Ligand-dependent activation of ER{beta} lowers blood pressure and attenuates cardiac hypertrophy in ovariectomized spontaneously hypertensive rats

AIMS: The biological effects of oestrogens are mediated by two different oestrogen receptor (ER) subtypes, ERalpha and ERbeta, which might play different, redundant, or opposing roles in cardiovascular disease. Previously, we have shown that the selective ERalpha agonist 16alpha-LE2 improves vascular relaxation, attenuates cardiac hypertrophy, and increases cardiac output without lowering elevated blood pressure in spontaneously hypertensive rats (SHR). Because ERbeta-deficient mice exhibit elevated blood pressure and since the ERbeta agonist 8beta-VE2 attenuated hypertension in aldosterone-salt-treated rats, we have now tested the hypothesis that the isotype-selective ERbeta agonist 8beta-VE2 might be capable of lowering elevated blood pressure in ovariectomized SHR. METHODS AND RESULTS: Treatment of ovariectomized SHR with 8beta-VE2 for 12 weeks conferred no uterotrophic effects but lowered elevated systolic blood pressure (-38 +/- 5 mmHg, n = 31, P < 0.001 vs. placebo) as well as peripheral vascular resistance (-31.3 +/- 4.6%, P < 0.001 vs. placebo). 8beta-VE2 enhanced aortic ERbeta expression (+75.7 +/- 7.1%, P < 0.01 vs. placebo), improved NO-dependent vasorelaxation, augmented phosphorylation of the vasodilator-stimulated phosphoprotein in isolated aortic rings (P < 0.05 vs. placebo), increased cardiac output (+20.4 +/- 2.5%, P < 0.01 vs. placebo), and attenuated cardiac hypertrophy (-22.2 +/- 3.2%, p < 0.01 vs. placebo). 8beta-VE2, in contrast to oestradiol, did not enhance cardiac alpha-myosin heavy chain expression. CONCLUSION: Ligand-dependent activation of ERbeta confers blood pressure lowering effects in SHR that are superior to those of 17beta-estradiol or the ERalpha agonist 16alpha-LE2 and attenuates cardiac hypertrophy primarily by a reduction of cardiac afterload without promoting uterine growth.     

Estradiol release kinetics determine tissue response in ovariectomized rats

Estrogen replacement is an effective therapy of postmenopausal symptoms such as hot flushes, bone loss, and vaginal dryness. Undesired estrogen effects are the stimulation of uterine and mammary gland epithelial cell proliferation as well as hepatic estrogenicity. In this study, we examined the influence of different estradiol release kinetics on tissue responsivity in ovariectomized (OVX) rats. Pulsed release kinetics was achieved by ip or sc administration of estradiol dissolved in physiological saline containing 10% ethanol (EtOH/NaCl) whereas continuous release kinetics was achieved by sc injection of estradiol dissolved in benzylbenzoate/ricinus oil (1+4, vol/vol). Initial 3-d experiments in OVX rats showed that pulsed ip estradiol administration had profoundly reduced stimulatory effects on the uterus and the liver compared with continuous release kinetics. On the other hand, both administration forms prevented severe vaginal atrophy. Based on these results, we compared the effects of pulsed (sc in EtOH/NaCl) vs. continuous (sc in benzylbenzoate/ricinus oil) estradiol release kinetics on bone, uterus, mammary gland, and liver in a 4-month study in OVX rats. Ovariectomy-induced bone loss was prevented by both administration regimes. However, pulsed estradiol resulted in lower uterine weight, reduced induction of hepatic gene expression, and reduced mammary epithelial hyperplasia relative to continuous estradiol exposure. We conclude that organ responsivity is influenced by different hormone release kinetics, a fact that might be exploited to reduce undesired estradiol effects in postmenopausal women.     

Expression of interleukin-4 and interleukin-13 and their receptors in colorectal cancer

Purpose

Interleukin-4 (IL-4) and interleukin-13 (IL-13) are anti-inflammatory and immunomodulatory cytokines which can influence cancer-directed immunosurveillance. Nothing is presently known about expression of these cytokines and their receptors (IL-4R and IL-13R) in colorectal cancer. The aim of this study was to characterize their expression in primary colorectal cancer specimens and to evaluate possible functions for this disease.

