ( P < 0.05). Breast WAT inflammation correlated with larger adipocytes ( P = 0.01) and higher circulating levels of C-reactive protein, leptin, insulin, and triglycerides ( P ≤ 0.05). A subclinical inflammatory state associated with elevated aromatase in the breast, adipocyte hypertrophy, and systemic metabolic dysfunction occurs in some normal BMI women and may contribute to the pathogenesis of breast cancer. Cancer Prev Res; 10(4); 235-43. ©2017 AACR See related article by Berger, p. 223-25 ., (©2017 American Association for Cancer Research.)

Two anthracenedione antineoplastic agents, mitoxantrone and the nonhydroxylated analog, ametantrone, were found to inhibit hepatic microsomal cytochrome P-450-dependent drug metabolism in vitro and in vivo. Ethoxycoumarin deethylase activity of phenobarbital-induced rabbit hepatic microsomes was inhibited 56 and 100% at 0.1 and 0.5 mM mitoxantrone, respectively, whereas activity was inhibited 38 and 88% at 0.1 and 0.5 mM ametantrone, respectively. Both mitoxantrone and ametantrone were noncompetitive inhibitors of ethoxycoumarin metabolism. Aryl hydrocarbon hydroxylase activity of hepatic microsomes was diminished 41 and 56% by 1 and 3 mM mitoxantrone, respectively; identical concentrations of ametantrone inhibited metabolism by 20 and 31%, respectively. In contrast to the inhibitory influence of both agents on monooxygenase activity, a differential effect on NADPH oxidation was observed. In the presence of benzo[alpha]-pyrene, mitoxantrone enhanced microsomal NADPH oxidation by 21%, whereas ametantrone produced a 22% decrease in cofactor oxidation relative to the control rate. The anthracenediones also inhibited hepatic cytochrome P-450-dependent monooxygenase activity in vivo, as evidenced by altered hexobarbital sleep times of mice. Mitoxantrone (20 and 40 mg/kg) prolonged sleep time by 59 and 68%, respectively; ametantrone (50 mg/kg) produced a 56% enhancement. These results demonstrate that both mitoxantrone and ametantrone inhibit drug metabolism in vitro and in vivo.

Nitrofurantoin is an antimicrobial agent that causes nonimmune hemolytic anemia in susceptible populations and produces oxidant stress and cellular damage by mechanisms that differ from those associated with oxidants such as phenylhydrazine, which has been shown to stimulate proteolysis in red cells (Goldberg and Boches, 1982). Thus a study of the effects of nitrofurantoin on proteolysis in normal human red cells and red cell hemolysate has been conducted. Nitrofurantoin produced greater than a 3- and an approximately 5-fold increase in the rate of tyrosine release from red cells at 100 and 800 microM, respectively, compared with untreated red cells. In hemolysates nitrofurantoin also effectively increased proteolysis with a 2.4- and 4.0-fold increase in the rate of tyrosine release monitored at 100 and 800 microM, respectively, relative to controls. Stimulation of proteolysis by nitrofurantoin occurred linearly with time and with hematocrit over the range 5-25%. The rate of nitrofurantoin-stimulated proteolysis varied with glucose concentration in the incubation medium with a 2-fold increase in activity monitored between 2 and 10 mM glucose. Inhibitors of flavoprotein activity (electron transport), such as 2'-AMP and NADP, decreased nitrofurantoin-enhanced proteolysis in red cells to control levels, whereas methylene blue provided only a slight increase in proteolysis and an anaerobic environment (N2) stimulated significantly the rate of tyrosine production. Although N-acetylcysteine protected against the stimulation of proteolysis produced by 10 microM nitrofurantoin, this protective effect was diminished at higher concentrations of drug.(ABSTRACT TRUNCATED AT 250 WORDS)