Methods

Expression of IL-4, IL-13, IL-4R, and IL-13R protein was characterized by immunohistochemistry in 359 patients with Union for International Cancer Control stage I–III colorectal cancer and evaluated by uni- and multivariate analysis for their prognostic relevance.

Results

All four proteins were expressed in colorectal cancer specimens. In the cancer cells, high IL-4, IL-13, IL-4R, and IL-13R immunoreactivity were present in 33 % (118/359), 50 % (181/359), 36 % (129/359), and 42 % (152/359), respectively. Patients with high expression of IL-4, IL-4R, and IL-13R had a lower frequency of lymph node metastases. Expression of IL-13 did not influence the frequency of lymph node metastases. However, high IL-13-immunoreactivity was associated with a better overall survival (p?=?0.041). Expression of IL-4, IL-4R, or IL-13R did not influence survival. Multivariate analysis revealed that besides pT classification and tumor recurrence, IL-13 expression was an independent prognostic factor for overall survival.

Conclusions

Expression of IL-4, IL-4R, and IL-13R are involved in the process of local metastases in colorectal cancer, while IL-13 expression has an impact on survival. These interleukins and their receptors may become attractive targets for the treatment of colorectal cancer.     

Raw and cooked vegetables, fruits, selected micronutrients, and breast cancer risk: a case-control study in Germany

In 1998-2000, a case-control study of breast cancer was conducted in Heidelberg, Germany. Three hundred ten consecutively recruited cases with primary breast cancer were matched according to 10-yr age groups to 353 controls with conditions unrelated to diet or endocrine disorders. Intake of raw vegetables, total vegetables, and whole-grain products was inversely associated with breast cancer risk (highest vs. lowest quartile adjusted odds ratio [OR] 0.51, 95% confidence interval [CI] 0.31-0.84; OR = 0.62, 95% CI = 0.38-1.02; and OR = 0.57; 95% CI = 0.34-0.95, respectively). Also, high intake of some selected vitamins and minerals possessing putative DNA-stabilizing properties displayed significant inverse risk associations. Adjusted ORs were as follows: vitamin C (OR = 0.49, 95% CI = 0.2-0.88), folate equivalents (OR = 0.47, 95% CI = 0.25-0.88), b-carotene (OR = 0.46, 95% CI = 0.27-0.80), zinc (OR = 0.35, 95% CI = 0.15-0.78), and copper (OR = 0.51, 95% CI = 0.31-1.03). In contrast, no significant association with risk was seen for an increased intake of fruits, cooked vegetables, fiber, calcium, manganese, or iron. In this population of German women, components of raw vegetables and some micronutrients appear to decrease breast cancer risk.     

Medroxyprogesterone acetate but not drospirenone ablates the protective function of 17 beta-estradiol in aldosterone salt-treated rats

Controversial results obtained from human and animal studies on the prevention of heart disease by estrogens and progestins warrant a better understanding of nuclear hormone receptor function and interaction. To address this issue and taking into account that effects of synthetic progestins are not only referable to action through the progesterone receptor but may also be mediated by other steroid receptors, we characterized cardiovascular function and inflammatory gene expression in aldosterone salt-treated rats on long-term administration of 17beta-estradiol, medroxyprogesterone acetate, and drospirenone, a new progestogen exhibiting antimineralocorticoid activity. The complex pattern of cardiovascular injury in ovariectomized Wistar rats induced by chronic aldosterone infusion plus a high-salt diet was significantly attenuated in sham-ovariectomized rats and by coadministration of 17beta-estradiol in ovariectomized animals after 8 weeks of continuous treatment. The beneficial role of 17beta-estradiol on blood pressure, cardiac hypertrophy, vascular osteopontin expression, perivascular fibrosis, and impaired NO-dependent relaxation of isolated aortic rings was completely abrogated by coadministration of medroxyprogesterone acetate. In contrast, drospirenone was either neutral or additive to 17beta-estradiol in protecting against aldosterone salt-induced cardiovascular injury and inflammation. The current results support the hypothesis of complex interactions among estrogen, progesterone, glucocorticoid, androgen, and mineralocorticoid receptor signaling in cardiovascular injury and inflammation. Novel progestins, such as drospirenone, confer superior effects compared with medroxyprogesterone acetate in a model of aldosterone-induced heart disease because of its antimineralocorticoid properties.     

Response prediction in metastasised colorectal cancer using intratumoural thymidylate synthase: results of a randomised multicentre trial

BackgroundMolecular markers to predict response to 5-fluorouracil (FU)-based treatment of recurrent or metastasised colorectal cancer (mCRC) are not established. The aim of this trial was to determine the value of thymidylate synthase (TS), a key enzyme of DNA synthesis and target of 5-FU, to predict response to chemotherapy of mCRC.MethodsTumour tissue was obtained from 168 patients with mCRC for relative thymidylate synthase (TS) mRNA quantitation. Patients were randomised to receive either 5-FU/folinic acid (FA, FUFA) alone or in combination with irinotecan 5-fluorouracil/folinic acid and irinotecan (FOLFIRI) stratified by TS (low versus high). Primary end-point was overall response to first-line treatment among TS high patients. All parties, except for the randomisation centre, were blinded for TS status.ResultsBiopsies (n = 168) were taken without complications. TS levels were available for 147 patients (87.5%). Analysing response to FUFA and FOLFIRI in the per protocol set (n = 119) after un-blinding TS in the data base revealed a trend to better overall response to FOLFIRI (9/19, 47%) in TS high compared to FUFA (5/23, 22%, p = 0.077). In patients with biopsies taken from liver lesions (n = 91) overall response to FOLFIRI and FUFA in TS high was 53% (9/17) and 18% (3/17), respectively (p = 0.035). In patients with low TS, no remarkable difference in overall response to FOLFIRI and FUFA was observed.ConclusionsTaking a pre-treatment biopsy is a safe and feasible procedure in mCRC. After validation of our data in a larger group TS determination may have the potential to better help direct systemic treatment in patients with primarily non-resectable mCRC.     

Pseudophakia in children with juvenile arthritis

Background: Cataract secondary to juvenile rheumatoid arthritis is a severe, vision-threatening complication in early childhood. Intraocular lens implantation is controversial. The follow-up of four pseudophakic eyes of three patients and their perioperative therapeutic regimen were retrospectively analyzed. Early and late postoperative complications are reported. Patients and methods: Both girls had lens aspiration and posterior lens implantation at the ages of 6 and 12 years, the boy at the age of 10 and 14 years. All patients had relapsing anterior uveitis. The follow-up time was 3 years (1–6 years). One girl was diagnosed with sarcoidosis, causing juvenile arthritis. Both girls had perioperative methothrexate and prednisolone therapy. The boy had azathioprine therapy at the time of his first cataract surgery; later he had no systemic therapy. Both girls' intraocular lenses were implanted at different eye hospitals. Results: Both girls had severe inflammatory reactions after surgery. At the hospitals both eyes had surgical revision for iris capture. In one case this was combined with exchanging the intraocular lens. Iris capture persisted for this eye and later vitrectomy with silicone oil filling was necessary to delay phthisis, resulting in amaurosis. For two pseudophakic eyes vitrectomy was necessary later because of severe vitreous opacities, but visual acuity was severely diminished by chronic cystoid macular edema and epiretinal membranes. The boy developed in his second eye intermittent iris bombata and persistent secondary glaucoma, visual acuity was stabilized at 0.5. Conclusions: Secondary cataract due to juvenile rheumatoid arthritis or sarcoidosis is a difficult situation for phacoemulsification with intraocular lens implantation in children. For severe inflammatory complications intense local and systemic anti-inflammatory therapy is mandatory. Visual prognosis is reduced for the uveitic posterior segment and glaucoma complications. IOL implantation can be recommended for only a very few patients.